<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>Chloramphenicol
    Evaluation of the effects on reproduction, recommendation for classification
</pre>

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<pre></pre>

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<pre>Aan de staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp             : aanbieding advies Chloramphenicol
Uw kenmerk            : DGV/MBO/U-932542
Ons kenmerk           : U-7379/HS/fs/543-V12
Bijlagen              :1
Datum                 : 30 oktober 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de effecten van Chlooramfenicol op de vrucht-
baarheid en het nageslacht; het betreft ook effecten op de lactatie en via de moedermelk op
de zuigeling.
Dit advies maakt deel uit van een uitgebreide reeks waarin voor de voortplanting giftige
stoffen worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stof-
fen waaraan mensen tijdens de beroepsuitoefening kunnen worden blootgesteld.
Dit advies is opgesteld door een vaste commissie van de Gezondheidsraad, de Subcommis-
sie Classificatie Reproductietoxische stoffen. Het is vervolgens getoetst door de Beraads-
groep Gezondheid en omgeving van de raad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                       Postadres
Parnassusplein 5                                                  Postbus 16052
2 5 11 V X D e n        Haag                                      2500 BB Den     Haag
E - m a il : h . st o u t e n @ g r. n l                          w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 0 0 4
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<pre></pre>

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<pre>Chloramphenicol
Evaluation of the effects on reproduction, recommendation for classification
Subcommittee on the Classification of Reproduction Toxic Compounds
A Committee of the Health Council of the Netherlands
to:
the State Secretary of Social Affairs and Employment
No. 2012/18, The Hague, October 30, 2012
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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 & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, Agriculture & Innovation, and Education,
Culture & Science. 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.
                  The Health Council of the Netherlands is a member of the European
                  Science Advisory Network for Health (EuSANH), a network of science
                  advisory bodies in Europe.
                  The Health Council of the Netherlands is a member of the International Network
                  of Agencies for Health Technology Assessment (INAHTA), an international
                  collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Chloramphenicol. Evaluation of the effects
on reproduction, recommendation for classification. The Hague: Health Council
of the Netherlands, 2012; publication no. 2012/18.
all rights reserved
ISBN: 978-90-5549-910-6
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Labelling for lactation 14
.4 Data 15
.5 Presentation of conclusions 15
.6 Final remark 15
   Chloramphenicol 17
.1 Introduction 17
.2 Human studies 19
.3 Animal studies 20
.4 Conclusion 26
   References 29
   Contents                       7
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<pre>  Annexes 35
A The Committee 37
B The submission letter (in English) 39
C Comments on the public draft 41
D Regulation (EC) 1272/2008 of the European Community 43
E Additional considerations to Regulation (EC) 1272/2008 55
F Fertility and developmental toxicity studies 57
  Chloramphenicol
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<pre>Samenvatting
In het voorliggende advies heeft de Gezondheidsraad chlooramfenicol onder de
loep genomen. Chlooramfenicol is een breedspectrum antibioticum, dat in
Nederland wordt gebruikt voor de behandeling van ooginfecties in mens en
huisdier. Dit advies past in een reeks adviezen waarin de Gezondheidsraad op
verzoek van de minister van Sociale Zaken en Werkgelegenheid de effecten van
stoffen op de voortplanting beoordeelt. Het gaat vooral om stoffen waaraan
mensen tijdens de beroepsuitoefening kunnen worden blootgesteld. De
Subcommissie Classificatie reproductietoxische stoffen van de Commissie
Gezondheid en beroepsmatige blootstelling aan stoffen van de raad, hierna
aangeduid als de commissie, kijkt zowel naar effecten op de vruchtbaarheid van
mannen en vrouwen als naar effecten op de ontwikkeling van het nageslacht.
Daarnaast worden effecten op de lactatie en via de moedermelk op de zuigeling
beoordeeld.
Op basis van Verordening (EG) 1272/2008 van de Europese Unie doet de
commissie een voorstel voor classificatie. Voor chlooramfenicol komt de
commissie tot de volgende aanbevelingen:
• voor effecten op de fertiliteit adviseert de commissie om chlooramfenicol
    niet te classificeren wegens onvoldoende geschikte gegevens
• voor effecten op de ontwikkeling adviseert de commissie chlooramfenicol in
    categorie 1B te classificeren (stoffen waarvan verondersteld wordt dat zij
Samenvatting                                                                   9
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<pre>     toxisch zijn voor de menselijke voortplanting ) en met H360D (kan het
     ongeboren kind schaden) te kenmerken
  •  voor effecten op en via lactatie adviseert de commissie om chlooramfenicol
     niet te kenmerken wegens onvoldoende geschikte gegevens.
0 Chloramphenicol
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<pre>Executive summary
In the present report, the Health Council of the Netherlands reviewed
chloramphenicol. Chloramphenicol is a broad-spectrum antibiotic that in the
Netherlands is used for the treatment of eye infections in humans and dogs and
cats. This report is part of a series, in which the Health Council evaluates the
effects of substances on reproduction, at the request of the Minister of Social
Affairs and Employment. It mainly concerns substances to which man can be
occupationally exposed. The Subcommittee on the Classification of
Reproduction Toxic Substances of the Dutch Expert Committee on Occupational
Safety of the Health Council, hereafter called the Committee, evaluates the
effects on male and female fertility and on the development of the progeny.
Furthermore, the Committee considers the effects of a substance on lactation and
on the progeny via lactation.
The Committee recommends classification according to Regulation (EC) 1272/
2008 of the European Union. For chloramphenicol, these recommendations are:
• for effects on fertility, the Committee recommends not classifying
    chloramphenicol
• for effects on development, the Committee recommends classifying
    chloramphenicol in category 1B (presumed human reproductive toxicant)
    and labelling with H360D (may damage the unborn child)
• for effects on or via lactation, the Committee recommends not labelling
    chloramphenicol due to a lack of appropriate data.
Executive summary                                                                11
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<pre>2 Chloramphenicol</pre>

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<pre> hapter 1
        Scope
1.1     Background
        As a result of the Dutch regulation on registration of compounds toxic to
        reproduction that came into force on 1 April 1995, the Minister of Social Affairs
        and Employment requested the Health Council of the Netherlands to classify
        compounds toxic to reproduction. This classification is performed by the Health
        Council’s Subcommittee on the Classification of Reproduction Toxic Substances
        of the Dutch Expert Committee on Occupational Safety (DECOS). The
        classification is performed according to European Union Regulation (EC) 1272/
        2008 on classification, labelling and packaging (CLP) of substances and
        mixtures. The CLP guideline is based on the Globally Harmonised System of
        Classification and Labelling of Chemicals (GHS). The subcommittee’s advice on
        the classification will be applied by the Ministry of Social Affairs and
        Employment to extend the existing list of compounds classified as reproductive
        toxicant (category 1A and 1B and 2) or compounds with effects on or via
        lactation.
1.2     Committee and procedure
        This document contains the classification of chloramphenicol by the Health
        Council’s Subcommittee on the Classification of Reproduction Toxic
        Substances, hereafter called the Committee. The members of the Committee are
        Scope                                                                             13
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<pre>    listed in Annex A. The submission letter (in English) to the State Secretary can
    be found in Annex B.
         In 2012, the President of the Health Council released a draft of the report for
    public review. The individuals and organizations that commented on the draft
    report are listed in Annex C. The Committee has taken these comments into
    account in deciding on the final version of the report.
    The classification is based on the evaluation of published human and animal
    studies concerning adverse effects with respect to fertility and development as
    well as lactation of the above mentioned compound.
    Classification for reproduction (fertility (F) and development (D)):
    Category 1              Known or presumed human reproductive toxicant (H360(F/D))
         Category 1A        Known human reproductive toxicant
         Category 1B        Presumed human reproductive toxicant
    Category 2              Suspected human reproductive toxicant (H361(f/d))
    No classification for effects on fertility or development
    Classification for lactation:
                            Effects on or via lactation (H362)
                            No labelling for lactation
    The classification and labelling of substances is performed according to the
    guidelines of the European Union (Regulation (EC)1272/2008) presented in
    Annex D. The classification of compounds is ultimately dependent on an
    integrated assessment of the nature of all parental and developmental effects
    observed, their specificity and adversity, and the dosages at which the various
    effects occur. The guideline necessarily leaves room for interpretation, dependent
    on the specific data set under consideration. In the process of using the
    regulation, the Committee has agreed upon a number of additional considerations
    (see Annex E).
1.3 Labelling for lactation
    The recommendation for classifying substances for effects on or via lactation is
    also based on Regulation (EC) 1272/2008. The guideline defines 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
 4  Chloramphenicol
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<pre>    independent of dosage), the labelling for effects on or via lactation is based on
    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 the general population, e.g. the acceptable daily
    intake (ADI).
1.4 Data
    Literature searches were conducted in the on-line databases XTOXLINE,
    MEDLINE and CAPLUS, up to April 2011 without a starting date. Literature
    was selected primarily on the basis of the text of the abstracts. Publications cited
    in the selected articles, but not selected during the primary search, were reviewed
    if considered appropriate. In addition, handbooks and a collection of most recent
    reviews were consulted. References are divided in literature cited and literature
    consulted but not cited.
         The Committee describes both human and animal studies in the text. The
    animal data are described in more detail in Annex F as well. Of each study the
    quality of the study design (performed according to internationally
    acknowledged guidelines) and the quality of documentation are considered.
1.5 Presentation of conclusions
    The classification is given with key effects, species and references specified. In
    case a substance is not classified as toxic to reproduction, one of two reasons is
    given:
    • lack of appropriate data precludes assessment of the compound for
         reproductive toxicity
    • sufficient data show that no classification for toxic to reproduction is
         indicated.
