<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Chromium and its inorganic compounds

Health-based recommended occupational exposure limit
(revised version)
</pre>

====================================================================== Einde pagina 1 =================================================================

<br><br>====================================================================== Pagina 2 ======================================================================

<pre></pre>

====================================================================== Einde pagina 2 =================================================================

<br><br>====================================================================== Pagina 3 ======================================================================

<pre>Gezondheidsraad Voorzitter
Health Council of the Netherlands

Aan de Minister van Volksgezondheid, Welzijn en Sport

Postbus 5406
2280 HK RIJSWIJK
Onderwerp : aanbieding advies

Uw kenmerk : DGV/BMO-U-932542
Ons kenmerk : U 3576/AB/ev/459-E23
Bijlagen 71

Datum : 24 september 1998

Bij brief van 3 december 1993, nr. DGV/BMO-U-932542, verzocht de Staatssecretaris
van Welzijn, Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en
Werkgelegenheid om gezondheidskundige advieswaarden af te leiden ten behoeve van
de bescherming van beroepsmatig aan stoffen blootgestelde personen.

Per 1 januari 1994 heeft mijn voorganger daartoe een commissie ingesteld die de
werkzaamheden voortzet van de Werkgroep van Deskundigen (WGD). De WGD was
een door genoemde Minister ingestelde adviescommissie.

Hierbij stuur ik u ter kennisname, een herziene versie van het rapport over chroom en
anorganische chroomverbindingen dat verscheen in maart van dit jaar. Deze publicatie
heb ik heden aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
aangeboden.

AT

prof. dr JJ Sixma

Postbus 1236 Bezoekadres
2280 CE Rijswijk Bogaard Centre
Telefoon 070 3407520 Sir Winston Churchilllaan 366-368

Telefax 070 3407523 2285 SJ Rijswijk

</pre>

====================================================================== Einde pagina 3 =================================================================

<br><br>====================================================================== Pagina 4 ======================================================================

<pre></pre>

====================================================================== Einde pagina 4 =================================================================

<br><br>====================================================================== Pagina 5 ======================================================================

<pre>Chromium and its inorganic compounds

Health-based recommended occupational exposure limit (revised version)

Report of the Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands

to

the Minister and State Secretary of Social Affaires and Employment

No. 1998/01(R)WGD, Rijswijk, 24 September 1998

</pre>

====================================================================== Einde pagina 5 =================================================================

<br><br>====================================================================== Pagina 6 ======================================================================

<pre>Preferred citation:

Health Council of the Netherlands: Dutch Expert Committee on Occupational
Standards (DECOS). Chromium and its inorganic compounds. Revised version.
Rijswijk: Health Council of the Netherlands, 1998; publication no. 1998/01(R)WGD.

all rights reserved

ISBN: 90-5549-241-8

</pre>

====================================================================== Einde pagina 6 =================================================================

<br><br>====================================================================== Pagina 7 ======================================================================

<pre>Contents

Samenvatting en advieswaarde 9

Executive Summary /5

Scope 21
Background 2/

1.2 Committee and procedures 2/

1.3 Data 22

2 Summary of previous recommendations (1985) 23
3 Present guidelines and standards 25

4 Chemical and physical characteristics 27

4,1 Chemical and physical properties 27

4.2 Monitoring 29

5 Effects 3/

5.1 Summary of the effects reported in the previous document (WGD, 1985) 3/
5.2 Effects reported in recent studies 32

5.3 Summary of effects 55

7 Contents
</pre>

====================================================================== Einde pagina 7 =================================================================

<br><br>====================================================================== Pagina 8 ======================================================================

<pre>Previous evaluation by other national and international bodies 59

Evaluation of human health risk 63

Groups at extra risk 63

Assessment of health risk 63

Recommended Occupational Exposure Limits 67
Additional consideration 67

References 69

Tow

8

Annexes 75

Request for advice 77

The committee 79

Comments on the public review draft 8/
Abbreviations 83

DECOS-documents 87

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 8 =================================================================

<br><br>====================================================================== Pagina 9 ======================================================================

<pre>Samenvatting en advieswaarde

Vraagstelling

Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid beveelt de
Gezondheidsraad gezondheidskundige advieswaarden aan voor beroepsmatige
blootstelling aan toxische stoffen in lucht op de werkplek. Deze aanbevelingen worden
opgesteld door de Commissie WGD van de Raad, de opvolgster van de Werkgroep van
Deskundigen (WGD). Zij vormen de eerste stap in een drietrapsprocedure die moet
leiden tot wettelijke grenswaarden (MAC waarden).

Het voorliggende rapport is een herziene versie van het rapport over de
gezondheidskundige gevolgen van beroepsmatige blootstelling aan chroom en
anorganische chroomverbindingen dat in maart van dit jaar verscheen. Dat rapport
vormde op zijn beurt een actualisering van een rapport van de Commissie WGD uit
1985. In de herziene versie heeft de Commissie WGD de evaluatie van de toxiciteit
van deze stoffen op een aantal punten verduidelijkt.

De conclusies van de commissie, die uitmonden in de presentatie van
gezondheidskundige advieswaarden, zijn gebaseerd op wetenschappelijke publicaties
die vóór 1995 zijn verschenen. Wetenschappelijke publicaties verschenen tussen 1995
en 1997 gaven de commissie geen reden af te wijken van haar aanbevelingen.

Samenvatting en advieswaarde
</pre>

====================================================================== Einde pagina 9 =================================================================

<br><br>====================================================================== Pagina 10 ======================================================================

<pre>2 Fysische en chemische eigenschappen

Gezien het bestaan van verschillen in zowel fysische en chemische eigenschappen als
toxiciteit, acht de commissie het aangewezen om onderscheid te maken tussen de
volgende categorieën: chroommetaalstof, chroom(II)verbindingen, oplosbare
chroom(II])verbindingen, onoplosbare chroom(II])verbindingen, chroom-
(IV)verbindingen en chroom(VI)verbindingen.

3 Monitoring

In het WGD-rapport over chroom en anorganische chroomverbindingen uit 1985 is een
methode beschreven voor de bepaling van zowel atmosferische concentraties als
concentraties van diverse chroomverbindingen in biologische substraten. De
commissie beveelt aan om de biologische monitoring te baseren op de
chroomconcentratie in urine.

4 Huidige grenswaarden

Op dit moment vigeren in Nederland de volgende wettelijke grenswaarden voor
beroepsmatige blootstelling:

chroommetaalstof 0,5 mg/m? gemiddeld over acht uur

oplosbare chroom(VI)verbindingen 0,025 mg/m? gemiddeld over acht uur
g gm 8
0,05 mg/m* gemiddeld over 15 minuten
mét huid-indicatie

chroom(H Dverbindingen 0,5 mg/m? gemiddeld over acht uur
1,0 mg/m* gemiddeld over 15 minuten
calcium-, strontium- en zink-chromaat 0,01 mg/m* gemiddeld over 15 minuten
lood- en bariumchromaat 0,025 mg/m’ gemiddeld over 15 minuten
gecombineerde chroomblootstelling 0,01 mg/m? gemiddeld over 15 minuten
5 Effecten

De huid, slijmvliezen, bovenste luchtwegen, nieren, longen en voortplantingsorganen
zijn de doelwitorganen bij blootstelling aan chroom of chroomhoudende verbindingen.
Chroomhoudende verbindingen kunnen irriterende en allergische/eczemateuze

lesies op de huid veroorzaken. Irriterende lesies ontstaan vooral door toedoen van

10 Chromium and its inorganic compounds

</pre>

====================================================================== Einde pagina 10 =================================================================

<br><br>====================================================================== Pagina 11 ======================================================================

<pre>chroom(VI), minder door chroom([III). Chroom(IV)verbindingen kunnen verzweringen
en doorboringen van het neustussenschot teweegbrengen; naar schatting gebeurt dit bij
CrO,-concentraties vanaf 0,1 mg/m’.

Oplosbare chroom(VI)verbindingen kunnen bij mensen lesies in de niertubuli
veroorzaken. Voor chroom(IIDverbindingen zijn geen nefrotoxische effecten
gerapporteerd. Met betrekking tot effecten op de nieren lijken er verschillen te bestaan
tussen kortdurende hoge en langdurige lage blootstelling. Uit onderzoek bij werkers in
een bedrijf dat chromaat en dichromaat produceert, is gebleken dat een
chroomconcentratie van 15 pg per gram creatinine in de urine correspondeert met de
drempel voor effecten op de tubulaire functies.

Blootstelling aan chroom kan op de longen de volgende niet-carcinogene effecten
hebben: pulmonaire fibrose, chronische bronchitis, bronchiale astma en
pneumoconiose. In een onderzoek naar langdurige inhalatoire blootstelling van ratten
aan chroomdioxide (Cr(1V)) — blootstelling gedurende twee jaar, vijf dagen per week,
zes uur per dag — leidde een concentratie van 0,5 mg/m’ tot een lichte type
II-pneumocyte hyperplasie; deze concentratie werd beschouwd als het
laagst-waargenomen-ongunstig-effectniveau (LOAEL) voor effecten op de longen.
Voor oplosbare chroom(lII)verbindingen is bij konijnen een
minimaal-waargenomen-ongunstig-effectniveau (MOAEL) van 0,6 mg/m’ gevonden.
Blootstelling aan deze concentratie gedurende vier tot zes weken, vijf dagen per week,
zes uur per dag, leidde tot functionele en morfologische veranderingen in de alveolaire
macrofagen.

Er zijn niet veel recente gegevens over de kankerverwekkendheid van chroom in
de longen van proefdieren. In het hierboven al genoemde
langdurige-blootstellingsonderzoek (chroom(lV verbindingen) ontstonden bij enkele
vrouwelijke ratten op kyste lijkende, keratiniserende squameuze celcarcinomen. Bij de
mannelijke dieren deed dit zich niet voor. Vermoedelijk is dit tumortype niet relevant
voor de mens. Uit een recent verschenen literatuuroverzicht inzake de
kankerverwekkendheid van chroomverbindingen bij dieren concludeert de commissie
dat er weinig evidentie is voor kankerverwekkende eigenschappen van oplosbare
chroom(VI)verbindingen in proefdieren. De carcinogeniteit van calcium-, zink- en
strontiumchromaat is daarentegen genoegzaam gebleken. In een groot retrospectief
cohort-onderzoek naar de mortaliteit onder mannelijke lassers in negen Europese
landen is een significant verhoogde sterfte aan longkanker gevonden, voornamelijk
onder lassers die met roestvrij staal omgaan. Overeenkomstige bevindingen zijn
verkregen in cohort-onderzoeken in twee Duitse chromaatfabrieken, Japanse
plaatwalserijen en onder lassers in 13 Franse bedrijven. In recent verschenen
epidemiologische overzichten is geconstateerd dat chroom(VI)verbindingen

11

Samenvatting en advieswaarde
</pre>

====================================================================== Einde pagina 11 =================================================================

<br><br>====================================================================== Pagina 12 ======================================================================

<pre>beschouwd moeten worden als carcinogeen voor de mens. Er is geen bewijs verkregen
voor het bestaan van kankerverwekkende eigenschappen van chroom(II)verbindingen.

Blijkens resultaten van onderzoek naar mutageniteit en genotoxiciteit is
chroom(II) niet genotoxisch; chroom(III) induceert in het algemeen geen DNA-schade,
genmutatie, ‘sister chromatid exchanges’ (SCE) of celtransformatie in celkweken van
dierlijke of menselijke oorsprong; chroom(VI)verbindingen van uiteenlopende
oplosbaarheid zijn consistent actief gebleken in talloze genotoxiciteitsonderzoeken
(DNA-schade, genmutatie, SCE, chromosomale afwijkingen, celtransformatie,
dominant-lethaal mutatie).

De effecten van chroomhoudende verbindingen op de lever en het centrale of
perifere zenuwstelsel bij proefdieren zijn onduidelijk. Hetzelfde geldt voor effecten op
de lever bij mensen. Er zijn geen aanwijzingen dat chroom(V1) voor mensen
neurotoxisch is.

Chroom(VI) bleek bij mannelijke ratten toxisch te zijn voor de
voortplantingsorganen. Zestig dagen na vijf dagelijkse intraperitoneale injecties van |
mg per kg lichaamsgewicht op vijf opeenvolgende dagen was het relatieve
testisgewicht verminderd en was er sprake van atrofie van de zaadbuisjes.

Chroom(lIT) had geen effect op de voortplantingsorganen van mannelijke ratten.
Bij mannelijke lassers met chroomconcentraties tussen 0,08 en 2,18 ug per g
creatinine was geen sprake van afwijkingen in de kwaliteit van het semen en van de
geslachtshormonen. Er zijn geen gegevens over het effect van chroom op de
voortplantingsorganen van vrouwen.

De Wereldgezondheidsorganisatie heeft geconcludeerd dat chroom(III) en
chroom(VI) bij proefdieren teratogeen zijn bij parenterale injectie van hoge dosis.

6 Gezondheidskundige advieswaarden

Chroommetaalstof, chroom(ll)verbindingen en niet in water oplosbare
chroom(llijverbindingen

Wegens gebrek aan wetenschappelijke gegevens kan de commissie voor
beroepsmatige blootstelling aan deze stoffen geen gezondheidskundige grenswaarde
aanbevelen.

12 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 12 =================================================================

<br><br>====================================================================== Pagina 13 ======================================================================

<pre>Chroom(lli)verbindingen die in water oplosbaar zijn

Voor deze stoffen stelt de commissie de gezondheidskundige advieswaarde voor
beroepsmatige blootstelling op 0,06 mg inhaleerbaar stof per m* lucht, gemiddeld over
acht uur. Deze waarde is afgeleid van een MOAEL van 0,6 mg/m’ voor effecten op de
longen van konijnen bij blootstelling gedurende vier tot zes weken. Zowel voor de
interspecies-variatie als de intrapolatie van MOAEL naar NOAEL acht de commissie
een veiligheidsfactor van 3 — dus samen een factor 10 — voldoende.

Chroom(lV)verbindingen

De commissie stelt voor beroepsmatige blootstelling van deze stoffen de
gezondheidskundige advieswaarde op 0,05 mg inhaleerbaar stof per m* lucht,
gemiddeld over acht uur. Deze waarde is gebaseerd op een LOAEL van 0,5 mg/m’
voor effecten op de longen van ratten in een 2-jaars onderzoek. De commissie acht een
veiligheidsfactor van 10 voldoende (factor 3 voor zowel de interspecies-variatie als de
extrapolatie van LOAEL naar NOAEL).

Chroom(Vi)verbindingen

De commissie beschouwt alle chroom(VI)verbindingen als carcinogeen voor de mens.
Er wordt een genotoxisch werkingsmechanisme verondersteld. Volgens de commissie
zijn er geen redenen om af te wijken van de methode van lineaire extrapolatie.
De commissie schat het extra kankerrisico op:
* 4x 10° bij beroepsmatige blootstelling aan 2 ug/m’ inhaleerbaar stof gedurende 40
jaar
* 4x 10° bij beroepsmatige blootstelling aan 0,02 g/m’ inhaleerbaar stof gedurende
40 jaar.

De commissie maakt in de evaluatie van dit rapport nog enkele aanvullende
opmerkingen over de vigerende MAC-waarden van chroom metaalstof en de
onoplosbare chroom(II)verbindingen.

13

Samenvatting en advieswaarde

</pre>

====================================================================== Einde pagina 13 =================================================================

<br><br>====================================================================== Pagina 14 ======================================================================

<pre>14 Chromium and its inorganic compounds

</pre>

====================================================================== Einde pagina 14 =================================================================

<br><br>====================================================================== Pagina 15 ======================================================================

<pre>Executive Summary

15

Scope

At the request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands recommends health-based occupational exposure limits for the
concentration of toxic substances in air at the workplace. These recommendations are
made by the Council’s Dutch Expert Committee on Occupational Standards (DECOS).
They constitute the first step in a three-step procedure that leads to legally-binding
limit values.

The present report is a revised version of the report, published in March 1998
concerning health effects of occupational exposure to chromium and its inorganic
compounds. The latter report was an update of a previous report of the DECOS from
1985. In the revised version, the committee clarifies the health hazard evaluation of
these compounds in more detail and recommends health-based occupational exposure
limits.

The committee’s conclusions are based on scientific publications prior to 1995.
Scientific publications between 1995 and 1997 were no reason for the committee to
adjust her recommendations.

Executive Summary
</pre>

====================================================================== Einde pagina 15 =================================================================

<br><br>====================================================================== Pagina 16 ======================================================================

<pre>2 Physical and chemical properties
Due to differences in physical and chemical properties as well as in toxicity, the
committee considers speciation of these agents expedient, and the following groups are
distinguished: chromium metal dusts, chromium(II) compounds, soluble
chromium(II}) compounds, insoluble chromium(III] compounds, chromium(IV)
compounds and chromium(VI) compounds.
3 Monitoring
A method to determine the atmospheric concentration as well as levels of different
chromium compounds in biological media is described in the DECOS document on
chromium published in 1985. For biological monitoring the committee recommends
the use of chromium concentration in urine.
4 Current limit values
The current legally-binding occupational exposure limits (TWA - time weighted
average) in the Netherlands are:
chromium meta! dusts 0.5 mg/m? TWA - 8h
soluble chromium(VI)compounds 0,025 mg/m? TWA - 8h
0.05 mg/m? TWA - 15 min
with a skin notation
chromium(II])compounds 0.5 mg/m? TWA - 8h
1.0 mg/m? TWA - 15 min
calcium-, strontium- en zinc-chromate 0.01 mg/m? TWA - 15 min
lead- en bariumchromate 0.025 mg/m? TWA - 15 min
combined chromium exposure 0.01 mg/m? TWA - 15 min
5 Effects
The target organs in occupational exposure to chromium and its compounds are the
skin, mucous membranes of the upper respiratory tract, the kidneys, the lungs and the
reproductive organs.
Chromium compounds may cause irritative lesions and allergic/eczematous
lesions on the skin. Irritative lesions are predominantly caused by chromium(V]), and
16 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 16 =================================================================

<br><br>====================================================================== Pagina 17 ======================================================================

<pre>less by chromium(IH). Chromium(IV) compounds may induce ulceration and
perforation of the nasal septum; it is estimated that levels of 0.1 mg CrO, per m* and
above induce lesions.

Soluble chromtum(VI) compounds may cause tubular lesions of the kidneys in
humans. No nephrotoxic effect has been reported for chromium (III) compounds.
There seem to be differences in the effects on the kidneys after short-term high dose
and long-term low dose exposure. Studies on workers employed in a chromate and
dichromate production plant showed that a chromiumconcentration of 15 ug per g
creatinine in the urine may correspond to the threshold for effects on the tubular
functions.

The non-carcinogenic effects in the lungs, caused by exposure to chromium are:
pulmonary fibrosis, chronic bronchitis, emphysema, bronchial asthma and
pneumoconiosis. In a long-term inhalation study on rats exposed to chromium dioxide
(Cr(IV)) for two years (6 hours per day, 5 days per week) slight Type II pneumocyte
hyperplasia was observed at 0.5 mg/m’; this concentration was considered to be the
lowest observed adverse effect level (LOAEL) for lung effects. For soluble chromium
(IT) compounds a minimal observed adverse effect level (MOAEL) for lung effects of
0.6 mg/m? was found in rabbits. Exposure to this concentration for 6 hours per day, 5
days per week, during 4 to 6 weeks resulted in functional and morphological changes
in alveolar macrophages.

Few recent animal data are available on the carcinogenic effect of chromium on
the lungs. In the two year study on rats exposed to chromium(IV) compounds
mentioned above, some female rats developed cystic keratinized squamous cell
carcinomas, but male rats did not. This kind of tumour is allegedly not relevant to
man. From a recent review on carcinogenicity of chromium compounds in animals the
committee concludes that there is limited evidence in experimental animals for
carcinogenicity of soluble chromium(VI) compounds. On the other hand, there is
sufficient evidence for the carcinogenicity of calcium-, zinc- and strontium-chromate.
In a large retrospective cohort mortality study on male welders in nine European
countries a statistical significant excess of mortality due to lung cancer was found,
predominantly among welders of stainless-steel. Comparable results were obtained
from cohort studies in two German chromate producing factories, in Japanese metal
plating plants and among welders from 13 French factories. In recent reviews on
epidemiological studies it was concluded that chromium(VI) compounds should be
considered carcinogenic to humans. No evidence was found for carcinogenicity of
chromium (III) compounds.

