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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
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.
Reference:
Composition 0
Qualifier:
according to
Guideline:
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 information:
Composition 1
Species:
rat
Strain:
other: CD® (Sprague-Dawley)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Male and female 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 prebreed exposure and two weeks of mating for F0 male and female parental animals. F0 females continued to be dosed for three weeks of gestation and through postnatal day (pnd) 3.
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.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Males = 4 weeks (2 weeks prebreed, 2 weeks mating)
Females = ~7 weeks (2 weeks prebreed, 2 weeks mating, 3 weeks gestation, and lactation through postnatal day 4)
Frequency of treatment:
Daily
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
Parental animals: Observations and examinations:
Body weights for the F0 males and females were recorded weekly during the prebreed and mating periods for both sexes and for F0 females during gestation. During lactation, F0 female body weights were obtained on pnd 0 and 4. Feed consumption was recorded weekly for the F0 males and females 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.
Litter observations:
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.
Postmortem examinations (parental animals):
F0 males were sacrificed following the breeding period (after 28 days of dosing). 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: testes, epididymides, prostate, seminal vesicles, ovaries, uterus. All gross lesions were also retained. Histopathology was performed on all retained reproductive tissues for the high dose and control males and females with special emphasis on stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure (10/sex/group). 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.
Postmortem examinations (offspring):
Any pups dying during lactation were necropsied, if possible. On pnd 4, all live pups were examined sexed and weighted, then euthanized and discarded without further evaluation.
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: estrous cycle:
not examined
Reproductive performance:
no effects observed
Males: There were no treatment-related deaths for the F0 males. For parental males at 1000 mg/kg/day, body weight was reduced on study days (sd) 21 and 28, by 7% and 5% respectively. Body weight change was reduced at 1000 mg/kg/day for sd 14 to 21 and 0 to 28. At 1000 mg/kg/day, feed consumption (g/day) was increased from sd 7 to 14 and feed consumption (g/kg/day) was increased throughout the entire prebreed period. At 100 mg/kg/day, there were no effects on body weight, body weight changes or feed consumption. At 1000 mg/kg/day, treatment-related clinical observations were recorded for five males with audible respiration, two males with gasping, four males with sneezing, and one male with chromodacryorrhea. Other findings were not considered related to treatment with the exception of post-dose rooting. Post-dose rooting was defined as the animal digging or moving its bedding with its snout post-dosing, possibly to mitigate the adverse taste. 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 (1, 2 and 5 males 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 the mean final body weight was reduced by 5% at 1000 mg/kg/day compared to controls, but the absolute and relative organ weights were equivalent across all groups. There were no treatment-related macroscopic or microscopic findings.

Females: 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.
Dose descriptor:
NOAEL
Remarks:
parental
Effect level:
ca. 100 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Remarks:
Reproduction
Effect level:
> 1 000 mg/kg bw/day
Sex:
male/female
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
There was no evidence of F1 offspring toxicity at any dose.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 000 mg/kg bw/day
Sex:
male/female
Reproductive effects observed:
not specified

Summary of F0 Adult Systemic Toxicity-Key Parameters and Statistically Significant Differences

Bisphenol A Dianhydride (mg/kg/day)

0

100

1000

F0 MALES

Deaths

0/10

0/10

0/10

Body Weights

sd 21

---

---

<

sd 2

---

---

<

Weight Change

sd 14-21

---

---

<

sd 0-28

---

---

<

Feed Consumption:      

g/day

sd 7-14

---

---

<<

                g/kg/day

sd 0-7

---

---

<<

sd 7-14

---

---

<<<

sd 0-14

---

---

<<<

Necropsy

Final Body Weight at Necropsy

---

---

<<<

Organ Weights

---

---

---

F0 FEMALES

Deaths

0/10

0/10

0/10

Prebreed, Mating, and Postmating (sd 0-42) Exposure

Body Weights

---

---

---

Weight Change

sd 7-14

---

---

<

Feed Consumption:       g/day

---

---

---

                                                g/kg/day

---

---

---

Gestation

Body Weights

---

---

---

Weight Change

---

---

---

Feed Consumption:      

g/day

---

---

---

                g/kg/day

gd 7-14

---

>>

>

Lactation (pnd 0-21)