1.6 Final remark
    The classification of compounds is based on hazard evaluation only (Niesink et
    al., 199523), which is one of a series of elements guiding the risk evaluation
    process. The Committee emphasizes that for derivation of health-based
    Scope                                                                                15
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<pre>  occupational exposure limits these classifications should be placed in a wider
  context. For a comprehensive risk evaluation, hazard evaluation should be
  combined with dose-response assessment, human risk characterization, human
  exposure assessment, and recommendations of other organizations.
6 Chloramphenicol
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<pre> hapter 2
        Chloramphenicol
2.1     Introduction
        Chloramphenicol (also known as chloramphenical) is a broad-spectrum
        antibiotic which inhibits protein synthesis in bacteria by binding reversibly to the
        50S ribosomal subunit at the peptidyltransferase site and inhibits the
        transpeptidation reaction and mitochondrial protein synthesis in mammalian
        cells.19,20 It is historically used veterinarily in all major food-producing animals
        and currently in humans and companion animals. Chloramphenicol has been
        reviewed several times by the Joint FAO/WHO Expert Committee on Food
        Additive (JECFA)19, the International Agency for Research on Cancer (IARC)18,
        and the European Committee for Veterinary Medicinal Products (ECVMP).6
        Concerns have been expressed about the genotoxicity of chloramphenicol and its
        metabolites, its embryo- and foetotoxicity, its carcinogenic potential in humans,
        and the lack of a dose-response relationship for aplastic anaemia caused by
        treatment with chloramphenicol in humans. Due to deficiencies in data on
        carcinogenicity and reproduction toxicity, an acceptable daily intake has never
        been allocated and consequently, no maximum residue limit has been assigned.
        In the EU, chloramphenicol is therefore listed among substances prohibited to be
        administered to food-producing animals.11 In the Netherlands, chloramphenicol
        is only registered for the treatment of eye infections in humans and dogs and
        cats.5 IARC has classified chloramphenicol as probably carcinogenic to humans
        Chloramphenicol                                                                      17
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<pre>  (group 2A)18, while in the EU chloramphenicol is not classified at all (http://
  esis.jrc.ec.europa.eu).
      Absorption of chloramphenicol results in peak concentrations of 10-20
  µg/mL within two to three hours after oral administration of 15 mg/kg bw.18,20 In
  infants and neonates, serum (peak) concentrations of 20-24 µg/mL and 14 µg/mL
  were observed after oral doses of 40 mg/kg bw to neonates and 26 mg/kg bw to
  infants, respectively.18 Chloramphenicol is extensively distributed in humans,
  regardless the route of administration. It penetrates the blood-brain barrier.
  Concentrations in cerebrospinal fluid can reach approximately 60% of those in
  plasma. Chloramphenicol may accumulate in the brain and may be present in
  bile, breast milk and placental fluid. About 50% is bound to plasma proteins. The
  major route of elimination is hepatic metabolism to the glucuronide.20 Excretion
  is primarily via the urine; 15% of the dose as parent compound and the remainder
  as metabolites, including conjugates.18 The half-life of chloramphenicol is 1.6-
  4.6 h in adults, but considerably longer in neonates:
  10->48 h in one- to eight-day-old infants and 5-16 h in 11-day- to eight-week-old
  infants18, due to limited glucuronyl transferase activity as well as limited renal
  excretion of unconjugated chloramphenicol.20
      The immature liver and kidney functions of the newborn may lead to such
  high plasma levels of chloramphenicol that the so-called ‘gray baby syndrome’,
  a serious, sometimes fatal, side effect may develop. This may occur at
  chloramphenicol doses resulting in plasma levels >75 mg/L. In order to prevent
  such levels, maximum doses no larger than 25 mg/kg bw/day were recommended
  for children younger than two weeks of age.20
  The identity and some physicochemical properties of chloramphenicol are
  presented below.
  chemical name     :   chloramphenicol
  CAS name          :   acetamide, 2,2-dichloro-N-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)-2-(4-
                        nitrophenyl)ethyl]-
  CAS number        :   56-75-7
  EC/EINECS number:     200-287-4
  synonyms          :   D-threo-2,2-dichloro-N-(β-hydroxy-α-hydroxymethyl-p-
                        nitrophenethyl)acetamide; 2,2-dichloro-N-[(αR,βR)-β-hydroxy-α-
                        hydroxymethyl-4-nitrophenethyl]acetamide; D-threo-2-dichloroacetamido-
                        1-para-nitrophenyl-1,3-propanediol; D-threo-N-dichloroacetyl-1-p-
                        nitrophenyl-2-amino-1,3-propanediol; D-threo-N-(1,1'-dihydroxy-1-p-
                        nitrophenylisopropyl)dichloro-acetamide; D-threo-p-nitrophenyl-1-
                        dichloroacetamido-2-propanediol-(1,3); acetamide, 2,2-dichloro-N-[2-
                        hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-[R-(R*,R*)]-
8 Chloramphenicol
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<pre>    colour and physical  : white to greyish-white or yellowish-white fine crystalline powder or fine
    state                  crystals, needles or elongated plates
    molecular weight     : 323.14
    molecular formula    : C11H12Cl2N2O5
    structure            :                  OH            Cl
                                                    H
                                                    N
                                                              Cl
                                                       O
                           O2 N                    OH
    melting point        : 149-153 °C (sublimes in high vacuum)
    optical rotation     : [α]27D = +18.6° (4.86% in ethanol)
    vapour pressure      : 2.31 x 10-10 Pa at 25 °C (estimated)
    Log P(octanol-water) : 1.14 (experimental)
    solubility           : 2.5 g/L in water at 25 °C; aqueous solutions are neutral; 151 g/L in
                           propylene glycol at 25 °C; very soluble in methanol, ethanol, butanol, ethyl
                           acetate, acetone; fairly soluble in diethyl ether
    Data from 4,18,31
2.2 Human studies
    Fertility studies
    No studies are available regarding the effects on human fertility.
    Developmental toxicity studies
    No adverse effects were reported in the children of 22 patients treated with
    chloramphenicol at various stages of pregnancy.18
    Czeizel et al. reported a population-based case-control study investigating the
    teratogenic potential of oral chloramphenicol treatment during pregnancy using
    the Hungarian Case-Control Surveillance of Congenital Abnormalities from
    1980-1996. Of 38,151 pregnant women who had babies without any defects
    (control group), 51 (0.13%) had been treated with chloramphenicol, while of
    22,865 pregnant women who had newborn infants or foetuses with congenital
    abnormalities, 52 (0.23%) had been treated. Exposure data were derived from
    maternal self-reported data and from medical documents. For self-reported
    treatment during the second-third months of gestation (critical period for major
    congenital abnormalities), only the group of undescended testes showed an
    increased risk (adjusted OR= 5.9; 95% CI: 1.2-28.7). The risk of cardiovascular
    congenital abnormalities was increased when comparing treatment during the
    Chloramphenicol                                                                                     19
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<pre>    entire pregnancy period (adjusted OR=2.1; 95% CI: 1.2-4.0). No risks were
    found when using only the medically documented treatments.7
        The Committee notes that there was insufficient information on the extent of
    exposure information from medical documents and on the over-the-counter
    availability of chloramphenicol to draw firm conclusions.
    Lactation
    No studies are available regarding the effects of chloramphenicol on human
    lactation.
    Plomp et al. studied the excretion of chloramphenicol into breast milk in normal
    puerpera after single and repeated (three times/day, two days) oral administration
    of 500 mg (approximately 8.5 mg/kg bw/day) of chloramphenicol. After
    administration of a single dose to four subjects, a peak level of 2.9 µg/mL was
    reached in breast milk after 1.4 hours. After repeated administration to five
    subjects, levels in breast milk amounted to 1.7 and 1.6 µg/mL at 24 and 48 hours
    after the first dose, respectively. From the excretion kinetic data, Plomp et al.
    calculated a maximum 24-hour excretion into breast milk of approximately
    14 mg after single oral administration of 500 mg to the lactating mother.29
    Havelka et al. reported average minimum and maximum daily milk
    concentrations of 0.5 and 2.8 µg/mL, respectively, in five subjects after oral
    administration of doses of 250 mg chloramphenicol (approximately 3-4 mg/kg
    bw), four times/day, for seven to ten days. Similar administration of doses of
    500 mg (approximately 5-8 mg/kg bw) to five subjects resulted in minimum and
    maximum daily levels of 1.8 and 6.1 µg/mL, respectively.17
    Vorherr presented breast milk levels of 15-25 µg/mL and stated that the
    percentage of administered dose in breast milk is 1.3% (no more details given).32
2.3 Animal studies
    Fertility and developmental toxicity studies in laboratory animals are
    summarized in Annex F.
 0  Chloramphenicol
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<pre>Fertility studies
Male and female rats were given 0 or 34 mg/kg bw chloramphenicol
intramuscularly during 20 days. Thereafter, rats were mated for 20 days: treated
males with treated females, treated males with untreated females, and untreated
males with treated females. Females were observed for 30 days and sacrificed.
