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EC number: 203-005-8 | CAS number: 102-09-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- sub-chronic toxicity: oral
- Remarks:
- one-generation study
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 416
- Principles of method if other than guideline:
- One-generation study following OECD TG 416 (2001) without treatment of F1 weanlings after developmental milestones had occurred (balano-preputial separation or vaginal opening at an age of about 8 weeks). The conduct of this study includes also recommendations of OECD TG 415 (adopted 1983) and OECD TG 407 (open field observation and Functional Observation Battery)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Age: about 6 weeks
- Weight at study initiation: males: 111-151 g; females: 96-132 g - Route of administration:
- oral: feed
- Vehicle:
- other: oral feeding in a diet containing 1% peanut oil
- Details on oral exposure:
- oral feeding in a diet containing 1% peanut oil
diets were prepared weekly - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The determination of the assay of diphenyl carbonate in the feed samples was done after extraction by gas chromatography under GLP. Formulations with 1500, 5000, and 15000 ppm diphenyl carbonate in the diet were found to be within their target values. Homogeneity requirements were met.
- Duration of treatment / exposure:
- about 18 weeks
Animals were exposed during the premating period of about 11 weeks, and during the mating period of up to 3 weeks. Males were sacrificed after the mating period. Females were further exposed during pregnancy and lactation, and were sacrificed when F1 offspring was weaned (after 4 weeks). At the same time most F1 animals were sacrificed, except for one F1 male and one F1 female per litter, which were sacrificed after a further treatment period of about 4 weeks, when developmental milestones had occurred (balano-preputial separation or vaginal opening). - Frequency of treatment:
- continuous
- Dose / conc.:
- 1 500 ppm
- Remarks:
- (nominal in diet)
- Dose / conc.:
- 5 000 ppm
- Remarks:
- (nominal in diet)
- Dose / conc.:
- 15 000 ppm
- Remarks:
- (nominal in diet)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Post-exposure period: no
Rationale for dose selection: based on a subchronic feeding pilot study (Eiben, 2002) Diphenylcarbonate (DPC) Subchronic study in Wistar rats (Pilot study for a one-generation study with administration in the diet), Report No. AT00045, Oct 22, 2002)
ACTUAL DOSE (mean) RECEIVED BY DOSE LEVEL BY SEX:
- low dose: 132 (m) or 219 (f) mg/kg bw/day; mid dose: 427 (m) or 710 (f) mg/kg bw/day; high dose: 1561 (m) or 2432 (f) mg/kg bw/day - Positive control:
- none
- Observations and examinations performed and frequency:
- CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: at least weekly
- Mortality: twice daily
- Body weight: weekly
- Food consumption: weekly
- Water consumption: not determined
- Ophthalmoscopic examination: not determined
- Haematology: not determined
- Biochemistry: not determined
- Urinalysis: not determined - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY:
- gross pathology: adrenals, liver, kidney, spleen, pituitary, vagina, uterus/cervix, ovaries, oviducts, seminal vesicles with coagulation glands, prostate, brain, trachea, larynx and esophagus, mammary glands with skin, epididymides, thyroids/parathyroids, urethra with preputium, coagulating glands
- organ weights: brain, pituitary gland (fixed), liver, kidneys, adrenals, spleen, thyroid (one fixed organ), uterus, seminal vesicles with coagulation glands, prostate, epididymis (only left organ), testes and ovaries
- Histopathology F0 (control and 15000 ppm group): adrenals, liver, kidney spleen, pituitary, vagina, uterus/cervix, ovaries, oviducts, seminal vesicles with coagulation glands, prostate, brain, mammary glands with skin, testes, epididymides, thyroids/parathyroids,
- Histopathology F1 weanlings: ovaries - Other examinations:
- - spermatology: yes (control and 15000 ppm group) spermatozoa motility and viability, spermatozoa morphology, quantitative determination of spermatozoa in epididymis, quantitative determination of homogenization resistant spermatid heads in the testis)
- functional observation battery (neurotoxicity screening: sensory reactivity to stimuli of different types): yes
- developmental milestones and investigations in post weaned F1 rats: yes - Statistics:
- Dunnett-Test with variance analysis for body and organ weights; Kruskal-Wallis-Test with a Steel-Test for food consumption data
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No effects were observed that were test material related.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- F0 males of 15000 ppm group showed significantly lower (about -7%) body weights compared to controls nearly throughout the total study; 15000 ppm females exhibited sporadically significantly lower body weights, which reached -8% during lactation.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No effects were observed that were test material related.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- no indication of neurotoxic potential
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- significantly increased relative liver weights in 5000 and 15000 ppm males (+10.1, +13.5%) and 15000 ppm females (+12%); significantly increased absolute (+11.5, +13.5, +17.3%) and relative (+9.5%, +14.3%, +19%) adrenal weights in females; significantly increased ovarian weights (absolute: +22.8%, +16.3%; relative: +27.1%, +22.9%) from 5000 ppm onwards.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- no significant findings
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- no indication of neurotoxic potential
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- LIVER: Hepatocellular hypertrophy was found in males of the mid and high dose group (0, 0, 4, 6) and in females of the high dose group (0, 0, 0, 2) in low frequency and severity score. The incidence of Kupffer cell foci was slightly increased in females of the high dose group (6, 5, 5, 10).
