<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>Tricresylphosphate
Evaluation of the effects on reproduction, recommendation for classification
To: the Minister of Social Affairs and Employment
No. 2023/17, The Hague, November 13, 2023
                                                                             2
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<pre>Contents                                                                                       Tricresylphosphate | page 2 of 28
contents
01 Scope8                                                 05 Toxicity to reproduction                                      16
     1.1  Background                                    8    5.1 Animal studies                                             16
     1.2  Committee and procedure                       8
     1.3  Labelling for lactation                     10  06 Conclusions on classification and labelling                   19
     1.4  Data                                        10
                                                              References20
02 Identity of the substance                          11     A   Supplementary tables                                       21
     2.1  Name and other identifiers of the substance  11    B   Literature search strategy                                 24
     2.2  Composition of the substance                 11
     2.3  Physico-chemical properties                 12
     2.4  International classifications               12
03 Manufacture and uses                               13
     3.1  Manufacture                                 13
     3.2  Identified uses                             13
04 Toxicokinetics14
     4.1  Absorption                                  14
     4.2  Distribution                                14
     4.3  Metabolism                                  14
     4.4  Elimination                                 14
Health Council of the Netherlands | No. 2023/17                                               2
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<pre>Samenvatting                                                                                                              Tricresylphosphate | page 3 of 28
samenvatting
Werknemers kunnen tijdens het werk worden blootgesteld aan stoffen die        Classificeren naar bewijskracht
mogelijk schadelijk zijn voor hun gezondheid. Op verzoek van de minister      Bij de beoordeling van effecten op de voortplanting kijkt de commissie
van Sociale Zaken en Werkgelegenheid (SZW) heeft de Gezondheidsraad           zowel naar effecten op de vruchtbaarheid van mannen en vrouwen als
beoordeeld of tricresylfosfaat (tricresylphosphate (TCP)) schadelijke         naar effecten op de ontwikkeling van het nageslacht. Daarnaast worden
eigenschappen heeft die invloed kunnen hebben op de voortplanting.            effecten op de lactatie (productie en afgifte van moedermelk) beoordeeld
                                                                              en effecten via de moedermelk op de zuigeling. Als er aanwijzingen
Dit advies is tot stand gekomen in de Subcommissie Classificatie              bestaan dat de stof schadelijke effecten heeft, stelt de commissie voor om
­reproductie toxische stoffen, van de Commissie Gezondheid en beroeps-        de stof te classificeren in gevarencategorieën die aangeven hoe groot de
   matige blootstelling (GBBS). Op www.gezondheidsraad.nl staat informatie    bewijskracht is voor de schadelijke effecten, zie kader. Bij categorie 1 is
   over de taken van deze vaste commissie van de Gezondheidsraad.             de bewijskracht het grootst en grotendeels gebaseerd op studies bij
   De samenstelling van de subcommissie is te vinden achterin dit advies.     mensen (1A) of dieren (1B). Bij categorie 2 is de bewijskracht beperkt en
                                                                              is er sprake van een ‘verdenking’. De commissie kan ook adviseren om
   Gebruik van tricresylfosfaat                                               een stof niet te classificeren omdat er onvoldoende gegevens beschikbaar
   Tricresylfosfaat wordt gebruikt als vlamvertrager in polystyreen en andere zijn of omdat de stof waarschijnlijk niet schadelijk is voor de voortplanting.
   thermoplasten, als PVC-weekmaker, smeermiddel en als hydraulische          Een classificatievoorstel zegt iets over de bewijskracht voor de schade-
   vloeistof. Het wordt gebruikt in beroepsmatige omgevingen zoals in         lijke eigenschappen van een stof, maar niet over de mate waarin mensen
 ­drukkerijen, in formulering van mengsels en in wetenschappelijk onder-      op de werkplek een gezondheidsrisico lopen. Dat hangt namelijk af van
zoek. Tricresylfosfaat wordt ook gebruikt als additief in motorolie van       de mate waarin mensen op hun werk worden blootgesteld aan de stof.
  ­vliegtuigen.                                                               Daar heeft de commissie geen zicht op.
Health Council of the Netherlands | No. 2023/17                                                                         2
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<pre>Samenvatting                                                                                                            Tricresylphosphate | page 4 of 28
Geraadpleegde onderzoeken                                                   Advies aan de minister
Er zijn geen gegevens beschikbaar uit onderzoeken onder mensen.             Op basis van de beschikbare wetenschappelijke gegevens
Met betrekking tot de effecten van blootstelling aan tricresylfosfaat op de ­adviseert de commissie om tricresylfosfaat:
vruchtbaarheid is een beperkte hoeveelheid gegevens beschikbaar uit          • te classificeren als een stof die ervan verdacht wordt schadelijk te zijn
dierstudies. Die gegevens wijzen op een verminderde vruchtbaarheid bij         voor de vruchtbaarheid (categorie 2) en te kenmerken met H361f
ratten na blootstelling aan tricresylfosfaat. Over de effecten op de           (verdacht van het schaden van vruchtbaarheid);
­ontwikkeling is slechts één dierstudie beschikbaar. De gegevens uit die     • niet te classificeren voor effecten op de ontwikkeling omdat er
 studie geven aanleiding tot bezorgdheid. Zo werd er een verband               onvoldoende geschikte onderzoeksgegevens zijn;
 gevonden tussen blootstelling aan tricresylfosfaat en een lager lichaams-   • niet te classificeren voor de effecten op of via lactatie omdat er geen
 gewicht van de foetussen. Of er sprake is van een effect op de ontwikke-      onderzoeksgegevens zijn.
 ling is onduidelijk, omdat er ook bij de moederdieren sprake was van een
 verminderde gewichtstoename.
 Er waren geen gegevens beschikbaar om de effecten van blootstelling
 aan tricresylfosfaat op of via lactatie te beoordelen.
Health Council of the Netherlands | No. 2023/17                                                                       2
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<pre>Samenvatting                                                                                                                            Tricresylphosphate | page 5 of 28
 Betekenis classificatievoorstellen                                                     Op die lijst staan kankerverwekkende en mutagene stoffen in categorie 1A en 1B
 In classificatievoorstellen gebruikt de Gezondheidsraad een indeling in                en voor de voortplanting giftige stoffen in categorie 1A, 1B en 2. Afhankelijk van de
 gevarencategorieën. De categorieën zijn afgeleid van EU-verordening (EG)               classificatie vraagt de wetgever de werkgever aanvullende maatregelen te nemen
 1272/2008 en geven aan hoe sterk de bewijskracht is voor schadelijke effecten.         om de werknemer te beschermen.
 EU-gevarencategorieën voor reproductie toxische stoffen
  • Categorie 1 Kan de vruchtbaarheid of het ongeboren kind schaden
     (EU-gevarenaanduiding H360)
     • Categorie 1A Stoffen waarvan bekend is dat zij toxisch zijn voor de
        menselijke voortplanting (hoofdzakelijk gebaseerd op gegevens bij mensen).