From mutagenicity and genotoxicity studies it was found that chromium(II) is
non-genotoxic; chromium(III) in general does not induce DNA damage, gene
mutation, sister chromatid exchange (SCE) or cell transformation in cultured animal

17

Executive Summary
</pre>

====================================================================== Einde pagina 17 =================================================================

<br><br>====================================================================== Pagina 18 ======================================================================

<pre>and human cells; chromium(VI) compounds of various solubility are consistently
active in numerous genotoxic studies (DNA damage, gene mutation, SCE,
chromosomal aberration, cell transformation, dominant lethal mutation).

The effects of chromium compounds on the liver and central or peripheral nervous
system of experimental animals are ambiguous, just as human data on liver effects.
There is no evidence that chromium(VI) is neurotoxic to humans.

Chromium(VI) was found to be toxic to the male reproductive system in rats. Sixty
days after five intraperitoneal injections of 1 mg per kg bodyweight on consecutive
days resulted in reduced relative testicular weights and atrophic seminiferous tubules.

Chromium(III) did not affect the male reproductive system in rats. Male welders
with chromium concentrations in urine between 0.08 and 2.18 ug per g creatine did not
show aberrations in the quality of semen and sexual hormones. No human data are
available on the effect of chromium on female reproduction.

The WHO concluded that chromium(III) and chromium(VI) are teratogenic in
experimental animals when injected parentally at high levels.

18

Recommended occupational exposure limit

Chromium metal dusts, chromium(Il) compounds and water-insoluble
chromium(ilt) compounds

The committee cannot recommend health-based occupational exposure limits
(HBR-OEL) for these compounds due to lack of scientific data.

Water-soluble chromiumdll) compounds

The committee recommends a health based occupational exposure limit for
water-soluble chromium(III) compounds in the form of inhalable dust of 0.06 mg/m’,
to be interpreted as a time weighted average over 8 hours ( TWA - 8 h). This
HBR-OEL is derived from a MOAEL of 0.6 mg/m’ for lung effects in a four to six
weeks rabbit study. For both interspecies variations and extrapolation from a MOAEL
to a NOAEL a factor of three, thus resulting in an overall safety factor of 10 was
considered sufficient by the committee,

Chromium(IV) compounds
The committee recommends a health based occupational exposure limit for these

compounds of 0.05 mg/m3 TWA - 8 h (as inhalable dust). The HBR-OEL is derived
from a LOAEL of 0.5 mg/m3 for lung effects in a two year rat study. For both

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 18 =================================================================

<br><br>====================================================================== Pagina 19 ======================================================================

<pre>interspecies variations and extrapolation from a LOAEL to a NOAEL a factor of three,
thus resulting in an overall safety factor of 10 was considered sufficient by the
committee.

Chromium(VI) compounds

The committee considers all chromium(VI) compounds to be carcinogenic in human.
A genotoxic mode of action is assumed and the committee has no reason to deviate
from the method of a linear exposure response relationships for these compounds.

The committee estimates that the additional cancer risk for chromium(VI) compounds
amounts to:

* 4x 10° for 40 years of occupational exposure to 2 g/m’ as inhalable dust.

* 4x 10° for 40 years of occupational exposure to 0.02 g/m’ as inhalable dust.

This report contains some additional considerations of the committee about the present
regulatory exposure limits on chromium metaldust and insoluble
chromium(lID)compounds.

19

Executive Summary

</pre>

====================================================================== Einde pagina 19 =================================================================

<br><br>====================================================================== Pagina 20 ======================================================================

<pre>20 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 20 =================================================================

<br><br>====================================================================== Pagina 21 ======================================================================

<pre>Chapter

1

Scope

1.1

Background

In the Netherlands occupational exposure limits for chemical substances are set using
a three-step procedure. In the first step a scientific evaluation of the data on the
toxicity of the substance is made by the Dutch Expert Committee on Occupational
Standards (DECOS), a committee of the Health Council of the Netherlands, on request
of the Minister of Social Affairs and Employment (Annex A). This evaluation should
lead to a health based recommended exposure limit for the concentration of the
substance in air. Such an exposure limit cannot be derived if sufficient data are not
available or if the toxic action cannot be evaluated using a threshold model. In the
latter case an exposure-response relationship is recommended for use in regulatory
standard setting.

In the next phase of the three-step procedure the Social and Economic Council
advises the minister on the feasibility of using the health based value as a regulatory
Occupational Exposure Limit (OEL) or recommends a different OEL. In the final step
of the procedure the State Secretary of the Ministry of Social Affairs and Employment
sets the official Occupational Exposure Limit.

1.2

Committee and procedures

The present document contains the assessment of DECOS, hereafter called the
committee, of the health hazard of chromium and inorganic chromium compounds.

21

Scope
</pre>

====================================================================== Einde pagina 21 =================================================================

<br><br>====================================================================== Pagina 22 ======================================================================

<pre>The members of the committee are listed in Annex B. The first draft of this report was
prepared by dr AAE Wibowo, Coronel Laboratory, Academic Medical Centre,
University of Amsterdam, by contract with the Ministry of Social Affairs and
Employment.

In 1995 the President of the Health Council released a draft of the report for public
review. The individuals and organisations that commented on the draft are listed in
Annex C. The committee has taken these comments into account in deciding on the
final version of the report.

1.3

22

Data

This document is a revised version of a report which contained an update of an earlier
criteria document of the committee, titled ‘Chromium and its compounds’ (DECOS,
1985). Only data published after 1985 will be discussed.

In preparing this report the following reviews have been consulted.

» International Agency for Research on Cancer (IARC), monographs on the
evaluation of carcinogenic risks to humans. Chromium, Nickel and Welding,
IARC) Lyon-France, 1990:49, 49-256 (IARC90).

* World Health Organisation (WHO); International Programme on Chemical Safety
(IPCS). Environmental health criteria 61. Chromium. WHO, Geneva, 1988
(WHO88).

» Wibowo AAE. Short evaluation on the carcinogenicity of potassium dichromate,
sodium dichromate and ammonium dichromate. Report on behalf of the
Directorate-General of Labour, 1993. Report no 93-05 Coronel Laboratorium,
Amsterdam (Wib93).

*  Langard S. Criteria document for Swedish occupational standards. Arbete och
Hälsa 1993:5 (Lan93).

» Environmental Protection Agency. Health assessment document for chromium.
Final report,1984. EPA-600/8-83-014F (EPA84).

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 22 =================================================================

<br><br>====================================================================== Pagina 23 ======================================================================

<pre>Chapter 2

Summary of previous recommendations
(1985)

In its 1985 report the committee concluded that the hazard of chromium compounds

depends on the chemical speciation, and perfomed separate assessments for the

following classes of compounds:

* chromium metal

* soluble chromium (VI)-compounds, including chromic acid, sodium-, potassium-,
ammonium-, rubidium-(bi)chromate

* chromium (Hf) compounds, including chromium acetate, oxyde, phosphate and
sulphate

* non soluble and/or moderate soluble chromium (VI) compounds particularly
calcium, strontium, and zinc chromate

= non soluble and/or moderate soluble chromium (VI) compounds, particularly lead
and barium chromate.

Chromium metal
Only very limited scientific data were available at that time. The committee concluded

to retain the then existing OEL of 0.5 mg/m’, TWA - 8 hour. There were no reasons to
assume that this agent is carcinogenic.

23 Summary of previous recommendations (1985)
</pre>

====================================================================== Einde pagina 23 =================================================================

<br><br>====================================================================== Pagina 24 ======================================================================

<pre>Soluble chromium (VI) compounds

For chromic acid (CrO,), irritation of the upper respiratory tract was thought to be of
importance leading to the recommendation of a short-term occupational exposure
limit. Another target organ for soluble chromium (VI) compounds is the kidney in
which aberrations may occur after long-term exposure. The committee recommended
HBR-OEL”s of 0.025 mg/m*, TWA - 8 hour, and 0.050 mg/m’, TWA - 15 min for
these compounds. A ‘skin’ notation was advised.

Given the existence of a biological monitoring method, the committee concluded
that a chromium level in urine of 20 ug per g creatinine at the end of workday and
workweek should serve as a warning signal for exposure to chromium.

Chromium (HI) compounds

In 1985 only very limited animal data were available. Chromium (III) compounds
were considered to be less hazardous than chromium (VI) compounds. In short-term
exposure the lung was thought to be the target organ. The committee did not object to
maintain the existing standard of 0.5 mg/m’, TWA - 8 hour.

Chromium (VI) compounds: calcium, strontium, and zinc chromate

For these compounds the committee concluded that they are carcinogenic to humans.
On the other hand, no dose-response relationship could be established. Quantitative
extrapolation from either human or animal data was deemed not possible. The
committee recommended to accept the standard advised by the OSHA of 0.01 mg/m’
chromium (VI), TWA - 15 minutes.

Chromium (VI) compounds: lead and barium chromate
The evidence that these compounds are carcinogenic was not substantial and

consistent at the time. The committee concluded that a HBR-OEL of 0.025 mg/m’,
TWA - 15 minutes was appropriate.

Combined exposure irrespective of speciation

For this particular case the committee recommended a health based occupational
exposure limit of 0.01 mg/m’ chromium, TWA - 15 minutes.

24

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 24 =================================================================

<br><br>====================================================================== Pagina 25 ======================================================================

<pre>Chapter 3

Present guidelines and standards

The table presents occupational exposure limits (OELs) proposed or set in the
Netherlands and elsewhere.

25 Present guidelines and standards
</pre>

====================================================================== Einde pagina 25 =================================================================

<br><br>====================================================================== Pagina 26 ======================================================================

<pre>country speciation OEL (mg/m?) comments

Netherlands* Cr metal 0.5 TWA - 8 hour
soluble Cr(VI)-compounds 0.025 TWA - 8 hour
0.05 TWA - 15 min
skin notation
Cr(IIT)-compounds 0.5 TWA - 8 hour
1.0 TWA - 15 min
Ca-, Sr-, Zn chromate 0.01 TWA - 15 min
Pb, Ba chromate 0.025 TWA - 15 min
Combined Cr exposure 0.01 TWA - 15 min
USA-ACGIH" chromite ore processing 0.05 TWA - 8 hour
(chromate), as Cr carc., Al
Cr metal 0.5
Cr(I1)-compounds 0.5 TWA - 8 hour
CrHIID)-compounds 0.5 TWA - 8 hour
water soluble Cr(VI)-compounds 0.05 TWA - 8 hour
certain water insoluble 0.05 TWA - 8 hour
Cr(VI)-compounds carc., Al
Germany® Cr(IH)-compounds - -
Cr(VI)-compounds (with exception of insoluble - care. group Ill A2
compounds, e.g. lead chromate and barium chromate)
chromylchloride - carc. group III A2
chromcarbonyl - carc. group III B
Sweden! chromates 0.02 TWA - 8 hour
C and S notation*
chromic acid 0.02 TWA - 8 hour
C and S notation*
0.06 TWA - short-term
chromium and other inorganic compounds 0.5 TWA - 8 hour
United Kingdom* chromium 0.5 TWA - 8 hour
Cr(11)-compounds 0.5 TWA - 8 hour
Cr(IID-compounds 0.5 TWA - 8 hour
CriVD-compounds 0.05 TWA - 8 hour

These MAC values of chromium and its inorganic compounds are legally binding since 1994 (Directoraat-Generaal van de
Arbeid: Nr. DGA/G/Tos/94/00981; Staatscourant no 243, december 1994). Moreover, some specific chromium compounds,
i.e. chromium III chromate and chromium trioxide, are classified as carcinogenic substances according to governmental
regulations (Staatsblad van Koninkrijk der Nederlanden, Jaargang 1994, no. 91).

American Conference of Governmental Industrial Hygienists (1993). Threshold Limit Values.
*_Deutsche Forschungsgemeinschaft. MAK- und BAT-Werte -Liste 1994.
Swedish National Board of Occupational Safety and Health. Occupational Exposure Limit Valucs (1993).

Health & Safety Executive. Occupational Exposure Limits 1993. The limit for Cr(VI) compounds is listed as confirmed
Maximum Exposure Limit and refers to the total inhalable dust fraction.

C means carcinogen, S means skin notation

26 Chromium and its inorganic compounds

</pre>

====================================================================== Einde pagina 26 =================================================================

<br><br>====================================================================== Pagina 27 ======================================================================

<pre>Chapter 4

Chemical and physical characteristics

4.1 Chemical and physical properties

The IARC monograph (IARC90) listed the information presented in the table.

chemical name atomic molecular melting point boiling point physical description solubility
weight (g/mol) (°C) (°C)
metallic chromium (0)
chromium 51.996 1900 2642 steel-grey, lustrous insoluble in water; soluble in dilute
metal or powder hydrochloric acid and sulfuric acid; insoluble
in nitric acid or nitrohydrochloric acid
chromium(II])-compounds
basis chromic sulfate 165.06 - - green powder soluble in water (approximately 700 g/l
at 35 °C)
chromic acetate 229.14 - - grey-green powder slightly soluble in water; insoluble in ethanol;
(hydrate) (247.15) (blue-violet needles) soluble in cold water, acetone (2g/1 at 15 °C)
and methanol (45.4 g/l at 15 °C)
chromic chloride 158.36 1150 sublimes at — violet crystalline scales anhydrous form is insoluble in cold water,
(hexahydrate) (266.45) (83) 1300 slightly soluble in hot water, but insoluble in

ethanol, acetone, methanol and diethy! ether.
The hydrated form is very soluble in water
(585 g/l), soluble in ethanol, slightly soluble
in acetone and insoluble in diethyl ether

27 Chemical and physical characteristics
</pre>

====================================================================== Einde pagina 27 =================================================================

<br><br>====================================================================== Pagina 28 ======================================================================

<pre>chemical name atomic/molecular melting point boiling point = typical physical solubility
weight (°C) (°C) description

chromium(Ill)-compounds

chromic nitrate (7.5 238.03 - - pale-green powder soluble in water. Both hydrated forms

hydrate) (373.13) (100) decomposes (brouwn crystals) soluble in water; the nonahydrate is soluble

(nonahydrate) (400.15) (60) decomposes at (deep-violet crystals) in acids, alkali, ethanol and acetone

100
chromic oxide 151.99 2435 4000 light to dark-green, insoluble in water, acids, alkali and ethanol
fine crystals

chromic phosphate 147 >1800 °C - violet crystalline solid insoluble in water. Hydrated form is slightly

(dihydrate) (183.00) soluble in cold water; soluble in most acids
and alkali but not in acetic acid

chromic sulphate 392.16 - - violet of red powder insoluble in water; slightly soluble in
ethanol; insoluble in acids

potassium chromic 283.23 (89) (400) (violet ruby-red to hydrated form is soluble in water (243.9 g/i

sulphate (499.39) black crystals) at 25 °C; 500 g/l in hot water); slightly

(dodecahydrate) soluble in dilute acids; insoluble in ethanol

chromium(VI)-compounds

ammonium chromate 152.07 180 - yellow cicular crystals soluble in water (405 g/l); insoluble in
thanol, slightly soluble in ammonia, acotone
and methanol

ammonium 252.06 170 (dec) - orange-red crystals soluble in water (308 g/l at 15 °C; 890 g/l at

dichromate 30 °C) and ethanol; insoluble in acetone

barium chromate 253.33 - - vellow chrystals very slightly soluble in water (4.4 mg/l at 28
°C); soluble in mineral acids

basic lead chromate 546.37 - - red crystalline powder insoluble in water; soluble in acids and alkali

calcium chromate 156.09 - yellow erystalline slightly soluble in water and ethanol; soluble

(dihydrate) (192.10) (200) powder in acids. Hydrated form is soluble in water
(163 g/l at 20 °C; 182 g/l at 45 °C), acids and
ethanol

chromium trioxide 99.99 196 decomposes at dark-red crystals, soluble in water (625 g/l at 20 °C; 674.5 g/l

250 flakes or granular at 100 °C), ethanol, diethyl ether and sulfuric
powder and nitric acids

chromyl chloride 154.90 -96.5 117 dark-red volatile liquid decomposes in water and ethanol; soluble in
ether, acetic acid, carbon tetrachloride,
carbon disulphide, benzene, nitrobenzene,
chloroform and phosphorous oxychloride

lead chromate 323.18 844 decomposes = yclow to very slightly soluble in water (0.58 mg/l at

orange-yellow
crystalline powder

25 °C), soluble in most acids and alkali but
not in acetic acid or ammonia

28 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 28 =================================================================

<br><br>====================================================================== Pagina 29 ======================================================================

<pre>chemical name atomic/molecular melting point boiling point = typical physical solubility
weight (°C) (°C) description

chromium-(VI)-compounds

nickel chromate 174.71 - - - insoluble in water; soluble in nitric acid and
hydrogen peroxide

potassium chromate 194.20 968.3 decomposes lemon-yellow crystals soluble in water (629 g/l at 20 °C; 792 g/l at
100 °C). insoluble in ethanol

potassium dichromate 294.19 398 decomposes at bright orange-red soluble in water (49 g/l at 0 °C; 1020 g/l at

500 erystals 100 °C), insoluble in ethanol

sodium chromate 161.97 792 decomposes yellow crystals soluble in water (873 g/l at 30 °C) and
methanol (3.44 g/l at 25 °C), slightly soluble
in ethanol

sodium dichromate 262.00 356.7 decomposes at reddish to soluble in water (2380 g/l at 0 °C; 5080 g/l at

(dihydrate) (298.00) 400 bright-orange crystals 80 °C) and methanol (513.2 g/l at 19.4 °C),
insoluble in ethanol

strontium chromate 203.61 decompose" - yellow crystalline slightly soluble in water (1.2 g/l at 15 °C; 30

powder g/l at 100 °C), soluble in hydrochloric, nitric

and acetic acids and ammonium salts

zinc chromate 181.37 - - lemon-yellow crystals insoluble in cold water: decomposes in hot
water: soluble in acids and liquid ammonia

zinc chromate 280.74 - - fine yellow powder slightly soluble in water; soluble in dilute

hydroxide

other chromium compounds

acids, including acetic acid

chromium carbonyl 220.06 decomposes at explodes at colourless crystals or —_ insoluble in water; slightly soluble in carbon
110 210 white solid tetrachloride and iodoform; insoluble in
ethanol, diethylether and acetic acid
chromium(ll) chloride 122.90 824 - white lustrous needles soluble in water; insoluble in ethanol and
or fused fibrous mass = diethyl ether
chromium dioxide 83.99 300 - brown-black insoluble in water; soluble in nitric acid
crystalline powder
4.2 Monitoring

A method to determine the atmospheric concentration as well as levels of different
chromium compounds in biological media is described in the previous DECOS
document on chromium. For biological monitoring the committee recommends the use

of chromium concentration in urine.

29 Chemical and physical characteristics
</pre>

====================================================================== Einde pagina 29 =================================================================

<br><br>====================================================================== Pagina 30 ======================================================================

<pre>30 Chromtum and its inorganic compounds
</pre>

====================================================================== Einde pagina 30 =================================================================

<br><br>====================================================================== Pagina 31 ======================================================================

<pre>Chapter

5

Effects

5.1

Summary of the effects reported in the previous document (WGD, 1985)

Chromium(lII) and chromium(VI) compounds were found to induce local effects on
the skin in the form of ulcerations, ortho-ergic and allergic dermatitis.

Zine chromate(VI) was found to cause ulceration of the nasal septum; the
no-observed adverse effect level was estimated at 30 g/m” (as Cr).

