Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental 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:
guideline study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

Source: Charles River Japan
Age at study initiation: 10 weeks
Weight at study initiation: Male 361 (334-396) g, Female 235 (216-260) g
Housing: 1/cage
Diet (e.g. ad libitum): MR(pellet), Nosan Corporation, Japan, ad libitum
Water (e.g. ad libitum): tap water(filtered and UV sterilized), ad libitum
Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS

Temperature (°C): 22.1-25.0
Humidity (%): 46-60
Air changes (per hr): >10/hr
Photoperiod (hrs dark / hrs light): 12 hr/12 hr

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE

Concentration in vehicle: 0, 30, 120, 500, 1000 mg/kg/day
Amount of vehicle (if gavage): 5 mL/kg
Lot/batch No. (if required): BH17
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Males: 42 days
Females: 42-47 days, from 14 days before mating to day 4 of lactation
Frequency of treatment:
Once a day
Details on study schedule:
12 of each sex exposed to 0, 30, 120, 500 and 1000 mg/kg bw per day.
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
120 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12 male and 12 female per group, with additional 5 per sex at 0 and 1000 mg/kg recovery group.
Control animals:
yes, concurrent vehicle
Details on study design:
Satellite group doses: 0, 1000 mg/kg
Post-exposure recovery period in satellite group: 14 days
Positive control:
No
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

Time schedule:

Cage side observations checked in table were included.

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: Day 1 of administration and once a week thereafter.



Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Slight salivation was observed at 500 mg/kg bw and 1,000 mg/kg bw in female and male rats during the administration period. No other significant clinical signs were detected in any of the test groups.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
There was no mortality recorded in either the male or female test groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
All animals gained body weight during the testing period, with the lowest body weight gain generally seen in the highest dose groups. The weight gain in the male group treated at 1000 mg/kg/bw was significantly (p<0.05) lower than the control group during the administration period. During the recovery period, animals from the 1,000 mg/kg bw had a significantly (p<0.05) higher body weight gain when compared to the control animals. Their final body weight was similar at the end of the recovery period between treated and control female and male rats.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
On Day 35 of the administration period, food consumption of male rats treated at 500 mg/kg bw/d was significantly (p<0.05) lower than for the control animals. This difference was not significant on Day 41 at the same dose level, and on Days 35 and 41 at 1,000 mg/kg bw/d.
On Day 0 of lactation, food consumption of female rats treated at 500 mg/kg bw/d was significantly (p<0.01) higher than for the control animals. This difference was not significant on Day 3 of lactation at the same dose level, and on Days 0 and 3 at 1,000 mg/kg bw/d.
Food consumption of the female rats from the satellite group treated at 1,000 mg/kg bw/d was significantly (p<0.05) higher than for the control animals on Day 28 of administration. On Day 35 the food consumption was similar between the treated and control animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Eye sight reaction and pupil reflex recorded as normal in all groups. No eye discharge recorded.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the recovery period, the number of platelets was significantly (p<0.05) lower in male rats treated at 1,000 mg/kg bw when compared to the control animals. This effects was not observed at the end of the administration period.
At the end of the administration period, the red blood cytes count, hemoglobin, and hematocrit were significantly (respectively p<0.05, p<0.01, and p<0.05) lower to the control animals, while the percentage of reticulocytes was significantly (p<0.05) higher. At the end of the recovery period these altered parameters were comparable between the treated and control female rats, while the activated partial thromboplastin time was significantly (p<0.05) in the treated female rats.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the administration period, a significantly (p<0.05) lower creatinine level was observed in male rats treated at 30 mg/kg bw/d.
At the end of the administration period, a significantly (p<0.01) lower creatinine level was observed in male rats treated at 120 mg/kg bw/d.
At the end of the administration period, a significantly (p<0.01) lower creatinine level and significantly (p<0.05) higher total-cholesterol and calcium levels were observed in male rats treated at 500 mg/kg bw/d.
At the end of the administration period, a significantly (p<0.01) lower creatinine level and significantly (p<0.01) higher total-cholesterol level were observed in male rats treated at 1,000 mg/kg bw/d.
At the end of the recovery period, these altered parameters were comparable between the treated and control male rats, while the glucose level was significantly (p<0.05) lower and the alanine aminotrans ferase significantly (p<0.05) higher in the treated animals.