Treated females did not become pregnant and in the group where only males
were treated, 6/20 females became pregnant compared to 17/20 in the control
group. Morphological investigation of the gonads of 15 treated females and 15
treated males showed cystic degeneration of the Graafian follicles in ovaries in
6/15 females. The oestrus cycle was affected in 14/15 females. No
morphological changes were observed in male gonads and uterine mucosa (paper
in Polish with summary in English).25
Beermann and Hansmann investigated the role of mitochondria in follicular
development, oocyte maturation and chromosomal segregation during the first
meiotic division. Female NMRI/Han mice were induced for superovulation with
pregnant mare serum followed 48 hours later by human chorionic gonadotrophin
(HCG) intraperitoneally. Females received an additional intraperitoneal injection
of 37.5 mg/kg bw chloramphenicol at 0, 15 or 48 hours after pregnant mare
serum injection or 18.8 mg/kg bw chloramphenicol at 0 hour. Controls were
injected with saline at the same time points. Females were sacrificed 15-16 hours
after HCG injection. Although all females showed follicular maturation and
ovulation, chloramphenicol reduced the ovarian weight relative to body weight
and the number of ovulated oocytes in females treated with 37.5 mg/kg bw
chloramphenicol. The progesterone concentration in the postovulatory ovary was
markedly reduced in all treated females. The number of diploid oocytes was
increased compared to control at 18.8 mg/kg bw and at 37.5 mg/kg bw at 15 and
48 hours.2
Oyeyemi and Adeniji found statistically significant decreases in sperm motility,
percentage viability, number of normal spermatozoa and sperm concentration in
Wistar rats given daily oral doses of 25 mg/kg bw for 20 and 25 days. Data on
general toxicity were not presented.28
Oral administration of doses of 28 mg/kg bw four times a day for ten consecutive
days to Wistar rats caused statistically significant decreases in sperm motility,
percentage viability and sperm count. The percentage of morphologically
abnormal sperm was not different from controls. At the end of the experiment,
Chloramphenicol                                                                   21
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<pre>  the treated animals had lost body weight by 7% compared to a body weight gain
  of 4% in controls. There was no effect on absolute and relative testis weights.27
  In a dominant lethal assay, male Swiss CD-1 mice (n=7-9/group) were treated
  with a single intraperitoneal injection of chloramphenicol of 333 or 666 mg/kg
  bw. A concurrent solvent control group (n=10) was included. Within two hours
  of injection, each male was paired with three untreated virgin females which
  were replaced weekly for eight consecutive weeks. Females were sacrificed 13
  days from mid-week of their mating, and animals were scored for pregnancy and
  for numbers of total implants, as comprised by live implants, early foetal deaths
  and late foetal deaths. As late foetal deaths were extremely rare, total implants
  and early foetal deaths were the only implant parameters analysed.
  Chloramphenicol did not produce early foetal deaths and pre-implantation losses
  exceeding control limits.9,10
  Developmental toxicity studies
  Oral
  Mackler et al. reported effects on foetal development in rats when 0, 2 or 3%
  chloramphenicol (200 or 300 mg/rat) was given in the diet during gestational
  days 0-20. Food intake was reduced at both dose levels but Mackler et al. did not
  report on maternal body weight or other effects. The number of resorptions was
  largely increased (5, 31 and 57%, respectively), foetal and placental weights
  were reduced as were the numbers of live foetuses at both dose levels. Similar
  effects were seen when a restricted diet (67% of control diet) was given, except
  that the number of resorptions was not increased; only the number of live
  foetuses was decreased. Oedema was found in foetuses of both dose levels and
  wavy ribs and fused ribs were found in foetuses at the highest dose level.21
      Additionally, dams were sacrificed on gestational day 20 after treatment with
  1.5% chloramphenicol in the diet for the first nine to 12 days of gestation or with
  3% chloramphenicol for the first two to eight days of gestation. Increased
  numbers of dams with no implantations were observed following treatment
  during gestational days 0-6 and onwards; increased numbers of resorptions
  following treatment during gestational days 0-5, 0-8, 0-9, 0-10 and 0-11.
  Treatment during gestational days 0-7 and onwards caused decreased foetal
  weights.21
      As part of the above-mentioned study, Mackler et al. tested the implication of
  electron transport and oxidative energy formation in rat embryos and foetuses
2 Chloramphenicol
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<pre>during the period of organogenesis influenced by chloramphenicol. They found
that mitochondrial activities of DPNH (reduced diphosphopyridine nucleotide)
oxidase, cytochrome c oxidase and ATPase were inhibited, while succinic
indophenol dehydrogenase and succinic oxidase were not inhibited suggesting
that inhibition of electron transport plays a role in chloramphenicol
developmental toxicity.21
Fritz and Hess reported a prenatal developmental study in Sprague-Dawley rats,
CD-1 mice and rabbits (mixed breed) and compared the embryotoxic and foetal
parameters and macroscopic and skeletal abnormalities with the spontaneous rate
of abnormalities recorded over a period of four years in untreated controls
belonging to the same breed. Rats and mice were given chloramphenicol by
gavage at doses of 500-2,000 mg/kg bw and rabbits at doses of 500 and 1,000
mg/kg bw for one or more days during gestation.
    The rat dams showed no toxic signs. In the groups treated with daily doses of
500 mg/kg bw on gestational days 5-15, of 1,000 mg/kg bw on gestational days
7-12, or of 2,000 mg/kg bw on gestational days 6-8, 7-9, 9-11, 11-13, 15-17, or
on day 8, 9 or 10, the percentages of embryonic or foetal deaths were statistically
significantly, sometimes largely, increased ranging from 39 to 100% (controls:
23%). In the groups treated with 1,500 mg/kg bw/day on gestational days 0-6 or
with 2,000 mg/kg bw/day on gestational day 15-17, or on day 5, 6 or 7,
embryonic or foetal mortality was similar to that in controls. Anomalies observed
included omphalocele or umbilical hernia in combination with costal fusion in
8/22 foetuses (1 litter) at 2,000 mg/kg bw/day on gestational day 6-8, 1/26
foetuses (1 litter) on gestational day 7-9, 2/84 foetuses (1 litter) on gestational
day 7, 5/46 foetuses (1 litter) on gestational day 8, and 5/64 foetuses (3 litters) on
gestational day 9. Two omphaloceles were seen in 6,326 control foetuses.
Skeletal development was retarded at 1,000 and 2,000 mg/kg bw: missing
ossification of phalangeal nuclei of forelegs and hind legs and of 5th sternebra at
1,000 mg/kg bw/day and 2,000 mg/kg bw/day on gestational day 11-13, a
decreased number of ossified cervical vertebrae, and an increased incidence of
fusion of sternebra 1+2 and bipartite vertebrae at 1,000 mg/kg bw/day.
    Data on toxicity in the mouse dams were insufficiently documented. The
number of resorptions (not further specified) was statistically significantly
increased at 1,000 mg/kg bw/day administered on gestational days 6-12 (71% vs.
24% in controls). All embryos were resorbed at 2,000 mg/kg bw/day
(administered on gestational days 8-10). At 500 mg/kg bw/day, administered on
gestational days 5-15, the percentage of embryonic and foetal deaths was 31
(controls: 24%; p<0.05); foetal weight was statistically significantly decreased,
Chloramphenicol                                                                        23
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<pre>  no malformations were observed. At 1,000 mg/kg bw/day, one foetus with
  malformations out of 81 foetuses (0.01%) was noted compared to 4/3,230
  (0.001%) in the control group. Skeletal development was retarded as indicated
  by an increased incidence of missing ossification of phalangeal nuclei of forelegs
  (37.5 % vs. 9% in controls) and hind legs (45% vs. 18%) and of 5th sternebra
  (15% vs. 0%), and increased incidence of fusion of sternebrae 1+2 (7.5%
  vs. 0%).
      In rabbits, no toxic signs were noted in the dams. The number of embryonal
  resorptions was statistically significantly increased at 1,000 mg/kg bw/day given
  on gestational day 6-9 or gestational day 8-11 (25 and 58%, respectively;
  controls: 10%). Administration of 500 mg/kg bw given on gestational days 6-15
  did not affect the percentage of prenatal deaths (12% vs. 10% in controls:) or
  average foetal body weight. No increased incidence of malformations in the live
  foetuses was noted. Skeletal development was delayed: at 500 mg/kg bw/day as
  indicated by an increased incidence of missing ossification of phalangeal nuclei
  of forelegs (50% vs. 33% in controls) and at 1,000 mg/kg bw/day given on
  gestational day 6-9 by an increased incidence of phalangeal nuclei of fore- and
  hind legs (51.5 and 12%, respectively; controls: 33 and 5%, respectively) and
  given on gestational day 8-11 by an increased incidence of the 5th sternebra (33%
  vs. 26%).13
  Al-Hachim & Al-Baker performed a prenatal developmental study in mice
  administering five to seven oral doses of 0, 25, 50, 100 or 200 mg/kg bw during
  the third stage of pregnancy and investigated behavioural parameters of the pups
  (conditioned avoidance response in 30-36-day-old, electroshock seizure
  threshold in 38-day-old, and open-field in 42-48-day-old pups). Conditioned
  avoidance response was statistically significantly decreased at all dose levels
  with a dose-response relation. Electroshock seizure threshold was not
  statistically significantly increased at 50-200 mg/kg bw/day with a dose-response
  relation. Open-field performance was statistically significantly decreased at all
  dose levels without a dose-response relation. The authors report that no gross
  congenital abnormalities were noted.1
  Subcutaneous injection
  Bertolini and Poggioli investigated the conditioned avoidance response in
  60-day-old rats. Four groups of pregnant Wistar rats were treated as follows: in
  one group, 50 mg/kg bw chloramphenicol (hemisuccinate) was given
  subcutaneously on gestational days 7-21; in two other groups, 50 or 100 mg/kg
4 Chloramphenicol
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<pre>bw was injected subcutaneously into pups for the first three days after birth; the
fourth group, receiving saline, served as controls. No effects on pregnancy, litter
size, pup weight, postnatal weight gain, or incidence of gross malformations
were seen; no mortality was observed. When 60-days old, animals were selected,
trained, then examined for avoidance learning at days 5, 10, 15 and 20 from the
start of the conditioning procedure. No difference in pain threshold was noted
between the groups. Conditioned avoidance response was statistically
significantly decreased in all treated groups, generally more marked in males
than in females and in intrauterine treated than in postnatally treated rats.3
Neumann reported a study in rats given 800-2,500 mg/kg bw chloramphenicol
sodium succinate subcutaneously on gestational days 6-10 or 11-14 compared to
a control group. In the group treated on gestational days 6-10, all live foetuses
showed retarded development, one foetus was malformed (clinodactyly), and
mean foetal weight was markedly reduced. In the group treated on gestational
days 11-14, an increased number of resorptions, reduced number of normal live
foetuses, and increased number of retarded live foetuses (predominantly
haemorrhages and oedemas) were observed compared to controls. Six foetuses
were malformed (all at 1,500 mg/kg bw; five from 1 litter); five had cleft palate
and one had cleft palate and anomalies of the limbs. The control group contained
no retarded or malformed foetuses. Foetal weight was again markedly reduced
compared to controls. The number of resorptions and reduced number of normal
live foetuses were dose related.22
     The Committee notes that the malformations were almost all found in one
litter at a high subcutaneous dose.