Workers in the ferrochroom and ferrosilicium industry who were exposed to
20-190 g/m’ total chromium (or 10-160 g/m’ insoluble Cr compounds) for long
duration, were reported to have aberrations of the lung functions and chronic
obstructive lung disease.

Stainless-steel welders with chromium in urine concentrations higher than 13 pg
chromium per g creatinine showed effects on the tubular functions of the kidney.
Reports on effects on the liver could not be substantiated.

Chromium(VI) compounds were found to be mutagenic, contrary to chromium(IID)
compounds. Experimental animal studies showed that moderate soluble and insoluble
chromium compounds(VI) were carcinogenic agents, although no dose-response
relationship could be established. Epidemiological studies also reported higher risks
for lung cancer, especially in the chromium chemical industry and to a lesser degree in
the metallurgic industry and in stainless-steel welders. A relationship was found
between intensity or duration of exposure and increased risk of lung cancer. From
these data, the most convincing evidence for carcinogenicity was found for the

31

Effects

</pre>

====================================================================== Einde pagina 31 =================================================================

<br><br>====================================================================== Pagina 32 ======================================================================

<pre>moderate soluble chromium(VI) compounds. Carcinogenicity of chromium(lII)
compounds could not be excluded.

In its earlier report, the committee concluded that people with diminished lung
function should be classified as groups at risk with respect to exposure to chromium
and its compounds.

5.2

Effects reported in recent studies

The target organs in occupational exposure to chromium and its compounds appear to
be: the skin, the mucous membranes of the upper respiratory tract, the kidneys, the
lungs and the reproductive organs.

5.2.1

Effects on the skin

Chromium is known to induce two different effects on the skin: irritative lesions and
allergic/eczematous lesions.

Chromium(VI) compounds can induce ulceration of the skin, developed from
painful crevices, or dryness of the skin to small ulcers, looking like pigeon eyes
(Bar92). Whether exposure to chromium(III) induces the same effects is questionable.
Von Burg and Liu (Bur93) reported that chromium(VI) as well as chromium(III)
compounds are strong skin irritants. On the other hand Baruthio (Bar92) stated that
trivalent chromium did not seem to have any effect on the skin. Gad (Gad89) reported
minimal effects after contact with chromium(III) as well.

Chromium contact allergies have been observed among workers in numerous
industrial activities: electrolyte chromium-plating, leather tanning, manufacturing of
pigments and paints, electroforming, offset printing, dry cleaning, mordanting of
textiles, ship building and work involving lime. Metallic chromium does not seem to
be to allergenic. Trivalent chromium was found allergenic, but to a much lesser degree
than the hexavalent form (Bar92). After an initial sensitization to Cr(VI) the subjects
studied also reacted to Cr(111), but to a lesser degree.

Hjerpe (Hje86) reported nine cases of chromate dermatitis in an assembly
department at a Volvo plant in Sweden since 1976. Yellow chromation was used for
corrosion protection in zinc-plated components. About 150 manual assembly workers
were diagnosed as having hand eczema and were positive in the patch test with
chromate.

Baruthio (Bar92) suggested the following pathogenesis: Cr(III) salts have the
property of binding to proteins of the skin after penetrating via the sweat glands and
forming stable complexes, contrary to Cr(VI) compounds. Cr(VI) crosses the skin
easily, diffuses through the organism and crosses cell membranes. The intracellular

32

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 32 =================================================================

<br><br>====================================================================== Pagina 33 ======================================================================

<pre>thio-amino acids reduce Cr(VI) to Cr(HI), which forms allergenic protein complexes.
Sensitization to the trivalent compounds is rare, and only observed with exposure to
high concentrations. According to Gochfeld (Goc91) irritation of the skin by
chromium increases the likelihood of sensitization. Chromium sensitivity is a so called
type IV delayed hypersensitivity. The reaction is stimulated by haptens, which have a
molecular weight of usually less than 500 and which combine with proteins in the skin
to stimulate the development of the sensitized lymphocytes.

Recently Wass and Wahlberg (Was91) published the results of a study concerning
the development of a simple procedure for the determination of leachable Cr(VI) that
could be used in industrial applications to check the leakage of Cr from the chromated
products and to establish a ‘threshold limit value’ for such products. Occlusive tests
were performed in chromate-sensitive patients using chromate products. Discs
representing a release of 0.6 g/cm’ or more elicited positive results in all patients
tested. The authors proposed that the mean release of Cr(VI) from chromated parts
should not exceed 300 g/m’.

5.2.2

Effects on the mucous membranes of the upper respiratory tract

Effects on the mucous membranes of the upper respiratory tract are still frequently
observed after chromium exposure. The hexavalent compounds of chromium are found
to induce immediate ulceration and then perforation of the nasal septum. The nasal
septum appears to be particularly sensitive to the effects of chromium given the very
low vascularization of its cartilaginous structure and the causticity of Cr(VI)
compounds. Atmospheric levels of chromiumtrioxide of approximately 100 ug/m*
were sufficient to induce lesions (Bar92). There were no indications that
chromium(III) induced effects on the mucous membrane.
The following upper respiratory tract disorders were also observed:
* inflammation and ulceration of the mucous membranes of the lips, mouth and
pharynx
* discoloration of the teeth, a yellowish gingival line
* papillomas on the soft palate.

5.2.3

Effects on the kidneys

Trivalent chromium was found to have no nephrotoxic effect. On the other hand,
tubular lesions caused by potassium bichromate (Cr VI) were responsible for urinary
release of intracellular enzymes, such as B-glucuronidase, maltase and alkaline
phosphatase, and for alterations in the sodium and potassium exchanges (Bar92).

33

Effects
</pre>

====================================================================== Einde pagina 33 =================================================================

<br><br>====================================================================== Pagina 34 ======================================================================

<pre>Verschoor et al. (Ver88) performed a cross-sectional study of the renal function of
chrome-plating workers and welders in the Netherlands. They determined the level of
chromium in urine (CrU), chromium clearance and sensitive renal function parameters
(creatinine in urine and serum, urea in serum, total protein in urine, albumin in urine,
B,-microglobulin in serum and urine, retinol-binding protein in urine, immunoglobulin
in serum and urine, N-acetyl-B-D-glucosaminidase in urine, B-galactosidase in urine
and lysozyme in urine). The glomerular function parameters of chrome-plating
workers (CrU 1-34 ug per g creat.*) and welders (CrU 1-62 ug per g creat.*) appeared
to differ from those of boilermakers (CrU 0.3-1.5 ug per g creat.*) and a control group
(CrU 0.1-2 pg/g creat.*). This study did not find any aberrations in the tubular
function of the kidneys. No environmental exposure levels were determined in this
study.

Franchini and Mutti (Fra88) performed a cross-sectional study on 43 male workers
employed in a chromate and dichromate production plant in Italy for seven years.
Their mean age was 41 years. A control group of 30 subjects with mean age of 39
years was also examined. Chromium concentrations in the plant were usually below 50
ug/m’ with peaks as high as 1000 pg/m’. The median chromium levels in the urine of
exposed workers was 26 ug per g creat. and about 40% of the concentrations exceeded
30 ug per g.creat. Comparison between the exposed and control groups showed that
there was no difference in the albumin levels in urine, but some divergence existed in
the retinol binding protein levels. 9 out of 43 samples from the exposed subjects
exceeded the upper limit of controls. Further analysis revealed no difference between
the controls and those workers with a CrU lower than 15 pg per g creatinine, showing
that this level may correspond to the threshold for effects on the tubular functions.

Vyskocil et al. (Vys92) recently reported a lack of renal changes in stainless steel
welders exposed to chromium and nickel. Biochemical markers were examined in 52
male welders (MMA welding**) and 51 control subjects. The chromium concentration
in workroom air as determined by personal air sampling had a geometric mean of 64
ug/m* (range 7-161). The chromium levels in urine of the exposed group had a
geometric mean of 17.8 ug per g creat. and those of the control group 1.1 ug per g
creat. No consistent clinically significant renal impairment was revealed among the
welders, however B2-microglobulin in urine was slightly increased in those welders
with a urinary chromium concentration higher than 30 ug per g. creat. (p < 0.05). The
MMA-welding of stainless steel carried out by these workers is a technique that
generated relatively high fume concentrations of soluble chromium. Seventy to ninety
percent of chromium in this type of welding fume is present as soluble Cr(VI).

CrU: chromium concentration in urine; usually per unit mass of creatinine.
MMA= manual metal are welding

34

Chromium and its inorganic compounds

</pre>

====================================================================== Einde pagina 34 =================================================================

<br><br>====================================================================== Pagina 35 ======================================================================

<pre>In a recently published review, Wedeen and Qian (Wed91) pointed at the
difference in effects on the kidneys between short-term and long-term exposure to
chromium. They reported that tn contrast to the paucity of evidence on
chromium-induced chronic renal disease, massive exposure to hexavalent chromium
consistently causes acute tubular necrosis, clinically evident as a marked reduction in
urine flow rate, if the patient survives for more than a few hours. Acute renal failure
from accidental exposure to Cr(VI) in the workplace is, however, quite rare.

The committee concludes that evidence that long-term low-dose exposure to
chromium has adverse effects on the kidneys arises from the finding of low molecular
weight proteinuria in chromium workers. Excessive urinary excretion of
B,-microglobulin, a specific proximal tubule brush border protein and an extra-renal
enzyme, retinol-binding protein, are reported among some chrome platers and welders.

Standeven and Wetherhahn (Sta91) studied the possible role of glutathione in
chromium(VI) toxicity in rats. The acute nephrotoxicity of 30 mg/kg sodium
dichromate was potentiated by depletion of renal glutathione. However, depletion of
glutathione did not seem to affect the incidence of glucosuria, haematuria or
lysozymuria over a range of Cr(VI) doses. Nor did it affect renal uptake of chromium.
In their experiment, the estimated NOAEL for acute effects on the kidneys after
intraperitoneal injection was 10 mg/kg body weight (as Cr(VI)) This level was
obtained irrespective of whether the animals were glutathione depleted or not.

5.2.4

Effects on the lungs

The committee makes a distinction between non-carcinogenic and carcinogenic effects
on the lungs.

Non-carcinogenic effects on the lungs

The following effects on the lungs have been reported in workers exposed to
chromium: pulmonary fibrosis, chronic bronchitis and emphysema, bronchial asthma
and pneumoconiosis (Bar92). Pneumoconiosis has been reported in a number of cases
in the pigment industry: among chromite workers, in chromates and ferrochromates
industries and in the metallurgy. A difficulty in using these data for risk assessment is
the simultaneous exposure to various other toxic agents, and the lack of environmental
monitoring in most of the cases. Recently animal studies have been performed to
investigate whether there are interactions between chromium and other elements.

35

Effects
</pre>

====================================================================== Einde pagina 35 =================================================================

<br><br>====================================================================== Pagina 36 ======================================================================

<pre>Animal studies

In 1989, Lee et al. (Lee89) reported a study on rats exposed to chromium dioxide
(Cr(IV)) dust at concentrations of 0, 0.5 (stabilized and unstabilized, resp.) and 25
mg/m’ (stabilized) for 6 hours per day, 5 days per week for two years. The dust had an
aerodynamic diameter of about 2.7 um. No exposure related pathological changes
were observed other than lung lesions. There were no significant differences in
pulmonary response between unstabilized and stabilized CrO, at the 0.5 mg/m’
exposure level. The lungs showed minute dust deposition in the alveoli, but maintained
an intact general architecture. The only changes were a slight socalled Type II
pneumocytes hyperplasia, which is a non-specific reparative response to damaged
Type I pneumocytes. At 25 mg/m’, dust deposition was confined to the alveoli in the
alveolar duct region. Alveolar walls enclosing dust-laden macrophage aggregates were
thickened with hyperplastic Type I] pneumocytes and slight collagenized fibrosis. The
lungs showed minute fibrotic pleuritis. These lesions occurred predominantly in
female rats. From this study it can be concluded that a level of 0.5 mg/m’ dust is the
LOAEL for CrO, exposure in rats. The critical organ is the lung, although the evidence
is limited.

Johansson et al. (Joh86a,b) studied the effects of subacute exposure to
chromium(III) and chromium(VI) compounds on the alveolar macrophages of rabbits.
The animals were exposed either to 0.9 mg/m’ Cr(VI) or 0.6 mg/m’ Cr(III) for 6 hours
per day, 5 days per week for 4-6 weeks. In the latter case chromium nitrate was used,
which is a soluble Cr(lll) compound. The mass median aerodynamic diameter of the
aerosols was | pm. Macroscopically the controls as well as the exposed animals had
all normal lungs. The number of macrophages washed from the lungs was significantly
increased in rabbits exposed to Cr(VI). Both Cr(Ill) and Cr(VI) produced
morphological changes in the alveolar macrophages. Although the concentration of
Cr(lll) was lower than Cr(VI), the former compound produced more conspicuous
changes. Most cells had very large lysosomes which contained membranous fragments
of different sizes surrounded by a more homogenous matrix. Laminated inclusions
similar to the lamellar bodies in the Type II cells increased in number as did the
percentage of cells with a smooth cell surface. Only Cr(IIT) produced functional
changes of the macrophages. This study shows that a level of 0.6 mg/m’ is probably
the MOAEL for soluble Cr(IID) compounds.

In 1987, Johansson et al (Joh87) repeated their study. They exposed rabbits to
mean chromium (Cr(111)) concentrations of 0.6 and 2.3 mg/m’ for about 4 months, 5
days per week, during 6 hours per day. Light microscopic examination of the lungs
revealed that both chromium exposures induced a nodular intra-alveolar accumulation
of enlarged macrophages with granular, eosinophilic cytoplasm. Some macrophages

36

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 36 =================================================================

<br><br>====================================================================== Pagina 37 ======================================================================

<pre>were multinucleated and some showed advanced degenerative changes with disruption
of cellular borders and nuclear pyknosis. The changes were most prominent in rabbits
exposed to the high concentration and were in some areas associated with a mild
interstitial infiltration of lymphocytes, neutrophils and eosinophils.

Johansson et al. (Joh92a) recently reported the effects of combined exposure to
Cr(111) and a soluble cobalt compound on the lungs. Eight rabbits were exposed to 0.7
mg/m? cobalt and 1.2 mg/m’ Cr(IID, eight to 0.6 mg/m’ cobalt only and another eight
animals to filtered air for 4 months, 5 days per week during 6 hours per day. All
rabbits in the cobalt+chromium group and the cobalt-only group showed nodular
aggregation of alveolar Type II cells. In lavage fluid the numbers of macrophages and
the percentage of these cells with smooth surface and intracellular surfactant-like
inclusions were more increased in the cobalt+chromium group than in the cobalt-only
group, as were oxidative metabolic and phagocytic activities of the macrophages.
These results imply that it is important to investigate effects of combined exposure of
cobalt and chromium in the occupational environment. The experiment indicates,
according to the committee, that these two metals act synergistically.

The effect of combined exposure of nickel, cobalt and chromium was reported by
Johansson et al. (Joh92b). They found that the combined exposure induced more
pronounced lung lesions than exposures for each of the metals alone. Chromium
potentiated the effects of nickel and cobalt on the Type II cells, which led to secondary
effects on the macrophages.

Hilaski ef a/. (Hi192) studied the acute toxicity of chromium in the form of
Whetlerite dust in rats. Whetlerite dust is a granular, activated carbon impregnated
with compounds of copper, silver and chromium to enhance its ability to absorb and
destroy toxic gasses. This dust contains both trivalent and hexavalent chromium. Two
groups, both 6 female and 6 male rats, were exposed to base carbon dust and three
groups, all 6 female and 6 male rats, were exposed to Whetlerite dust. The exposure
was by the nose-only method for a 4-hours period. The exposure concentration was the
same for both dusts, 5000 mg/m’, and the mass median aerodynamic diameter was 3
um for Whetlerite dust and 4 pm for base carbon dust. Necropsies were performed at
14, 28 and 180 days post exposure. The kidneys, liver and lungs were collected for
determination of copper and chromium content. The animals exposed to the Whetlerite
dust showed no gross pathological changes. Organ chromium concentrations were
below the detection limits of 0.5 ug chromium per g dry tissue in both exposure
groups. The auteurs concluded that neither Whetlerite dust nor base carbon dust
demonstrated acute inhalation toxicity. The committee agreed with this conclusion.

37

Effects
</pre>

====================================================================== Einde pagina 37 =================================================================

<br><br>====================================================================== Pagina 38 ======================================================================

<pre>Human studies

Rastogi ef al. (Ras91) performed a cross-sectional study of a group of 57 manual
welders with ages ranging from 13-60 years in India. The average exposure period was
12.4 years (1-35 years). Comparison was made with a reference group of 131 subjects.
The welders showed a significantly higher prevalence of respiratory impairment (28%)
than the controls (6.1%). Air concentrations during the welding process varied from:
zinc 0.3-1.2 ug/m’, copper 0.03-0.89 g/m’, chromium 0.002-0.015 g/m’, nickel
0.002-0.018 g/m’, lead 0.008-0.014 g/m’, and manganese 0.002-0.018 g/m”. It is
difficult to determine from this study whether the respiratory impairment was solely or
primarily due to exposure to chromium. The results of the pulmonary function tests
showed predominantly a restrictive type of pulmonary impairment followed by a
mixed ventilatory defect among the welders. A significant correlation was found
between the prevalence of respiratory abnormalities and the lenght of exposure.

Srivastava et al. (Sri92) studied 78 workers, occupationally exposed to fume and
dust in the glass industry in India, for respiratory symptoms. These workers were
exposed to products of coal furnaces in which various metal pigments were applied on
the hot molten glass to give colour and lustre. Compounds of chromium, copper,
manganese and cobalt were used. Other metals, such as nickel and lead were present as
impurities. Levels of chromium and nickel in blood were determined, but no
environmental monitoring was performed. A statistical significant association was
observed between respiratory symptoms and elevated blood nickel and chromium
levels. An interaction between nickel and chromium was found in relation to the
prevalence of respiratory symptoms. It is difficult to interpret the results of this study.
It is known that chromium in blood is a less reliable indicator of exposure than
chromium in urine. Furthermore, by determining chromium in blood by atomic
absorption spectrometry the speciation is not known.

Carcinogenic effects on the lungs
Animal data

Very few animal data on carcinogenic effects on the lungs have been published. In this
respect the situation did not change since the publication of the earlier document of the
committee, in which no animal studies on inhalatory exposure to Cr(VI) or Cr(IIT)
compounds were mentioned.

In 1986, Glaser and colleagues (Gla86) reported an inhalation study on male
Wistar rats which were continuously exposed to submicron aerosols of sodium
dichromate, Cr (VI), and to a pyrolized Cr(VIY/CrIII) (3:2) oxide mixture. After 18

38

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 38 =================================================================

<br><br>====================================================================== Pagina 39 ======================================================================

<pre>39

months of exposure the rats were held under conventional conditions for a further year.
The experimental groups consisted of 20 rats and the control group of 40 rats. More
than 90% of the rats in each group survived for 2 years.

The concentrations of sodium dichromate equalled 25, 50 and 100 ug
chromium/m’. At the end of the study the mortality in the experimental group was
35%, 45% and 25%, respectively. These values were not significantly different from
that of the controls (42.5%). In all exposed rats, no significant effects were found
neither clinically nor from hematological and clinical chemical analyses. Three
primary lung tumours (2 adenomas and | adenocarcinoma) and | malignant tumour of
the pharynx were found at the highest level of exposure. No primary lung tumours
were found in the lower exposure levels and the control group.

One group of rats was exposed to a chromium oxide mixture with a chromium
concentration of 100 ug/m’. The mortality rate at the end of the study was 50%, which
was not significantly different from that of the control group. In this group, however,
white and red blood cell counts and serum cholesterol were elevated and serum total
immunoglobulin levels were decreased at different stages of the study; also a few local
lung effects were observed. One primary adenoma of the lung was found in this group.
The incidence of treatment-related tumours at other sites was not increased. However,
the Working Group of the [ARC commented that the number of animals in this study
was to small for the results to be conclusive (IARC90).