     • Categorie 1B Stoffen waarvan verondersteld wordt dat zij toxisch zijn voor
        de menselijke voortplanting (hoofdzakelijk gebaseerd op dierstudies).
  • Categorie 2 Kan mogelijk de vruchtbaarheid of het ongeboren kind schaden
     (EU-gevarenaanduiding H361). Stoffen die ervan verdacht worden dat zij
     toxisch zijn voor de menselijke ­voortplanting
 EU-gevarencategorie voor effecten op of via lactatie
  • Kan schadelijk zijn via de borstvoeding (EU-gevarenaanduiding H362). Stoffen
     waarvan is aangetoond dat zij de lactatie beïnvloeden of die in zodanige
     hoeveelheden in moedermelk aanwezig kunnen zijn dat er reden is tot
     ­bezorgdheid voor de gezondheid van het kind dat borstvoeding krijgt.
 Betekenis voor de werkvloer
 Werkgevers zijn op grond van de Arbowet wettelijk verplicht om gezondheids- en
 veiligheidsrisico’s van het werken met stoffen zoveel mogelijk te voorkomen of te
 beperken. Op basis van de classificatievoorstellen van de Gezondheidsraad kan
 de minister van SZW besluiten stoffen op te nemen in de officiële lijst van ­­­kanker­
 verwekkende, mutagene en voor de voortplanting giftige stoffen.
Health Council of the Netherlands | No. 2023/17                                                                                        2
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<pre>Summary                                                                                                                   Tricresylphosphate | page 6 of 28
executive summary
At the request of the Minister of Social Affairs and Employment, the Health   and on the offspring via lactation. If the data indicate hazardous
Council of the Netherlands evaluated the effects of tricresylphosphate on     ­properties, the Committee recommends classification in a hazard
reproduction. This advisory report was drafted by the Subcommittee on          ­category. The classification is performed according to EU-regulation
the Classification of Substances Toxic to Reproduction of the Dutch Expert    (EC) 1272/2008.
Committee on Occupational Safety (DECOS) of the Health Council, here-
after called the Committee. The Health Council has a permanent task in        Reviewed literature
assessing the hazard of substances to which man can be occupationally         No human data were available. There were limited data from animal
exposed. More information about this task can be found at                     studies available regarding effects of exposure to TCP on fertility and
www.gezondheidsraad.nl.                                                       developmental effects. The fertility study showed reduced fertility in rats
                                                                              after exposure to TCP. The available data on functional developmental
Use of tricresylphosphate                                                     effects indicated concerns, but are not sufficient for classification.
Tricresylphosphate (TCP) is used as a flame retardant in polystyrene and      No data were available to assess the effects of exposure to TCP on or
other thermoplastics, as a PVC plasticiser, lubricant and as hydraulic fluid. via lactation.
It is used in occupational settings such as in the media printing industry,
formulation of mixtures and scientific research. TCP is also used as          Recommendations to the Minister
­additive in turbine engine oil.                                              Based on the available scientific data, the Committee
                                                                                ­recommends:
 Classification based on evidence                                                • to classify TCP as suspected to be a reproductive toxicant to humans,
 To assess effects on reproduction, the Committee evaluates the effects on          which corresponds with category 2 for reproduction, and to label TCP
 male and female fertility and on the development of the offspring.                 with H361f (suspected of damaging fertility);
 ­Moreover, the Committee considers effects of a substance on lactation
Health Council of the Netherlands | No. 2023/17                                                                          2
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<pre>Summary                                                                   Tricresylphosphate | page 7 of 28
• not to classify TCP for developmental toxicity due to a lack of
  appropriate data;
• not to classify TCP for effects during lactation due to a lack of data.
Health Council of the Netherlands | No. 2023/17
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<pre>chapter 01 | Scope                                                                                                        Tricresylphosphate | page 8 of 28
01 scope                                                                    human and animal studies concerning adverse effects with respect to
                                                                            fertility and offspring development as well as adverse effects on or via
1.1      Background                                                         lactation.
As a result of the Dutch regulation on registration of compounds toxic to
reproduction that came into force on April 1st 1995, the Minister of Social Classification for reproduction (fertility (F) and development (D)):
Affairs and Employment requested the Health Council of the Netherlands      • Category 1        Known or presumed human reproductive toxicant
to classify compounds toxic to reproduction. This classification is                             (H360(F/D)).
performed by the Health Council’s Subcommittee on the Classification of     • Category 1A Known human reproductive toxicant.
Substances Toxic to Reproduction of the Dutch Expert Committee on           • Category 1B Presumed human reproductive toxicant.
Occupational Safety (DECOS). The classification is performed according      • Category 2        Suspected human reproductive toxicant (H361(f/d)).
to European Union Regulation (EC) 1272/2008 on classification, labelling    • No classification for effects on fertility or development.
and packaging (CLP) of substances and mixtures. The CLP regulation is
based on the Globally Harmonised System of Classification and Labelling     Classification for lactation:
of Chemicals (GHS). The Subcommittee’s advice on the classification will    • Effects on or via lactation (H362).
be applied by the Ministry of Social Affairs and Employment to extend the   • No labelling for lactation.
existing list of compounds classified as reproductive toxicant (category 1A
and 1B and 2) or compounds with effects on or via lactation.                Hazard statement codes:
                                                                            H360F         May damage fertility.
1.2      Committee and procedure                                            H360D         May damage the unborn child.
This document comprises the recommendations for classification of           H361f         Suspected of damaging fertility.
­tricresylphosphate (TCP) by the Health Council’s Subcommittee on the       H361d         Suspected of damaging the unborn child.
 Classification of Substances Toxic to Reproduction, hereafter called the   H360FD        May damage fertility. May damage the unborn child.
 Committee. The members of the Committee are listed on the last page of     H361fd        Suspected of damaging fertility. Suspected of damaging the
 this report. The classification is based on the evaluation of published                  unborn child.
 Health Council of the Netherlands | No. 2023/17                                                                        2
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<pre>chapter 01 | Scope                                                                                                                  Tricresylphosphate | page 9 of 28
                                                                              Additional considerations to Regulation (EC) 1272/2008
H360Fd       May damage fertility. Suspected of damaging the unborn child.
                                                                              If there is sufficient evidence to establish a causal relationship between human
H360Df       May damage the unborn child. Suspected of damaging fertility.
                                                                              exposure to the substance and impaired fertility or subsequent developmental
H362         May cause harm to breast-fed children.                           toxic effects in the offspring, the compound will be classified in category 1A,
                                                                              irrespective of the general toxic effects (see Regulation (EC) 1272/2008,
The classification and labelling of substances is performed according to      3.7.2.2.1.).
the guidelines of the European Union (Regulation (EC) 1272/2008).