Other studies
Chloramphenicol affected mitochondrial function or morphology following
intravenous injection into pregnant rats26, intraperitoneal injection into pregnant
mice24 or into newborn rats (0-two-hours and up to eight-days old)16,15, or
incubation in in vitro systems such as rat yolk sacs12 and perfused, isolated hearts
from one-four-day-old piglets33.
Lactation
No studies were found regarding the effects of chloramphenicol on lactation in
animals.
Chloramphenicol                                                                      25
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<pre>        Following a single intravenous dose of chloramphenicol of 100 mg/kg bw to
    four goats, a maximum level of chloramphenicol of 15 mg/L was detected in
    milk one hour after administration (the first measurement point).29
        Intramuscular administration of a single dose of 10 mg/kg bw to five cows
    resulted in maximum levels in milk between 0.5 and 1.3 mg/L, six and nine
    hours after injection. In a separate experiment, chloramphenicol was determined
    in both whole and skimmed milk after a single intramuscular dose of 10 mg/kg
    bw (n=5 cows). Average concentrations in skimmed milk were almost similar to
    those in whole milk amounting to 2.0 and 1.9 mg/L, three and six hours after
    injection, respectively (whole milk: 1.9 and 1.8 mg/L, respectively). After oral
    administration of 10 mg/kg bw, no chloramphenicol was detected in milk
    measured up to 24 hours after administration.8,30
2.4 Conclusion
    No human studies on fertility effects of chloramphenicol were available.
        No guideline studies were available regarding the effects of exposure to
    chloramphenicol on (functional) fertility in laboratory animals.
        Oral administration of chloramphenicol to rats affected certain sperm
    characteristics.27,28 In one of these studies, treatment caused decreased body
    weight.27
        The Committee could not assess the relevance of effects on several stages on
    fertility observed in rats and mice2,14,25 for workers occupationally exposed to
    chloramphenicol. In these studies, no information was reported on general
    toxicity which could have caused or contributed to these effects. Furthermore,
    administration was through routes less relevant to occupational exposure (i.e.
    intramuscular and intraperitoneal injections).
        Overall, the Committee proposes not to classify chloramphenicol for effects
    on fertility due to a lack of appropriate human and animal data.
    Both human and animal data were available to evaluate the developmental
    toxicity of chloramphenicol.
        A population-based case-control study7 investigating the teratogenic
    potential of oral chloramphenicol treatment during pregnancy suggested
    increased risks on undescendent testes and cardiovascular congenital
    abnormalities.
        In laboratory animal experiments in which high, not maternally toxic, oral
    doses of chloramphenicol (500-2,000 mg/kg bw) were administered during
    gestational days 0-20 to rats 21, or during selected gestational day(s) to rats, mice
 6  Chloramphenicol
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<pre>or rabbits13, the main effect was a, sometimes large, increase in embryonic and/or
foetal mortality while delayed development or malformations (in rats only) were
seen in the survivors. Lower doses (25-200 mg/kg bw) given orally to mice
during the third stage of gestation1 or subcutaneously to rats during gestational
days 7-213 affected neurobehavioural parameters in their offspring.
    Following intravenous injection into pregnant rats26, intraperitoneal injection
into pregnant mice24 or into newborn rats (0-two-hours and up to eight-days
old)16,15, or incubation in in vitro systems such as rat yolk sacs12 and perfused
isolated hearts from one-four-day-old piglets33, affected mitochondrial function
or morphology was observed.
    Overall, the Committee concludes that the human data are not sufficient for
classification. Based on the prenatal and postnatal effects found in laboratory
animals, the Committee proposes to classify chloramphenicol for developmental
effects in category 1B (presumed human reproductive toxicant).
There were no human or animal data on effects on or via lactation. There were no
data on background concentrations of chloramphenicol in breast milk or on
concentrations in breast milk in occupationally exposed women.
Chloramphenicol was found in milk following oral administration to
women17,29,32 and intravenous and intramuscular administration to animals8,30.
     In the absence of data on the toxicity of chloramphenicol in breast milk, the
Committee is not able to calculate a safe level for chloramphenicol in human
breast milk. Therefore, the Committee proposes not labelling chloramphenicol
for effects on or via lactation due to a lack of appropriate data
Proposed classification for fertility
Lack of appropriate data precludes the assessment of chloramphenicol for effects
on fertility.
Proposed classification for developmental toxicity
Category 1B; H360D
Proposed labelling for effects on or via lactation
Lack of appropriate data precludes the assessment of chloramphenicol for
labelling for effects on or via lactation.
Chloramphenicol                                                                     27
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<pre>8 Chloramphenicol</pre>

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<pre>  References
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<pre>1 European Commission. Commission Regulation (EU) No 37/2010 of 22 December 2009 on
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3 Fritz H, Hess R. Effect of chloramphenicol on the prenatal development of rats, mice, and rabbits.
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4 Giavini E, Prati M, Vismara C, Bonanomi L, Aliverti V. The preimplantation embryo as a target
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5 Nowkunski J. Studies on the effect of chloramphenicol on the morphology and function of the gonads
  in rats. Patol Pol 1963; 14: 449-454.
0 Chloramphenicol
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<pre>6 Oerter D, Bass R. Embryonic development and mitochondrial function. 1. Effects of chloramphenicol
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7 Oyagbemi AA, Adedara IA, Saba AB, Farombi EO. Role of oxidative stress in reproductive toxicity
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8 Oyeyemi MO, Adeniji DA. Morphological characteristics and haematological studies in Wistar rats
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9 Plomp TA, Thiery M, Maes RAA. The passage of thiamphenicol and chloramphenicol into human
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2 Vorherr H. Drug excretion in breast milk. Postgrad Med 1974; 56: 97-104.
3 Werner JC, Whitman V, Schuler HG, Fripp RR, Rannels AM, Kasales CJ et al. Acute myocardial
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  References                                                                                           31
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<pre>  Davis LE, Abbitt B. Clinical pharmacology of antibacterial drugs in the uterus of the mare. J Am Vet
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  system for drugs and heavy metals. Organ-Directed Toxic: Chem Indices Mech, Proc Symp 1981;
  311-315.
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  Khera KS, Whalen C. Detection of neuroteratogens with an in vitro cytotoxicity assay using primary
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  Laschinski G, Vogel R, Spielmann H. Cytotoxicity test using blastocyst-derived euploid embryonal
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  Mulhall A, de Louvois J, Hurley R. The pharmacokinetics of chloramphenicol in the neonate and
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  Rajchgot P, Prober C, Soldin S, Golas C, Good F, Harding L, et al. Chloramphenicol
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2 Chloramphenicol
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<pre>pharmacokinetics in infants less than three months of age in the Philippines and The Gambia. Pediatr
Infect Dis J 1999; 18: 896-901.
References                                                                                           33
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<pre>4 Chloramphenicol</pre>

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<pre>A The Committee
B The submission letter (in English)
C Comments on the public draft
D Regulation (EC) 1272/2008 of the European Community
E Additional considerations to Regulation (EC) 1272/2008
F Fertility and developmental toxicity studies
  Annexes
                                                         35
</pre>

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<pre>6 Chloramphenicol</pre>

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<pre>nnex A
     The Committee
     •  A.H. Piersma, chairman
        Professor of Reproductive and Developmental Toxicology, Utrecht
        University, Utrecht; National Institute for Public Health and the
        Environment, Bilthoven
     •  D. Lindhout
        Professor of Medical Genetics, Paediatrician (not practising), Clinical
        Geneticist, University Medical Centre, Utrecht
     •  N. Roeleveld
        Reproductive Epidemiologist, Radboud University Nijmegen Medical
        Centre, Nijmegen
     •  J.G. Theuns-van Vliet
        Reproductive Toxicologist, TNO Triskelion BV, Zeist
     •  D.H. Waalkens-Berendsen
        Reproductive Toxicologist, Zeist
     •  P.J.J.M. Weterings
        Toxicologist, Weterings Consultancy BV, Rosmalen
     •  A.S.A.M. van der Burght, scientific secretary
        Health Council of the Netherlands, Den Haag
     •  J.T.J. Stouten, scientific secretary
        Health Council of the Netherlands, Den Haag
     The Committee                                                              37
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<pre>  The first draft of this report was prepared by Dr. H.M. Barentsen, from the
  Regulatory Affairs Department of NOTOX BV, Den Bosch, by contract with the
  Ministry of Social Affairs and Employment.