Also in 1986, Adachi et al. (Ada86) reported on an experiment on a group of 50
female ICR/Jel mice which was exposed by inhalation to chromium trioxide mist (Cr
VI) (particle size, 84.5% greater than 5 jm) at a chromium concentration of 3.63
mg/m’ for 30 min per day, 2 days per week for up to 12 months. Mice surviving at that
time were maintained for a further six months; two groups of ten mice were killed at
12 and 18 months and served as controls. A single lung adenoma was reported in 1/15
mice that died or were killed between six and nine months. Lung adenomas occurred
in 3/14 mice that died between 10 and 14 months, and 1/19 adenoma and 2/19
adenocarcinomas in mice that died at 15 - 18 months. In the control group, no lung
tumour was reported in 10 mice killed at 12 months, but 2/10 adenomas occurred in
those killed at 18 months. The authors observed nasal perforations in six mice exposed
for more than ten months and time-related inflammatory changes, including squamous
metaplasia, in the trachea and bronchus of exposed mice. It should be noted that the
duration of exposure was rather short for a carcinogenicity study and mice of only one
sex (female) was used. The committee considers the results to be inconclusive, but
does not interpret the outcome as indicating the effects of chromium exposure as non-
carcinogenic,

In a consecutive study by the same research group (Ada87), 43 female C57B1
mice were exposed to chromium trioxide mist (particle size: 85% greater than 5 pm)

Effects
</pre>

====================================================================== Einde pagina 39 =================================================================

<br><br>====================================================================== Pagina 40 ======================================================================

<pre>generated by a miniaturized electroplating system, during 120 min twice a week for 12
months. The chromium concentration was 1.81 mg/m’. At the end of the 12 months
study period 23 mice were killed. The remaining 20 were killed six months later. Nasal
perforation was seen in 3/23 and 3/20 mice killed at 12 and 18 months, respectively;
0/23 and 6/20 nasal papillomas occurred in these groups. A single lung adenoma was
reported in the group killed at 18 months. No nasal inflammatory change or lung
tumour was seen in a group of 20 untreated control mice. The committee considers the
results of this experiment also inconclusive with respect to the nose and lung
carcinogenicity of chromium(VI).

Langard (Lan88) has summarised the experimental data on the carcinogenicity of
chromium compounds in animals. Surgical implantation of potassium dichromate or
sodium dichromate in the left bronchiolus of the rat lung did not increase the incidence
rate of lung tumours, but implantation of calcium chromate and zinc potassium
chromate did. In an experiment in which rabbits were exposed to mixed chromate dust,
potassium dichromate, sodium chromate or pulverized residue dust by inhalation for 4
days per week during 50 months, no increase in tumour rate was found compared to
controls.

In 1989, Lee et al. (Lee89) reported a study with rats exposed to chromium
dioxide (Cr (IV)) dust at concentrations of 0, 0.5 (stabilized and unstabilized, resp.)
and 25 mg/m’ (stabilized) for 6 hours per day, 5 days per week for two years. The dust
had an aerodynamic diameter of about 2.7 um. Of 108 female rats, six developed
keratin cysts and two had cystic keratinizing squamous cell carcinoma at 25 mg/m’.
None of the 106 male rats had either a keratin cyst or a carcinoma. This kind of tumour
has been reported to be induced in rats by the inhalation of high concentrations of
relatively inert materials. They are of benign nature, without invasions or metastases
and are different from the type of spontaneous lung tumours generally seen in man or
animals. The relevance of this type of lung tumour to man appears to be questionable,
especially since no explanation can be forwarded on the sex differences in the
induction of tumours. More studies in this case are needed.

Based on an analysis of results from experiments with other exposure routes than
inhalation the IARC (IAR90) came to the following conclusions: There is sufficient
evidence in experimental animals for the carcinogenicity of calcium chromate, zinc
chromate, strontium chromate and lead chromate. There is limited evidence in
experimental animals for the carcinogenicity of chromium trioxide (chromic acid) and
sodium dichromate (soluble chromium(VI) compounds). They used the following
arguments. Chromium trioxide has been tested as a mist by inhalation at two dose
levels in mice and as a solid by intrabronchial surgical implantation in three studies in
rats. In mice, a non-significant number of lung adenocarcinomas was observed at the
higher chromium concentration (1810 g/m’) and of nasal papillomas at the lower

40

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 40 =================================================================

<br><br>====================================================================== Pagina 41 ======================================================================

<pre>dose; perforation of the nasal septum was observed at both dose levels. A few lung
tumours were seen in two of six studies by intrabronchial administration in rats.
Sodium dichromate has been tested in rats by inhalation, and after intratracheal,
intrabronchial, intrapleural and intramuscular administration. Lung tumours, benign
and malignant, were observed in inhalation studies and after intratracheal
administration. Two lung adenomas and one lung adenocarcinoma were induced at the
highest dose of three chromium concentrations (25, 50 and 100 ug/m”) in inhalation
experiments. No increase in the occurrence of local tumours was seen after
intrabronchial, intrapleural or intramuscular administration.

There is inadequate evidence in experimental animals for the carcinogenicity of
metallic chromium, barium chromate and chromium(II]) compounds.

Human data

In the committee’s previous document an extensive assessment was made of the
induction of lung cancer in workers occupationally exposed to chromium. Recently
Langard (Lan93) reviewed epidemiological studies on respiratory cancer in the
chromate manufacturing industry. Table 1 presents a summary of this review.

Worth to be mentioned is the retrospective cohort study performed by Langärd and
Vigander (Lan83). The prime objective of this study was to re-evaluate the incidence
of lung cancer in a working population studied previously. In the previous
investigation, the study population was followed from 1948, when chromium pigment
production was started, up to December 1972. Three cases of lung cancer were
observed in the 24 workers, out of the total number of 133, who had worked in the
plant for over three years by the end of 1972. Three years later the same population
was updated. No new cases of lung cancer were observed in these three years. The
expected numbers of tumours of the respiratory organs were calculated by using the
age-specific incidence rates for lung cancer in the whole Norwegian male population
for the period 1955 - 1976. The production process in the plant had been altered
considerably since the initial study was carried out. Lead chromate was no longer
produced since 1956. The dust concentration had been reduced since 1973. The level
of zinc chromate dust in this plant had been monitored at regular intervals, and few
measurements had exceeded a chromium concentration of 50 ug/m?, Most of the
routine measurements during the period 1975 - 1980 showed dust concentrations with
chromium concentrations between 10 and 30 g/m’. The whole group of workers was
followed up to the end of 1980. By the end of 1980, the following malignant tumours
had occurred among the 133 workers: lung (7), pancreas (1), stomach (1), large
intestine (2), prostate (1) and nasal cavity (1).

41

Effects

</pre>

====================================================================== Einde pagina 41 =================================================================

<br><br>====================================================================== Pagina 42 ======================================================================

<pre>Table | Review of epidemiological studies on respiratory cancer in chromate manufacturing workers as reported by Langard
(1993).

study population reference site number estimated estimated exposure ref.
population of cases relative absolute risk
risk
six chromate plants; active cancer mortality in bronchialand 32 26 Mac48
employees; 4-17 years before an refining lung
1948 company,
1933-1938
seven US chromate factories; US male lung Gaf53
active workers 1940-1948 white 10 14,3"
included; 5522 person years black 16 80.0
US chromate producing no separate lung 41 crude rate <15 years Lan75
plant; workers employed one reference group 37x10* _ observation;
or more years 1931-37; all 9.7x10" to a
jobs related to exposure to high of
soluble and insoluble 55x10" after
chromium 36 years
observation
a cohort of 133 of zinc incidence of cancer lung 6 44 150x10* exposure to Lan83
chromate workers in Norway in Norway 1953-80 0.01-1.35 mg/m?
of zinc chromate
new Jersey zinc and lead standard death lung exposure She82
chromate workers employed rates among US >3 months 16 14 ns estimated from
more than three months males employment below 0.1 mg
between 1940-1969; 1296 >10 years 9.3 1.7° Cr/m’ to above
white and 650 non-white employment 2.0 mg/m*; no
subjects specification
UK chromium platers first Compared with Lung males 63 1.6° A few high air Sor87
employed between 1946 and mortality ratesin = Lung females 6 1.2 ns concentrations
1975 England and Wales Nose cavities (2) (oy measured before
Larynx 1973; after 1973
(m) 3 3.0 ns generally less
(f) 0 - than 50 ug Cr/m?
Same population as Langärd (A) General Lung 10 AlSns  9.5x10" Lan89
et al (1980); also expansion = population; (B) (ferrochromium B 3.0
of population to include internal reference workers) C26
entries 1960-65; 1235 with non exposed;
workers (C) local
population lung,
cancer

a

Significant at 95% level; ns = Non significant

42 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 42 =================================================================

<br><br>====================================================================== Pagina 43 ======================================================================

<pre>Four new cases of lung cancer had occurred since the initial study was carried out.
Three of the four new cases of lung cancer occurred in the above mentioned group of
24 workers who had been employed for more than three years before 1973. The
expected number of tumours was 0.135, while the observed number of cases was 6.
This gave an O/E (Observed/Expected) ratio of 44. The total number of
man-years-at-risk in this sub-cohort was 391. It should be noted that five of the six
patients smoked. Only one had been exposed to chromates other than zinc chromate.

Hayes ef al. (Hay89) studied the mortality among 1879 male workers employed in
a Baltimore chromium pigment factory; they were followed from 1940 up to 1982.
The vital status of 1737 (92%) of the eligible cohort members was determined. For all
malignant neoplasms, 101 deaths were observed while 108.8 were expected (US
national rates), SMR* = 93. For the entire study group, no significant excess was
observed for respiratory cancer (SMR for lung cancer was 116 with a 95% confidence
interval of 83 - 158), nor for cancer at other sites. However, the total number of years
of employment in the factory and the total number of years of exposure to chromate
dusts were both statistical significantly (p < 0.05, for trend) associated with an
increased risk of lung cancer. The excess risk of lung cancer was associated with
duration of exposure to chromate dusts. This was, however, only clearly apparent for
subjects followed for 30 years or more after initial employment. For this group, the
SMRs were 81, 139, 201 and 321 for the subjects with 0 years, less than 1 year, 1 - 9
years, and 10+ years of exposure to chromate dusts (p < 0.01, for trend), respectively.
The risk of digestive cancer was only weakly associated with exposure to chromate
dusts. Although detailed environmental data were not available, the ratio of lead to
zinc chromate concentrations in the study plant was reported to be approximately nine
to one. The smoking habits of the cohort were not taken into consideration in this
study.

Korallus et al. (Kor93) studied the mortality of 1417 workers who had been
employed for at least one year between 1948 and 1988 (a total of 25982.7 man-years)
in two German chromate producing factories in the North Rhein Westphalia region.
The main objective of the study was to establish whether the change-over to a
production process using lime-free conversion of chromite ore, thus eliminating the
formation of calcium chromate, had resulted in the reduction of lung cancer among the
workers (the change was effectuated in 1958 in one and in 1964 in the other factory).
In the earlier period, the exposure was characterized as ‘high’; between 1977 to 1987
the mean annual chromium concentrations were between 12 and 73 g/m’. The results
showed that in a group of 739 workers exposed before the process change, the SMR
for lung cancer was 2.27 (95% CL 1.78-2.85). On the other hand, the SMR for lung

SMR - standardized mortality ratio

43

Effects
</pre>

====================================================================== Einde pagina 43 =================================================================

<br><br>====================================================================== Pagina 44 ======================================================================

<pre>cancer of the 678 workers exposed after the process change-over, was 126 (95%
confidence interval 58-238). Confounding factors in this study were: smoking which
was more common in the industrial cohorts than in the general population, additional
exposure to asbestos, a short latency period.

In 1990, Moulin et al. (Mou90) reported a mortality study with 2269 male workers
of a plant producing ferrochromium and stainless steel in France. Their vital status was
recorded between 1952 and 1982, and smoking habits of 67% of cohort members were
registered. The cohorts were divided into two groups based on administrative data: the
exposed (N = 1717) and the unexposed (N = 552) groups. There were no levels of
exposure reported in this paper. It was surmised that the ‘exposed’ workers were
exposed to chromium, nickel and polycyclic aromatic hydrocarbons (PAH). Among
the exposed group, a significant excess of lung cancer mortality was observed (SMR
204, 95% CI* 102-364), which was not found in the unexposed group (SMR 32, 95%
CI 1-177). A nested case-control analysis performed on the cohort showed that the
excess of mortality due to lung cancer was associated with former PAH exposures in
the ferrochromium production workshops rather than with exposures in the stainless
steel manufacturing areas.

In 1991, Simonato et al. (Sim91) published a report on a retrospective cohort
mortality study which was the result of an extensive co-operation between the JARC,
WHO Europe and the Danish Welding Institute. It is a multicentre cohort study of
11092 male welders from 135 companies located in nine European countries with a
total of 164 077 person-years. The aim was to investigate the relation of potential
cancer risk, lung cancer in particular, to occupational exposure. The observation period
and the criteria for inclusion of welders varied from country to country. Follow-up was
successful for 96.9% of the cohort. The observed numbers of deaths were compared
with expected numbers, calculated from national reference rates. Mortality and cancer
incidence ratios were analyzed by disease category, time since first exposure, duration
of employment and estimated cumulative exposure to total fumes, chromium, Cr(VI)
and nickel. Overall, a statistical significant excess for mortality due to lung cancer was
reported (116 observed v. 86.81 expected deaths, SMR = 134; 95% CI: 110-160). An
increase with time since first exposure was present for both mild steel and stainless
steel welders, which was more noticeable for the subcohort of predominantly stainless
steel welders. On the other hand no clear association was apparent between mortality
from lung cancer and estimated duration of cumulative dose of nickel or chromium.
The confounding effect of smoking habits had not been taken into account. Also a
Statistically significant excess of bladder cancer was observed (SMR=191; 95% CI:
107-315). However, no association was found with time since first exposure, nor with

CI - confidence interval

44

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 44 =================================================================

<br><br>====================================================================== Pagina 45 ======================================================================

<pre>45

duration of employment. These data suggest a possible role of occupational exposure
to stainless steel welding fumes in the occurrence of lung cancer mortality.

Takahashi and Okubo (Tak90) performed a prospective cohort mortality study of
workers employed in 415 small-scale chromeplating plants in Japan between 1970 and
1976. A group of 1193 male metal platers was identified in 1976 and divided into a
chromium platers subgroup (N = 626) and a non-chromium plater subgroup (N = 567).
Both subgroups were followed from 1976 to December 1987. For the entire period of
follow-up a total of 12606 person-years was enumerated. The observed number of
deaths (all causes) was slightly below the expected value, particularly in the chromium
plater subgroup. Among specific causes of deaths, only the observed number of cancer
of the lung was found to be significantly higher than the expected number for all
platers (SMR 179, 95% CI 102 -290). However, the SMR in either of the two plater
subgroups did not differ significantly from 100. In the chromium plater subgroup, the
highest SMR was observed for leukaemia; this value was based on two cases only.
Smoking history was not obtained in this study.

A cohort mortality study was performed by Moulin et al. (Mou93). This study
included a group of 2721 welders (34 131 person years) and a control group of 6683
manual workers (84 429 person years) employed in 13 factories in France. The
mortality of the two cohorts was studied from 1975 to 1988. Data on smoking habits
were collected from medical records. The smoking habits of 87% of the study
population were known. The expected number of deaths was based on national rates
after adjustments for age, sex and calendar time. There were no data on levels of
exposures to metals in the past. The main welding techniques initially used in most
factories, were MMA welding and oxyacetylene welding to a lesser extent. SMR for
lung cancer was 124 (95% CL 75-194) for welders; the corresponding value for the
controls was lower (SMR 94, 95% CI 68-126). For the subgroup of stainless-steel
welders, the SMR was 92 (95% CL 19-269),

Raithel ef al. (Rai89) studied the levels of chromium and nickel in the pulmonary
tissues of lung cancer patients and in a control group. They examined 34 deceased
persons, 21 men and 13 women; in 15 cases death resulted from lung cancer and in the
other 19 cases there was no indication of a malignant disease of the airways. There
was no difference in the levels of nickel, but on the other hand, the concentration of
chromium in patients who had died of lung cancer and who had all been smokers, were
significantly higher than in the non-smokers or in those with healthy lungs. An
accumulation of nickel or chromium in the tumour matrix could not be detected.

A similar study was reported by Antilla et al. (Ant89). These authors examined the
chromium content of the lungs of 53 lung cancer and 43 control patients. They found
that the levels of chromium in the lung cancer patients were higher than those in
(smoking and non-smoking) control patients. A positive correlation between the

Effects
</pre>

====================================================================== Einde pagina 45 =================================================================

<br><br>====================================================================== Pagina 46 ======================================================================

<pre>pulmonary chromium concentration and smoking time and the severity of emphysema
was found in the control but not in the cancer patients. This group of lung cancer
patients included subjects with occupational exposure to chromium.

Akslen et al. (Aks90) also found increased concentrations of chromium in lung
tissues from patients with bronchial carcinoma. In this study, central and peripheral
lung tissue, bronchial tissue and hilar lymph nodes were collected from 20 patients
with bronchial carcinoma and 21 control individuals. Lung tissue concentration of
chromium was doubled, compared to the level in control individuals. Smokers showed
a dose-related increase in the deposition of chromium. Furthermore, in cancer patients
an inverse relationship between smoking and the tissue concentration of chromium in
regional lymph nodes was found, possibly indicating a decrease on pulmonary
clearance mechanisms by smoking.

More recently, Adachi ef al. (Ada91) analyzed the concentrations of nine metals
(iron, calcium, magnesium, zinc, copper, cobalt, nickel, lead and chromium) in lung
tissues from 224 lung cancer cases in Japan. Comparisons were made with controls.
There were no significant differences in the chromium, nickel and lead concentrations
between lung cancers and other cases, although these values were lower in lung
cancers.

Since 1985 a few reviews have published epidemiological evidence of the
carcinogenicity of chromium in particular branches of the industry. Langard (Lan90)
wrote an extensive review on “one hundred years of chromium and cancer”. He
concluded that all Cr(VI) compounds should be considered as carcinogenic, and that
no evidence has been presented indicating that human exposure to Cr(IIT) is associated
with increased cancer risk. Lees (Lee91) in his review on chromium and disease
observed that the relationship between employment in industries producing chromium
compounds from chromite ore and Jung cancer has been well established in numerous
studies. The relationship between exposure to certain chromium-based pigments and
chromic acid and lung cancer, although not strong, is well accepted. The data
concerning emissions from stainless-steel manufacturing are contradictory.
Hypotheses about the carcinogenicity of specific chromium compounds generally
relate to their solubility in body fluids. These hypotheses, however, have generally
been determined from toxicological, not epidemiological, investigations. Well
designed epidemiological studies, with detailed assessments of exposure of the
workers, have the potential to help to elucidate causality, to identify specific
carcinogenic compounds, and to quantify risk in humans eliminating the need to
extrapolate from animal data. Although the need for exposure data crucial to this effort
was identified in the earliest epidemiologic studies of chromium, such studies have not
been conducted.

46

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 46 =================================================================

<br><br>====================================================================== Pagina 47 ======================================================================

<pre>Recently Marini et al. (Mar95) wrote a comment on a “Letters to Editor’ column
stating their disagreement in the interpretation that welding of stainless steel is an
activity with potentially a carcinogenic risk. It was based on a study performed by the
IARC and reported by Simonato et al. (Sim92), in which a comparison was made
between mild steel welding, predominantly stainless steel welders, stainless steel and
shipyard welders. Marini ef al. (Mar95) concluded that mild steel welders in this
cohort were at higher risk for lung cancer than stainless steel welders; other
conclusions could not be drawn from this material. Langard (Mar95) replied to this
letter, stating that the existence of confounding factors like smoking habits and
asbestos pointed to the need for further clarification of the significance of exposure to
hexavalent chromium as a determinant of respiratory cancer among stainless steel
welders. There was also a need to elucidate whether the different methods of welding
may contribute differently to the risk of cancer in the respiratory organ of welders.