                                                                              Adverse effects in a reproductive study, reported without information on the
The classification of compounds is the result of an integrated assessment
                                                                              paternal or maternal toxicity, may lead to a classification other than category 1B,
of the nature of all parental and developmental effects observed, their       when the effects occur at dose levels which cause severe toxicity in general
specificity and adversity, and the dosages at which the various effects       toxicity studies.
occur. The guideline necessarily leaves room for interpretation, dependent
                                                                              Clear adverse reproductive effects will not be disregarded on the basis of
on the specific data set under consideration. In the process of using the
                                                                              ­reversibility per se.
regulation, the Committee has agreed upon a number of additional
­considerations.                                                               The Committee does not only use guideline studies (studies performed according
                                                                               to OECDa standard protocols) for the classification of compounds, but
                                                                               ­non-guideline studies are taken into consideration as well.
                                                                           Regarding fertility, the Committee considers data on parameters related to
                                                                           fertility, such as seminal fluid volume and spermatozoa concentration, that
                                                                           are related to male fertility. The Committee excludes publications
                                                                           containing only data on sex hormone levels from the assessment,
                                                                           because the relationship between these hormone levels and functional
                                                                           fertility (ability to conceive children) is too uncertain.
                                                                           a
                                                                             Organisation for Economic Cooperation and Development
Health Council of the Netherlands | No. 2023/17                                                                                    2
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<pre>chapter 01 | Scope                                                                                                          Tricresylphosphate | page 10 of 28
In 2023, the President of the Health Council released a draft of the report      level is unknown, the exposure limit for the general population, e.g. the
for public review. The Committee has taken the comments received into            acceptable daily intake (ADI).
account in deciding on the final version of the report. These comments,
and the replies by the Committee, can be found on the website of the             1.4      Data
Health Council.                                                                  A literature search for publications on reproductive toxicity of TCP was
                                                                                 performed using various databases up to September 2022, with an
1.3       Labelling for lactation                                                ­additional search using “tricresyl phosphate reproductive”. Additionally, the
The recommendation for classifying substances for effects on or via               search strategy included publications on (toxico)kinetics and monitoring.
­lactation is also based on Regulation (EC) 1272/2008. The criteria define        Details on the literature search strategy can be found in annex B.
 that substances which are absorbed by women and have been shown to
 interfere with lactation or which may be present (including metabolites) in
 breast milk in amounts sufficient to cause concern for the health of a
 breastfed child, shall be classified and labelled. Unlike the classification of
 substances for fertility and developmental effects, which is based on
 hazard identification only (largely independent of dosage), the labelling for
 effects on or via lactation is based on a risk characterization and t­herefore,
 it also includes consideration of the level of exposure of the breastfed
 child.
 Consequently, a substance should be labelled for effects on or via
 ­lactation when it is likely that the substance would be present in breast
  milk at potentially toxic levels. The Committee considers a concentration
  of a compound as potentially toxic to the breastfed child when this
  concentration leads to exceeding the exposure limit for children, or if that
Health Council of the Netherlands | No. 2023/17                                                                            2
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<pre>chapter 02 | Identity of the substance                                                                                                                   Tricresylphosphate | page 11 of 28
02 identity of the substance                                                                  2.2           Composition of the substance
                                                                                              TCP consists of multiple isomers and is registered as a multi-constituent
2.1        Name and other identifiers of the substance                                        substance in the REACH-dossier. The composition consists of
 Name(s) in the IUPAC nomenclature or other tris(4-methylphenyl) phosphate                    ­tri-m-cresylphosphate (CAS 653-04-2), 4-methylphenyl di-3-methylphenyl
 international chemical name(s)
 Other names (usual name, trade name,       Tricresylphosphate, tris(2-methylphenyl)           phosphate, and 3-methylphenyl di-4-methylphenyl phosphate. Formation
 abbreviation)                              phosphate, tritolyl phosphate, Tris(methylphenyl)
                                            phosphate, TCP
                                                                                               of the neurotoxic o-isomer (tri-o-tolyl phosphate (TOCP)) is prevented as
 ISO common name                                                                               much as possible during manufacturing of the commercial products and
 (if available and appropriate)
 EC/EINECS number                           809-930-9                                          this isomer occurs only as an impurity.1, 2 The presence of one or more
 (if available and appropriate)
                                                                                                o-tolyl groups among the three phenolic moieties of TCP is considered
 EC name (if available and appropriate)
 CAS number                                 1330-78-5                                           necessary to induce these neurotoxic effects.a Therefore, the presence of
 Other identity code (if available)         1259372-53-6, 2107376-26-9, 25013-17-6,
                                            34902-62-0, 56499-45-7, 56573-10-5, 69234-
                                                                                                TOCP can complicate the evaluation of TCP. According to the guidelines
                                            04-4, 73299-28-2                                    for classification (see section 1.2), a multi-constituent substance is
 Molecular formula                          C21H21O4P
 Structural formula                                                                            ­classified as category Repro 1B if a constituent is already classified as
                                                      CH3
                                                                                                category Repro 1B and is present at more than 0.3% in the substance.
                                                                        CH3                     If a constituent is classified as category Repro 2, the limit is 3%.
                                                        O                                       The Committee therefore considers only studies where TCP contains
                                                 O
                                                      P                                         <0.3% TOCP.
                                                          O
                                                   O
                                                                                                The Committee notes that a continuous breeding study is referenced in
                                                   H 3C
                                                                                                the REACH dossier of TCP in support of a self-classification for effects on
 SMILES notation (if available)                                                                 fertility. This continuous breeding study was first described in a National
 Molecular weight or molecular weight range 368.4 g/mol                                         Toxicology Program (NTP) report in 1985 and the data were later
 Degree of purity (%)                       >= 87 - <= 100 % (w/w)
                                                                                                a
                                                                                                   https://www.inchem.org/documents/ehc/ehc/ehc110.htm#SectionNumber:10.1
Health Council of the Netherlands | No. 2023/17                                                                                                         2
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<pre>chapter 02 | Identity of the substance                                    Tricresylphosphate | page 12 of 28
published by Chapin et al. (1988).3, 4 In this publication, the specified
amount of pure TOCP is <0.1%. However, it is also stated that the amount
of pure and/or mixed ortho- meta- and para-cresyl isomers composed
74.9% of the total, leading to uncertainty regarding the total amount of
ortho-cresyl isomers. Therefore, this study is not further considered for
evaluation.
2.3       Physico-chemical properties
 State of substance at normal temperature and Liquid
 pressure
 Melting/freezing point                       -20 °C
 Boiling point                                400 °C
 Density                                      1.172 g/cm3
 Partition coefficient (Log Kow)              5.93
 Water solubility                             0.271 mg/L
 Viscosity                                    80 mPa · s (dynamic)
2.4       International classifications
No European harmonized classifications exist for TCP (CAS 1330-78-5).
Some notified self classification and labelling data were mentioned for
reproduction (H361) based on testicular effects and sperm concentration
and motility.
