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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD Test Guideline 421 (1995). GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Due to the limited toxicity observed in previous studies for a similar test substance, only two BPA-DA dose groups were used
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Bisphenol A Dianhydride (BPA-DA; CAS RN 38103-06-9); Lot U10054 from General Electric Company; Purity: 98.2%

Test animals

Species:
rat
Strain:
other: CD® (Sprague-Dawley)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
CD (Sprague-Dawley) rats (the F0 generation) were administered BPA-DA orally by gavage at 0, 100, and 1000 mg/kg/day at a dose volume of 5 mL/kg/day in corn oil, ten/animals/sex/dose, for two weeks of pre-breed exposure and two weeks of mating followed by three weeks of gestation and through postnatal day (pnd) 3.
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
After the two-week prebreed exposure period, animals were randomly mated within treatment groups for a two-week mating period to produce the F1 generation.
Duration of treatment / exposure:
~7 weeks (2 weeks prebreed, 2 weeks mating, 3 weeks gestation, and lactation through postnatal day 4)
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, and 1000 mg/kg/day
Basis:
analytical conc.
No. of animals per sex per dose:
10/sex/group
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Body weights were recorded weekly during the prebreed, mating and gestation periods. During lactation, F0 female body weights were obtained on pnd 0 and 4. Feed consumption was recorded weekly during the prebreed period, but not during the mating period. Feed consumption was recorded for the F0 females during gestation and through pnd 4 of lactation. Clinical signs were recorded at least once daily for all animals.

F0 females with litters were sacrificed on pnd 4 and F0 females that did not produce a litter were sacrificed on gestation day (gd) 26 or 26 days after mating.
At the F0 parental animal necropsy, the following tissues were weighed and retained: ovaries and uterus. All gross lesions were also retained. Histopathology was performed on all retained reproductive tissues for the high dose and control animals. The uteri from the F0 females that failed to produce a litter by gd 26 or by 26 days post-mating were stained with potassium ferricyanide for confirmation of pregnancy.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Fetal examinations:
On the day of birth (pnd 0), all live F1 pups were counted, sexed, weighed and examined as soon as possible. All stillborn pups or pups that died on the date of birth were sexed and counted. All pups were examined daily from birth through pnd 4 for survival and physical abnormalities.

Any pups dying during lactation were necropsied, if possible. On pnd 4, all live pups were examined sexed and weighed, then euthanised and discarded without further evaluation.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
There were no treatment-related deaths for the F0 females. There were no significant changes in F0 female body weights or feed consumption during the prebreed and mating periods; however, there was a decrease in body weight change from sd 7-14 at 1000 mg/kg/day. During gestation, there were no significant changes in body weight or body weight change for the F0 females; however, feed consumption (g/kg/day) was increased from gd 7 to 14 at 100 and 1000 mg/kg/day compared to controls. During lactation, there were no significant differences between groups in F0 maternal body weights, body weight change or feed consumption values. Treatment-related clinical observations at 1000 mg/kg/day included two to three females with audible respiration, sneezing and/or chromodacryorrhea. Other findings were not considered related to treatment except for an increase in the incidence of post-dose rooting. Post-dose rooting is considered to be a behavioral response to taste aversion to the dosing formulations and not a toxic sign. Since there was a dose-related increase in the incidence of post-dose rooting (0, 2 and 3 females in the 0, 100 and 1000 mg/kg/day groups, respectively), it was presumed that the increasing concentrations of BPA-DA across groups caused the adverse taste reaction. At necropsy, mean final body weights of the F0 females were equivalent across all dose groups. The absolute weight and weight relative to final body weight of the paired ovaries were significantly reduced at 1000 mg/kg/day. There were no treatment-related macroscopic or microscopic findings.
During the post mating period, there were 9, 9, and 8 females in the 0, 100, and 1000 mg/kg/day dose groups, respectively, that were determined to be sperm positive; however, the total number of females confirmed pregnant at study completion was 9, 10 and 9, respectively. One pregnant female in the 100 mg/kg/day group was not identified as being sperm positive; one female each in the control and 1000 mg/kg/day groups was not pregnant, and one pregnant female at 1000 mg/kg/day did not deliver a litter. There was a statistically significant increase in precoital interval at 1000 /mg/kg/day although the increase was only approximately one day longer than the controls. There were no significant effects of exposure to BPA-DA on F0 fertility, mating, pregnancy, preimplantation or postimplantation loss per litter, or the number of dead pups at birth.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There was no evidence of F1 offspring toxicity at any dose.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Summary of F1 Offspring Toxicity

F1

Bisphenol A Dianhydride (mg/kg/day)

0

100

1000

No. Live Litters

Postnatal Day 0

9

10

8

Postnatal Day 4

9

10

8

Average No. of Live Pups per Litter (pnd 0)

14.8 ± 1.2

12.7 ± 1.7

13.4 ± 1.1

Average No. of Live Pups per Litter (pnd 4)

14.6 ± 1.1

12.3 ± 1.7

13.3 ± 1.2

Average Pup Body Weight (g) per Litter (pnd 0)

6.33 ± 0.14

7.03 ± 0.17**

6.40 ± 0.14

Average Male Body Weight (g) per Litter (pnd 0)

6.45 ± 0.17

7.16 ± 0.19*

6.49 ± 0.16

Average Female Body Weight (g) per Litter (pnd 0)

6.22 ± 0.13

6.91 ± 0.17**

6.30 ± 0.13

Average Pup Body Weight (g) per Litter (pnd 4)

9.96 ± 0.33

11.22 ± 0.52

10.81 ± 0.51

Average Male Body Weight (g) per Litter (pnd 4)

10.20 ± 0.36

11.44 ± 0.58

11.02 ± 0.52

Average Female Body Weight (g) per Litter (pnd 4)

9.71 ± 0.30

10.93 ± 0.54

10.63 ± 0.52

% Percent Male Pups per Litter (pnd 0)

54.9 ± 5.1

48.5 ± 3.5

44.4 ± 3.9

% Percent Male Pups per Litter (pnd 4)

55.0 ± 5.2

60.2 ± 6.5

48.8 ± 2.7

* p 0.05; ** p 0.01

Applicant's summary and conclusion

Conclusions:
Minimal systemic toxicity was present in parental animals through the course of the study at 1000 mg/kg/day. In the F0 females, the only adverse effects were decreases in high dose body weight change (sd 7 to 14) and treatment related clinical signs at the high dose. At the high dose there was an increase in the precoital interval, but no effect on fertility. There was no evidence of reproductive toxicity in the F0 females at any dose, or any toxicity in the F1 offspring. At necropsy there were no treatment effects with the exception of decreases in the absolute and relative paired ovary weights. Based on these results, the NOAEL for the F0 systemic toxicity was 100 mg/kg/day. The NOAEL for F0 reproductive toxicity was >1000 mg/kg/day for both sexes. The NOAEL for F1 offspring toxicity was >1000 mg/kg/day.