In a recent Symposium on Epidemiology in Occupational Health in September
1995 in the Netherlands, Lees et al. (Lee95) presented their preliminary results on a
retrospective cohort mortality study of chromate production workers (Letter from Gibb
from EPA to Swaen, January 1996). This study has been performed by a co-operative
agreement between John Hopkins University and the US Environmental Protection
Agency. The cohort studied by Dr Richard Hayes which had been published in his
disertation in 1976 was used, and the vital status was updated till 1992 and
employment records till 1985. Exposure data were available in the form of 200,000
industrial hygiene measurements, most of them by personal sampling. The population
characteristics were as follows: cohort size 2357 males, dates first employed 1950 -
1974, ethnic background 51% white and 49% non-white, smoking information 57%,
total deaths 857, lung cancer deaths 122 and observation time 70,736 person-years,
through 1992, The SMR for respiratory cancer was 154 (95% CI 129 - 183), for lung
cancer 156 (95% CI 129 - 186) and for all cancers combined 107 (95% CI 94 - 122),
When the exposure was expressed as a concentration times exposure period (mg/m* x
years) and grouped into quartiles, there was a positive exposure - response (SMR)
relationship. From a logiste regression analysis the following relationship between
odds ratio (OR) and cumulative exposure was obtained: OR = exp(cumulative
exposure x 0.744). The final results of this study are not yet published.

Sjogren et al. (Sjo94) performed a meta-analysis of five case-referent studies of
stainless steel welders and the risk of lung cancer. Stainless steel welding is associated
with exposure welding fumes, including airborne chromium and nickel. Between 50%
and 90% of the chromium generated in manual metal arc welding is hexavalent. The
five studies originated from Canada, Denmark, France, Norway and Sweden. The
relative risk (RR) was computed, weighting the estimates of the individual studies with
their reciprocal variance. The variances were calculated from the 95% Cls published

47

Effects
</pre>

====================================================================== Einde pagina 47 =================================================================

<br><br>====================================================================== Pagina 48 ======================================================================

<pre>by the authors of the original studies. Asbestos exposure and smoking habits had been
taken into account. The resulting value was 1.94 with a 95% confidence interval of
1.28 - 2.93. This result suggests an association between exposure to stainless steel
welding fumes and lung cancer.

Mancuso (Man75) studied 332 white male workers who were employed in a
chromate plant in the US between 1931 and 1937, and who were followed to 1974; In
his study Mancuso reported lung cancer death rates by levels of exposure to soluble,
insoluble, and total chromium concentrations. His results have been assessed by the
US Environmental Protection Agency (EPA84). According to the EPA, a life-time (75
years) exposure to 0.001 mg/m’ total chromium dust entailed an additional lung cancer
mortality risk of 1.4 x 10°.

5.2.5 Genotoxicity / Mutagenicity

Most short-term tests to study the genotoxicity of chromium(VI) compounds are
carried out using soluble compounds, i.e. potassium, sodium and ammonium
chromates or dichromates. This is not surprising because for a chromium compound to
interact with the test cells it must be soluble in biological fluid. Occasionally, tests
were performed with moderate and poorly soluble chromium compounds like calcium,
zinc, strontium and lead chromates.

In the present document only the more recent data are listed.

DNA damage induced by exposure to potassium dichromate (K,CrO,) in in vitro
experiments have been reported. Wolf ef a/. (Wol89) studied the occurrence of DNA
strand breaks induced in vitro by chromium (VI), which was reduced by gluthation to
different chromium species. Using DNA agarose gel electrophoresis and nick
translation assay, strand breaks were detected only when chromium(VI) was reduced
by hydrogen peroxide. The reduction of chromium(VI) by an excess of glutathione led
to no alteration in the DNA agarose gel electrophoresis pattern of the double-stranded
plasmid pBR322 DNA and in the nick translation assay, indicating that no strand
breaks had occurred under these conditions. Borges et al. (Bor91) also studied the
ability of the thiols in glutathione, cysteine, B-mercaptoethanol and dithiothreitol
(DTT) to effect chromium(VI)-induced DNA damage in vitro, using supercoiled
plasmid DNA pBR322 (form 1) isolated from Escherichia coli HB101. Chromium(VI)
in the form of potassium dichromate was used. Reaction of pBR322 DNA with
chromium(VI) in the presence of the thiols led to the formation of chromium(V) and
chromium-DNA adducts. Transmission electromicroscopy of chromium-DNA
complexes revealed aggregates of several plasmids, as well as condensation of
individual plasmids into compact kinked forms. These effects may be due to

48 Chromium and its inorganic compounds

</pre>

====================================================================== Einde pagina 48 =================================================================

<br><br>====================================================================== Pagina 49 ======================================================================

<pre>cross-linking of DNA induced by chromium complexes. Witmer and Park (Wit89)
reported that 5-20 HM chromium(VI) (potassium dichromate and sodium dichromate)
caused single strand breaks as well as DNA-protein crosslinks in A549 lung cells when
studied by alkaline elution, while with L1210 mouse leukaemia cells only
DNA-protein crosslinks were found. This means that the DNA lesions are different in
different cells.

Data on the genotoxicity of potassium dichromate on Escherichia Coli was
reported by Gaur and Bhattacharjee (Gau91). Concentrations potassium dichromate of
50 and 80 pg/ml lead to respectively 56 and 69% loss of plasmid born resistance.
Sugden et al. (Sug90) reported that potassium dichromate required the presence of
oxygen to revert the Salmonella typhimurium strain TA102 but induced a moderate
reversion frequency in TA2638 under anaerobic conditions. These data support a role
of oxygen radicals in chromium-mediated mutagenesis and suggests at least two
pathways by which chromium compounds can induce mutations.

The mutational specificity of chromium(VI) compounds in the hprt locus of
Chinese hamster ovary-K 1 cells was studied by Tang et al. (Tan92). Among the effects
of potassium dichromate on the mutants, single base substitutions, two base
substitutions, four base substitutions, splicing mutations and single base pair insertions
or deletions were shown. All the base substitutions and most of the frameshift
mutations observed were located at the A/T-rich sequences.

De Marco et al. (Mar88) reported that potassium dichromate significantly
increases the frequency of micronucleated cells in Vicia faba root tips with a clear
dose-effect relationship. On the same experiments, potassium chromate also induces
increased lagging chromosomes/chromatids and chromatid bridges or acentric
fragments by 24 hours treatment. Chorvatovicova et al. (Cho91) studied the effects of
simultaneous pretreatment with vitamins C and E on the toxicity and mutagenicity of
potassium dichromate in rats and guinea pigs by using the micronucleus test in bone
marrow. The results showed that vitamin C caused an antimutagenic effect against
bichromate. The effect of vitamin E was demonstrated only in an increase of the ratio
of NCE (normochromatic erythrocytes) to PCE (polychromatic erythrocytes), i.e., in a
decrease of the cytotoxic but not the mutagenic effects of hexavalent chromium.

It should be noted that the above mentioned experiments have been performed to
study the interaction between the kinetics and the dynamics of the carcinogenicity of
some hardly soluble hexavalent chromium compounds, e.g. calcium, zinc and
strontium chromates. An ‘uptake-reduction’ model explaining the carcinogenicity of
these compounds has been forwarded, which also explains the lack of carcinogenicity
of Cr(111) compounds. The model takes into account that Cr(V1) readily enters cells by
diffusion through a non-specific anion channel, whereas cells are relatively
impermeable to Cr(III). Some factors appear to facilitate Cr(VI) uptake by reducing

49

Effects

</pre>

====================================================================== Einde pagina 49 =================================================================

<br><br>====================================================================== Pagina 50 ======================================================================

<pre>50

SD - standard deviation

Cr(VD to Cr(IID after it enters the cell, presumably keeping intracellular Cr(VI)
concentration low and allowing for further Cr(VI) uptake. Cr(VI), once reduced
intracellularly, produces various forms of DNA damage including DNA interstrand
crosslinks, DNA-protein crosslinks, DNA strand breaks and Cr-DNA adducts (Sta89;
Wet89a,b; Gib89). Recently, De Flora et al. (Flo90) have published a comprehensive
review on the genotoxicity of chromium compounds, including potassium-, sodium-
and ammonium dichromate.

Gennart et al. (Gen93) studied the sister-chromatid exchange (SCE) in blood
lymphocytes, serum tumour markers, carcinoembryonic antigen (CEA) and tissue
polypeptide antigen (TPA), and urinary excretion of chromium, cobalt and nickel in 26
male workers occupationally exposed to chromium, cobalt and nickel dust and in 25
control subjects matched for age and smoking habits. An analyses of variance on the
SCE rank values revealed that both exposure status and smoking habits had a
statistically significant effect. The tumour markers did not reveal a significant
difference between exposed and contro! groups. However, CEA serum levels were
significantly correlated not only with smoking habits but also with duration of
exposure. Popp et al. (Pop91) investigated the frequency of DNA strandbreakage and
cross-linking and of SCE in the lymphocytes of 39 electric welders exposed to
chromium and nickel with 18 controls standardized for age, smoking habits and sex.
The study on the DNA was performed by using the alkaline filter elution technique
and the results were expressed as relative elution rates based on the elution of V79
cells (hamster fibroblasts). The SCE determination was carried out by examining 25
complete second metaphases per subject and the proliferation index was determined
based on a total of 100 metaphases. The mean levels of chromium and nickel in the
urine of the welders were 28.4 (SD* 19.8) and 11.7 (SD 7.82) ug/l, respectively. The
results surprisingly showed that the welders exhibited significantly lower SCE
frequency than did the controls. On the other hand, a significant correlation was found
between the frequency of SCE, the frequency of individual DNA strand breakage and
the concentration of chromium in urine. In the case of welders less DNA was eluted
through the two filter types used than in the case of the control group, which according
to the authors must be interpreted as resulting from the presence of DNA-protein
cross-links. Nagaya ef al. (Nag91) studied the SCE in lymphocytes from 12 male
chromium-platers in a 5-year follow-up study in Japan. Multiple regression of SCE
frequency on age, urinary chromium and smoking habits was analyzed. It was found
that neither age nor urinary chromium was a significant predictor for SCE frequency.
It was concluded that although urine analysis revealed that workers were exposed to

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 50 =================================================================

<br><br>====================================================================== Pagina 51 ======================================================================

<pre>chromium, this exposure did not influence the SCE frequency: on the other hand
smoking habits were a highly significant positive predictor for this effect.

The following conclusions were drawn by IARC (IARC90):

Chromium(VI) compounds of various solubilities in water are consistently active
in numerous studies covering a wide range of tests for genetic and related effects. In
particular, potassium dichromate, sodium dichromate, ammonium dichromate,
potassium chromate, sodium chromate, ammonium chromate, chromium trioxide,
calcium chromate, strontium chromate and zinc yellow induced a variety of effects
(including DNA damage, gene mutation, sister mutation, sister chromatid, exchange
chromosomal aberrations, cell transformation and dominant lethal mutation) in a
number of targets, including animal cells in vivo and animal and human cells in vitro.
Potassium chromate induced aneuploidy in insects, while chromium trioxide did not.
Various compounds induced gene mutation in insects. Potassium dichromate produced
recombination, gene mutation and aneuploidy in fungi. All of these chromium(VI)
compounds induced DNA damage and gene mutation in bacteria. Similar patterns
were observed with zinc chromate, barium chromate, lead chromate and the derived
pigments chromium organ, chromium yellow and molybdenum orange, which,
however, often required preliminary dissolution in alkali or acids. A liquid
chromium(V1) compound (chromy! chloride) and its vapours induced gene mutation in
bacteria.

Although chromium(I1]) compounds are generally more reactive than chromium
(VI) compounds with purified DNA and isolated nuclei, 12 chromium(III) compounds
of various solubilities (chromic chloride, chromic acetate, chromic nitrate, chromic
sulphate, chromic potassium sulphate, chromium alum, neochromium, chromic
hydroxide, chromic phosphate, chromic oxide, chromite ore and cupric chromite) gave
positive results in only a minority of studies using cellular test systems, often under
particular treatment conditions or at very high concentrations, which were generally
orders of magnitude higher than those needed to obtain the same effect with
chromium(VI) compounds. Some of the positive results could be ascribed to
contamination with traces of chromium(VI) compounds. In particular, no DNA
damage was observed in cells of animals treated in vivo with chromic chloride, and no
micronuclei were seen in cells of animals given chromic nitrate. The chromium(III)
compounds tested generally did not produce DNA damage, gene mutation, sister
chromatid exchange or cell transformation in cultured animal and human cells.
Chromosomal aberrations were often observed with high concentrations of
chromium(III) compounds. Weak effects on gene mutation and mitotic gene
conversion were observed in fungi. Negative results were obtained in the large
majority of tests for DNA damage and gene mutation in bacteria. Certain complexes of

51

Effects
</pre>

====================================================================== Einde pagina 51 =================================================================

<br><br>====================================================================== Pagina 52 ======================================================================

<pre>chromium(III) with organic ligands, which favour the penetration of chromium(III)
into cells, were reported to induce DNA damage and gene mutation in bacteria and in
cultured mammalian cells.

A chromium(ll) compound (chromous chloride) gave negative results in in vitro
tests with animal cells (DNA damage, chromosomal aberrations and aneuploidy). A
water-insoluble chromium(0) compound (chromium carbonyl) did not induce DNA
damage in bacteria.

No relevant study on the genetic and related effects of metallic chromium was
available to the Working Group of the IARC.

5.2.6

Effects on the reproduction

The following conclusions were drawn by the IARC (IARC90) on the effects of
chromium on reproduction. Chromium(VI) compounds cross the placental barrier in
greater amounts than chromium(III) compounds. Chromium trioxide increases fetal
death rate, causes growth retardation and increases the frequency of skeletal
deformaties and cleft palate in rodents. Developmental effects have also been reported
in mice exposed to chromic chloride.

More recent data are listed below.
Male reproduction

Ernst (Ern90) studied the toxicity of Cr(VI) and Cr(III) compounds on the testes of rats
after short-term exposure. Groups of 8 male rats were injected intra-peritoneally daily
for 5 consecutive days with 1, 2 or 4 mg/kg Cr(III) doses (as chromium chloride) or
Cr(VD doses (as sodium chromate). The animals were sacrificed 7 and 60 days after
administration of the last dose. 7 days after the last dose, testicular effects were not
seen in any of the groups. When investigated after 60 days, a significant reduction in
relative testicular weight was seen in the groups injected with Cr(VI). Histological
examination revealed a dose-dependent increase in the number of atrophic
seminiferous tubules with a loss of spermiogenetic epithelium. In the group receiving
4 mg Cr (VI)/kg the cellular organization was lost. Complete degeneration was
observed in almost every seminiferous tubule and the Leydig cells appeared to be
atrophic. In addition, a substantial loss of epididymal! spermatozoa was observed. From
this study the committee concludes that the NOAEL of Cr(VI) on the male
reproduction is far lower than 1 mg/kg body weight. No significant treatment-related
alterations, either in testicular histopathology or in epididymal sperm number, were

52

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 52 =================================================================

<br><br>====================================================================== Pagina 53 ======================================================================

<pre>53

seen after Cr(III) administration. No clinical signs of toxicity were observed in any
experimental animal during the study.

More recently, Ernst and Bonde (Ern92) reported on the effects of Cr(VI) after
subchronic treatment on rats. The rats were injected intraperitoneally with a Cr(VI)
dose of 0.5 mg/kg (as sodium chromate), 5 days per week, for 8 weeks. The authors
found a significant reduction in epididymal sperm motility at the end of exposure
period. The reduction was reversed after an unexposed period of a further 8 weeks.
Furthermore, the percentage of abnormal spermatozoa was similar between the groups
of animals. A decrease in serum testosterone and an increase in FSH were found at the
end of exposure period. The results indicate that a number of mechanisms may be
involved in the deleterious effects of chromate on male rat fertility. Since the effect is
reversible the committee concludes that a Cr(VI) dose of 0.5 mg/kg body weight is the
MOAEL for male rat reproduction.

In 1992, Bonde and Ernst (Bon92) published a cross-sectional study on the
spermatotoxic effects of water soluble hexavalent chromium in welders. They
examined the relationship between semen quality and chromium in urine and blood of
a population of 30 tungsters inert gas (TIG) stainless steel welders, 30 mild steel
welders and 47 non-welding workers (controls). For each subject, the semen volume,
sperm concentration, total sperm count, proportion of normal sperm forms, proportion
of motile sperm and linear penetration rate in chicken egg white were determined. In
addition, the serum concentration of testosterone, follicle stimulating hormone (FSH)
and luteinizing hormone (LH) were analyzed. A spot urine sample was delivered at
end of the semen sample collection period for determination of chromium. Information
on occupational exposure, personal habits and urogenital disorders was gathered by
interview. No environmental monitoring was performed. The concentration of
chromium in blood was determined in a blood sample obtained before the start of a
workshift. The chromium concentrations in urine ranged from 0.08 to 2.18 ug per g
creatinine and the chromium concentration in blood from 0.3 to 2.4 ug/l. This study
did not reveal any association between the level of chromium in biological fluids and
the quality of semen or male sexual hormones. However, after adjustments for
confounding factors, the serum concentration of testosterone showed a borderline
significant decrease with a corresponding increase in urinary chromium (p=0.05). By
separate regression analysis this negative regression coefficient was found only on the
stainless steel welders.

Female reproduction

Ratnasooriya and Balasuriya (Rat92) reported antigestational effects of Cr(VI) in the
rat. Groups of pregnant rats were given sodium chromate doses of either 1, 4 or 8

Effects
</pre>

====================================================================== Einde pagina 53 =================================================================

<br><br>====================================================================== Pagina 54 ======================================================================

<pre>mg/kg (as sodiumchromate) per day by intraperitoneal injections from day | through
day 7 of pregnancy. Another three groups were given the same doses but between day
7 and day 14 of pregnancy. With each group a control group was associated, that was
given saline by i.p. injections. Laparotomy was done on day 11 and 15 of the
pregnancy and the numbers of uterine implants, resorption and corpora lutea were
counted. Pre- and post-implantation losses were also computed. The results showed no
significant effect on any of the reproductive parameters studied when given the lowest
and the highest doses, either during days 1-7 or days 7-14 of pregnancy. On the other
hand, the intermediate dose altered the number of uterine implants and
post-implantation losses, when administered during days 7-14 of pregnancy. None of
the chromium treatments had any effect on fetal size. The absence of a dose-response
relationship makes interpretation of the results difficult.

In 1988, the WHO cited a report from Glaser et al, (Gla84) to the
Umweltbundesamt, Germany. An inhalation study was performed to investigate the
effects of sodium dichromate on the reproduction and teratogenicity in three
generations of rats. The animals were exposed to aerosols of this compound in the
atmosphere at a level of 200 g/m’ during 130 days per generation. No effects on
reproduction were found. All teratogenicity tests were negative, and there was no
increase in fetal chromium content. However, from generation to generation, there was
an increase in immunosuppression and hyperplasia of organs (especially in the lungs)
and changes in haematological variables.

The WHO drew the following conclusion on the teratogenicity of chromium
(WH088): “Both chromium oxidation states, when injected at high levels parentally
into animals, are teratogenic, with the hexavalent form accumulating in the embryos to
much higher concentrations than the trivalent. The Task Group was not aware of any
report indicating teratogenicity in human populations”.

5.2.7

Miscellaneous effects

The reports on effects of chromium exposure on the liver are ambiguous. Baruthio
(Bar92) mentioned hepatocellular deficiency, and Anonymus (Ano88) liver damage.
These effects probably occurred at very high doses in which case general toxicity was
induced. The WHO (WHO88) reported that statistics on liver disease are usually
included in the group of diseases of the digestive system and seldomly published
separately. The rate of diseases of the digestive system for chromate industry workers
was reported to be similar to that in many other industries. In an epidemiological study
a low rate of cirrhosis of the fiver in chromium workers was reported, and liver
function test results that did not differ significantly from those of controls (WHO88).

