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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted in a manner similar to O.E.C.D. Test Guideline No. 414 with GLP compliance.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1987

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4'-isopropylidenediphenol
EC Number:
201-245-8
EC Name:
4,4'-isopropylidenediphenol
Cas Number:
80-05-7
Molecular formula:
C15H16O2
IUPAC Name:
2,2-bis(4-hydroxyphenyl)propane
Constituent 2
Reference substance name:
4,4’-isopropylidenediphenol
IUPAC Name:
4,4’-isopropylidenediphenol
Constituent 3
Reference substance name:
Phenol, 4,4’-(1-methylethylidene)bis-
IUPAC Name:
Phenol, 4,4’-(1-methylethylidene)bis-
Constituent 4
Reference substance name:
Bisphenol A
IUPAC Name:
Bisphenol A
Details on test material:
As per IUCLID5 Sections 1.1. -1.4. for Bisphenol A.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
CD rats [(COBS) CrI:CD (SD)BR] from charles River were housed on Ab-Sorb-Dri cage litter in solid-bottom polypropylene or polycarbonate cages with stainless-steel wire lids and molded filter tops. Feed and deionized/filtered water were available ad libitum throughout the study. Animal rooms were equipped with automatic light cycles (lights on 7:00 AM to 7:00 PM). Temperature and relative humidity were maintained at 21-23"C and approximately 40%, respectively. Air in each animal room was exchanged 12 to 14 times per hour.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Pregnant animals were dosed by gavage with BPA solutions or corn oil (vehicle) on gestation days (GD) 6 through 15. The volume administered (5.0 ml/kg was based on body weight recorded on each day of the dosing period.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration analysis was conducted by a combination of thin-layer and HPLC, and infared, uv/visible and NMR spectroscopy. For details see George, et. al. 1985 U.S. NTP Final study reports.
Details on mating procedure:
A female rat in estrus or proestrus was placed overnight in the home cage of a singly housed male. On the following morning, vaginal
smears were examined for the presence of sperm.
Duration of treatment / exposure:
From GD 6 to GD 15.
Frequency of treatment:
Daily
Duration of test:
GD 20
No. of animals per sex per dose:
Minimun of 20
Control animals:
yes, concurrent vehicle
Details on study design:
Pregnant animals were assigned to dose groups by the method of stratified randomization so that body weight on GD 0 was not significantly different across dose groups. Rats were weighed on GD 0, 6 through 15. Dams were observed daily during treatment for clinical signs of toxicity. On GD 20, all mated rats were anesthetized with carbon dioxide and sacrificed by cervical dislocation.

Examinations

Maternal examinations:
Maternal liver weight, gravid uterine weight, and number of corpora lutea were recorded. The uteri of dams with no apparent implantations were treated with a solution of 10% ammonium sulfide in order to visualize possible implantation sites. Uterine contents (i.e., number of implantation sites, resorptions, dead fetuses, and live fetuses) were evaluated.
Ovaries and uterine content:
Uterine contents (i.e., number of implantation sites, resorptions, dead fetuses, and live fetuses) were evaluated, and live fetuses were dissected from the uterus and anesthetized by placing on ice.
Fetal examinations:
Each live fetus was weighed and examined for external morphological abnormalities, and the viscera were examined by a fresh tissue technique (Staples, 1974). Half of the fetuses were decapitated prior to dissection and the heads were fixed in Bouin's solution for free-hand sectioning and examination (Wilson, 1965). All fetal carcasses were prepared with Alizarin Red S stain and examined for skeletal malformations, as modified from Peltzer and Schardein (1966) and Crary (1962).
Statistics:
Analyses of data were carried out by the General Linear Model (GLM) procedure in the SAS software library (SAS Institute). Dose-response relationships for selected measures were evaluated with a test for linear trend. Analysis of variance (ANOVA) was used to deterine whether significant dose effects had occurred. When ANOVA revealed significant differences among groups, then Williams' multiple comparison test (Williams, 1971,
1972) and Dunnett's test (Dunnett, 1955, 1964) were used to compare BPA-treated groups with the vehicle control group (a level = 0.05). A one-tailed test was used for all parameters except measures of maternal body and organ weight, fetal body weight, and percentage males per litter for which a two-tailed test was used.
Indices:
For all litters the no. of implantation sites/litter, % resorptions/litter and % litters with resorptions were calculated. For live litters the following the indicies were presented: No. live fetuses/litter, % males/litter, Average fetal body weight/litter, % fetuses with malformations/litter and % litters with malformed fetuses.
Historical control data:
Not presented.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Dose-related significant reduction of gruop mean body weight gain at all dose levels. High dose (640 mg/kg/day) mean body weight was reduced approximately 14% by GD 20. During the treatment period (GD 6-15) the high dose mean body weight was reduced approximately 54% relative to the control value at GD 15. At the low dose of 160 mg/kg/day the mean body weight was reduced approximately 35% relative to the untreated control group.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEL
Effect level:
ca. 160 mg/kg diet
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 640 mg/kg diet
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: upto the high dose level of 640 mg.kg/day.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 640 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Treatment of rat dams with upto a maternally toxic dose level of bisphenol A of 640 mg/kg/day did not induce any evidence of developmental toxicity. This dose level of Bisphenol A resulted in a significant 14% reduction in maternal body weight during the 20 day gestation period. These findings suggest that 2-Acetone polymer with phenol (BPA-Tars) will not be a developmental toxicant to rats due to its structural similarity to the test substance, Bisphenol A.
Executive summary:

Pregnant rats were assessed for adverse developmental effects in an O.E.C.D. Test Guideline No. 414 Prenatal Developmental Toxicity Study by oral gavage exposure with Bisphenol A doses of: 0, 160, 320 and 640 mg/kg/day. Treatment of rat dams with upto a maternally toxic dose level of Bisphenol A of 640 mg/kg/day did not induce any evidence of developmental toxicity. This dose level of Bisphenol A resulted in a significant 14% reduction in maternal body weight during the 20 day gestation period. These findings suggest that 2-Acetone polymer with phenol (BPA-Tars) will not be a developmental toxicant to rats due to its structural similarity to the test substance, Bisphenol A.