Body Weights

---

---

---

Weight Change

---

---

---

Feed Consumption:       g/day

---

---

---

                                                g/kg/day

---

---

---

Necropsy

Final Body Weight at Necropsy

---

---

---

Organ Weights

Paired Ovary Weight

---

---

<<

Relative Paired Ovary Weight

---

---

<

>, >>, >>> = statistically significant increase; p0.05, p0.01 and p0.001, respectively

<, <<, <<< = statistically significant decrease; p0.05, p0.01 and  p0.001, respectively

--- = no statistically significant difference

Summary of F0 Parental Male and Female Reproductive Toxicity

F0

Bisphenol A Dianhydride (mg/kg/day)

0

100

1000

F0 Females

No. Females on Study

10

10

10

No. Females Paired

10

10

10

No. Females that Mated

10

10

9

Mating Index (# females mated/# females paired)

100.0

100.0

90.0

No. Pregnant Females

9

10

9

Fertility Index (# pregnant females/# females that mated)

90.0

100.0

100.0

No. of Females with Live Litters (pnd 0)

9

10

8a

Gestational Index (# females with live litters/# females pregnant)

100.0

100.0

88.9

F0 Males

No. Males on Study

10

10

10

No. Males Paired

10

10

10

No. Males that Mated

10

10

9

Mating Index (# males mated/# males paired)

100.0

100.0

90.0

No. Males Siring Litters

9

10

9

Fertility Index (# males siring litters/# males that mated)

90.0

100.0

100.0

Pregnancy Index (# females with live litters/# males that mated)

90.0

100.0

88.9

Precoital Interval (days)

1.8 ± 0.2

2.1 ± 0.4

3.1 ± 0.5*

Gestational Length (days)

22.0 ± 0.0

22.3 ± 0.2

22.3 ± 0.2

No. Live Litters

Postnatal Day 0

9

10

8

Postnatal Day 4

9

10

8

No. Corpora Lutea per Dam

15.33 ± 1.25

14.30 ± 1.32

14.10 ± 1.51

% Preimplantation Loss per Litter

5.20 ± 2.45

8.69 ± 3.88

6.33 ± 2.91b

Average No.  Implantation Sites per Litter

15.89 ± 1.12

14.20 ± 1.55

16.00 ± 1.00

% Postimplantation Loss per Litter

5.77 ± 1.69

14.70 ± 5.52

19.82 ± 10.37

Average No. of Live Pups on Postnatal Day 0

14.8 ± 1.2

12.7 ± 1.7

13.4 ± 1.1

Average No. of Dead Pups on Postnatal Day 0

0.2 ± 0.1

0.0 ± 0.0

0.6 ± 0.3

Average Total Number of Pups on Postnatal Day 0

15.0 ± 1.1

12.7 ± 1.7

14.0 ± 1.0

Stillbirth Index (# dead on pnd 0/total # on pnd 0)

1.9 ± 1.3

0.0 ± 0.0

5.0 ± 2.9

Live Birth Index (# live on pnd 0/total# on pnd 0)

98.1 ± 1.3

100.0 ± 0.0

95.0 ± 2.9

4 Day Survival Index (# surviving 4 days/# live on pnd 0)

98.8 ± 0.8

92.8 ± 4.9

98.2 ± 1.8

a  A female was pregnant (20 implantation sites at necropsy) but did not deliver a litter.

bOne female had corpora lutea, but no implantation sites; therefore, preimplantation loss could not be calculated.

Summary of F1 Offspring Toxicity

F1

Bisphenol A Dianhydride (mg/kg/day)

0

10

100

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

Conclusions:
Minimal systemic toxicity was present in males and females through the course of the study at 1000 mg/kg/day. In the F0 males, the only adverse effects were respiratory signs (considered to be related to the irritant properties of BPA-DA), a 5 to 7 % reduction in body weights, and reductions in body weight changes. 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, for the F0 males and females, 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 male and female 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.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was conducted in accordance with a standardised guideline and under GLP conditions. The quality of the database is therefore considered to be good.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A screening reproduction/development test was conducted using methods comparable to OECD guideline 421 under GLP conditions (RTI International, 2005). The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Sprague-Dawley male and female rats were exposed to the test material via gavage in corn oil at dose levels of 0, 100, and 1000 mg/kg/day (10/sex/group). Due to the limited toxicity observed in previous studies for a similar test substance, only two BPA-DA dose groups were used.