At the end of the administration period, levels of alanine aminotransferase, total cholesterol, and calcium were significantly (respectively p<0.05, p<0.01, p<0.01) higher in female rats treated at 1,000 mg/kg bw/d when compared to the control animals.
At the end of the recovery period, these altered parameters were comparable between the treated and control male rat, while the glucose level was significantly (p<0.05) lower and the alanine aminotransferase significantly (p<0.05) higher in the treated animals. At the end of the recovery period, these altered parameters were comparable between the treated and control female rats.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
At the end of the recovery period, grip strength of hindlimbs and motor activity (30 minutes) were significantly (respectively p<0.01 and p<0.05) reduced in animal treated at 1,000 mg/kg bw/d when compared to the control animals. Grip strength of forelimbs and motor activity (60 min) were not significantly different between the treated and control animals.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Hypertrophy, hepatocyte, centrilobular were observed in liver of female rats treated at 1,000 mg/kg bw/d. These were not apparent in recovery group animals suggesting transitory effects.
Slight to moderate changes were observed in kidneys of male rats treated at 1,000 mg/kg bw/d. These were not apparent in recovery group animals suggesting transitory effects.

No abnormalities were detected in the brain, thyroid, parathyroid, thymus, trachea, small intestine, large intestine, adrenal, urinary bladder, testis, epididymis, seminal vesicle, spinal cord, sciatic nerve, bone, bone marrow, lymph nodes and mammary gland from animals of control and 1000 mg/kg/bw groups of male rats. No abnormalities were detected in the brain, pituitary, thyroid, parathyroid, trachea, small intestine, large intestine, heart, adrenal, urinary bladder, ovary, uterus, spinal cord, sciatic nerve, bone, bone marrow, lymph nodes and mammary glands of control and 1000 mg/kg/bw groups of female rats.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
The oestrus cycle was comparable between the treated and control female rats along with fertility index, number of corpora lutea and implantation sites, and gestation index.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
The number of cells in seminiferous epithelia was comparable between the male rats treated at 1,000 mg/kg bw/d and the control male rats. Animals treated at other concentrations were not investigated
Reproductive performance:
no effects observed
Description (incidence and severity):
The pairing until copulation and copulation index were comparable between the treated and control animals.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Critical effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Critical effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
System:
urinary
Organ:
kidney
Clinical signs:
no effects observed
Description (incidence and severity):
Sex ratio was comparable between the treated and control animals.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
The number of pups born, live birth index, and viability index were comparable between the treated and control animals.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The bodyweight of pups was comparable between the treated and control animals.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
1/175 of the examined pups born from animals treated at 30 mg/kg bw/d showed an external malformation (missing tail). Pups from other groups including control did not display any observable external malformation. This malformation was not considered as significant and treatment-related.
Histopathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
1/120 of the examined pups born from animals treated at 120 mg/kg bw/d and 2/146 of the examined pups born from animals treated at 500 mg/kg bw/d showed a visceral malformation (persistent left umbilical artery). Pups from other groups including control did not display any observable external malformation. These malformations were not considered as significant and treatment-related.
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Reproductive effects observed:
not specified
Conclusions:
The NOAEL for general toxicity on the parent animals was determined to be 500 mg/kg bw/d on the basis of the significant bodyweight reduction observed at 1,000 mg/kg bw/d. In regard to the toxicity to reproduction, no significant treatment-related effects were observed in parent animals and pups at concentrations up to 1,000 mg/kg bw/d, it is therefore proposed a NOAEL of 1,000 mg/kg bw/d for the toxicity to reproduction.
Executive summary:

A combined short-term toxicity and screening for toxicity to reproduction study was performed on BPA-5EO according to OECD Testing Guideline 422. Groups of 12 rats per sex were exposed for 42 days to the substance by the oral route. The concentrations selected for this study were 0, 30, 120, 500, and 1,000 mg/kg bw/d. Two additional groups of five animals per sex were included for a 14-day recovery period and received 0 or 1,000 mg/kg bw/d. Mortality, clinical signs, bodyweights, and food consumption were recorded during the study. Before termination samples of blood and urine were collected to investigate the haematology and blood chemistry parameters and perform the urinalysis. Ophthalmological examination and FOB were performed. At termination, pathological and histopathological examinations were undertaken and organs were weight.

No animal died as a result of the exposure to the substance at up to 1,000 mg/kg bw/d. Slight salivation was observed at 500 and 1,000 mg/kg bw but this was not considered as a significant effect and salivation stopped during the recovery period. A significantly reduced bodyweight gain was observed in male animals treated at 1,000 mg/kg bw/d however the bodyweight was comparable at the end of the recovery period between treated and control animals. A momentary reduced found consumption was observed at 500 mg/kg bw or 1,000 mg/kg bw during the administration period. Some changes were observed at 1,000 mg/kg bw/d during the FOB. Some parameters in the haematology, biochemistry, and urinalysis were altered at the end of the administration period but recovered. Reversible variations in organ weights were observed at the end of the administration period. No effects were observed during the ophthalmological examination. Changes were observed in liver of female rats treated at 1,000 mg/kg bw/d. Slight to moderate changes were observed in kidneys of male rats treated at 1,000 mg/kg bw/d. These were not apparent in recovery group animals suggesting transitory effects. No abnormalities were detected in the brain, thyroid, parathyroid, thymus, trachea, small intestine, large intestine, adrenal, urinary bladder, testis, epididymis, seminal vesicle, spinal cord, sciatic nerve, bone, bone marrow, lymph nodes and mammary gland from animals of control and 1000 mg/kg/bw groups of male rats. No abnormalities were detected in the brain, pituitary, thyroid, parathyroid, trachea, small intestine, large intestine. heart, adrenal, urinary bladder, ovary, uterus, spinal cord, sciatic nerve, bone, bone marrow, lymph nodes and mammary glands of control and 1000 mg/kg/bw groups of female rats.

The reproductive function and performance were comparable between the treated and control parent animals. Pups born from the different groups were in comparable number and did not display significant treatment-related mortality, clinical signs, effects on sex ratio or bodyweight, or malformations. 1/175 of the examined pups born from animals treated at 30 mg/kg bw/d showed an external malformation (missing tail). 1/120 of the examined pups born from animals treated at 120 mg/kg bw/d and 2/146 of the examined pups born from animals treated at 500 mg/kg bw/d showed a visceral malformation (persistent left umbilical artery). Pups from other groups including control did not display any observable external malformation. These malformations were not considered as significant and treatment-related.

The NOAEL for general toxicity on the parent animals was determined to be 500 mg/kg bw/d on the basis of the significant bodyweight reduction observed at 1,000 mg/kg bw/d. In regard to the toxicity to reproduction, no significant treatment-related effects were observed in parent animals and pups at concentrations up to 1,000 mg/kg bw/d, it is therefore proposed a NOAEL of 1,000 mg/kg bw/d for the toxicity to reproduction.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
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 combined short-term toxicity and screening for toxicity to reproduction study was performed on BPA-5EO according to OECD Testing Guideline 422. The NOAEL for general toxicity on the parent animals was determined to be 500 mg/kg bw/d on the basis of the significant bodyweight reduction observed at 1,000 mg/kg bw/d. In regard to the toxicity to reproduction, no significant treatment-related effects were observed in parent animals and pups at concentrations up to 1,000 mg/kg bw/d, it is therefore proposed a NOAEL of 1,000 mg/kg bw/d for the toxicity to reproduction.

