Registration Dossier

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

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:
2003
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

Constituent 1
Chemical structure
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 %

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)

PARAMETERS OF REPRODUCTION IN F0: 
- 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)

- malformations: none
- 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.