  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
8 Chloramphenicol
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<pre>nnex B
     The submission letter (in English)
     Subject          : Submission of the advisory report Chloramphenicol
     Your reference   : DGV/MBO/U-932342
     Our reference    : U 7401 /HS/fs/543-V12
     Enclosed         :1
     Date             : October 30, 2012
     Dear State Secretary,
     I hereby submit the advisory report on the effects of Chloramphenicol on fertility
     and on the development of the progeny; it also concerns effects on lactation and
     on the progeny via lactation. This advisory report is part of an extensive series in
     which reproduction toxic substances are classified in accordance with European
     guidelines. This involves substances to which people may be exposed
     occupationally.
     The advisory report was prepared by a permanent committee of the Health
     Council of the Netherlands, the Subcommittee on the Classification of
     Reproduction Toxic Compounds. The advisory report was consequently
     reviewed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter (in English)                                                   39
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<pre>  Today I sent copies of this advisory report to the State Secretary of Infrastructure
  and the Environment and to the Minister of Health, Welfare and Sport, for their
  information.
  Yours sincerely,
  (signed)
  Prof. dr. W.A. van Gool,
  President
0 Chloramphenicol
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<pre>nnex C
     Comments on the public draft
     • T.J. Lenz, Q. Ma. National Institute for Occupational Safety and Health,
       Cincinnati OH, USA.
     Comments on the public draft                                               41
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<pre>2 Chloramphenicol</pre>

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<pre>nnex D
     Regulation (EC) 1272/2008 of the
     European Community
     3.7            Reproductive toxicity
     3.7.1          Definitions and general considerations
     3.7.1.1        Reproductive toxicity includes adverse effects on sexual function and fertility in adult
     males and females, as well as developmental toxicity in the offspring. The definitions presented
     below are adapted from those agreed as working definitions in IPCS/EHC Document No 225, Princi-
     ples for Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classi-
     fication purposes, the known induction of genetically based heritable effects in the offspring is
     addressed in Germ Cell Mutagenicity (section 3.5), since in the present classification system it is con-
     sidered more appropriate to address such effects under the separate hazard class of germ cell muta-
     genicity.
     In this classification system, reproductive toxicity is subdivided under two main headings:
     (a) adverse effects on sexual function and fertility;
     (b) adverse effects on development of the offspring.
     Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function
     and fertility or to developmental toxicity. Nonetheless, substances with these effects, or mixtures con-
     taining them, shall be classified as reproductive toxicants.
     Regulation (EC) 1272/2008 of the European Community                                                      43
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<pre>  3.7.1.2         For the purpose of classification the hazard class Reproductive Toxicity is differentiated
                  into:
  •     adverse effects
        •    on sexual function and fertility, or
        •    on development;
  •     effects on or via lactation.
  3.7.1.3         Adverse effects on sexual function and fertility
  Any effect of substances that has the potential to interfere with sexual function and fertility. This
  includes, but is not limited to, alterations to the female and male reproductive system, adverse effects
  on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour,
  fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in
  other functions that are dependent on the integrity of the reproductive systems.
  3.7.1.4         Adverse effects on development of the offspring
  Developmental toxicity includes, in its widest sense, any effect which interferes with normal devel-
  opment of the conceptus, either before or after birth, and resulting from exposure of either parent
  prior to conception, or exposure of the developing offspring during prenatal development, or postna-
  tally, to the time of sexual maturation. However, it is considered that classification under the heading
  of developmental toxicity is primarily intended to provide a hazard warning for pregnant women, and
  for men and women of reproductive capacity. Therefore, for pragmatic purposes of classification,
  developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of
  parental exposure. These effects can be manifested at any point in the life span of the organism. The
  major manifestations of developmental toxicity include (1) death of the developing organism, (2)
  structural abnormality, (3) altered growth, and (4) functional deficiency.
  3.7.1.5         Adverse effects on or via lactation are also included in reproductive toxicity, but for
  classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is
  desirable to be able to classify substances specifically for an adverse effect on lactation so that a spe-
  cific hazard warning about this effect can be provided for lactating mothers.
4 Chloramphenicol
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<pre>3.7.2        Classification criteria for substances
3.7.2.1      Hazard categories
3.7.2.1.1    For the purpose of classification for reproductive toxicity, substances are allocated to
one of two categories. Within each category, effects on sexual function and fertility, and on develop-
ment, are considered separately. In addition, effects on lactation are allocated to a separate hazard cat-
egory.
Table 3.7.1(a) Hazard categories for reproductive toxicants.
Categories                      Criteria
CATEGORY 1                      Known or presumed human reproductive toxicant
                                Substances are classified in Category 1 for reproductive toxicity when
                                they are known to have produced an adverse effect on sexual function
                                and fertility, or on development in humans or when there is evidence
                                from animal studies, possibly supplemented with other information, to
                                provide a strong presumption that the substance has the capacity to
                                interfere with reproduction in humans. The classification of a sub-
                                stance is further distinguished on the basis of whether the evidence for
                                classification is primarily from human data (Category 1A) or from
                                animal data (Category 1B).
                Category 1A Known human reproductive toxicant
                                The classification of a substance in Category 1A is largely based on
                                evidence from humans.
                Category 1B Presumed human reproductive toxicant
                                The classification of a substance in Category 1B is largely based on
                                data from animal studies. Such data shall provide clear evidence of an
                                adverse effect on sexual function and fertility or on development in
                                the absence of other toxic effects, or if occurring together with other
                                toxic effects the adverse effect on reproduction is considered not to be
                                a secondary non-specific consequence of other toxic effects. However,
                                when there is mechanistic information that raises doubt about the rele-
                                vance of the effect for humans, classification in Category 2 may be
                                more appropriate.
CATEGORY 2                      Suspected human reproductive toxicant
                                Substances are classified in Category 2 for reproductive toxicity when
                                there is some evidence from humans or experimental animals, possi-
                                bly supplemented with other information, of an adverse effect on sex-
                                ual function and fertility, or on development, and where the evidence
                                is not sufficiently convincing to place the substance in Category 1. If
                                deficiencies in the study make the quality of evidence less convincing,
                                Category 2 could be the more appropriate classification.
                                Such effects shall have been observed in the absence of other toxic
                                effects, or if occurring together with other toxic effects the adverse
                                effect on reproduction is considered not to be a secondary non-specific
                                consequence of the other toxic effects.
Regulation (EC) 1272/2008 of the European Community                                                        45
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<pre>  Table 3.7.1(b) Hazard category for lactation effects.
  EFFECTS ON OR VIA LACTATION
  Effects on or via lactation are allocated to a separate single category. It is recognised that for many
  substances there is no information on the potential to cause adverse effects on the offspring via lacta-
  tion. However, substances which are absorbed by women and have been shown to interfere with lac-
  tation, 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 to indicate this property
  hazardous to breastfed babies. This classification can be assigned on the:
  (a) human evidence indicating a hazard to babies during the lactation period; and/or
  (b) results of one or two generation studies in animals which provide clear evidence of adverse effect
  in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or
  (c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the sub-
  stance is present in potentially toxic levels in breast milk.
  3.7.2.2        Basis of classification
  3.7.2.2.1      Classification is made on the basis of the appropriate criteria, outlined above, and an
  assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is
  intended to be used for substances which have an intrinsic, specific property to produce an adverse
  effect on reproduction and substances shall not be so classified if such an effect is produced solely as
  a non-specific secondary consequence of other toxic effects.
  The classification of a substance is derived from the hazard categories in the following order of pre-
  cedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lac-
  tation. If a substance meets the criteria for classification into both of the main categories (for example
  Category 1B for effects on sexual function and fertility and also Category 2 for development) then
  both hazard differentiations shall be communicated by the respective hazard statements. Classifica-
  tion in the additional category for effects on or via lactation will be considered irrespective of a clas-
  sification into Category 1A, Category 1B or Category 2.
  3.7.2.2.2      In the evaluation of toxic effects on the developing offspring, it is important to consider
  the possible influence of maternal toxicity (see section 3.7.2.4).
  3.7.2.2.3      For human evidence to provide the primary basis for a Category 1A classification there
  must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classifi-
  cation shall ideally be from well conducted epidemiological studies which include the use of appro-
  priate controls, balanced assessment, and due consideration of bias or confounding factors. Less
  rigorous data from studies in humans shall be supplemented with adequate data from studies in
  experimental animals and classification in Category 1B shall be considered.
6 Chloramphenicol
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<pre>3.7.2.3         Weight of evidence
3.7.2.3.1       Classification as a reproductive toxicant is made on the basis of an assessment of the
total weight of evidence, see section 1.1.1. This means that all available information that bears on the
determination of reproductive toxicity is considered together, such as epidemiological studies and
case reports in humans and specific reproduction studies along with sub-chronic, chronic and special
study results in animals that provide relevant information regarding toxicity to reproductive and
related endocrine organs. Evaluation of substances chemically related to the substance under study
may also be included, particularly when information on the substance is scarce. The weight given to
the available evidence will be influenced by factors such as the quality of the studies, consistency of
results, nature and severity of effects, the presence of maternal toxicity in experimental animal stud-
ies, level of statistical significance for inter-group differences, number of endpoints affected, rele-
vance of route of administration to humans and freedom from bias. Both positive and negative results
are assembled together into a weight of evidence determination. A single, positive study performed
according to good scientific principles and with statistically or biologically significant positive results
may justify classification (see also 3.7.2.2.3).