54

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 54 =================================================================

<br><br>====================================================================== Pagina 55 ======================================================================

<pre>The effects of chromium on the central and peripheral nervous system are also

vague. There is no evidence that Cr(VI) is neurotoxic to humans. But Von Burg and
Liu (Bur93) cited a report from 1977, claiming that intraperitoneal injections of 2
mg/kg Cr(VI) every day for 3 or 6 weeks in rabbits resulted in neuronal degeneration
of the cerebral cortex, marked chromolysis and meningeal congestion. No more recent
data are available.

5.3

Summary of effects

The committee summarizes its findings as follows:

The target organs in occupational exposure to chromium and its compounds are
the skin, mucous membranes of the upper respiratory tract, the kidneys, the lungs
and the reproductive organs.

Chromium exposure of the skin may cause irritative lesions and
allergic/eczematous lesions. Irritative lesions are mostly caused by Cr(VI), and to
a much lesser extent by Cr(111). Chromium sensitivity is a type IV delayed
hypersensitivity. Cr(VI) and Cr(111) compounds are allergenic, but the latter
compound to a much lesser degree. Chromiumdlll & VI) contact allergies haven
been observed among workers in numerous industrial activities.

The hexavalent chromium compounds may induce ulceration and perforation of
the nasal septum after inhalatory exposure. The nasal septum is particularly
sensitive because of the very low vascularisation of its cartilaginous structure in
combination with the causticity of Cr(VT). It is estimated that CrO, concentrations
as low as 100 ug/m’ can induce lesions.

No nephrotoxic effect has been reported for trivalent chromium. Soluble Cr(VI)
compounds may cause tubular lesions of the kidneys. The committee concludes
that the NOAEL in rats for acute effects on the kidneys corresponds to a
chromium(VI) dose of 10 mg/kg body weight after intraperitoneal injections. The
critical effects are changes in the serum urea nitrogen and relative kidney weight.
Cross-sectional studies on workers employed in a chromate and dichromate
production plant showed that a concentration of 15 ug chromium per g creatinine
in the urine corresponds to the threshold for effects on the tubular functions. In
these studies the most sensitive kidney variable was the retinol-binding protein
level in urine. A different study on stainless-steel welders, however, showed that
B,-microglobulin in urine was slightly increased in workers with a urinary
chromium concentration exceeding 30 ug per g creatinine. There appear to be
differences in the effects on the kidneys after short-term high dose and long-term
low dose exposure.

55

Effects
</pre>

====================================================================== Einde pagina 55 =================================================================

<br><br>====================================================================== Pagina 56 ======================================================================

<pre>56

The non-carcinogenic effects with respect to aberrations of the lung of workers
caused by exposure to chromium and its components are: pulmonary fibrosis,
chronic bronchitis, emphysema, bronchial asthma and pneumoconiosis. A
long-term inhalation study with rats exposed to CrO, (CrlV !) for two years
showed the lungs to be the critical organ. The estimated LOAEL is 0.5 mg/m’, In
another study in which rabbits were exposed to soluble chromium (Cr(lH))
compounds for 4-6 weeks, a MOAEL of 0.6 mg/m'was found.

Experiments have been performed in rabbits to study the effects of administrating
two different compounds simultaneously. It was found that the combination of
Cr(III) and a soluble cobalt compound produces a stronger effect on the lung than
would expected from the effects of the exposure to the single compounds. The
effects of combined exposure to nickel, cobalt and chromium have also been
reported. Cross-sectional epidemiological studies on a group of manual welders
exposed to various metals (zinc, copper, chromium, nickel, lead and manganese)
showed a predominantly restrictive type of pulmonary impairment followed by a
mixed ventilatory defect. However, it is not possible to deduce the contribution of
chromium to these aberrations.

Few recent animal data are available on the carcinogenic effect of chromium on
the lungs. In a two-year study on rats exposed to a Cr(1V) compound, some female
rats, developed cystic keratinized squamous cell carcinomas in the lungs. Such
tumours were not induced in male rats. This kind of tumour is allegedly not
significant to man. There is limited evidence in experimental animals for the
carcinogenicity of soluble chromium(VI) compounds (chromium trioxide and
sodium dichromate). On the other hand the commitee deems that there is
sufficient evidence for the carcinogenicity of the slight soluble calcium, zinc and
strontium chromate (Cr(VT)).

In a large retrospective cohort mortality study consisting of 11092 male welders
from 135 companies in nine European countries, a statistical significant excess of
mortality due to lung cancer was found. When analyzed according to the type of
welding, the excess lung cancer mortality was predominantly noticeable in the
subcohort of stainless-steel welders. In another cohort mortality study, on workers
of chromeplating plants in Japan, a significant excess mortality was observed for
lung cancer and not for other causes of deaths. Few studies have reported on the
levels of chromium in the pulmonary tissue of lung cancer patients. The chromium
levels were elevated in the lungs of the lung cancer patients.

For the mutagenicity and genotoxicity of chromium compounds the committee
concludes the following:

» Metallic chromium: no relevant studies are available.

- Chromium(ll): non-genotoxic.

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 56 =================================================================

<br><br>====================================================================== Pagina 57 ======================================================================

<pre>- Chromium(lII): in vivo experiments show no DNA damage. In general these

Cr(IIT) compounds did not induce DNA damage, gene mutation, SCE or cell
transformation in cultured animal and human cells.

- Chromium(IV): no tests have been performed on Cr(IV).

- Chromium(VI1): compounds of various solubilities in water were consistently
active in numerous studies (including DNA damage, gene mutation, SCE,
chromosomal aberrations, cell transformation and dominant lethal mutation).

Chromium(III) compounds do not affect the male reproductive system. On the

other hand Cr(VD is toxic to the male reproductive system in a dose-dependent

manner. From a study on rats the committee estimates that the NOAEL of Cr(VI)
for effects the male reproductive system should be much lower than a dose of |
mg/kg body weight by intraperitoneal injection per day. In a more recent study on
rats, a MOAEL of 0.5 mg/kg body weighy per day after intraperitoneal injection
was found. The effect found was a reversible reduction of epididymal sperm
motility.

The results of a cross-sectional study on welders demonstrated that workers with

urinary chromium concentrations between 0.08 and 2.18 ug per g creatinine did

not show aberrations in the quality of semen or sexual hormones like testosterone,

follicle stimulating hormone and luteinizing hormone, although after adjustments
of confounding factors a slight decrease of testosterone levels in serum was found.

No human data are available on the effect of chromium on the female reproductive

system. Cr(1I1) and Cr(VI) compounds are teratogenic in experimental animals

when injected parentally at high levels, the latter compounds being more toxic
than the former. In a three generation study on rats exposed to aerosols of sodium
dichromate with chromium concentrations 0.2 mg/m’ (as Cr) showed no effects on
the reproduction. However, comparisons between successive generations disclosed
an increase of the immunosuppression, hyperplasia of especially the lungs and
changes in haematological variables. This implies that a chromium(V1)
concentration of 0.2 mg/m’ Cr(VI) in ambient air cab be considered as a MOAEL
of this compound.

The effects of chromium on the liver and the central or peripheral nervous system

of experimental animals are ambiguous. Human data are limited.

57

Effects
</pre>

====================================================================== Einde pagina 57 =================================================================

<br><br>====================================================================== Pagina 58 ======================================================================

<pre>58 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 58 =================================================================

<br><br>====================================================================== Pagina 59 ======================================================================

<pre>Chapter

6

Previous evaluation by other national
and international bodies

Dutch Expert Committee on Occupational Standards (1985)
The earlier report op the committee was summarized in chapter 2.
Health Council of the Netherlands (1991)

[n 1991, another committee of the Health Council assessed a criteria document on
chromium. That committee did not take speciation of chromium(VI) compounds into
account, as it is most often impossible to determine the chemical form of
chromium(VI) compounds in the ambient environment. Chromium(VI) compounds
were classified as genotoxic carcinogens in case of inhalatory exposure, and
consequently a linear extrapolation method was used for risk assessment. The other
Health Council committee concluded that chromium(III) compounds are not
carcinogenic to humans.

American Conference of Governmental Industrial Hygienists (ACGIH) (1986)

The recommended TLV’s are listed in chapter 3.
The TLV* for water soluble Cr(VI) compounds is considered adequate in
protecting against irritation of the respiratory tract and possible kidney and liver

Treshold limit value

59

Previous evaluation by other national and international bodies
</pre>

====================================================================== Einde pagina 59 =================================================================

<br><br>====================================================================== Pagina 60 ======================================================================

<pre>damage. For certain water insoluble Cr(VT) compounds, a classification in class Ala
(confirmed human carcinogen) is recommended. A TLV of 0.05 mg/m’ is
recommended because monitoring data on exposures associated with an increased
respiratory risk are scarce. This value should provide an adequate safety margin.

For exposures to mixtures of soluble and insoluble hexavalent chromium
compounds a TLV of 0.05 mg/m? as Cr(VI) is recommended.

For chromite ore processing and chromate pigment manufacture the ACGIH
proposed a TLV of 0.05 mg/m’ (as chromium concentration) with inclusion in Class
Ala.

National Institute for Occupational Health and Safety (1973)

The NIOSH in the US recommended an Ocuppational Exposure Limited of 0.05
mg/m’, TWA - 8 h for chromic acid, and a ceiling value of 0.1 mg/m’, TWA - 15 min.
These limits are based on prevention of nasal ulceration and chronic effects, such as
lung cancer and liver damage.

Deutsche Forschungsgemeinschaft (1992)

The DFG does not recommend MAK values for any chromium compounds, as these
compounds were classified as carcinogenic agents: zinc chromate - class Al
(confirmed human carcinogen); Cr(VI) compounds in the form of dust and aerosols
(with the exception of those water insoluble compounds such as lead chromate and
barium chromate) - class A2 (confirmed animal carcinogen); lead chromate - class B
(confirmed suspected carcinogen).

Swedish Criteria Group for Occupational Standards (1993)

The most recent report of the SCG concluded that only those subjects who are exposed
to hexavalent chromium compounds are at higher risk of developing cancer, and that
the excess cancer risk is mainly related to cancer of the respiratory organs. Water
soluble compounds are more potent human carcinogens than are those with low
solubility. This report does not recommend a occupational exposure limit for
chromium compounds. Of interest is the estimation of cancer risk based on a cohort of
Norwegian workers exposed to zinc chromates, with 15 cases of lung cancer in 1000
man-years at risk. This is equivalent to a unit risk of 1.3 x 107 (1 case per 100000 per
1 ug Cr VI). It is not clear whether the risk is calculated for one year or the whole 40
years of work-life. The method of estimation of exposure is not reported.

60

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 60 =================================================================

<br><br>====================================================================== Pagina 61 ======================================================================

<pre>European Union - Scientific Expert Group (1993)

The SEG recommended an occupational exposure limit (OEL) of 0.5 mg/m’ TWA - 8
hours for chromium (III) compounds based on the same data that the committee had
used in its former report, ie. the results of a rabbit study of Johansson et al. (Joh86,
87). The SEG concluded that the exposure at the level of 0.5 mg/m’ did not result in
adverse effects on the lungs (which means the NOAEL). The DECOS concluded
differently on this experiment.

The same value of 0.5 mg/m’ TWA - 8 h was recommended with respect to
chromium(II) compounds and chromium metal based on the assumption that the
biological activities of chromium(II) compounds are similar with that of
chromium(III) compounds, and chromium metal would be less biologically active.

The SEG did not recommend an occupational exposure limit for Cr(VI)
compounds.

USA - Environmental Protection Agency (1984)

In 1984, the US EPA drew the following conclusion: From epidemiological studies of
chromate production workers there is, using the [ARC criteria, sufficient evidence of
carcinogenicity. Using the same criteria, there is sufficient evidence of carcinogenicity
of hexavalent chromium in animal bioassay studies. The results in animals appear to
be determined to some extent by the solubility of hexavalent chromium compounds.
Trivalent chromium has not been found to be carcinogenic in animal studies.
Hexavalent chromium is mutagenic, and this supports the findings that hexavalent
chromium is carcinogenic in animal bioassays.

61

Previous evaluation by other national and international bodies
</pre>

====================================================================== Einde pagina 61 =================================================================

<br><br>====================================================================== Pagina 62 ======================================================================

<pre>62 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 62 =================================================================

<br><br>====================================================================== Pagina 63 ======================================================================

<pre>Chapter

7

Evaluation of human health risk

TA

Groups at extra risk

Chromium skin contact allergies have been observed among workers in numerous
industrial activities. Sensitized subjects to chromium are at extra risk and should not
be placed in jobs where skin contact with chromium and chromium compounds can
occur. In contrast with the previous document, the committee concluded that it is
inappropriate to consider people with a dimished lungfunction at extra risk.

7.2

63

Assessment of health risk

Chromium trioxide is used in chrome plating, copper stripping, aluminium anodizing,
as a catalyst, refractories, in organic synthesis and photography. Occupations in which
exposure may occur include: anodizers, copper etchers, electro-platers, glass workers,
lithographers, metal workers, oil purifiers, photoengraphers, photographers, process
engravers, stainless steel workers, textile workers, painters and welders (Sit79).

Theory and practice show that the kinetics and toxic effects induced by chromium
compounds depend on the valency of the chromium ion and the water solubility of the
compounds.

Evaluation of human health risk
</pre>

====================================================================== Einde pagina 63 =================================================================

<br><br>====================================================================== Pagina 64 ======================================================================

<pre>Chromium metal dust (Cr?)

There are almost no toxicological data on chromium metal dust. Given this lack of
scientific data the committee can not establish a HBR-OEL*, see however 7.4.

Chromium(ll) compounds (chromium dichloride)

Limited relevant data are available on these compounds. It has been shown that
chromium(I]) is non-genotoxic. No human data are available. The committee can not
recommend a HBR-OEL* due to the lack of scientific data.

Soluble chromium(lll) compounds (chromic acetate, chromic nitrate, chromic
chloride hexahydrate, potassium chromic sulphate dodecahydrate)

The target organ of chromium(III) compounds after inhalatory exposure are the lungs.
A MOAEL of 0.6 mg/m’ was found in rabbits exposed to soluble chromium(III)
compounds by inhalation for six hours per day, five days per week during four to six
weeks. At this concentration morphological as well as functional changes in the
alveolar macrophages were found. Human data are lacking. Chromium(II!) compounds
have been shown to be not mutagenic, nor clastogenic, nor carcinogenic. The
committee considers chromium(III) compounds to be non nephrotoxic.

In establishing a HBR-OEL a large safety factor for the extrapolation of animal
data to humans is not indicated since chromium(HI) compounds induce only local
effects. The committee recommends a HBR-OEL of 0.06 mg/m’ for soluble
chromium(III) compounds, TWA - 8 hour by dividing the MOAEL value of 0.6 mg/m’
in rabbits by a factor of 10. This safety factor is the product of a factor of 3 for
interspecies variations and 3 for using a MOAEL as starting point resulting in a safety
factor 10 . The HBR-OEL should be applied to inhalable dusts.

Insoluble chromium(lii) compounds (chromic oxide, chromic phosphate,
chromic sulphate)

There are almost no recent toxicological data on insoluble chromium(III) compounds.
No human data are available. Given this lack of data the committee can not
recommend a HBR-OEL for insoluble chromium(III) compounds, see however 7.4.

* HBR-OEL - Health Based Recommended Occupational Exposure Limit

64 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 64 =================================================================

<br><br>====================================================================== Pagina 65 ======================================================================

<pre>Chromium(IV) compounds (chromium dioxide)

A long-term inhalation study in rats showed the lungs to be the target organ. A
LOAEL of 0.5 mg/m’ was found in a two year study in rats. Exposure to this
concentration resulted in slight Type II pneumocyte hyperplasis. At higher levels of
exposure, hyperplastic Type II pneumocytes and slightly collagenized fibrosis were
found. The lungs showed minute fibrotic pleuritis. The committee recommends a
HBR-OEL of 0.05 mg/m? for chromium(IV) compounds, TWA - 8 hour. This value is
derived by dividing the LOAEL value in rats of 0.5 mg/m’ by a factor of 10. This
safety factor is the product of a factor of 3 for the interspecies variations and 3 using a
LOAEL as the starting point. The HBR-OEL should be applied to inhalable dusts.

Chromium(Vt) compounds Includes: soluble chromium(VI) compounds (e.g.
ammonium dichromate, chromium trioxide, potassium dichromate, sodium
dichromate); slightly soluble chromium(VI) compound (e.g. calcium chromate,
strontium chromate, zinc chromate); very slightly soluble chromium(VI)
compounds (e.g. barium chromate, lead chromate)

Several epidemiological studies of workers mainly exposed to zinc chromate (a
slightly soluble chromium(VI) compound) report a clear excess of lung cancer
mortality. The same holds for lead chromate (a very slightly soluble chromium(VI)
compound). No cohort studies of workers that were exclusively exposed to soluble
chromium(VI) compounds were found in the literature. However, there are some series
of lung cancer cases that provide circumstantial evidence for the carcinogenicity of
sodium dichromate and potassium dichromate (soluble chromium(VI) compounds).
These lung cancer cases were listed by Langard (Lan90).

Carcinogenicity studies with experimental animals are scarce and of limited value
for human risk estimation, due to limitations in the experimental design. Nevertheless,
most of these studies point to a carcinogenic effect of chromium(VI) compounds in the
lungs. In any case these studies can certainly not be considered as ‘negative’ with
respect to carcinogenesis. It appears that the carcinogenicity of chromium(VI)
compounds in animals varies with the solubility of the compound. Moreover, all
chromium(VI) compounds are mutagenic, irrespective of their solubility. How the
solubility interferes with the carcinogenic potential of chromium(VI) compounds is
not known.

65

Evaluation of human health risk
</pre>

====================================================================== Einde pagina 65 =================================================================

<br><br>====================================================================== Pagina 66 ======================================================================

<pre>The committee draws the following conclusions. Epidemiological studies provide
clear and unambiguous evidence for the carcinogenicity of slightly soluble and very
slightly soluble chromium(VI) compounds and circumstantial evidence for the
carcinogenicity of soluble chromium(VI) compounds. Experimental animal studies
indicate that chromium(VI) compounds possess carcinogenic potential and that there
are quantitative differences between soluble, slightly soluble and very slightly soluble
chromium(VI) compounds. Therefore, the committee considers al! chromium(VI)
compounds as carcinogenic. It considers a worst case approach warranted and has
therefore selected the study of Mancuso (Man75) on slightly soluble chromium(VI)
compounds as a basis for human risk assessment.

The committee decided to adopt the data from the EPA as starting point for the
estimation of the additional life time cancer risk. The EPA risk assessment was based
on the results of the Mancuso study (Man75) complemented with additional exposure
data and follow-up. In agreement with the EPA the committee prefers to use the
Mancuso study because of the availability of reliable historic exposure data and the
availability of a substantial number of observed lung cancer deaths. The EPA used a
low-dose linear extrapolation model for the estimation of the cancer risk. A life time
(75 years) exposure of 1 ug/m* chromium(VI) total dust entails an additional lung
cancer risk of 1.4 x 107. This risk is calculated on the basis of the total chromium
concentration in the chromate plant. The EPA noted that the use of total chromium as a
surrogate for hexavalent chromium could result in an underestimate of the risk by no
more than 7 times; on the other hand, underestimation of plant exposures and of
smoking habits in the workers could lead to a overestimation of the risk by roughly 4
times. Overall, the EPA found the Mancuso study was the best possible estimate of the
risk (EPA84).

For the occupational situation the analysis implies that exposure to 8 g/m’ total
dust may result in an additional cancer mortality risk of 1.4 x 10°. The committee is
of the opinion that in the type of industry involved in the Mancuso study, exposure to
8 ug/m? measured as total dust will not differ considerably from an identical exposure
measured as inhalable dust, since particulates in these type of industries have relatively
small aerodynamic diameters.