ADRENAL GLANDS: In mid and high dosed males the frequency of mixed-size vacuolation of zona fasciculata and partly also glomerulosa cells was slightly and the severity moderately increased (incidence: 18, 21, 25, 25; grade 2: 5, 6, 13, 9; grade 3: 0, 0, 5, 15). In females microvesicular vacuolation (0, 17, 23, 24) and hypertrophy (0, 17, 23, 25) of the zona fasciculata cells were found in high incidences in all dose groups. The severity score increased dose-dependently.
OVARIES: The number of corpora lutea (severity score grade 2) increased slightly from 1500 ppm onwards (8, 12, 17, 16). The total number of corpora lutea per group was also slightly elevated (365, 391, 443, 428). At 1500 ppm and above, large corpora lutea exhibited an infiltration of predominantly mononuclear cells (0, 21, 24, 21). In addition, many of these corpora lutea contained granulated luteal cells (0, 20, 18, 9). Hypertrophic ovarian interstitial cells increased (0, 16, 24, 24) with severity score increasing in a dose dependent manner. - Histopathological findings: neoplastic:
- not examined
- Dose descriptor:
- NOAEL
- Remarks:
- parental males
- Effect level:
- 1 500 ppm
- Sex:
- male
- Basis for effect level:
- other: corresponding to about 132 mg/kg bw/day
- Dose descriptor:
- LOAEL
- Remarks:
- parental males
- Effect level:
- 5 000 ppm
- Sex:
- male
- Basis for effect level:
- other: corresponding to about 427 mg/kg bw/day based on increased relative liver weights with hepatocellular hypertrophy
- Dose descriptor:
- LOAEL
- Remarks:
- parental females
- Effect level:
- 1 500 ppm
- Sex:
- female
- Basis for effect level:
- other: corresponding to about 219 mg/kg bw/day based on increased relative and absolute adrenal weights with histopathological changes in the zona fasciculata, and morphological changes in the ovaries
- Critical effects observed:
- not specified
- Conclusions:
- The NOAEL in males was 1500 ppm (about 132 mg/kg bw/day). In females a NOAEL could not be determined; the LOAEL was 1500 ppm (about 219 mg/kg bw/day), based on increased relative and absolute adrenal weights with histopathological changes in the zona fasciculata, and morphological changes in the ovaries.
- Executive summary:
The repeated dose toxicity of the test material was investigated in a GLP study which was conducted in accordance with the standardised guideline OECD 416 without treatment of F1 weanlings after developmental milestones had occurred. The conduct of this study also includes recommendations of the standardised guidelines OECD 415 and OECD 407 (open field observation and Functional Observation Battery).
During the study male and female Wistar rats were dosed with the test material at 1500, 5000, and 1 5000 ppm, administrated in feed containing 1 % peanut oil. Animals were exposed during the premating period (about 11 weeks) and during the mating period (up to 3 weeks). Males were sacrificed after the mating period. Females were further exposed during pregnancy and lactation, and were sacrificed when F1 offspring was weaned (after 4 weeks).