3.7.2.3.2       Toxicokinetic studies in animals and humans, site of action and mechanism or mode of
action study results may provide relevant information which reduces or increases concerns about the
hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or
mode of action has no relevance for humans or when the toxicokinetic differences are so marked that
it is certain that the hazardous property will not be expressed in humans then a substance which pro-
duces an adverse effect on reproduction in experimental animals should not be classified.
3.7.2.3.3       If, in some reproductive toxicity studies in experimental animals the only effects
recorded are considered to be of low or minimal toxicological significance, classification may not
necessarily be the outcome. These effects include small changes in semen parameters or in the inci-
dence of spontaneous defects in the foetus, small changes in the proportions of common foetal vari-
ants such as are observed in skeletal examinations, or in foetal weights, or small differences in
postnatal developmental assessments.
3.7.2.3.4       Data from animal studies ideally shall provide clear evidence of specific reproductive
toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs
together with other toxic effects in the dam, the potential influence of the generalised adverse effects
shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the
embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely
to have influenced these effects, as part of the weight of evidence. In general, developmental effects
that are observed at maternally toxic doses shall not be automatically discounted. Discounting devel-
Regulation (EC) 1272/2008 of the European Community                                                         47
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<pre>  opmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis
  when a causal relationship is established or refuted.
  3.7.2.3.5      If appropriate information is available it is important to try to determine whether devel-
  opmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary
  mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of mater-
  nal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be clearly dem-
  onstrated that the effects are secondary non-specific effects. This is especially the case when the
  effects in the offspring are significant, e.g. irreversible effects such as structural malformations. In
  some situations it can be assumed that reproductive toxicity is due to a secondary consequence of
  maternal toxicity and discount the effects, if the substance is so toxic that dams fail to thrive and there
  is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.
  3.7.2.4        Maternal toxicity
  3.7.2.4.1      Development of the offspring throughout gestation and during the early postnatal stages
  can be influenced by toxic effects in the mother either through non-specific mechanisms related to
  stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In
  the interpretation of the developmental outcome to decide classification for developmental effects it
  is important to consider the possible influence of maternal toxicity. This is a complex issue because
  of uncertainties surrounding the relationship between maternal toxicity and developmental outcome.
  Expert judgement and a weight of evidence approach, using all available studies, shall be used to
  determine the degree of influence that shall be attributed to maternal toxicity when interpreting the
  criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be
  first considered, and then maternal toxicity, along with any other factors which are likely to have
  influenced these effects, as weight of evidence, to help reach a conclusion about classification.
  3.7.2.4.2      Based on pragmatic observation, maternal toxicity may, depending on severity, influ-
  ence development via non-specific secondary mechanisms, producing effects such as depressed foe-
  tal weight, retarded ossification, and possibly resorptions and certain malformations in some strains
  of certain species. However, the limited number of studies which have investigated the relationship
  between developmental effects and general maternal toxicity have failed to demonstrate a consistent,
  reproducible relationship across species. Developmental effects which occur even in the presence of
  maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivo-
  cally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal
  toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the
  offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality, signifi-
  cant post-natal functional deficiencies.
8 Chloramphenicol
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<pre>3.7.2.4.3      Classification shall not automatically be discounted for substances that produce devel-
opmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated
mechanism has been demonstrated. In such a case, classification in Category 2 may be considered
more appropriate than Category 1. However, when a substance is so toxic that maternal death or
severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable
to assume that developmental toxicity is produced solely as a secondary consequence of maternal
toxicity and discount the developmental effects. Classification is not necessarily the outcome in the
case of minor developmental changes, when there is only a small reduction in foetal/pup body weight
or retardation of ossification when seen in association with maternal toxicity.
3.7.2.4.4      Some of the end points used to assess maternal effects are provided below. Data on
these end points, if available, need to be evaluated in light of their statistical or biological signifi-
cance and dose response relationship.
Maternal mortality:
an increased incidence of mortality among the treated dams over the controls shall be considered evi-
dence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the
systemic toxicity of the test material. Maternal mortality greater than 10 % is considered excessive
and the data for that dose level shall not normally be considered for further evaluation.
Mating index
(no. animals with seminal plugs or sperm/no. mated × 100) (*)
Fertility index
(no. animals with implants/no. of matings × 100)
Gestation length
(if allowed to deliver)
Body weight and body weight change:
Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight
shall be included in the evaluation of maternal toxicity whenever such data are available. The calcula-
() It is recognised that the Mating index and the Fertility index can also be affected by the male.
Regulation (EC) 1272/2008 of the European Community                                                       49
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<pre>  tion of an adjusted (corrected) mean maternal body weight change, which is the difference between
  the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the
  weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the
  body weight gain may not be useful indicators of maternal toxicity because of normal fluctuations in
  body weight during pregnancy.
  Food and water consumption (if relevant):
  The observation of a significant decrease in the average food or water consumption in treated dams
  compared to the control group is useful in evaluating maternal toxicity, particularly when the test
  material is administered in the diet or drinking water. Changes in food or water consumption need to
  be evaluated in conjunction with maternal body weights when determining if the effects noted are
  reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.
  Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):
  The observation of increased incidence of significant clinical signs of toxicity in treated dams relative
  to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the
  assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be
  reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity,
  loss of righting reflex, ataxia, or laboured breathing.
  Post-mortem data:
  Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity.
  This can include gross or microscopic pathological findings or organ weight data, including absolute
  organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by find-
  ings of adverse histopathological effects in the affected organ(s), the observation of a significant
  change in the average weight of suspected target organ(s) of treated dams, compared to those in the
  control group, may be considered evidence of maternal toxicity.
  3.7.2.5        Animal and experimental data
  3.7.2.5.1      A number of internationally accepted test methods are available; these include methods
  for developmental toxicity testing (e.g. OECD Test Guideline 414), and methods for one or two-gen-
  eration toxicity testing (e.g. OECD Test Guidelines 415, 416).
  3.7.2.5.2      Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/
  Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with
0 Chloramphenicol
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<pre>Reproduction/Development Toxicity Screening Test) can also be used to justify classification,
although it is recognised that the quality of this evidence is less reliable than that obtained through
full studies.
3.7.2.5.3      Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies,
which are judged likely to impair reproductive function and which occur in the absence of significant
generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the
gonads.
3.7.2.5.4      Evidence from in vitro assays, or non-mammalian tests, and from analogous substances
using structure-activity relationship (SAR), can contribute to the procedure for classification. In all
cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate
data shall not be used as a primary support for classification.
3.7.2.5.5      It is preferable that animal studies are conducted using appropriate routes of administra-
tion which relate to the potential route of human exposure. However, in practice, reproductive toxic-
ity studies are commonly conducted using the oral route, and such studies will normally be suitable
for evaluating the hazardous properties of the substance with respect to reproductive toxicity. How-
ever, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action
has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that
the hazardous property will not be expressed in humans then a substance which produces an adverse
effect on reproduction in experimental animals shall not be classified.
3.7.2.5.6      Studies involving routes of administration such as intravenous or intraperitoneal injec-
tion, which result in exposure of the reproductive organs to unrealistically high levels of the test sub-
stance, or elicit local damage to the reproductive organs, including irritation, must be interpreted with
extreme caution and on their own are not normally the basis for classification.
3.7.2.5.7      There is general agreement about the concept of a limit dose, above which the produc-
tion of an adverse effect is considered to be outside the criteria which lead to classification, but not
regarding the inclusion within the criteria of a specific dose as a limit dose. However, some guide-
lines for test methods, specify a limit dose, others qualify the limit dose with a statement that higher
doses may be necessary if anticipated human exposure is sufficiently high that an adequate margin of
exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a specific
limit dose may not be adequate for situations where humans are more sensitive than the animal
model.
3.7.2.5.8      In principle, adverse effects on reproduction seen only at very high dose levels in animal
studies (for example doses that induce prostration, severe inappetence, excessive mortality) would
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<pre>              not normally lead to classification, unless other information is available, e.g. toxicokinetics informa-
              tion indicating that humans may be more susceptible than animals, to suggest that classification is
              appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further guidance in this
              area.
              3.7.2.5.9      However, specification of the actual ‘limit dose’ will depend upon the test method that
              has been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose tox-
              icity studies by the oral route, an upper dose of 1 000 mg/kg has been recommended as a limit dose,
              unless expected human response indicates the need for a higher dose level.
              3.7.3          Classification criteria for mixtures
              3.7.3.1        Classification of mixtures when data are available for all ingredients or only for some
              ingredients of the mixture
              3.7.3.1.1      The mixture shall be classified as a reproductive toxicant when at least one ingredient
              has been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present
              at or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A, Cat-
              egory 1B and Category 2 respectively.
              3.7.3.1.2      The mixture shall be classified for effects on or via lactation when at least one ingredi-
              ent has been classified for effects on or via lactation and is present at or above the appropriate generic
              concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.
 able 3.7.2 Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or foreffects on or via
actation that trigger classification of the mixture.
 ngredient classified as:     Generic concentration limits triggering classification of a mixture as:
                              Category 1A                Category 1B               Category 2                Additional category
                              reproductive toxicant reproductive toxicant reproductive toxicant for effects on or via l
                                                                                                             actation
Category 1A                   ≥ 0,3 %
 eproductive toxicant         [Note 1]
  ategory 1B                                             ≥ 0,3 %
eproductive toxicant                                     [Note 1]
Category 2                                                                         ≥ 3,0 %
 eproductive toxicant                                                              [Note 1]
Additional category                                                                                          ≥ 0,3 %
or effects on or via                                                                                         [Note 1]
actation
  ote The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).
  ote 1 If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in
he mixture as an ingredient at a concentration above 0,1 %, a SDS shall be available for the mixture upon request.