Therefore for the chromium(VI) compounds the committee derives an:

« additional cancer mortality risk of 4 x 10° after 40 years of occupational exposure
to 2 g/m’ as inhalable dust.

" additional cancer mortality risk of 4 x 10° after 40 years of occupational exposure
to 0.02 g/m’ as inhalable dust.

66

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 66 =================================================================

<br><br>====================================================================== Pagina 67 ======================================================================

<pre>7.3

Recommended Occupational Exposure Limits

The recommendations of the committee with respect to health based occupational
exposure limit can be summarized as:

speciation occupational exposure limit

chromium metal dust not possible to determine, see however 7.4
chromium(II) compounds not possible to determine

soluble chromium(III) compounds 0.06 mg/m’, TWA - 8 h (as inhalable dust)
insoluble chromium(III) compounds not possible to determine, see however 7.4
chromium(IV) compounds 0.05 mg/m’, TWA - 8 h (as inhalable dust)

chromium(VI) compounds additional cancer mortality risk of 4 x 10° after 40 years of
occupational exposure to 2 g/m! inhalable dust
additional cancer mortality risk of 4 x 10° after 40 years of
occupational exposure to 0.02 g/m’ inhalable dust

7.4

Additional considerations
Chromium metal dust (Cr°)

The committee concluded that it is not possible to determine a health based
occupational exposure limit for chromium metal dust because of a lack of scientific
data. However, taking all data into account and until more pertinent data are available,
the committee does not object to maintain the present regulatory exposure limit
(MAC-value*) of 0.5 mg/m’, TWA - 8 hours.

Insoluble chromium(lil) compounds (chromic oxide, chromic phosphate,
chromic sulphate)

As stated above, given the lack of scientific data, the committee cannot recommend a
health-based occupational exposure limit for insoluble chromium(II])compounds.
However, the committee has reason to believe that the insoluble chromium(II])
compounds are probably less toxic than the soluble chromium(II]}compounds.
Therefore, in line with the recommendation in its 1985 report, the committee is of the
opinion that applying the occupational exposure limit of 0.5 mg/m’, TWA 8-hours, for

MAC - Maximal Accepted Concentration, see chapter 1

67

Evaluation of human health risk
</pre>

====================================================================== Einde pagina 67 =================================================================

<br><br>====================================================================== Pagina 68 ======================================================================

<pre>the soluble chromium(II])compounds in case of the insoluble chromium(IIL)
compounds is justifiable.

Rijswijk, 24 September 1998
For the committee,

Bi A

dr ASAM van der Burght, prof. dr VJ Feron,
scientific secretary chairman

68 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 68 =================================================================

<br><br>====================================================================== Pagina 69 ======================================================================

<pre>References

ACGIH86

Ada86

Ada87

Ada91

Aks90

Ano88
Ant89

Bar92
Bie90

Bon92

American Conference of Governmental Industrial Hygienists. Chromium. Documentation of the treshold
limit values and biological exposure indices. ACGIH, Cincinnati: 1986. OH, p. 139.

Adachi, 8, Yoshimura H, Katayama H, e.a. Effects of chromium compounds on the respiratory system.
Part 4. Long term inhalation of chromic acid mist in electroplating to ICR female mice. Jpn J Ind Health
1986; 28: 283-87.

Adachi 8. Effects of chromium compounds on the respiratory system. Part 5. Long term inhalation of
chromic acid mist in electroplating by C57BL female mice and recapitulation on our experimental studics.
Jpn J Ind Health 1987; 29: 17-33,

Adachi 5, Takemoto K, Ohshima S, e.a. Metal concentrations in lung tissue of subjects suffering from
lung cancer. Int Arch Occup Environ Health 1991; 63: 193-97.

Akslen LA, Myking AO, Morkve 0, e.a. Increased content of chromium and nickel in lung tissues from
patients with bronchial carcinoma. Path Res Pract 1990; 186: 717-22.

Anonimus. Chromium. Rev Environ Contam Toxicol 1988; 107: 39-52, based on several EPA reports.
Antilla 8, Kokkonen P, Paakko P, e.a. High concentrations of chromium in lung tissue from lung cancer
patients. Cancer 1989; 63: 457-73.

Baruthio F. Toxic effects of chromium and its compounds. Biol Trace Element Res 1992; 32: 145-53.
Biederman KA, Landolph JR. Role of valence state and solubility of chromium compounds on induction
of cytotoxicity, mutagenesis and anchorage independence in diploid human fibroblasts. Cancer Res 1990;
50: 7835-42.

Bonde JP, Ernst E. Sex hormones and semen quality in welders exposed to hexavalent chromium. Human
Exp Toxicol 1992; 11: 259-63.

69

References
</pre>

====================================================================== Einde pagina 69 =================================================================

<br><br>====================================================================== Pagina 70 ======================================================================

<pre>Bor91 Borges KM, Boswell JS, Liebross RH, e.a. Activation of chromium (VI) by thiols results in chromium (V)
formation, chromium binding to DNA and altered DNA conformation. Carcinogenesis 1991; 12: 551-61.

Bra90 Brandi G, Schiavano GF, Albano A, e.a. Growth delay and filamentation of Escherichia coli wild-type and
Rec A cells in response to hexavalent chromium and other metal compounds. Mut Res 1990; 245: 201-4.

Bri88 Briggs J, Briggs RC. Characterization of chromium effects on a rat liver epithelial cell line and their
relevance to in vitro transformation. Cancer Res 1988; 48: 6484-90.

Bur93 Von Burg R, Liu D. Toxicology update. Chromium and hexavalent chromium. J Appl Toxicol 1993; 13:
225-30.

Cho91 Chorvatovicova D, Ginter E, Kosinova A, e.a, Effect of vitamin C and E on toxicity and mutagenicity of
hexavalent chromium in rat and guinea pig. Mut Res 1991; 262: 41-46.

DFG92 Deutsche Forschungsgemeinschaft. Chromium and its compounds. In: Occupational toxicants. Critical
data evaluation for MAK values and classification of carcinogens. VCH Verlagsgesellschaft mbH,
Weinheim: 1992; 3: 101.

Eli91 Elias Z, Baruthio F, Daniere MC. Role of solubilized chromium in the induction of morphological
transformation of Syrian hamster embryo (SHE) cells by particulate chromium (VI) compounds.
Carcinogenesis 1991; 12: 1811-16.

EPA84 Environmental Protection Agency. Health assessment document for chromium. Final Report.
EPA-600/8-83-014F. US EPA, North Carolina: 1984.

Ern90 Ernst E. Testicular toxicity following short-term exposure to tri- and hexavalent chromium: an
experimental study in the rat. Toxicol Lett 1990; 51: 269-75.

Ern92 Ernst E, Bonde JP. Sex hormones and epididymal sperm parameters in rats following sub-chronic
treatment with hexavalent chromium. Human Exp Toxicol 1992; 11: 255-58.

EU93 European Union - Scientific Expert Group. Recommendation from the Scientific Expert Group on
Occupational Exposure Limits for Chromium Metal, Inorganic Chromium (11) Compounds, and Inorganic
Chromium (IE) Compounds, 1993: SEG/SUM/50A, 2 pp.

Far89 Farrell RP, Judd RJ, Lay PA, e.a. Chromium (V)-induced cleavage of DNA: Are chromium (V) complexes
the active carcinogens in chromium (VI)-induced cancers? Chem Res Toxicol 1989; 2: 227-29.

Flo90 De Flora S, Bagnasco M, Serra D, e.a. Genotoxicity of chromium compounds. A review. Mut Res 1990;
238: 99.172.

Fra88 Franchini I, Mutti A. Selected toxicological aspects of chromium (VI) compounds. Sc Total Environ
1988; 71: 379-87.

Fri89 Friess SL. Carcinogenic risk assessment criteria associated with inhalation of airborne particulates
containing chromium (VI/III). Sc Total Environ 1989; 86: 109-12.

Gad89 Gad SC. Acute and chronic systemic chromium toxicity. Sc Total Environ 1989; 86: 149-57.

Gaf53 Gafafer WM, Health of workers in chromate producing industry: A study (US Public Health Service,
Division of Occupational Heaith publications No 192), Washinton, 1953.

Gao92 Gao M, Binks SP, Chipman JK, e.a. Assessment of cytotoxicity and unscheduled DNA synthesis in rat
hepatocytes induced by soluble chromium compounds in vitro. Human Exp Toxicol 1992; 11: 408-9.

70 Chromium and its inorganic compounds

</pre>

====================================================================== Einde pagina 70 =================================================================

<br><br>====================================================================== Pagina 71 ======================================================================

<pre>Gao93

Gau91

Gen93

Gib89

Gla86

Goc91

GR85

GR85

GRY]

Gra92

Hat89

Hay88

Hay89

Hil92

Hje86

IARC87

IARC90

IPCS90
Joh86a

Gao M, Binks SP, Chapman JK, e.a. Hexavalent chromium produces DNA strand breakage but not
unscheduled DNA synthesis at sub-cytotoxic concentrations in hepatocytes. Toxicology 1993; 77: 171-80.
Gaur A, Bhattacherjee JW. Toxicity of selected chromium compounds in microbial bioassay system.
Water Air Soil Poll 1991; 59: 193-97.

Gennart J Ph, Baleux C, Verellen-Dumoulin Ch, e.a. Increased sister chromatid exchanges and tumor
markers in workers exposed to elemental chromium-, cobalt-, and nickel-containing dusts. Mut Res 1993;
299: 55-61.

Gibb H, Chen C. Evaluation of issues relating to the carcinogen risk assessment of chromium. Sc Total
Environ 1989; 86: 181-86.

Glaser U, Hochrainer D, Kloppel H, e.a. Carcinogenicity Of sodium dichromate and chromium (VII)
oxide aerosols inhaled by male Wistar rats. Toxicology 1986; 42: 219-32.

Gochfeld M. Panel discussion: epidemiologic and toxicologic studies of chromium. Environ Health
Perspect 1991; 92: 121-25,

Gezondheidsraad: Commissie WGD. Rapport inzake grenswaarde chroom en chroomverbindingen.
Voorburg: 1985. Ra 6/85, 64 pp.

Gezondhcidsraad: Commissie WGD. Rapport inzake grenswaarde Chroom en Chroom-verbindingen, RA
6/85. Voorburg: 1985.

Gezondheidsraad. Chroom toetsing van cen basisdocument (Chromium assessment of an integrated
criteria document). Den Haag: Gezondheidsraad, 1991; U 642/MMHE/mk 63/7-C, 68 pp.

Graf U, Heo O, Ramirez OO. The genotoxicity of chromium (VI) oxide in the wing spot test of
Drosophila melanogaster is over 90% due to mitotic recombination. Mut Res 1992; 266: 197-203.
Hathaway JA. Role of epidemiologic studies in evaluating the carcinogenicity of chromium compounds.
Sc Total Environ 1989; 86: 169-79.

Hayes RB. Review of occupational epidemiology of chromium chemicals and respiratory cancer. Sc Total
Environ 1988; 71: 331-39.

Hayes RB, Sheffet A, Spirtas R. Cancer mortality among a cohort of chromium pigment workers. Am J
Ind Med 1989; 16: 127-33.

Hilaski R, Katz S, Salem H. Inhalation toxicity of chromium from Whetlerite dust in rats. Toxicol Lett
1992; 62: 25-31.

Hjerpe L. Chromate dermatitis at an engine assembly department. Contact Derm 1986; 14: 66-67.
International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks
to humans. Genetic and related effects: An updating of selected IARC monographs from volumes 1 to 42.
IARC, Lyon: 1987; 1-42 (suppl 6).

International Agency for Research on Cancer. Chromium and chromium compounds. In: IARC
monographs. IARC, Lyon: 1990; 49,

International Programme on chemical Safety. Chromium ICSC 0029, IPCS 1990.

Johansson A, Wiernik A, Jarstrand C, e.a. Rabbit alveolar macrophages after inhalation of hexa- and
trivalent chromium. Environ Res 1986; 39: 372-85.

71

References
</pre>

====================================================================== Einde pagina 71 =================================================================

<br><br>====================================================================== Pagina 72 ======================================================================

<pre>Johš6b Johansson A, Robertson B, Curstedt T, e.a. Rabbit lung after inhalation of hexa- and trivalent chromium.
Environ Res 1986; 41: 110-19.

Joh87 Johansson A, Robertson B, Curstedt T, e.a. Alveolar macrophage abnormalities in rabbits exposed to low
concentrations of trivalent chromium. Environ Res 1987; 44: 279-93.

Joh92a Johansson A, Curstedt T, Rasool O, e.a. Rabbit lung after combined exposure to soluble cobalt and
trivalent chromium. Environ Res 1992; 58: 80-96.

Joh92b Johansson A, Curstedt T. Jarstrand C, e.a. Alveolar macrophages and lung lesions after combined
exposure to nickel, cobalt and trivalent chromium. Environ Health Perspect 1992; 97: 215-19,

Kat93 Katz SA, Salem H. The toxicology of chromium with respect to its chemical speciation: a review. J Appl
Toxicol 1993; 13: 217-24.

Kor89 Kortenkamp A, Ozolins Z, Beyersmann D, e.a. Generation of PM2 DNA breaks in the course of reduction
of chromium (VI) by glutathione. Mut Res 1989; 216: 19-26,

Kor93 Korailus U, Ulm K, Steinmann-Steiner-Haldenstaett W. Bronchial carcinoma mortality in the German
chromate-producing industry: the effects of process modification. Int Arch Occup Environ Health 1993;
65: 171-78.

Lan75 Langärd $, Kommedal TM, Bronchialkarsinom hos en ung mann ekspomert for kromater, Tidsskr Nor
Laegeforen 1975, 95:819-820.

Lan83 Langärd S, Vigander T. Occurrence of lung cancer tn workers producing chromium pigments. Brit J Ind
Med 1983; 40: 71-74,

Lan88 Langard S. Chromium carcinogenicity : a review of experimental animal data. Sc Total Environ 1988: 71:
341-50.

Lanš3 Langärd S, Andersen AA, Gylseth B, Incidence of cancer among ferrochromium and ferrosilicon workers;
An extented observation peroid. Br J Ind Med 1989, 47:14-19,

Lan90 Langärd S, One hundred years of chromium and cancer: a review of epidemiological evidence and
selected case reports. Amer J Ind Med 1990; 17: 189-215.

Lan93 Langard $. Criteria document for Swedish Occupational Standards. Arbete och Hälsa 5, National Institute
of Occupational Health, Solna, Sweden: 1993.

Lee89 Lee KP, Ulrich CE, Geil RG, e.a. Inhalation toxicity of chromium dioxide dust to rats after two years
exposure. Sc Total Environ 1989; 86: 83-108.

Lee91 Lees PSJ. Chromium and disease: Review of epidemiological studies with particular reference to etiologic
information provided by measures of exposure. Environ Health Perspect 1991; 92: 93-104,

Lee95 Lees PSJ, Gibb HJ, Rooney BC. Derivation of exposure-response relationship for chromium from historic
exposure data. 11th International Symposium on Epidemiology in Occupational Health, September 1995
in the Netherlands.

Mac48 Macle W, Gregorius F, Cancer of the respiratory system in the United States chromate-producing industry.
Pub] Health Rep (Wash) 1948. 63:1114-1127.

Man75 Mancuso TF. Consideration of chromium as an industrial carcinogen. In: International conference of
heavy metals in the environment. Toronto: 1975; 343-56.

72 Chromium and its inorganic compounds

</pre>

====================================================================== Einde pagina 72 =================================================================

<br><br>====================================================================== Pagina 73 ======================================================================

<pre>Mar88 De Marco A, Paglialunga S, Rizzoni M, e.a. Induction of micronuclei in Vicia faba root tips treated with
heavy metals (cadmium and chromium) in the presence of NTA. Mut Res 1988; 206: 311-15.

Mar95 Marini F, Ferre M-P, Gross H, e.a. Does welding stainless steel cause cancer? Letters to the Editor. Scand
J Environ Health 1995; 21: 65-68.

Mor78 Morning JL, In: US Department of Interior, Minerals Yearbook 1978, 291-301.

Mou90 Moulin JJ, Portefaix P, Wild P, e.a. Mortality study among workers producing ferro alloys and stainless
steel in France. Br J Ind Med 1990; 47: 537-43.

Mou93 Moulin JJ, Wild P, Haguenoer JM, e.a. A mortality study among mild steel and stainless steel welders. Br
J Ind Med 1993; 50: 234-43.

Nag91 Nagaya T, Ishikawa N, Hata H, e.a. Sister chromatid exchanges in lymphocytes from 12 chromium
platers: a $-year follow-up study. Toxicol Lett 1991; 58: 329-35.

NIOSH73 National Institute for Occupational Safety and Health. Criteria for a recommended standard. Occupational
exposure to chromic acid. US Dept Health Education and Welfare, 1973.

Pau91 Paustenbach DJ, Meyer DM, Sheehan PJ, e.a. An assessment and quantitative uncertainty analysis of the
health risks to workers exposed to chromium contaminated soils. Toxicol Ind Health 1991; 7: 159-96.

Pop91 Popp W, Vahrenholz C, Schmieding W, c.a. Investigations of the frequency of the DNA strand breakage
and cross-linking and of sister chromatid exchange in the lymphocytes of electric welders exposed to
chromium and nickel containing fumes. Int Arch Occup Environ Health 1991; 63: 115-20.

Rai89 Raithel HJ, Schaller KH, Akslen LA, e.a. Analyses of chromium and nickel in human pulmonary tissuc.
Int Arch Occup Environ Health 1989; 61: 507-12.

Ras91 Rastogi SK, Gupta BN, Husain T, e.a. Spirometric abnormalities among welders. Environ Res 1991; 56:
15-24,

Rat92 Ratnasooriya WD, Balasuriya R. Antigestational effects of hexavalent chromium in the rat. Med Sci Res
1992; 20: 383-84,

She83 Sheffet A, Thind 1, Mileer AM, Louria DB, Cancer mortality in a pigment plant utilizing lead and zinc
chromates, Arch Environ Health 1982, 37:44-52.

Sim91 Simonato L, Fletcher AC, Andersen A, c.a. A historical prospective study of European stainless steel, mild
steel and shipyard welders. Brit J Ind Med 1991: 48: 145-54.

Sit79 Sittig M (ed). In: Hazardous and toxic effects of industrial chemicals. Noyes Data Corporation, New
Jersey USA: 1979; 137.

Sjö94 Sjögren B, Hansen KS, Kjuus H, e.a. Exposure to stainless steel welding fumes and lung cancer: a
meta-analysis. Occup Environ Med 1994; 51: 335-36.

Sno9la Snow ET, Sha Xu L. Chromium (III) bound to DNA templates promotes increased polymerase
processivity and decreased fidelity during replication in vitro. Biochemistry 1991: 30: 11238-45.

Sno9lb Snow ET. A possible role for chromium (III) in genotoxicity. Environ Health Perspect 1991; 92: 75-81.

Sor87 Sorahan T, Burges DCL, Waterhouse JAH, a mortality study of nickel/chrmium platers, Br J Ind Med
1987, 44:250-258.

Sri92 Srivastava AK, Gupta BN, Mathur N, e.a. Blood chromium and nickel in relation to respiratory symptoms
among industrial workers. Vet Human Toxicol 1992; 34: 232-34,

73 References
</pre>

====================================================================== Einde pagina 73 =================================================================

<br><br>====================================================================== Pagina 74 ======================================================================

<pre>Sta89

Sta91

Sug90

Tan91

Ver88

Vys92

Was91

Wed92
Wet89a

Wet89b

WHO88

Wib93

Wit89

Wol89

Wor92

Yan92

Standeven AM, Wetterhahn KE. Chromium (VI) toxicity: uptake, reduction and DNA damage. J Amer
Coll Toxicol 1989; 8: 1275-83.