Repeated oral dosing led to changes in weight and histopathology of the liver and adrenals in males at a dietary concentration of 5000 ppm (about 427 mg/kg bw/day), and in females of 1500 ppm (about 219 mg/kg bw/day). At 1500 ppm, females also exhibited morphological changes in the ovaries.
Under the conditions of this study, the NOAEL in males was 1500 ppm (about 132 mg/kg bw/day). In females a NOAEL could not be determined; the LOAEL was 1500 ppm (about 219 mg/kg bw/day), based on increased relative and absolute adrenal weights with histopathological changes in the zona fasciculata, and morphological changes in the ovaries.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Principles of method if other than guideline:
- One-generation study following OECD TG 416 (2001) without treatment of F1 weanlings after developmental milestones had occurred (balano-preputial separation or vaginal opening at an age of about 8 weeks). The conduct of this study includes also recommendations of OECD TG 415 (adopted 1983) and 407 (only open field observations and Functional Observation Battery)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Diphenyl carbonate
- EC Number:
- 203-005-8
- EC Name:
- Diphenyl carbonate
- Cas Number:
- 102-09-0
- Molecular formula:
- C13H10O3
- IUPAC Name:
- diphenyl carbonate
- Details on test material:
- purity 99.98 %
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- -number of animals F0: 25/sex/group
- number of viable pups F1: 196-244/group
- Age: about 6 w
- Weight at study initiation: males: 111-151 g; females: 96-132 g
Administration / exposure
- Route of administration:
- oral: feed
- Details on exposure:
- oral feeding in a diet containing 1 % peanut oil
diets were prepared twice weekly - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: up to 21 days
- Proof of pregnancy: sperm in vaginal smear - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The determination of diphenyl carbonate in the feed samples was done after extraction by gas chromatography. Content, homogeneity and stability of diphenyl carbonate in food was confirmed under GLP.
- Duration of treatment / exposure:
- Exposure period: about 18 weeks (see test conditions)
Premating exposure period (males): 11 weeks
Premating exposure period (females): 11 weeks - Frequency of treatment:
- continuous
- Details on study schedule:
- Animals were exposed during the premating period of about 11 weeks, and during the mating period of up to 3 weeks. Males were sacrificed after the mating period. Females were further exposed during pregnancy and lactation, and were sacrificed when F1 offspring was weaned (after 4 weeks). At the same time most F1 animals were sacrificed, except of one F1 male and one F1 female per litter, which were sacrificed after a further treatment period of about 4 weeks, when developmental milestones had occurred (balano-preputial separation or vaginal opening).
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 500 ppm
- Remarks:
- (nominal in diet)
- Dose / conc.:
- 5 000 ppm
- Remarks:
- (nominal in diet)
- Dose / conc.:
- 15 000 ppm
- Remarks:
- (nominal in diet)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Rationale for dose selection:
based on a subchronic feeding pilot study (Eiben, 2002. Diphenylcarbonate (DPC) Subchronic study in Wistar rats (Pilot study for a one-generation study with administration in the diet). Report No. AT00045. Oct 22, 2002) See also chapter 7.5.1 (repeated dose toxicity: oral).