  2           Chloramphenicol
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<pre>3.7.3.2        Classification of mixtures when data are available for the complete mixture
3.7.3.2.1      Classification of mixtures will be based on the available test data for the individual
ingredients of the mixture using concentration limits for the ingredients of the mixture. On a case-by-
case basis, test data on mixtures may be used for classification when demonstrating effects that have
not been established from the evaluation based on the individual components. In such cases, the test
results for the mixture as a whole must be shown to be conclusive taking into account dose and other
factors such as duration, observations, sensitivity and statistical analysis of reproduction test systems.
Adequate documentation supporting the classification shall be retained and made available for review
upon request.
3.7.3.3        Classification of mixtures when data are not available for the complete mixture:
               bridging principles
3.7.3.3.1      Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine
its reproductive toxicity, but there are sufficient data on the individual ingredients and similar tested
mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance
with the applicable bridging rules set out in section 1.1.3.
3.7.4          Hazard Communication
3.7.4.1        Label elements shall be used for substances or mixtures meeting the criteria for
               classification in this hazard class in accordance with Table 3.7.3
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<pre> able 3.7.3 Label elements for reproductive toxicity.
 lassification              Category 1A or Category 1B              Category 2                             Additional category
                                                                                                           for effects on or via
                                                                                                           lactation
GHS Pictograms                                                                                             No pictogram
 ignal Word                 Danger                                  Warning                                No signal word
Hazard Statement            H360: May damage fertility or the       H361: Suspected of damaging fertil- H362: May cause
                            unborn child (state specific effect if ity or the unborn child (state specific harm to breast-fed
                            known)(state route of exposure if it is effect if known) (state route of expo- children.
                            conclusively proven that no other       sure if it is conclusively proven that
                            routes of exposure cause the hazard) no other routes of exposure cause the
                                                                    hazard)
 recautionary Statement     P201                                    P201                                   P201
 revention                  P202                                    P202                                   P260
                            P281                                    P281                                   P263
                                                                                                           P264
                                                                                                           P270
 recautionary Statement     P308 + P313                             P308 + P313                            P308 + P313
 esponse
 recautionary Statement     P405                                    P405
 torage
 recautionary Statement     P501                                    P501
Disposal
 4            Chloramphenicol
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<pre>nnex E
     Additional considerations to
     Regulation (EC) 1272/2008
     The classification and labelling of substances is performed according to the
     guidelines of the European Union (Regulation (EC)1272/2008) presented in
     Annex B. The classification of compounds is ultimately dependent on an inte-
     grated assessment of the nature of all parental and developmental effects
     observed, their specificity and adversity, and the dosages at which the various
     effects occur. The guideline necessarily leaves room for interpretation, dependent
     on the specific data set under consideration. In the process of using the regula-
     tion, the Committee has agreed upon a number of additional considerations:
     • If there is sufficient evidence to establish a causal relationship between
         human exposure to the substance and impaired fertility or subsequent devel-
         opmental toxic effects in the offspring, the compound will be classified in
         category 1A, irrespective of the general toxic effects (see Annex B,
         3.7.2.2.1.).
     • Adverse effects in a reproductive study, reported without information on the
         parental or maternal toxicity, may lead to a classification other than category
         1B, when the effects occur at dose levels which cause severe toxicity in gen-
         eral toxicity studies.
     • Clear adverse reproductive effects will not be disregarded on the basis of
         reversibility per se.
     Additional considerations to Regulation (EC) 1272/2008                              55
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<pre>  •   The Committee does not only use guideline studies (studies performed
      according to OECD* standard protocols) for the classification of compounds,
      but non-guideline studies are taken into consideration as well.
  Organisation for Economic Cooperation and Development
6 Chloramphenicol
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<pre>  nnex       F
             Fertility and developmental toxicity
             studies
 able 1 Fertility studies in laboratory animals with chloramphenicol: oral administration.
 uthors        species         experimental period/design   dose           general         effects on reproductive organs/effects
                                                                           toxicity        on reproduction
Oyeyemi/       male Wistar     20, 25 d                     0, 25 mg/kg    not reported    decreases (p<0.05) in sperm motility,
Adeniji        rats                                         bw/d                           % viability, number of normal sperm,
2010)          (n=5/group)                                                                 sperm concentration
Oyagbemi et    male Wistar     4 times/d, 10 consecutive d; 0, 28 mg/kg    bw loss of 7% no effect on % of morphologically
 l. (2010)     rats            sacrifice 24 h after last    bw             vs. bw gain abnormal sperm; decreases (p<0.05)
               (n=6/group)     treatment                                   of 4% in        in sperm motility, number of normal
                                                                           controls        sperm, sperm concentration
 w=body weight; d=day(s); h=hour(s); ; n=number
 able 2 Fertility studies in laboratory animals with chloramphenicol: parental administration.
 uthors        species         experimental period/design   dose/          general         effects on reproductive organs/effects
                                                            route          toxicity        on reproduction
Nowkunski      white rats      20 d; then mating: treated   0, 34 mg/kg    not reported    male gonads, uterine mucosa not
1963)          (n=10 males; males with treated females, or bw; im                          affected; in ovaries, cystic
               20 females treated males with untreated                                     degeneration of Graafian follicles;
                               females, or untreated males                                 oestrus cycle affected in 6/15 treated
                               with treated females;                                       females; no pregnant females when
                               morphology of gonads of 15                                  treating both sexes or only females;
                               males and 15 females                                        when treating only males, 6/20 female
                                                                                           pregnant vs. 17/20 in controls
             Fertility and developmental toxicity studies                                                                      57
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<pre> eermann/      female          mice induced for               0, 18.8 (t=0 not reported relative ovarian weight and the
Hansmann       NMRI/Han        superovulation with pregnant only), 37.5                    number of ovulated oocytes reduced
1986)          mice            mare serum followed 48 h       mg/kg bw; ip                 at 37.5 (all time points); progesterone
               (n=8-18)        later by ip HGC; groups                                     concentration markedly reduced in all
                               received saline or                                          treated females; number of diploid
                               chloramphenicol at 0, 15 or                                 oocytes increased compared to
                               48 h after pregnant mare                                    control at 18.8 mg/kg bw and at 37.5
                               serum; sacrificed 15-16 h                                   mg/kg bw at 15 and 48 h.
                               after HCG
 pstein/       male Swiss single injection; males mated 0, 333, 666 not reported no effect on number of early foetal
 hafner        CD-1 mice with 3 untreated females             mg/kg bw; ip                 deaths and on pre-implantation losses
1968);         (n=7-9/         which were replaced weekly
 pstein et al. group)          for 8 consecutive wk; females
1972)                          sacrificed 13 d from mid-
                               week of their mating
 w=body weight; d=day(s); h=hour(s); HGC=human chorionic gonadotrophin; im=intramuscular; ip=intraperitoneal;
wk=week(s); n=number
 able 3 Developmental toxicity studies in laboratory animals with chlorampenicol: oral administration.
 uthors      species        experimental   dose              general      developmental toxicity
                            period/                          toxicity
                            design
 ritz/Hess Sprague-         sacrifice gd   gd 5-15: 0, 500   no toxic     500 mg/kg bw: reduced number of live foetuses
1971)        Dawley rats 21; skeletal      mg/kg bw/d        signs        (p<0.05); increased % of embryonic or foetal deaths
             (n=5-15;       development    gd 7-12: 0,                    (63% vs. 22.6%; p<0.05)
             controls:      only           1,000 mg/kg                    1,000 mg/kg bw: decreased average foetal weight
             n=553 over a examined in      bw/d                           (p<0.05); % embryonic or foetal deaths: 38.5% (vs.