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<pre>chapter 03 | Manufacture and uses                                            Tricresylphosphate | page 13 of 28
03 manufacture and uses
3.1     Manufacture
TCP is a multi-constituent substance that is formulated in a mixture of
isomers. Commercial TCP is manufactured by reaction of phosphorous
oxychloride with a mixture of alkyl phenols derived from petroleum or coal
tar.5 The major components that are formed within this reaction are based
on m-cresol and p-cresol. The levels of o-alkyl phenols are minimized by
the manufacturers to avoid production of o-isomers.
3.2     Identified uses
TCP is used as a flame retardant in polystyrene and other thermoplastics,
as a PVC plasticiser, lubricant and as hydraulic fluid.2 TCP is used in
occupational settings such as in the media printing industry, formulation of
mixtures and scientific research. TCP is also used as additive in turbine
engine oil. TCP is manufactured in and/or imported to the EU at >/= 1000
to <10 000 tonnes per year.
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<pre>chapter 04 | Toxicokinetics                                                                                                 Tricresylphosphate | page 14 of 28
04 toxicokinetics                                                           4.3          Metabolism
                                                                            TPCP was metabolized by oxidation and diarylation. Using radiolabelled
The available information on toxicokinetics for TCP was limited to one      TPCP, Kurebayashi et al. proposed a metabolic pathway starting with
study on the p-isomer. Kurebayashi et al studied tri-p-cresylphosphate      TPCP being absorbed by the gastrointestinal tract after which it gets
(TPCP) in male Wistar rats by orally administrating 7.8 mg/kg or 89.6 mg/   oxidized to di-p-cresyl p-carboxyphenyl phosphate (1coTPCP) and
kg [14C]TPCP in DMSO and evaluated the toxicokinetic properties of          p-cresyl di-p-carboxyphenyl phosphate (2coTPCP) in the liver.
 TPCP related to absorption, distribution, metabolism and elimination.6     These triesters are excreted through the bile after which they get
 The authors did not define the exact location of the radiolabel in the     ­deesterified in the intestine. The intestinal microflora would degrade part
 TPCP molecule.                                                              of the p-hydroxybenzoic acid to CO2.
4.1     Absorption                                                           4.4         Elimination
Following oral administration TPCP was absorbed from the intestines.         In rats, TPCP and its metabolites were excreted in the urine, bile, faeces
The authors conclude that the main faecal metabolite was unchanged           and breath. The oral 7.8 mg/kg administered [methyl-14C]TPCP was
TPCP, indicative of incomplete absorption.4                                     excreted in the urine (41%) and faeces (44%) within 7 days. For 3 days,
                                                                                the excretion through breath expressed in 14CO2 was 18% of the
4.2     Distribution                                                         ­radioactivity. In individual rats, the biliary excretion was 28% of the 7.8 mg/
After 24, 72 and 168 hours of oral administration (89.6 mg/kg) in rats, the   kg administered dose after 24 hours. At a dose of 89.6 mg/kg the
radioactivity was relatively high in adipose tissue, liver and kidney.        ­radioactivity in urine was 12% and in faeces was 77% after 7 days.
Also, the stomach and intestine showed radioactivity. Intermediate              In air this was 6% after 3 days.
­radioactivity was detected in blood, thymus, spleen, testes and lungs.
 The brain, muscle and heart contained the least amount of reactivity.          The major excreted urinary metabolites were p-hydroxybenzoic acid,
 Overall, after 72 hours the concentrations were reduced to one fourth of      ­di-p-cresyl phosphate, and p-cresyl p-carboxyphenyl phosphate.
 the concentrations at 24 hours. This was decreased to one-tenth at 168     The metabolites excreted in the bile were di-p-cresyl phosphate,
 hours.                                                                     p-carboxyphenyl phosphate, and the oxidized triesters, 1coTPCP and
Health Council of the Netherlands | No. 2023/17                                                                            2
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<pre>chapter 04 | Toxicokinetics                                          Tricresylphosphate | page 15 of 28
2coTPCP. The main excreted faecal substances were TPCP or similar to
those of bile.
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<pre>chapter 05 | Toxicity to reproduction                                                                                    Tricresylphosphate | page 16 of 28
05 toxicity to reproduction                                                started which consisted of a cross-over mating period. Based on the fact
                                                                           that naive and vehicle control groups showed no differences in phase 1,
No human data were available related to TCP and reproductive or devel-     indicative of no effects of gavaging or daily handling, the following
opmental effects.                                                          schedule was selected for phase 2: Naive control males were mated with
                                                                           naive control females and vehicle controls were mated with TCP treated
5.1     Animal studies                                                     animals for 8 days followed by a 28-day period for the females to deliver
The studies in which animals were exposed to TCP are summarized in         their offspring.
annex A.
                                                                           Effects on reproduction of TCP were found during phase 1 in terms of a
5.1.1   Fertility studies                                                  decreased fertility index (the percentage of cohabited pairs producing one
Latendresse et al (1994) examined the effects on reproduction after an     or more (live or dead) litters) and fewer litters per breeding pair.
oral administration of BTP (butylated triphenyl phosphate; CAS 115-86-6)   Furthermore, the number of live pups per litter was decreased (6.67 ±
or TCP (CAS 1330-78-5, as a positive control) in F-344 rats (20 breeding   1.26 vs. 10.15 ± 0.04 in controls (mean ± standard error, p ≤0.05)).
pairs per group).7 TCP was composed of mostly p- and m-isomers (62         The proportions of pups born alive was not affected indicating a reduced
wt%) of TCP and a mixture of substantial amounts of cresyl-xylyl (18 wt%)  litter size, suggesting an effect on fertility rather than on development.
and cresyl-ethylphenyl (18 wt%) phosphates. No o-isomer (TOCP) was         Cross-over mating in phase 2 of TCP treated males with control females
detected. A naive control group and vehicle (sesame oil) control group (40 resulted in a mating index of 84.2% (controls 100%), but resulted in no
breeding pairs) were also included. The dosing of test groups consisted of offspring indicating complete infertility in males. This was not observed
600 mg, 1,000 g or 1,700 mg BTP/kg/day or only one dose group of 400       after cross-over mating of TCP treated females with control males for
mg TCP/kg bw/day. In phase 1 of the study, a continuous breeding period    which the reproductive efficiency did not differ from controls. In TCP
allowed birth of multiple litters per breeding pair and a postbreeding     treated groups, testicular and epididymal weights were decreased and
interval. The continuous breeding period provided a constant breeding      ovarian weights were increased as compared to controls. Additionally, an
challenge with the possibility for all spermatogenesis phases to complete. increase in adrenal gland and liver weight was detected in the TCP treated
Immediately after the postbreeding interval of phase 1, phase 2 was        rats as compared to controls. An additional general toxic effect of TCP
Health Council of the Netherlands | No. 2023/17                                                                         2
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<pre>chapter 05 | Toxicity to reproduction                                                                                    Tricresylphosphate | page 17 of 28
was noted as a decrease in body weight was observed in males after 96      Conclusion on fertility
days (part of phase 1) and in females after 131 days (part of phase 2).    Exposure to a single dose of 400 mg TCP/kg bw leads to a reduced
                                                                           fertility in rats (decreased fertility index and fewer litters per breeding
5.1.2   Repeated dose studies assessing effects on reproductive            pair).7 Furthermore, treated males were incapable to produce offspring
        organs                                                             after confirmed mating with untreated females in a cross-over study.