ACTUAL DOSE (mean) RECEIVED BY DOSE LEVEL BY SEX:
- low dose: 132 (m) or 219 (f) mg/kg bw/day
- mid dose: 427 (m) or 710 (f) mg/kg bw/day
- high dose: 1561 (m) or 2432 (f) mg/kg bw/day - Positive control:
- none
Examinations
- Parental animals: Observations and examinations:
- CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: at least weekly
- Mortality: twice daily
- Body weight: weekly
- Food consumption: weekly
- Water consumption: no data
- Ophthalmoscopic examination: no data
- Haematology: no data
- Biochemistry: no data
- Urinalysis: no data
- functional observation battery : yes - Oestrous cyclicity (parental animals):
- yes
- Sperm parameters (parental animals):
- yes (control and 15000 ppm group) spermatozoa motility and viability, spermatozoa morphology, quantitative determination of spermatozoa in epididymis, quantitative determination of homogenization resistant spermatid heads in the testis
- Litter observations:
- - determination of offspring toxicity according to OECD TG 416
- Postmortem examinations (parental animals):
- - gross pathology F0: organs as given in OECD TG 416
- organ weights F0: as given in OECD TG 416
- Histopathology F0 (control and 15000 ppm group): adrenals, liver, kidney spleen, pituitary, vagina, uterus/cervix, ovaries, oviducts, seminal vesicles with coagulation glands, prostate, brain, mammary glands with skin, testes, epididymides, thyroids/parathyroids - Postmortem examinations (offspring):
- - gross pathology F1: organs as given in OECD TG 416
- organ weights F1: brain, spleen, thymus, testes, epididymides, uterus were determined for the first male and female living F1 weanling of each litter
- Histopathology F1 weanlings: ovaries - Statistics:
- Dunnet-Test with variance analysis for body and organ weights; Kruskal-Wallis-Test with a Steel-Test for food consumption data
- Reproductive indices:
- - Reproduction parameters: estrus cycle staging, insemination rate, duration of pregnancy, data on pups
- Offspring viability indices:
- - determination of offspring toxicity according to OECD TG 416
- developmental milestones and investigations in post weaned F1 rats: age and body weight at which balano-preputial separation and vaginal opening occurred
- Functional Observation Battery: yes
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Slightly reduced mean body weights (up to 8%) became obvious in high dosed animals
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No treatment-related effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- no indication of neurotoxic potential
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- no indication of neurotoxic potential
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- OVARIES: Number of corpora lutea slightly elevated in all dose groups; large corpora lutea exhibited an infiltration of predominantly mononuclear cells and contained granulated luteal cells. Number of hypertrophic ovarian interstitial cells increased with severity score increasing in a dose dependent manner.
LIVER: Hepatocellular hypertrophy was found in low frequency and severity score predominantly in males. ADRENAL GLANDS: In mid and high dosed males the frequency of mixed-size vacuolation of Zona fasciculata and partly also glomerulosa cells was slightly and the severity moderately increased. In females microvesicular vacuolation and hypertrophy of Zona fasciculata cells were found in high incidences in all dose groups. The severity score increased dose-dependently. - Histopathological findings: neoplastic:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- No significant findings were noted
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects
Details on results (P0)
- fertility index (91.7%, 100%, 91.7%, 100%)
- gestation index (95.5%, 100%, 100%, 100%)
- duration of gestation (21.9, 22.29, 22.70, 22.33 days)
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- parental toxicity
- Effect level:
- 1 500 ppm
- Sex:
- male
- Basis for effect level:
- other: about 132 mg/kg bw/day
- Dose descriptor:
- LOAEL
- Remarks:
- parental toxicity
- Effect level:
- 1 500 ppm
- Sex:
- female
- Basis for effect level:
- other: about 219 mg/kg bw/day based on increased relative and absolute adrenal weights with histopathological changes in the zona fasciculata, and morphological changes in the ovaries
- Dose descriptor:
- NOAEL
- Remarks:
- fertility
- Effect level:
- 15 000 ppm
- Sex:
- male
- Basis for effect level:
- other: about 1561 mg/kg bw/day
- Dose descriptor:
- NOAEL
- Remarks:
- fertility
- Effect level:
- 15 000 ppm
- Sex:
- female
- Basis for effect level:
- other: about 2432 mg/kg bw/day
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- body weights at weaning: in 15000 ppm pups reduced by 11-12% (this is most likely directly induced by compound consumption rather than a reprotoxic effect)
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- organ weights at weaning: at 15000 ppm reduced absolute spleen weights in both sexes (ca. -20%; relative weights not affected) and reduced absolute (-29%) and relative (-16%) thymus weights in females
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment related effects
- Histopathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- histopathology F1 at weaning: at 1500 ppm and above in ovaries large corpora lutea exhibited an infiltration of predominantly mononuclear cells (1/5/9/11); many of corpora lutea contained granulated luteal cells (0/2/7/8); hypertrophy of ovarian interstitial cells (0/4/10/23) with severity score increasing in a dose dependent manner
- Description (incidence and severity):
- OFFSPRING TOXICITY F1:
- total number of pups (228, 249, 204, 220)
- mean litter size (10.71, 9.72, 8.73, 9.91)
- sex ratio (% males: 49.31, 53.41, 45.66, 52.67)
- live birth index (98.74%, 97.47%, 93.12%, 99.04%)
- mean pup weight in g (m: 5.71, 5.97, 5.94, 5.79; f: 5.48, 5.57, 5.65, 5.39)
- viability index day 4 (98.68%, 86.67%, 85.51%, 94.17%)
Details on results (F1)
- developmental milestones in F1 weanlings: no treatment effect on sexual maturation
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- toxicity
- Generation:
- F1
- Effect level:
- 5 000 ppm
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Dose descriptor:
- LOAEL
- Remarks:
- toxicity
- Generation:
- F1
- Effect level:
- 1 500 ppm
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Reproduction parameters and fertility were not affected up to the highest administered dose. The NOAEL for fertility can therefore be considered as 15000 ppm or 1551 mg/kg bw for males and 2432 mg/kg bw for females.
