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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
multi-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to a U.S. National toxicology Program (NTP) study protocol with GLP compliance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
According to Fertility Assessment by Continuous Breeding in the mouse developed by the U.S. National Toxicology Program (NIEHS).
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
As per IUCLID5 Sections 1.1. - 1.4. for Bisphenol A.

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
COBS® CD-l®, (ICR)BR outbred albino mice supplied by the Charles River Breeding Laboratories, Inc. (Kingston, NY). were used for the study. The males and females were 6 weeks of age at the time of arrival at the laboratory. Males and females were group housed (ten per cage by sex) in solid bottom polypropylene or polycarbonate cages (6" x 19" x 10 1/2") with stainless steel wire lids. Deionized/filtered water and NIH-07 open formula ground rodent chow was available to the animals ad libitum. Temperature was maintained at 70 +/- 2 degrees F in the animal room. Air in each animal room was 12 to 14 times per hour.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Dose-feed ad libitium.
Details on mating procedure:
Females and males from the same treatment group were paired and cohabited for 98 days (14 weeks), one breeding pair per cage (40 breeding pairs per vehicle control group and 20 breeding pairs per dose group). Thereafter each male and female will be housed individually for a period of 21 days.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Following methanol extraction of the feed samples and dilution with methanol the Bisphenol A content was measured by gas chromatography with the following conditions: Instrument: Varian 3700 Gas Chromatograph wich AutoSampler and Varian CDS 111-C integrator; Column - 3% OV-17 on 100/120 mesh Supelcoport, 1.3 m x 2 rom ID, glass, silanized; Detection - Flame ionization; Temperature -: Inlet, 250°C,Oven, 210°C, Detector, 300°C; Carrier Gas - Nitrogen; Flow Rate - 35 cc/min. Volume of Solution Injected ~ed: 4.5 uL; Retention Times - Bisphenol A - 8.0 min. Triphenylmethane (Internal Standard) - 4.0 min. Validation was by Bisphenol a spiked feed samples. Actual concentrations ranged from 93% to 113% of nominal.
Duration of treatment / exposure:
Continuous
Frequency of treatment:
Daily in the feed.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.25, 0.5 and 1.0% or approximately 0, 437.5, 875 and 1759 mg/kg/day.
Basis:
nominal in diet
Concentration range was 93% to 113% based on analysis.
No. of animals per sex per dose:
40 for untreated diet, 20 animals per Bisphenol a dose.
Control animals:
yes, plain diet
Positive control:
no

Examinations

Parental animals: Observations and examinations:
Clinical signs and body weights
Oestrous cyclicity (parental animals):
Yes
Sperm parameters (parental animals):
Yes
Litter observations:
Yes
Postmortem examinations (parental animals):
Selected organ weights and histopathology.
Postmortem examinations (offspring):
Selected organ weights and histopathology.
Statistics:
Yes
Reproductive indices:
Yes
Offspring viability indices:
Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
High dose (1.0%) females only.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
High dose (1.0%) females only.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Liver and kidney males and females, high dose only.
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
Mean seminal vesicle and sperm motility were significantly reduced at 1.05 in the feed.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
At 1.0% Bisphenol A in the diet there was a significant reduction in: number of litters produced/pair, number of live pups/litter and proportion of pups born alive.

Details on results (P0)

For the F0 parental animals there was a significant 10% relative reduction in the mean number of litters produced at the high dose level of 1.0% Bisphenol A in the diet (~ 1750 mg.kg/day). There was s significant reduction in mean live pups/litter of approximately 48% at the high doe level. In a cross-over mating study conducted at 1.0% Bisphenol A in the diet there was a significant reduction in the number of live pups/litter born to the treated males X control females. In addition, the the number of live pups/litter born to control males X treated females was significantly reduce relative to the control males X contol females and treated males X control females. Seminal vesicle weight and sperm motility were significantly reduced at the high dose level. Mean liver and kidney weights were significantly increased in the male and fmale animals at the high dose level. At 1.0% in the feed treatment-related histopethological lesions were observed in the liver and kidneys of both the male and female animals. The hepatic lesions were centrilobular hepatocyte hypertrophy and multifocal necrosis.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
0.25 other: 0.25% wt/wt or approximately 437.5 mg/kg/day.
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the observation of adverse target organ findings including histopathology and reproductive parameters in adult (F0) and F1 generation mice at o.5% and 1.0% in the feed.

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Significant at the high dose of 1.0%.
Body weight and weight changes:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Significant at the high dose.
Gross pathological findings:
not examined
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
High dose liver and kidney.

Details on results (F1)

Mortality was significant among F1 pups reaching 37.5% at the high dose of Bisphenol A of 1.0% in the diet (~1750 mg/kg/day). The mean liver and kidney weights were significantly increased in F1 pups at 1.0% while mean seminal vesicle weight was significantly reduced. High dose mean liver and kidney weights were significantly increased in the F1 females. These increases of organ weights were accompanied by histopathological findings in the liver and kidney tissues.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The No-Observed-Adverse-Effect-Level (NOAEL) for systemic effects in both the parental (F0) and F1 generations was 0.5% Bisphenol A in the diet (~875 mg/kg/day). The NOAEL for adverse reproductive findings was 0.25% in the diet (~ 437.5 mg/kg/day). Significant evidence of reproductive toxicity included: Significantly reduced group mean litters produced /breeding pair, number of live pups/litter, seminal vesicle weight, sperm motility and F1 pup survival at the two hghest does levels of Bisphenol A. The results of cross-over mating studies at 1.0% Bispheniol A suggested that the testr substance had a greater adveres impact on the female reproductive system. These findings for Bisphenol A suggest that 2-Acetone polymer with phenol (BPA-Tars) will also be a rodent reproductive toxicant under similar experimental and exposure conditons.
Executive summary:

Bisphenol A, a structural analog for 2 -Acetone polymer with phenol (BPA-Tars) was assessed for adverse effects on reproduction in a U.S. National Toxicology Program "Fertility Assessment by Continuous Breeding" study protocol conducted in mice by dietary exposure. The study was conducted under the GLP regulations at dietary dose levels of: 0, 0.25%, 0.5% and 1.0% or approximately, 0, 437.5, 875, and 1750 mg/kg/day respectively. The No-Observed-Adverse-Effect-Level (NOAEL) for systemic effects in both the parental (F0) and F1 generations was 0.5% Bisphenol A in the diet (~875 mg/kg/day). The NOAEL for adverse reproductive findings was 0.25% in the diet (~ 437.5 mg/kg/day). Significant evidence of reproductive toxicity included: Significantly reduced group mean litters produced /breeding pair, number of live pups/litter, seminal vesicle weight, sperm motility and F1 pup survival at the two hghest does levels of Bisphenol A. The results of cross-over mating studies at 1.0% Bispheniol A suggested that the test substance had a greater adveres impact on the female reproductive system. These findings for Bisphenol A suggest that BPA-Tars will also be a rodent reproductive toxicant under similar experimental and exposure conditons.