Standeven AM, Wetterhahn KE. Possible role of glutathione in chromium (VI) metabolism and toxicity in
rats. Pharmacol Toxicol 1991; 69: 469-76.

Sugden KD, Burris RB, Rogers 5J. An oxygen dependence in chromium mutagenesis. Mut res 1990; 244:
239-44.

Tanigawa T, Araki S, Araki T, e.a. A decrease in Leu-1 la negative lymphocytes in relation to natural
killer cell activity in chromate workers. Brit J. Ind Med 1991; 48: 211-13.

Verschoor MA, Bragt PC, Herber RFM, e.a. Renal function of chrome-plating workers and welders. Int
Arch Occup Environ Health1988; 60: 67-70.

Vyscocil A, Smejkalova J, Tejral J, e.a. Lack of renal changes in stainless steel welders exposed to
chromium and nickel. Scand J Work Environ Health 1992; 18: 252-56.

Wass U, Wahlberg JE. Chromated steel and contact allergy. Recommendation concerning a “threshold
limit value” for the release of hexavalent chromium. Cont Derm 1991; 24:114-18.

Wedeen RP, Qian L. Chromium-induced kidney disease, Environ Health Perspect 1992; 92: 71-74.
Wetterhahn KE, Hamilton JW, Aiyar J, ¢.a. Mechanism of chromium (VI) carcinogenesis. Reactive
intermediates and cffect on gene expression. Biol Trace Element Res 1989; 21: 405-11.

Wetterhahn KE, Hamilton JW. Molecular basis of hexavalent chromium carcinogenicity: effect on gene
expression. Sc Total Environ 1989; 86: 113-29.

World Health Organisation, Environmental Health Criteria, Chromium, Geneva 1988.

Wibowo AAE. Short evaluation on the carcinogenicity of potassium dichromate, sodium dichromate and
ammonium dichromate. Report on behalf of the Directorate-General of Labour. Coronel Laboratorium
Report No 9305, Amsterdam, 1993.

Witmer CM, Park H-S. Mutagenicity and disposition of chromium. Sc Total Environ 1989; 86: 131-48.
Wolf T, Bolt HMand Ottenwalder H. Nick translation studies on DNA strand breaks in pBR322 plasmid
induced by different chromium species. Toxicol Lett 1989; 47: 295-301.

Wortley P, Vaughan TL, Davis 5, e.a. A case-control study of occupational risk factors for laryngeal
cancer. Brit J Ind Med 1992; 49: 837-44.

Yang J-L, Hsieh Y-C, Wu C-W, e.a. Mutational specificity of chromium (VI) compounds in the hprt locus
of Chinese hamster ovary - Kl cells. Carcinogenesis 1992; 13: 2053-57.

74

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 74 =================================================================

<br><br>====================================================================== Pagina 75 ======================================================================

<pre>Request for advice

The committee

Comments on the public review draft

Abbreviations

DECOS-documents

75

Annexes
</pre>

====================================================================== Einde pagina 75 =================================================================

<br><br>====================================================================== Pagina 76 ======================================================================

<pre>76 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 76 =================================================================

<br><br>====================================================================== Pagina 77 ======================================================================

<pre>Annex

A

Request for advice

77

In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State Secretary
of Welfare, Health and Cultural Affairs, the Minister of Social Affairs and
Employment wrote:

Some time ago a policy proposal has been formulated, as part of the simplification of the governmental
advisory structure, to improve the integration of the development of recommendations for health based
occupation standards and the development of comparable standards for the general population, A
consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established by
ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational exposure
limits as the first step in the process of establishing Maximal Accepted Concentrations (MAC-values) for

substances at the work place.
In an addendum, the Minister detailed his request to the Health Council as follows:

The Health Council should advice the Minister of Social Affairs and Employment on the hygienic aspects

of his policy to protect workers against exposure to chemicals. Primarily, the Council should report on

health based recommended exposure limits as a basis for (regulatory) exposure limits for air quality at the

work place. This implies:

+ A scientific evaluation of all relevant data on the health effects of exposure to substances using a
eriteria-document that will be made available to the Health Council as part of a specific request for

advice. If possible this evaluation should lead to a health based recommended exposure limit, or, in

Request for advice
</pre>

====================================================================== Einde pagina 77 =================================================================

<br><br>====================================================================== Pagina 78 ======================================================================

<pre>the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calculated
concentration in air corresponding with reference tumour incidences of 10° and 10° per year.

The evaluation of documents review the basis of occupational exposure limits that have been recently
established in other countries.

Recommending classifications for substances as part of the occupational hygiene policy of the
government. In any case this regards the list of carcinogenic substances, for which the classification
criteria of the Directive of the European Communities of 27 June 1967 (67/548/EEG) are used.

Reporting on other subjects that will be specified at a later date.

In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of Social
Affairs and Employment the President of the Health Council agreed to establish
DECOS as a Committee of the Health Council. The membership of the Committee is
given in annex B.

78 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 78 =================================================================

<br><br>====================================================================== Pagina 79 ======================================================================

<pre>Annex

B

The committee

79

VJ Feron, chairman

professor of toxicology; TNO Nutrition and Food Research Institute, Zeist

RB Beems

toxicologic pathologist; National Institute of Public Health and the Environment,
Bilthoven

JJAM Brokamp, advisor

Social and Economic Council, The Hague

DJJ Heederik,

epidemiologist; Agricultural University, Wageningen

PTh Henderson

professor of toxicology; Maastricht University, Maastricht

LCMP Hontelez, advisor

Ministry of Social Affairs and Employment, The Hague

G de Jong

occupational physician; Shell International Petroleum Maatschappij, The Hague
G de Mik

toxicologist; National Institute of Public Health and the Environment, Bilthoven
J Molier-Bloot

occupational physician; Academic Medical Centre (AMC), Amsterdam

H Roelfzema, advisor

Ministry of Health, Welfare and Sport, Rijswijk

The committee

</pre>

====================================================================== Einde pagina 79 =================================================================

<br><br>====================================================================== Pagina 80 ======================================================================

<pre>- TSmid
occupational hygienist; KLM Health Safety & Environment, Schiphol and
professor of working conditions, Free University, Amsterdam.
* GMH Swaen
epidemiologist; Maastricht University, Maastricht
* HG Verschuuren
toxicologist, DOW Europe, Horgen, Switzerland
» AAE Wibowo
toxicologist; Coronel Institute, Amsterdam
* Fde Wit
occupational physician; Labour Inspectorate, Arnhem
= CA Bouwman, scientific secretary
Health Council of the Netherlands, Rijswijk.
* ASAM van der Burght, scientific secretary
Health Council of the Netherlands, Rijswijk.

The first draft of the present advisory report was prepared by dr AAE Wibowo,
Coronel Institute, Academic Medical Centre, University of Amsterdam, by contract
with the Ministry of Social Affairs and Employment.

Secretarial assistance was provided by E Vandenbussche-Parméus.
Lay-out: J van Kan.

80

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 80 =================================================================

<br><br>====================================================================== Pagina 81 ======================================================================

<pre>Annex C

Comments on the public review draft

A draft of the present report was released in 1995 for public review. The following
organisations and persons have commented on the draft document:
" _W ten Berge, Th Scheffers
DSM, The Netherlands
* Dr HD Brommer
The European Manufacturers of Lead Chromate and Lead Molybdate Pigments
E.V., Germany
* G Darrie
International Chromium Development Association (ICDA), United Kingdom
(through ECETOC)
«= DrL Erkens, E Claeys
Ciba - Geigy Maastricht BV, The Netherlands
"dr S Fairhurst
Health and Safety Executive, United Kingdom
« dr AO Gamer
BASF Aktiengesellschaft, Germany
» CJ Halm
FME, The Netherlands
« dr Hochgeschender
Bayer AG, Germany (through ECETOC)
"mr CW van der Horst
BASF Nederland BV, The Netherlands

81 Comments on the public review draft

</pre>

====================================================================== Einde pagina 81 =================================================================

<br><br>====================================================================== Pagina 82 ======================================================================

<pre>82

» dr EC Rietveld
AKZO Nobel, The Netherlands
* dr Scherhag
Bayer AG, Germany
"  R Schmitt
European Catalysts Manufacturers Association, Belgium (through ECETOC)
: _drB Sjögren,
Swedisch National Institute for Working Life, Sweden

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 82 =================================================================

<br><br>====================================================================== Pagina 83 ======================================================================

<pre>D

Annex
a ,

Abbreviations

bp boiling point

EC sa concentration at which a described effect is found in 50% of the exposed animals or at

which the effect is decreased up to 50% of the control value

HBR-OEL health based recommended occupational exposure limit

h hour

IC sn concentration at which inhibition of a certain function is found up to 50% of the control

value

LC sq lethal concentration for 50% of the exposed animals

LC, lowest lethal concentration

LD yy lethal dose for 50% of the exposed animals

LD, lowest lethal dose

LOAEL lowest observed adverse effect level

MAC maximaal aanvaarde concentratie (maximal accepted concentration)
MAEL minimal adverse effect level

MAK Maximale Arbeitsplatz Konzentration

MOAEL minimal observed adverse effect level

MTD maximum tolerated dose

NAEL no adverse effect level

NEL no effect level

NOAEL no observed adverse effect level

OEL occupational exposure limit

PEL permissible exposure limit

ppb parts per billion (v/v)10”

ppm parts per million (v/v)10*

RD, dose at which a 50% decrease of respiratory rate is observed

REL recommended exposure limit

83 Abbreviations
</pre>

====================================================================== Einde pagina 83 =================================================================

<br><br>====================================================================== Pagina 84 ======================================================================

<pre>STEL short term exposure limit

gg tijd gewogen gemiddeide

TLV threshold limit value

TWA time weighted average

Var maximal reaction velocity of an enzyme

Organisations

ACGIH American Conference of Governmental Industrial Hygienists
CEC Commission of the European Communities

DECOS Dutch Expert Committee on Occupational Standards

DFG Deutsche Forschungsgemeinschaft

EPA Environmental Protection Agency (USA)

FDA Food and Drug Administration (USA)

HSE Health and Safety Executive (UK)

IARC International Agency for Research on Cancer (WHO)
INRS Institut National de Recherche et de Sécurité (France)
NIOSH National Institute for Occupational Safety and Health (USA)
NTP National Toxicology Programme (USA)

OECD Organisation for Economic Cooperation and Development
OSHA Occupational Safety and Health Association (USA)
RTECS Registry of Toxic Effects of Chemical Substances

SER Social and Economic Council (Sociaal-Economische Raad NL)
WATCH Working Group on the Assessment of Toxic Chemicals (UK)
WHO World Health Organisation

Toxicological terms

bid bis in diem (twice per day)

bw body weight

CARA chronic non-specific respiratory diseases

CHD coronary heart disease

CNS central nervous system

ECG electrocardiogram

EEG electro encephalogram

FCA Freunds Complete Adjuvans

FEV forced expiratory volume

FSH follicle stimulating hormone

GD gestation day(s)

GPMT guinea pig maximisation test

GSH glutathione

HLiA hamster liver activated

IHD ischaemic heart disease

im intramuscular

ip intraperitoneal

ipl intrapleural

il intratracheal

iv intravenous

LH lutheinising hormone

MAC minimal alveolar concentration

84 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 84 =================================================================

<br><br>====================================================================== Pagina 85 ======================================================================

<pre>MFO mixed function oxidase

NA not activated

PNS peripheral nervous system
po per os (= oral)

RBC red blood cells

RLiA rat liver activated

SCE sister chromatid exchange
SC subcutaneous

UDS unscheduled DNA-synthesis
Statistical terms

CI confidence interval

GM geometric mean

OR Odds Ratio

RR relative risk

SD standard deviation

SEM standard error of mean

SMR standard mortality ratio
Analytical methods

AAS atomic absorption spectroscopy
BEEL biological equivalent exposure limit
BEI biological exposure index
BEM biological effect monitoring
BM biological monitoring

ECD electron capture detector
EM environmental monitoring
FID flame ionisation detector
GC gas chromatography

GLC gas liquid chromatography
GSC gas solid chromatography
HPLC high performance liquid chromatography
IR infrared

MS mass spectrometry

NMR nuclear magnetic resonance
PAS personal air sampling

TLC thin layer chromatography
UV ultraviolet

Additional abbreviations in the present report

Cru

chromium in urine
chromium
carcinoembryonic antigen
tissue popypeptide antigen

85 Abbreviations

</pre>

====================================================================== Einde pagina 85 =================================================================

<br><br>====================================================================== Pagina 86 ======================================================================

<pre>86 Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 86 =================================================================

<br><br>====================================================================== Pagina 87 ======================================================================

<pre>E

Annex
DECOS-documents
DECOS has produced documents on the following substances.
To be ordered from the Health Council of the Netherlands:
Acetone cyanohydrin 1995/05WGD
p-Aramid fibres 1997/07WGD
Bisphenol A and its diglycidylether 1996/02WGD
Butanol (1,2- and t-) 1994/10
Cadmium and inorganic cadmium compounds 1995/04WGD
Calculating cancer risk 1995/06WGD
Carbon disulphide 1994/08
Chlorine dioxide 1995/07 WGD
1,2-Dichloroethane 1997/01WGD
Diphenylamine 1997/05WGD
1,2-Ethanediamine 1996/03 WGD
Ethyleneglycol ethers 1996/01 WGD
Formamide and dimethylformamide 1995/08WGD
Hydrazinoethanol, phenylhydrazine, isoniazid, maleic hydrazide 1997/03 WGD
Isopropyl acetate 1997/04WGD
Man made mineral fibers 1995/02WGD
Methy! Methacrylate 1994/09
Methacry lates. Ethyl methacrylate, n-butyl methacrylate and isobuty! methacrylate 1994/11
Methyl-t-butylether 1994/23
Methyl chtoride 1995/01WGD
Pentaerythritol 1997/06WGD
Phenol 1996/04 WGD
Propanol (1- and 2-) 1994/24
87 DECOS-documents
</pre>

====================================================================== Einde pagina 87 =================================================================

<br><br>====================================================================== Pagina 88 ======================================================================

<pre>Propylene oxide 1997/02WGD
Thrichloroethane (-1,1,1) 1995/03 WGD
Trichloropropane (1,2,3-) 1994/25

The following documents, that were published before 1994, can be ordered from the
Sdu Uitgeverij Den Haag.

Acetaldehyde RA 6/92
Acrylaten RA 13/87
Aflatoxine Bl, B2, Gl en G2 RA 6/87
Allylglycidylether RA 1/92
Amy] acetate RA 4/90
Aniline RA 2/89
Anorganisch Lood RA 2/80
Anorganische Kwikzouten RA 3/82
Arc welding fume particles not containing chromium and nikkel RA 1/93
Arseenverbindingen (anorganische) RA 2/84
Asbest RA 1/84
Asbest, Evaluatie van risico op kanker bij beroepshalve blootstelling aan

(aanvullend op RA 1/84) RA 9/89
Benzeen RA 5/89
Beryllium and beryllium compounds RA 4/88
Blootstelling, Gezondhcidskundige aspecten van het begrip en van het

meten/schatten ervan RA 8/90
Butadiene (1,3-) RA 5/90
Cadmium RA 5/80
Caprolactam RA 4/84
Carbon monoxide RA 7/92
Carbonylfluoride and PTFE pyrolysis products RA 3/88
Carcinogene stoffen RA 3/80
Chloor RA 6/80
Chloroform RA 7/87
B-Chloroprene RA 4/93
Chroom en chroomverbindingen RA 6/85
Cyclohexane RA 15/90
Cyclohexanol RA 3/90
Cyclohexanone RA 9/93
Dibroomethaan RA 5/87
Dichloorethaan (1,1-) RA 8/87
Diisocyanates RA 3/91
Dimethyl- en diethylsulfaat RA 12/90
Dimethy lamine RA 10/90
Dimethylbutane (2,2- & 2,3-) RA 7/93
Dimethylhydrazine RA 2/87
Dinitro-ortho-cresol (4,6-) RA 4/87
Dioxaan (1,4-) RA 1/87
Epichloorhydrine RA 1/86

88 Chromium and its inorganic compounds

</pre>

====================================================================== Einde pagina 88 =================================================================

<br><br>====================================================================== Pagina 89 ======================================================================

<pre>Ethytacrylate

Ethylacetate

Ethyl Methanesulphonate (EMS)
Ethylamine

Ethylbenzene

Ethyleenoxide

Fenylhydrazine

Fluorcarbons (except FC11)
Fluorine compounds (inorganic)
Fluorine

Formaldehyde

Fosfine

Fijn hinderlijk stof; gezondheidskundige aspecten van bijlage 3 bij de Nationale

MAC-lijst 1989

Gasoline

Heptaan (n-)

Heptane (n-)

Hexaan (n-)

Hexachlorobenzene

Hexanone (2-)

Hydrazine

Hydrogenfluoride
Hydroxyethylhydrazine
Ísopropy!glycidylether
Isopropoxyethanol (2-)
Koolmonoxide (Carbon monoxide)
Kwikalkylverbindingen - Korte keten
Kwikverbindingen (Organische)
Lachgas (Nitrous oxide)

Lasrook (Arc welding fume......... nickel)
Mangaan

Metallisch Kwik
1-Methoxypropanol-2
2-Methoxypropanol-1
1-Methoxypropylacetate-2
2-Methoxypropylacetate-]
Methylacrylate

Methyleenchloride (Methylene chloride)
Methyl ethyl ketone

Methyl isobutyl ketone

Methyl Methanesulphonate (MMS)
Methylbromide

Methyipentane (2- & 3-)
Monochloorethaan

Monoketones (7/8 carbon chain aliphatic)
Nikkel en nikkelverbindingen
Nitropropaan (2-)

Nitrous oxide

RA 6/90
RA 10/91
RA 4/89
RA 7/90
RA 9/91
RA 6/89
RA 2/87
RA 15/87
RA 1/89
RA 1/89
RA 3/87
RA 1/80

RA 9/90
RA 3/92
RA 1/81
RA 6/93
RA 11/87
RA 2/88
RA 2/90
RA 2/87
RA 1/89
RA 12/87
RA 1/92
RA 2/87
RA 2/79 (7/92)
RA 5/82
RA 4/82
RA 2/85 (2/92)
RA 1/93
RA 1/82
RA 5/81
RA 5/93
RA 5/93
RA 5/93
RA 5/93
RA 1/90
RA 1/83 (8/92)
RA 16/90
RA 4/91
RA 4/89
RA 13/90
RA 7/93
RA 2/82
RA 14/90
RA 3/85
RA 1/85
RA 2/92

DECOS-documents
</pre>

====================================================================== Einde pagina 89 =================================================================

<br><br>====================================================================== Pagina 90 ======================================================================

<pre>90

Ozone

para-Dichloorbenzeen

Pentaan

Phthalate esters

Phthalic anhydride

Piperazine

Polyvinyl chloride (PVC) dust
Propoxyethanol (2-)
Propoxyethylacctate (2-)

Pyridine

Selenium en -verbindingen
Silicon dioxide, crystaltine forms of
Stikstofdioxide (Nitrogen dioxide)
Styreen

Tale dusts

Tetrahydrofuran

Thiourea

Tolueen diisocyanaat

Tolueen

Trichloorethaan (1, 1, 1-)
Trichloorethyleen
Trichlorofluoromethane
Triethylamine

Trimethylamine

Vadium metaal en anorganische verbindingen
Wood dust

Xylene

Zwaveldioxide (sulphur dioxide)

RA 4/92
RA 1/88
RA 2/81
RA 8/93
RA 3/89
RA 7/91
RA 2/93
RA 12/87
RA 12/87
RA 3/93
RA 7/89
RA 5/92
RA 5/85
RA 8/89
RA 6/91
RA 1/91
RA 11/90
RA 4/80
RA 2/91
RA 3/81
RA 3/83
RA 14/87
RA 2/83
RA 9/87
RA 10/87
RA 8/91
RA 5/91
RA 4/85

Chromium and its inorganic compounds
</pre>

====================================================================== Einde pagina 90 =================================================================

<br><br>