- Executive summary:
The reproductive toxicity of diphenyl carbonate was investigated in a one-generation study in rats, following the two-generation study protocol of OECD 416 (2001) without treatment of F1 weanlings after developmental milestones (balano-preputial separation or vaginal opening at an age of about 8 weeks) had occurred. The conduct of this study included also recommendations of OECD 415 (adopted 1983) and OECD 407 (open field observations and Functional Observation Battery).
Durng the study diphenyl carbonate was administered via the diet to 25 male and 25 female Wistar rats per group in doses of 1500, 5000, or 15 000 ppm. The rationale for dose selection was based on a sub chronic feeding pilot study. The calculated actual doses for parental animals were 132, 427, and 1561 mg/kg bw/day for males and 219, 710, and 2432 mg/kg bw/day for females.
The animals were dosed for a period of 11 weeks prior to mating, then for a period of up to three weeks during mating. Males were sacrificed after the mating period, females were further treated during pregnancy and weaning and were sacrificed together with F1 animals when 28 day-old F1 offspring was weaned.
One F1 male and one F1 female per litter were necropsied after a further treatment period of about 4 weeks, when sexual maturity was reached.
Mortality and clinical appearance of F0 and F1 animals were unchanged throughout all dose groups. Slightly reduced mean body weights (up to 8 %) became obvious in the high dose parental animals. F1 animals of the high dose group gained less body weight. This effect became significant at weaning when pups increasingly ingested diphenyl carbonate via their own food and can therefore be regarded as a primary effect.
Organ weight determination and histopathology revealed diphenyl carbonate dependent changes in the liver, adrenals and ovaries of F0 animals. Changes in ovarian morphology was also observed in treated F1 females in a dose dependent manner throughout all doses, showing a similar appearance to that observed in F0 females. Observations on spermatology parameters, performed on control and high dose males with regard to spermatozoa motility, viability and morphology, quantitative determination of spermatozoa in epididymis, and quantitative determination of homogenisation resistant spermatid heads in the testis, were not adversely affected by treatment.
Reproduction parameters such as insemination index, mating performance, fertility index, gestation index, duration of pregnancy, live birth index, birth weights, prenatal loss and percentages of pups born, litter size, viability and lactation index were not affected by diphenyl carbonate. Iin post weaned F1 animals (1 male and 1 female per litter; sacrificed at an age of 8 weeks) sexual maturation was not affected. The histopathological changes observed in F0 and F1 ovaries and F0 adrenals therefore did not influence reproductive performance.
The NOAEL for fertility in rats was determined to be 15 000 ppm diphenyl carbonate in the diet, equating to about 1561 mg/kg bw/day for males and 2432 mg/kg bw/day for females. For F1 males the NOAEL for general toxicity was 5000 ppm, with a LOAEL at 15 000 ppm based on reduced body weight gain. A NOAEL for F1 females could not be determined as changes in the ovaries were seen down to the lowest tested dose (1500 ppm). The NOAEL for general toxicity in parental males was 1500 ppm (about 132 mg/kg bw/day), with the LOAEL at 5000 ppm (about 427 mg/kg bw/day) based on increased relative liver weights with hepatocellular hypertrophy, and histopathological changes in adrenals. For parental females a NOAEL for general toxicity could not be determined in this study because of histopathological changes in adrenals and ovaries in all dose groups.
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