Somkuti et al (1987) tested the effects of TOCP and TPCP in male rats      Furthermore, effects were observed also on reproductive organs in male
and assessed the effects on their reproductive organs during subchronic    and female exposed animals as compared to controls with respect to
administration of 63 days.8 One dose of TPCP was tested of 100 mg/kg/      testicular, epididymal (both decreased) and ovarian (increased) weights.9, 10
 day by gavage in male F-344 rats. No general toxic effects were observed.
 Testosterone values in testicular interstitial fluid were 25% lower than  The Committee concludes that classification for effects on fertility is
 controls and a lower epididymal sperm density was observed as             warranted as in rats severe effects on fertility and reproductive organs
 compared to controls. TPCP administration had no effect on testicular     have been observed in a reproductive toxicity study. These effects
 morphology or sperm morphology and motility.                              however, have only been observed in one non-guideline study in which
                                                                           only one dose was applied. The Committee therefore considers the
 Latendresse et al (1993) administered TCP and butylated triphenyl         ­available evidence insufficient for a classification in Category 1B and
­phosphate (BTP) to female F-344 rats and studied the effects on their      recommends classifying TCP in Category 2.
 reproductive organs in a study of 40 days.9 TCP was composed of mostly
p- and m-isomers and a mixture of cresyl-xylyl, cresyl-ethylphenyl, and     5.1.3    Developmental studies
ethylphenyl-xylyl phosphates. No o-isomer TCP was detected. Only one        In an EPA OPPTS 870.3700-guideline developmental toxicity study in rats,
dose group was investigated of 400 mg TCP/kg/day by gavage, which           no effects on pup viability were observed.11 In this study, a to the
affected the adrenal glands and resulted also in increased ovarian weights Committee unknown isomer composition of TCP was administered to
with hypertrophy and cytoplasmic vacuolization of interstitial cells.      female rats in dosages of 20, 100, 400, and 750 mg/kg/day from gestation
                                                                           day 0 to gestation day 19. Effects on body weights and body weight gains
                                                                           were observed at the two highest dose groups in a dose-responsive
Health Council of the Netherlands | No. 2023/17                                                                         2
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<pre>chapter 05 | Toxicity to reproduction                                                                                    Tricresylphosphate | page 18 of 28
manner. Over a period of day 18-20 of gestation, the 400 mg/kg bw/day       found including unossified sternebrae. Various incidental findings were
dosed rats gained 22 grams and the rats dosed 750 mg/kg bw/day lost 0.3     observed at all dose levels which were not statistically significant from
grams, whereas the controls were gaining 35 grams. Over the entire 0-20     controls, specifically at the external level (gastroschisis, mouth, jaw eyes),
day gestational period, the 400 mg/kg bw/day dosed rats gained 126.5        visceral level (renal pelvic cavitation) and skeletal level (misshapen
grams (14% lower than controls (146.6 grams), p<0.01), and the 750 mg/      ­squamosal bone and small mandible, absent jugal bone and small
kg bw/day dosed rats gained 94.9 grams (35% lower than controls,             ­squamosals, absent rib and defects of lumbar and thoracic vertebrae).
p<0.01). Food consumption was statistically lower in the 750 mg/kg/day
group as compared to controls. The dose groups 400 and 750 mg/kg/day          Conclusion on development
exhibited lower gravid uterine weights as compared to controls. Also, the     Dose-dependent reduced foetal body weights (below historical control
adjusted GD20 body weights (body weight minus uterine weight) and             data) have been observed in a guideline-compliant developmental study in
adjusted body weight gains (GD0-20) were lower in the 750 mg/kg/day           rats. Incidental findings of malformation were found at all doses and in the
group as compared to controls. The authors considered this effect likely to   highest dose group incomplete ossified bones were reported. At the two
be secondary to the reduced foetal body weights, which were below             highest doses reduced maternal weight gain was observed. As such, it
historical control data.                                                      could not be excluded that the observed effects on foetal body weights
                                                                              were secondary to the observed maternal toxicity.
No effects were seen on the number of dead or live foetuses at scheduled      The Committee concludes that the available evidence from this
necropsy. Developmental effects were observed in all dose groups by           ­developmental study raises concerns, but is not conclusive, for functional
means of statistically significant reduced foetal body weights. Compared       developmental effects after exposure to TCP. The Committee therefore
to controls that weighed 3.76 g, reductions were reported in a range of        concludes that a classification for developmental toxicity is not possible
4.4-6.3% for 20 and 100 mg/kg bw, and as reductions of 9% and 18%, in          based on the available data.
the 400 and 750 mg dose groups, respectively. The foetal body weight of
controls was within historical control values, although in the lower limit     5.1.4  Lactation studies
range. In all dose groups foetal body weights were below the historical        No studies were found regarding the effects of TCP on or via lactation in
controls. In the highest dose group, also incomplete ossified bones were       animals.
Health Council of the Netherlands | No. 2023/17                                                                         2
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<pre>chapter 06 | Conclusions on classification and labelling                 Tricresylphosphate | page 19 of 28
06 conclusions on classification
           and labelling
The Committee recommends classification according to Regulation (EC)
1272/2008 of the European Union. TCP is regarded as a mixture of
isomers for which the composition can differ. The consulted studies that
are described within this advisory report reflect the effects of TCP on
fertility and development of offspring. From the described evidence for
TCP, the Committee concludes the following:
Proposed classification for fertility
Category 2, H361f.
Proposed classification for developmental toxicity
Lack of appropriate data precludes the assessment of TCP for effects on
development.
Proposed labelling for effects on or via lactation
Lack of data precludes the assessment of TCP for effects on or via
­lactation.
Health Council of the Netherlands | No. 2023/17                          2
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<pre>References                                                                                                            Tricresylphosphate | page 20 of 28
references                                                                 8
                                                                              Somkuti SG, Lapadula DM, Chapin RE, Lamb IV JC and Abou-Donia
                                                                              MB. Reproductive tract lesions resulting from subchronic administration
1
  Lassen C, Løkke S and Hansen LI. Brominated Flame Retardants:               (63 days) of tri-o-cresyl phosphate in male rats. Toxicology and applied
  Substance Flow Analysis and Substitution Feasability Study.                 pharmacology 1987; 89(1): 49-63.
  Miljøstyrelsen; 1999.                                                    9
                                                                              Latendresse JR, Azhar S, Brooks CL and Capen CC. Pathogenesis of
2
  van der Veen I and de Boer J. Phosphorus flame retardants: properties,      cholesteryl lipidosis of adrenocortical and ovarian interstitial cells in
  production, environmental occurrence, toxicity and analysis.                F344 rats caused by tricresyl phosphate and butylated triphenyl
  Chemosphere 2012; 88(10): 1119-53.                                          phosphate. Toxicol Appl Pharmacol 1993; 122(2): 281-9.