Males were dosed for 4 weeks (2 weeks prior to breeding, 2 week mating period) and females were dosed for ~7 weeks (2 weeks prior to breeding, 2 week mating period, 3 week gestation period and lactation through postnatal day 4).

Minimal systemic toxicity was present in males and females through the course of the study at 1000 mg/kg/day. In the F0 males, the only adverse effects were respiratory signs, a 5 to 7 % reduction in body weights, and reductions in body weight changes. In the F0 females, the only adverse effects were decreases in high dose body weight change (Days 7 to 14) and treatment related clinical signs at the high dose. At the high dose there was an increase in the pre-coital 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, for the F0 males and females, 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 male and female 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. 

In accordance with section 8.7.3 of Column 1 of REACH Annex IX, the Extended One-Generation Reproductive Toxicity Study should be proposed if the available repeated dose toxicity studies indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity. As there is no evidence of reproductive toxicity associated with this substance, it is considered justified to omit this study.


Short description of key information:
In a screening reproduction/development test conducted in the rat using methods comparable to OECD guideline 421, 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.

Justification for selection of Effect on fertility via oral route:
Only one study available.

Effects on developmental toxicity

Description of key information
In a screening reproduction/development test conducted in the rat using methods comparable to OECD guideline 421, the NOAEL for F0 reproductive toxicity was >1000 mg/kg/day. The NOAEL for F1 offspring toxicity was >1000 mg/kg/day.
In a developmental test conducted in the rabbit using methods comparable to OECD 414 and EPA OPPTS 870.3700, the NOAEL for developmental toxicity was considered to be ≥1000 mg/kg bw.
In a developmental test conducted in the rat using methods comparable to OECD 414 and EPA OPPTS 870.3700, the NOAEL for developmental toxicity was considered to be ≥1000 mg/kg bw.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
other: The NOAEL was determined to be >1000 mg/kg in both rats and rabbits
Quality of whole database:
Three studies are available to address this endpoint. All were conducted under GLP conditions using methodology equivalent to standardised guidelines. The quality of the database is therefore considered to be high.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

A screening reproduction/development test was conducted using methods comparable to OECD guideline 421 under GLP conditions (RTI International, 2005). The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Sprague-Dawley male and female rats were exposed to the test material via gavage in corn oil at dose levels of 0, 100, and 1000 mg/kg/day (10/sex/group). Due to the limited toxicity observed in previous studies for a similar test substance, only two BPA-DA dose groups were used. Females were dosed for ~7 weeks (2 weeks prior to breeding, 2 week mating period, 3 week gestation period and lactation through postnatal day 4).

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 (Days 7 to 14) and treatment related clinical signs at the high dose. At the high dose there was an increase in the pre-coital 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, for the F0 females 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. 

The developmental toxicity potential of BPA-DA in the rabbit was investigated in a study conducted using methodology equivalent to OECD 414 and EPA OPPTS 870.3700 under GLP conditions (Hazleton Laboratories America, Inc., 1983). The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Sixteen New Zealand White rabbits were dosed with the test material at 1000 mg/kg bw by gavage in CMC (carboxymethyl cellulose) on Days 6 through 18 of gestation. A further 16 were dosed with the vehicle alone.

A reduction in maternal bodyweight was seen at 1000 mg/kg. There were no effects on any foetal parameters from BPA-DA treatment and the NOAEL for developmental toxicity was considered to be ≥1000 mg/kg bw.

Based on the results of this study, BPA-DA is not a developmental toxin.

 

The developmental toxicity potential of BPA-DA in the rat was investigated in a study conducted using methodology equivalent to OECD 414 and EPA OPPTS 870.3700 under GLP conditions (Hazleton Laboratories America, Inc., 1987). The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Twenty-four Sprague-Dawley rats were dosed with the test material at 1000 mg/kg bw by gavage in CMC (carboxymethyl cellulose) on Days 6 through 15 of gestation. A further 24 were dosed with the vehicle alone.

A reduction in maternal bodyweight was seen at 1000 mg/kg. There were no effects on any foetal parameters from BPA-DA treatment and the NOAEL for developmental toxicity was considered to be ≥1000 mg/kg bw.

Based on the results of this study, BPA-DA is not a developmental toxin.


Justification for selection of Effect on developmental toxicity: via oral route:
No key study was selected on the basis that several key studies have been provided to address this endpoint.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to reproductive or developmental toxicity.