Monograph on the Potential Human Reproductive and ... - OEHHA

362 CHAPIN ET AL.
Table 94
Treatment-Related Effects in Developing Rats in a Multigeneration Reproductive Toxicity Study of Bisphenol A a
Endpoint
0.015
[0.0095]
0.3
[0.019]
4.5
[0.285]
Live pups/litter
F1 2 2 2
F2 2 2 2
F3 Pup body weight
2 k 11% 2
F1, PND 4 2 2 2
F1, PND 7 2 2 2
F2, PND 7 2 2 2
F3, PND 7 2 2 2
F1, PND 14 2 2 2
F2, PND 14 2 2 2
F3, PND 14 2 2 2
2 c
F1. PND 21 2 2
F2, PND 21 2 2
2 c
2 c
F 3, PND 21 2 2
Anogenital distance, F 2 females m 3% m 3% m 3%
Age of vaginal opening adjusted for body weight
F 1 2 2 2
F 2 2 2 2
F 3 2 2 2
Age of preputial separation adjusted for body weight
F1 2 2 2
F2 2 2 2
F 3 2 2 2
75
[4.75]
2
2
2
2
2
2
2
2
2
2
2 c
2 c
2 c
2
2
2
2
2
2
2
Dose, ppm diet [mg/kg bw/day b ]
750 7500
[47.5] [475] BMD10 BMDL 10 BMD 1SD BMDL 1SD
2
2
2
2
2
2
2
2
2
2
2 c
2 c
2 c
m4%
2
2
2
m 1.7 days
2
2
k 20%
k 26%
k 26%
k 11%
k 23%
k 15%
k 13%
k 27%
k 20%
k 20%
k 27%
k 20%
k 19%
2
m 3.6 days
m 4 days
m 3.2 days
m 4.9 days
m 7.4 days
m 4 days
a
Tyl et al. (2002b).
b
Based on target doses provided by the study authors and expressed as an average of the dose for males and females.
c
A significant (B5%) decrease in pup body weights observed only in F1 and/or F2 litters was apparently not considered treatmentrelated
by study authors.
m,k Statistically significant increase, decrease, 2 no statistically significant effect.
implants makes the extrapolation for human risk assessment
difficult in the absence of an improved pharmacokinetic
understanding.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate but of limited utility for the
evaluation process.
NTP (1985a) and Morrissey et al. (1989) sponsored a
continuous breeding study in CD-1 mice exposed to
bisphenol A (98% purity). Additional information on
ovarian follicle counts in F0 and F1 females was
published in a report by Bolon et al. (1997). In this study,
mice were fed NIH-07 open formula rodent chow and
housed in polypropylene or polycarbonate cages containing
Ab-Sorb-Dri litter. The laboratory at which the study
was conducted was stated to be in full compliance with
GLP regulations. In the preliminary study (Task 1), 8
mice/sex/group (8 weeks old) were fed diet containing
bisphenol A at 0, 0.3125, 0.625, 1.25, 2.5, or 5.0% for 14
days. By assuming that a 40-g mouse ingests 7 g feed/
day, the study authors estimated bisphenol intake at 0,
437.5, 875.0, 1750.0, 4375.0, 8750.0 mg/kg bw/day. The
aim of the preliminary study was to determine a
maximum tolerated dose that induced significant toxicity
but resulted in Z90% survival and r10% decrease in
weight gain. Statistical analyses included ANOVA, and
w 2 test. Lethality was significantly increased in the highdose
group. Body weight gain was depressed in groups
exposed to Z1.25% bisphenol A. Clinical signs of toxicity
were observed in the 2.5 and 5.0% dose groups and
4232
6661
3733
6412
3432
5179
4976
2890
3840
3704
3284
4253
3972
6225
6381
7444
7350
4740
8637
[268]
[422]
[236]
[406]
[217]
[328]
[315]
[183]
[243]
[235]
[208]
[269]
[252]
[394]
[404]
[471]
[466]
[300]
[547]
3033
2405
2742
4473
2891
4059
3854
2570
3302
3224
2621
3566
3423
5422
5307
6325
6485
4025
7466
[192]
[152]
[174]
[283]
[183]
[257]
[244]
[163]
[209]
[204]
[166]
[226]
[217]
[343]
[336]
[401]
[411]
[255]
[473]
8823
7241
5943
8860
4179
6023
6474
2789
3579
3323
3523
4219
3575
3248
4367
6249
2974
3809
3503
[559]
[459]
[376]
[561]
[265]
[381]
[410]
[177]
[227]
[210]
[223]
[267]
[226]
[206]
[277]
[396]
[188]
[241]
[222]
6225
4645
4518
6317
3448
4653
4940
2415
3013
2827
2763
3473
3016
2786
3600
3198
2580
3201
2984
[394]
[294]
[286]
[400]
[218]
[295]
[313]
[153]
[191]
[179]
[175]
[220]
[191]
[176]
[228]
[203]
[163]
[203]
[189]
included dehydration, dyspnea, lethargy, tremors, ptosis,
piloerection, and diarrhea.
In the reproduction and fertility study (Task 2), 11week-old
mice were randomly assigned to treatment
groups according to body weight. The mice were fed
diets containing 0, 0.25, 0.5, or 1.0% bisphenol A. The
NTP stated that a 40-g mouse consuming 7 g of feed/day
would be exposed to bisphenol A at 437.5, 875, and
1750 mg/kg bw/day. [Based on body weight and feed
intake values reported for males at B3 week intervals,
CERHR estimated mean bisphenol A intake at B365,
740, and 1630 mg/kg bw/day. Feed intakes were
reported only at Week 1 and 18 for females, and Week
18 most likely represented the lactation period. For
Week 1, bisphenol A intake by females was estimated
at 410, 890, and 1750 mg/kg bw/day. At Week 18,
bisphenol A intake by females was estimated at 1090,
1785, and 3660 mg/kg bw/day.] There were 40 mice/sex
in the vehicle control group and 20/sex in each bisphenol
A group. Exposure to bisphenol A began during a 7-day
premating period. Following the premating period,
males and females from the same treatment group were
randomly paired and housed together for 98 days and
following the mating period, each male and female was
housed separately for 21 days. Bisphenol A dosing was
continued throughout the mating and separation period.
Concentration and stability of bisphenol A in feed were
verified. During the 98-day cohabitation period, pups
born were counted, sexed, and weighed. All litters
Birth Defects Research (Part B) 83:157–395, 2008