             period of 4 y) foetuses at    gd 0-6: 1,500                  22.6%; p<0.05); 2 litters totally aborted
                            1,000 mg/kg    mg/kg bw/d                     1,500 mg/kg bw: no effects
                            bw/d and       gd 5, 6, 7, 8, 9,              2,000 mg/kg bw/d:
                            2,000 mg/kg    10, or gd                      gd 6-8, 7-9, 11-13: increased % of embryonic or foetal
                            bw/d on gd     6-8, 7-9, 9-11,                deaths (67-75%; p<0.05); decreased number of live
                            11-13          11-13, 13-15,                  foetuses/dam (p<0.05); decreased average foetal
                                           15-17: 0, 2,000                weights (p<0.05)
                                           mg/kg bw/d                     gd 9-11: % embryonic or foetal deaths: 100%; 3 litters
                                           in 2% CMC;                     totally aborted
                                           gavage                         gd 13-15: % embryonic or foetal deaths: 95.9%;
                                                                          decreased average foetal weights (p<0.05)
                                                                          gd 15-17: decreased average foetal weights (p<0.05)
                                                                          gd 5: no effects
                                                                          gd 6, 7: decreased average foetal weight (p<0.05)
                                                                          gd 8: % of embryonic or foetal deaths: 45.9%; p<0.05);
                                                                          decreased number of live foetuses/dam (p<0.05);
                                                                          decreased average foetal weights (p<0.05); 1 litter
                                                                          totally aborted
                                                                          gd 9: % of embryonic or foetal deaths: 43,9%; p<0.05);
                                                                          decreased average foetal weights; 2 litters totally
                                                                          aborted
                                                                          gd 10: % of embryonic or foetal deaths: 46.4%;
                                                                          p<0.05); decreased number of live fetuses/dam
                                                                          (p<0.05); decreased average foetal weights (p<0.05)
 8            Chloramphenicol
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<pre>                                                                   malformations:
                                                                   controls: 1 brachygnathia, 1 oxygcephaly+agnathia, 1
                                                                   brachymelia, 2 omphaloceles in 6,326 foetuses
                                                                   500 mg/kg bw: no malformations
                                                                   1,000 mg/kg bw: hypognatia in 1/83 foetuses
                                                                   1,500 mg/kg bw: harelip in 1/65
                                                                   2,000 mg/kg bw:
                                                                   gd 6-8: omphalocele (umbilical hernia) + unilateral/
                                                                   bilateral costal fusion in 8/22 foetuses (1 litter)
                                                                   gd 7-9: idem in 1/26
                                                                   gd 7: idem in 2/84 (1 litter)
                                                                   gd 8: idem in 5/46 (1 litter)
                                                                   gd 9: idem in 5/64 (3 litters)
                                                                   gd 10: no malformations
                                                                   skeletal effects:
                                                                   1,000 mg/kg bw: increased missing ossification of
                                                                   phalangeal nuclei of forelegs and hind legs and of 5th
                                                                   sternebra; decreased number of ossified cervical
                                                                   vertebrae; increased fusion sternebra 1+2 and bipartite
                                                                   vertebrae
                                                                   2,000 mg/kg bw, gd 11-13: increased missing
                                                                   ossification of phalangeal nuclei of forelegs and hind
                                                                   legs and of 5th sternebra
ritz/Hess CD-1 mice sacrifice gd      gd 5-15: 0, 500 bw effects 500 mg/kg bw: decreased average foetal weight
1971)     (n=7-19;       18; skeletal mg/kg bw/d        insuffi-   (p<0.05)
          controls:      development  gd 6-12: 0, 1,000 ciently    1,000 mg/kg bw: % embryonic or foetal deaths: 71.1%
          n=307 over a only           mg/kg bw/d        documented (vs. 24.4% in controls; p<0.05); decreased number of
          period of 4 y) examined in  gd 8-10: 0, 2,000            live fetuses/dam (p<0.05); decreased average foetal
                         foetuses at  mg/kg bw/d                   weight (p<0.05)
                         1,000 mg/kg  in 2% CMC;                   2,000 mg/kg bw:
                         bw/d         gavage                       gd 8-10: % embryonic or foetal deaths: 100%
                                                                   malformations:
                                                                   controls: 2 cranioschisis+exophthalmos, 1
                                                                   exencephaly, 1 median cleft palate in 3,230 foetuses
                                                                   1,000 mg/kg bw: cranioschisis+exophthalmos in 1/ 81
                                                                   foetuses
                                                                   skeletal effects:
                                                                   1,000 mg/kg bw: increased missing ossification of
                                                                   phalangeal nuclei of forelegs and hind legs and 5th
                                                                   sternebra; iincreased fusion sternebra 1+2
ritz/Hess mixed breed sacrifice gd    gd 6-15: 0, 500 no toxic     500 mg/kg bw: no effects
1971)     rabbit         28; skeletal mg/kg bw/d        signs      1,000 mg/kg bw:
          (n=5-8;        development  gd 6-9, 8-11: 0,             gd 6-9: % embryonic or foetal deaths: 24.6% (vs. 10%
          controls:      examined in  1,000 mg/kg bw/              in controls; p<0.05); decreased average foetal weight
          n=192 over a all foetuses   d in 2% CMC;                 (p<0.05)
          period of 4 y)              gavage                       gd 8-11: % embryonic or foetal deaths: 58.1% (vs. 10%
                                                                   in controls; p<0.05); decreased number of live fetuses/
                                                                   dam (p<0.05); decreased average foetal weight
                                                                   (p<0.05)
                                                                   malformations:
                                                                   no malformations observed
           Fertility and developmental toxicity studies                                                                 59
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<pre>                                                                      skeletal effects:
                                                                      500 mg/kd bw: increased missing ossification of
                                                                      phalangeal nuclei of forelegs
                                                                      1000 mg/kg bw:
                                                                      gd 6-9: increased missing ossification of phalangeal
                                                                      nuclei of forelegs and hind legs;
                                                                      gd 8-11: increased missing ossification of 5th sternebra
Al-      albino mice 5-7 doses      0, 25, 50, 100,      not reported conditioned avoidance response: statistically
Hachim/  (n=8/       during 3rd     200 mg/kg bw/d;                   significant decrease in response at all dose levels with a
Al-Baker group)      stage of       gavage                            dose-response relationship
1974)                pregnancy;                                       electroshock seizure threshold: non-significant
                     offspring: 10/                                   increase at 50-200 mg/kg bw/d with a dose-response
                     group tested                                     relationship
                     for                                              open-field performance: statistically significant
                     conditioned                                      decrease at all dose levels without a dose-response
                     avoidance                                        relationship;
                     response                                         no gross congenital abnormalities
                     (pnd 30-36),
                     electroshock
                     seizure
                     threshold
                     (pnd 38),
                     open-field
                     (pnd 42-48)
Mackler  Sprague-    gd 0-20;       0, 2, 3%; diet (i.e. decreased 200 mg/rat: % resorptions: 31.4% (controls: 4.7%); n
1975)    Dawley rats sacrifice      200, 300 mg/rat); food intake of live foetues: 117 (controls: 201); decreased foetal
         (n not      gd 20          additional group at both dose weight (p<0.001)
         specified)                 with restricted      levels       300 mg/rat: % resorptions: 57.0%; n live fetuses: 31;
                                    diet (67% of                      decreased foetal weight (p<0.001); decreased placental
                                    control)                          weight (p<0.001)
                                                                      [restricted diet group: % resorptions: 1.5%; n live
                                                                      foetuses: 64]
                                                                      developmental effects:
                                                                      200 mg/rat: oedema (12%)
                                                                      300 mg/rat: oedema (71%); wavy ribs (7%); fused ribs
                                                                      (7%)
                                                                      control diet: no effects
                                                                      [restricted diet: no effects]
                                                                      mitochondrial activities in homogenates of gd 14
                                                                      foetuses:
                                                                      200 mg/rat: decreased activities of DPNH oxidase
                                                                      (p<0.001), cytochrome c oxidase (p<0.001), ATPase
                                                                      (p<0.01); no effect on succinic oxidase and succinic
                                                                      indophenol dehydrogenase
                                                                      300 mg/rat: decreased activities of DPNH oxidase
                                                                      (p<0.001); no effect on succinic oxidase (cytochrome c
                                                                      oxidase, ATPase, and succinic indophenol
                                                                      dehydrogenase activities not measured)
 0        Chloramphenicol
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<pre>Mackler    Sprague-     sacrifice gd    1.5 % on gd 0-9, not reported increased number of females without implantations
1975)      Dawley rats 20               0-10, 0-11, 0-12,               when treated during gd 0-6 and onwards (18-67%);
           (n=3-11)                     3% on gd 0-2, 0-                increased number of resorptions when treated during
                                        3, 0-4, 0-5, 0-6,               gd 0-5 (8%) and gd 0-8, 0-9, 0-10, 0-11 (16-40%);
                                        0-7, 0-8; diet                  decreased foetal weights when treated during gd 0-7
                                        (i.e.150, 300                   and onwards
                                        mg/rat)
 MC=carboxymethyl cellulose; gd: gestational day(s); n=number; pnd=postnatal day(s); y=year(s)
 able 4 Developmental toxicity studies in laboratory animals with chlorampenicol: subcutaneous administration.
 uthors     species      experimental period/      dose/route    general      developmental toxicity
                         design                                  toxicity
Neumann     Wistar rats  gd 6-10 or 11-14;         0, 800-2500   not          controls (n=15): % resorptions: 7.6%; % dead
1976)                    sacrifice gd 21           mg/kg bw;     reported     foetuses: 0.6%; no retarded or malformed
                                                   as sodium                  foetuses
                                                   succinate                  gd 6-10 group (n=13): % resorptions: 9.6%; %
                                                                              dead foetuses: 1.9 %; % retarded fetuses: 87.9%;
                                                                              % malformed fetuses: 0.6% (clinodactily);
                                                                              reduced average foetal weight (2.4 g vs. 4.4 g)
                                                                              gd 11-14 group (n=43): % resorptions: 59.3%; %
                                                                              dead foetuses: 0.6 %; % retarded foetuses:
                                                                              19.4% (predominantly haemorrhages and
                                                                              oedemas); % malformed foetuses: 1.3% (n=6; all
                                                                              at 1500 mg/kg bw; 5 cleft palate, 1 cleft
                                                                              palate+limb anomalies; 5 in 1 litter); reduced
                                                                              average foetal weight (3.0 g vs. 4.4 g)
                                                                              (increased number of resorptions, reduced
                                                                              number of normal live foetuses are dose related)
 ertolini/  Wistar rats dams: gd 7-21              dams: 0, 50   course of dams: no effect on litter size, pup weight,
 oggioli    (n=15/       pups: pnd 1-3;            mg/kg bw/d; pregnancy postnatal weight gain; no gross malformations in
1981)       group)       intrauterine exposed pups: 0, 50        not affected offspring; no mortality in all groups;
                         pups and pups             100 mg/kg                  pups: statistically significantly decreased
                         exposed on pnd 1-3        bw/d; as                   conditioned avoidance response in all treated
                         (n=10/group/ sex)         hemisuccinate              groups (more marked in males than in females
                         trained for                                          and in intrauterine treated than in postnatally
                         conditioned avoidance                                treated pups); no difference in pain threshold; no
                         response at pnd 60;                                  mortality
                         response tests at pnd
                         65, 70, 75, 80; pain
                         threshold also tested
 w=body weight; gd=gestational day(s); n=number; pnd=postnatal day(s)
            Fertility and developmental toxicity studies                                                                      61
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<pre>2 Chloramphenicol</pre>

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<br><br>