3
  Chapin RE, George JD and Lamb JCt. Reproductive toxicity of tricresyl    10
                                                                              Latendresse JR, Brooks CL, Flemming CD and Capen CC.
  phosphate in a continuous breeding protocol in Swiss (CD-1) mice.           Reproductive toxicity of butylated triphenyl phosphate and tricresyl
  Fundam Appl Toxicol 1988; 10(2): 344-54.                                    phosphate fluids in F344 rats. Fundam Appl Toxicol 1994; 22(3): 392-9.
4
  NTP. Tricresyl Phosphate: Reproduction and Fertility Assessment in       11
                                                                              LANXESS. Rat oral prenatal developmental toxicity study PMI 1038-
  CD-1 Mice When Administered in the Feed., 1985.                             003. November 23, 2004.
5
  De Nola G, Kibby J and Mazurek W. Determination of ortho-cresyl
  phosphate isomers of tricresyl phosphate used in aircraft turbine engine
  oils by gas chromatography and mass spectrometry. Journal of
  Chromatography A 2008; 1200(2): 211-6.
6
  Kurebayashi H, Tanaka A and Yamaha T. Metabolism and disposition of
  the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat.
  Toxicology and Applied Pharmacology 1985; 77(3): 395-404.
7
  Latendresse JR, Brooks CL and Capen CC. Pathologic effects of
  butylated triphenyl phosphate-based hydraulic fluid and tricresyl
  phosphate on the adrenal gland, ovary, and testis in the Fischer-344
  rat. Toxicol Pathol 1994; 22(4): 341-52.
Health Council of the Netherlands | No. 2023/17                                                                      2
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<pre>Annexes                                                                                                                                                          Tricresylphosphate | page 21 of 28
annex A
supplementary tables
Table 1 Fertility studies
 Reference     Species     Dose/route       Experimental period/design                            General toxicity                                       Effects on reproduction
 Latendresse   Rats        0.4 g TCP/kg/    Phase 1: 98-day period; 7 days before pairing,        • decrease in body weight: males 9.2% compared to      Phase 1:
 et al. (1994) (F-344),    day oral dose in 63-day breeding period, and 28-day postbreeding         controls on day 96 (=phase 1) and females 6.5%       • decreased fertility index of approximately 45% in
               20 breeding sesame oil       interval.                                               compared to controls on day 131 (=phase 2)             the TCP group vs. 100% in controls.
               pairs per                                                                                                                                 • fewer litters per fertile pair. 0.5 litters in the TCP
               group                        Phase 2: immediate follow-up of phase 1 with          Phase 2:                                                 group vs. 2.7 in controls.
                                            crossover mating for 8 days with 28-day cohabitation  • increase in adrenal gland weight (males: 160 mg      • number of live pups per litter was decreased in
                                            period for females to deliver.                          +/- 10 in TCP group vs. 60 mg +/- 0 in controls;       TCP group compared to control group. All other
                                            Assessment of body weights, fertility rate, number of   females: 140 mg +/- 10 in TCP group vs. 60 mg          parameters not affected (including portion of live /
                                            litters/pups, proportion live/dead pups, body weights   +/- 0 in controls)                                     litter).
                                            pups. Phase 2: also organ weights                     • increase in liver weight (males: 17.43 g +/- 0.25 in
                                                                                                    TCP group vs. 13.24 g +/- 0.25 in controls.          Phase 2:
                                                                                                    females: 10.34 g +/- 0.16 in TCP group vs. 8.18 g    • TCP male rats produced no litters
                                                                                                    +/- 0.15 in controls)                                • decreased testicular weight (2.16 g +/- 0.07 in TCP
                                                                                                                                                           group vs 3.09 g +/- 0.02 in controls) and epididymal
                                                                                                                                                           weights (710 mg +/- 20 in TCP group vs. 970 mg
                                                                                                                                                           +/- 10 in controls)
                                                                                                                                                         • increased ovarian weight (170 +/- 10 mg in TCP
                                                                                                                                                           group vs. 130 mg +/- 0 in controls)
Health Council of the Netherlands | No. 2023/17                                                                                                                 2
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<pre>Annexes                                                                                                                                                    Tricresylphosphate | page 22 of 28
Table 2 Repeated dose toxicity studies assessing effects on reproductive organs
 Literature    Species        Dose/route            Experimental period/design                         General toxicity                                 Effects on reproductive organs
 Somkuti et al Rats (F-344),  TPCP 100 mg/kg/day    Exposure for 63 days. 5 animals were perfused      –                                                • 25% lower testosterone values in testicular
 (1987)        10 M per group in corn oil by gavage for histopathology. The remaining animals were                                                        interstitial fluid
                                                    used for examination of testicular esterase                                                         • lower epididymal sperm density (+/- 50 *10^4
                                                    activities, spermatid counts, motility, and                                                           cells/mg cauda epididymis vs. +/- 65*10^4
                                                    morphology. Testis weight, plasma and interstitial                                                    cells/mg cauda epididymis in controls)
                                                    testosterone concentration, and plasma
                                                    a-tocopherol.
                                                    Daily observation for neurological dysfunction or
                                                    acute toxicity. Body weights were monitored
                                                    weekly
 Latendresse   Rats (F-344),  TCP 0.4 g/kg/day in   40-day exposure and assessment of body             • increased adrenal gland weight (0.122 g vs.    • increased ovarian weights from 0(0.094 g vs.
 et al. (1993) 12 F per group sesame oil by gavage weights, adrenal glands and ovaries                   0.054 g in controls)                             0.072 g in controls)
                                                                                                       • cellular hypertrophy and fine cytoplasmic      • cellular hypertrophy and fine cytoplasmic
                                                                                                         vacuolization of adrenocortical cells (no        vacuolization of ovarian interstitial cells (no
                                                                                                         statistics)                                      statistics)
                                                                                                       • inhibited adrenal neutral cholesteryl ester    •
                                                                                                         hydrolase (nCEH) activity (4% of controls) and
                                                                                                         ovary nCEH activity (% not indicated).
                                                                                                       • decreased adrenal ACAT activity (73% vs.
                                                                                                         100% in controls).
                                                                                                       • elevated cholesteryl ester in adrenal glands
                                                                                                         (~20 to ~85 mg/g vs. ~20 mg/g in controls) and
                                                                                                         ovaries (~25 mg/g vs ~5 mg/g in controls).
                                                                                                       • elevated cholesterol in adrenal glands ~10
                                                                                                         mg/g vs ~3 mg/g in controls) and ovaries (~5
                                                                                                         mg/g vs. ~2 mg/g in controls).