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study planned
Study period:
2021
Justification for type of information:
Justification for type of information - Testing Proposal for Developmental toxicity teratogenicity

TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) (EC 500-082-2).

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- Available GLP studies: No GLP studies were identified on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.
- Available non-GLP studies: No non-GLP studies were identified on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.
- Historical human data: No historical human data were identified on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.
- (Q)SAR: According to ECHA Endpoint Specific Guidance Chapter R.7a, considering the large number of potential targets and mechanisms associated with reproductive toxicity, this endpoint cannot be adequately covered by a battery of QSAR models. QSAR models could only be used to identify likely mode of actions for toxicity to reproduction and there is currently no (Q)SAR model allowing to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of a substance.
- In vitro methods: According to ECHA Endpoint Specific Guidance Chapter R.7a, there is currently no in vitro method accepted for regulatory use to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of a substance. In vitro testing can only be used in order to identify potential targets and mechanisms associated with reproductive toxicity, but in vivo situation is considered to be more than the sum of the areas modelled by a series of in vitro assays.
- Weight of evidence: There is not sufficient data available on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) and read-across substances that could be used in a weight-of-evidence approach in order to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.
- Grouping and read-across: The substance 4,4'-Isopropylidenediphenol, propoxylated (1 – 4.5 moles propoxylated) (CAS 37353-75-6 / EC 500-097-4) was identified as a potential read-across substance for 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated). Both substances are UVCB whose constituents are 4,4-isopropylidenediphenol with various degrees of ethoxylation or propoxylation. These constituents have a mean chain length comprised between 1 and 4.5 ethoxy or propoxy groups. A GLP-compliant Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test was performed on both substances according to OECD Testing Guideline 422 using Sprague-Dawley rats. Maternal toxicity was observed in animals treated with 4,4'-Isopropylidenediphenol, propoxylated (1 – 4.5 moles propoxylated) during the Dose-Range Finding study performed at up to 1,000 mg/kg bw/d, along with developmental findings with a decrease of pup body weights observed at 500 mg/kg/day during the main study. As for the 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated), a significant bodyweight reduction was observed in animals treated at 1,000 mg/kg bw/d during the main study, while no significant treatment-related developmental effects were observed in pups from parents exposed at up to 1,000 mg/kg bw/d. It can be concluded from these results that 4,4'-Isopropylidenediphenol, propoxylated (1 – 4.5 moles propoxylated) can be expected to be more toxic to reproduction than 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) and therefore cannot be considered as a suitable read-across substance in order to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- In accordance to Annex IX of REACH, Column 2, a Pre-natal developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure studies does need to be conducted as:
—4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) is not known to be a genotoxic carcinogen.
— 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) is not known to be a germ cell mutagen.
— Available data suggests that systemic absorption occurs following an exposure to 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) by the oral route.
—4,4- isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) is not known to have adverse effects on fertility, meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage fertility (H360F).
—4,4- isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) is not known to cause developmental toxicity, meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage the unborn child (H360D).

ADDITIONAL INFORMATION
4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) (EC 500-082-2) has been added to the definitive CO-RAP list and will be evaluated in 2020 by the French MSCA. The evaluating MSCA may want to comment on the study design required for the purpose of the evaluation of the developmental toxicity / teratogenicity of the substance. Therefore, it is proposed to wait for Final CO-RAP Decision on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) (EC 500-082-2) before performing this test in order to avoid the potential duplication of any unnecessary animal testing.
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not applicable
Species:
rat
Strain:
Crj: CD(SD)
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Toxicity to reproduction: other studies

Additional information

The NOAEL for general toxicity on the parent animals was determined to be 500 mg/kg bw/d on the basis of the significant bodyweight reduction observed at 1,000 mg/kg bw/d. In regard to the toxicity to reproduction, no significant treatment-related effects were observed in parent animals and pups at concentrations up to 1,000 mg/kg bw/d, it is therefore proposed a NOAEL of 1,000 mg/kg bw/d for the toxicity to reproduction.

Justification for classification or non-classification

Additional information