Health Council of the Netherlands | No. 2023/17                                                                                                           2
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<pre>Annexes                                                                                                                                                Tricresylphosphate | page 23 of 28
Table 3 Developmental toxicity study
 Literature   Species        Dose/route         Experimental period/design                        Maternal toxicity                                 Effects on development
 Study report Rats (Sprague- TCP 20, 100, 400,  EPA OPPTS 870.3700 prenatal developmental         400 and 750 mg/kg/day:                            20, 100, 400, 750 mg/kg/day:
 (2004)       Dawley), 25 F  750 mg/kg/day in   toxicity study                                    • reduced overall body weight gain of 126.5 gr in • reduced foetal body weight (3.54 g, 3.58 g,
              per dose       corn oil by gavage                                                     400 mg/kg/day group vs 146.6 gr in controls       3.41 g, and 3.07 g, respectively) vs. controls
                                                20-day exposure period (gestation day 0 - day       and 94.9 gr in 750 mg/kg/day group vs 146.6 gr    (3.76 g)
                                                19) and assessment of body weights, ovarian         in controls
                                                and uterine examinations, foetal examinations     • lower gravid uterine weights (not quantified)   750 mg/kg/day:
                                                (external malformations, soft tissue examination,                                                   • increase in incomplete ossified bones with
                                                skeletal examination)                             750 mg/kg/day:                                      100% of litters with at least one incidence
                                                                                                  • reduced food consumption (15.7 g/animal/day       versus 75% in controls
                                                                                                    vs.24.1 g/animal/day in controls)
Health Council of the Netherlands | No. 2023/17                                                                                                       2
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<pre>Annexes                                                                                                                 Tricresylphosphate | page 24 of 28
annex B                                                                    animal study[tiab] OR animal experiment[tiab] OR laborator*[tiab] OR
                                                                           hospital-based[tiab] OR clinical-based[tiab]
literature search strategy                                                 8 hits on 15-7-2021
PubMed                                                                     Tritolyl Phosphates + reproductive toxicity + study types
                                                                           Tritolyl Phosphates[MeSH] OR Tritolyl Phosphates[tiab] OR CAS 1330-
Tritolyl Phosphates + general toxicity + study types                       78-5 OR Tricresyl Phosphate*[tiab]
Tritolyl Phosphates[MeSH] OR Tritolyl Phosphates[tiab] OR CAS 1330-        AND
78-5 OR Tricresyl Phosphate*[tiab]                                         Prenatal exposure delayed effects[MeSH] OR Prenatal exposure delayed
AND                                                                        effects[tiab] OR prenatal exposure[tiab] OR pregnancy outcomes[MeSH]
Toxicity[tiab] OR toxicogenetic*[tiab] OR toxicokinetic*[tiab] OR          OR pregnancy outcomes[tiab] OR pregnancy[MeSH] OR pregnancy[tiab]
toxicological[tiab] OR human, biologic*[tiab] OR teratogen*[tiab] OR       OR maternal exposures[tiab] OR paternal exposure[tiab] OR fertility
­occupational exposure[MeSH] OR “occupational exposure* “[tiab] OR         effects[tiab] OR fertility agents[tiab] OR fertility[tiab] OR infertility[tiab] OR
 exposure, occupational[tiab] OR “adverse health effects”[tiab] OR “health subfertility[tiab] OR fecundity[tiab] OR fecundability[tiab] OR differential
 damage”[tiab] OR hazard assessment[tiab] OR hazard, acute toxicity[tiab]  fertility[tiab] OR milk[tiab] OR lactation[tiab] OR milk secretion[tiab] OR
 OR “chronic toxicity”[tiab] OR “acute effects”[tiab] OR “chronic          breast milk[tiab] OR prolonged lactation[tiab] OR embryo toxicity[tiab] OR
 effects”[tiab] OR adme[tiab] OR absorption[MeSH] OR absorption[tiab] OR   organogenesis[tiab] OR reproductive toxic[tiab] OR developmental
 metabolism[MeSH] OR metabolism[tiab] OR distribution[tiab] OR             toxicity[tiab] OR fetotoxic*[tiab] OR reprotox*[tiab] OR embryotox*[tiab] OR
 excretion[tiab]                                                           embryo*[tiab]
 AND                                                                       AND
 Cohort*[tiab] OR epidemiological stud*[tiab] OR epidemiolog*[tiab] OR     Cohort*[tiab] OR epidemiological stud*[tiab] OR epidemiolog*[tiab] OR
 meta-analysis[tiab] OR meta-analyses[tiab] OR cross-sectional[tiab] OR    meta-analysis[tiab] OR meta-analyses[tiab] OR cross-sectional[tiab] OR
 case-control[tiab] case-cohort[tiab] OR longitudinal[tiab] OR nested      case-control[tiab] case-cohort[tiab] OR longitudinal[tiab] OR nested
 ­case-control[tiab] OR pooled-analysis[tiab] OR pooled-analyses[tiab] OR  ­case-control[tiab] OR pooled-analysis[tiab] OR pooled-analyses[tiab] OR
Health Council of the Netherlands | No. 2023/17                                                                        2
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<pre>Annexes                                                                                                         Tricresylphosphate | page 25 of 28
animal study[tiab] OR animal experiment[tiab] OR laborator*[tiab] OR     biologic*) OR TITLE-ABS(teratogen*) OR TITLE-ABS( “occupational expo-
hospital-based[tiab] OR clinical-based[tiab]                             sure*“) OR TITLE-ABS(exposure, occupational) OR TITLE-ABS( “adverse
2 hits on 15-7-2021                                                      health effects”) OR TITLE-ABS( “health damage”) OR TITLE-ABS(hazard
                                                                         assessment) OR TITLE-ABS(hazard, acute toxicity) OR TITLE-ABS(
Tritolyl Phosphates + study types                                        “chronic toxicity”) OR TITLE-ABS(“acute effects”) OR TITLE-ABS(“chronic
Tritolyl Phosphates[MeSH] OR Tritolyl Phosphates[tiab] OR CAS 1330-      effects”) OR TITLE-ABS(adme) OR TITLE-ABS(absorption) OR TITLE-
78-5 OR Tricresyl Phosphate*[tiab]                                       ABS(metabolism) OR TITLE-ABS(distribution) OR TITLE-ABS(excretion)
AND                                                                      AND
Cohort*[tiab] OR epidemiological stud*[tiab] OR epidemiolog*[tiab] OR    TITLE-ABS(Cohort*) OR TITLE-ABS(epidemiological stud*) OR TITLE-
meta-analysis[tiab] OR meta-analyses[tiab] OR cross-sectional[tiab] OR   ABS(epidemiolog*) OR TITLE-ABS(meta-analysis) OR TITLE-ABS(meta-
case-control[tiab] case-cohort[tiab] OR longitudinal[tiab] OR nested     analyses) OR TITLE-ABS(cross-sectional) OR TITLE-ABS(case-control)
­case-control[tiab] OR pooled-analysis[tiab] OR pooled-analyses[tiab] OR OR TITLE-ABS(case-cohort) OR TITLE-ABS(longitudinal) OR TITLE-
 animal study[tiab] OR animal experiment[tiab] OR laborator*[tiab] OR    ABS(nested case-control) OR TITLE-ABS(pooled-analysis) OR TITLE-
 hospital-based[tiab] OR clinical-based[tiab]                            ABS(pooled-analyses) OR TITLE-ABS(animal study) OR TITLE-
 19 hits on 15-7-2021                                                    ABS(animal experiment) OR TITLE-ABS(laborator*) OR
                                                                         TITLE-ABS(hospital-based) OR TITLE-ABS(clinical-based)
 Scopus                                                                  8 hits on 15-7-2021
 Tritolyl Phosphates + general toxicity + study types                    Tritolyl Phosphates + reproductive toxicity + study types
 TITLE-ABS(“Tritolyl Phosphates”) OR TITLE-ABS(CAS no. 1330-78-5)        TITLE-ABS(“Tritolyl Phosphates”) OR TITLE-ABS(CAS no. 1330-78-5)
 OR TITLE-ABS(“Tricresyl Phosphate*”)                                    OR TITLE-ABS(“Tricresyl Phosphate*”)
 AND                                                                     AND
 TITLE-ABS(Toxicity) OR TITLE-ABS(toxicogenetic*) OR TITLE-              TITLE-ABS(“Prenatal exposure delayed effects”) OR TITLE-ABS(“prenatal
 ABS(toxicokinetic*) OR TITLE-ABS(toxicological) OR TITLE-ABS(human,     exposure”) OR TITLE-ABS(“pregnancy outcomes”) OR TITLE-
Health Council of the Netherlands | No. 2023/17                                                                 2
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<pre>Annexes                                                                                                         Tricresylphosphate | page 26 of 28
ABS(pregnancy) OR TITLE-ABS(“maternal exposures”) OR TITLE-               Tritolyl Phosphates + study types
ABS(“paternal exposure”) OR TITLE-ABS(“fertility effects”) OR TITLE-      TITLE-ABS(“Tritolyl Phosphates”) OR TITLE-ABS(CAS no. 1330-78-5)
ABS(“fertility agents”) OR TITLE-ABS(fertility) OR TITLE-ABS(infertility) OR TITLE-ABS(“Tricresyl Phosphate*”)
OR TITLE-ABS(subfertility) OR TITLE-ABS(fecundity) OR TITLE-              AND
ABS(fecundability) OR TITLE-ABS(“differential fertility”) OR TITLE-       TITLE-ABS(Cohort*) OR TITLE-ABS(epidemiological stud*) OR TITLE-
ABS(milk) OR TITLE-ABS(lactation) OR TITLE-ABS(“milk secretion”) OR       ABS(epidemiolog*) OR TITLE-ABS(meta-analysis) OR TITLE-ABS(meta-
TITLE-ABS(“breast milk”) OR TITLE-ABS(“prolonged lactation”) OR           analyses) OR TITLE-ABS(cross-sectional) OR TITLE-ABS(case-control)
TITLE-ABS(“embryo toxicity”) OR TITLE-ABS(organogenesis) OR TITLE-        OR TITLE-ABS(case-cohort) OR TITLE-ABS(longitudinal) OR TITLE-
ABS(“reproductive toxic”) OR TITLE-ABS(“developmental toxicity”) OR       ABS(nested case-control) OR TITLE-ABS(pooled-analysis) OR TITLE-
TITLE-ABS(fetotoxic*) OR TITLE-ABS(reprotox*) OR TITLE-                   ABS(pooled-analyses) OR TITLE-ABS(animal study) OR TITLE-
ABS(embryotox*) OR TITLE-ABS(embryo*)                                     ABS(animal experiment) OR TITLE-ABS(laborator*) OR
AND                                                                       TITLE-ABS(hospital-based) OR TITLE-ABS(clinical-based)
TITLE-ABS(Cohort*) OR TITLE-ABS(epidemiological stud*) OR TITLE-          35 hits on 15-7-2021
ABS(epidemiolog*) OR TITLE-ABS(meta-analysis) OR TITLE-ABS(meta-          36 hits on 22-9-2022
analyses) OR TITLE-ABS(cross-sectional) OR TITLE-ABS(case-control)
OR TITLE-ABS(case-cohort) OR TITLE-ABS(longitudinal) OR TITLE-
ABS(nested case-control) OR TITLE-ABS(pooled-analysis) OR TITLE-
ABS(pooled-analyses) OR TITLE-ABS(animal study) OR TITLE-
ABS(animal experiment) OR TITLE-ABS(laborator*) OR
TITLE-ABS(hospital-based) OR TITLE-ABS(clinical-based)
3 hits on 15-7-2021
Health Council of the Netherlands | No. 2023/17                                                                2
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<pre>Committee                                                                                                    Tricresylphosphate | page 27 of 28
Committee
Members of the Subcommittee on the Classification of Substances Toxic to Reproduction
for the advisory report Tricresylphosphate
•   Prof. M.B.M. van Duursen, Professor of Environmental Health and Toxicology, VU Amsterdam, chair
•   Dr. M.M.H.J. van Gelder, assistant professor in Pharmaco Epidemiology, Radboudumc, Nijmegen
•   W.M.L.G. Gubbels-Van Hal, MSc, former director IGCON BV, former consultant registration and
    toxicology, Oss
•   Dr. M.W.G.D.M. van de Loo, Study Director Developmental and Reproductive Toxicology, Charles
    River Laboratories, Den Bosch
•   Prof. L.J.M. Smits, Professor of Clinical Epidemiology and Risk-Based Care, Maastricht University
•   Dr. E.C.M. Tonk, regulatory toxicologist, Charles River Laboratories, Den Bosch
Observera
•   Dr. L. Geraets, National Institute of Public Health and the Environment, Bilthoven
Scientific secretaries
•   Dr. R.H. Mennen, Health Council of the Netherlands, Den Haag
•   Dr. S.R. Vink, Health Council of the Netherlands, Den Haag
a
  Observers are entitled to speak during the meeting. They do not have any voting rights and do not bear any
  responsibility for the content of the committee’s advisory report.
Health Council of the Netherlands | No. 2023/17                                                              2
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<pre>The Health Council of the Netherlands, established in 1902, is an independent scientific advisory body. Its remit is “to advise the government and
Parliament on the current level of knowledge with respect to public health issues and health (services) research...” (Section 22, Health Act).
The Health Council receives most requests for advice from the Ministers of Health, Welfare and Sport, Infrastructure and Water Management, Social
Affairs and Employment, and Agriculture, Nature and Food Quality. The Council can publish advisory reports on its own initiative. It usually does this in
order to ask attention for developments or trends that are thought to be relevant to government policy.
Most Health Council reports are prepared by multidisciplinary committees of Dutch or, sometimes, foreign experts, appointed in a personal capacity.
The reports are available to the public.
This publication can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Tricresylphosphate.
The Hague: Health Council of the Netherlands, 2023; publication no. 2023/17.
All rights reserved
Health Council of the Netherlands | No. 2023/17                                                                         2
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