2-Propanone, polymer with phenol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The UVCB substance did not affect the reproductive organs of male and female rats in a 90-day repeated dose toxicity study (Beerens-Heijnen, 2016) in doses up to and including 250 mg/kg bw/day. No specific reproductive toxicity study is available for the UVCB substance. However, due to an existing legal classification for the main constituent Bisphenol A for reproductive toxicity (fertility) with Cat. 1B this classification for reproductive toxicity is also applied to the UVCB substance as worst-case consideration. The BMDL10 for Bisphenol A of 8.9 mg/kg bw/day established on the basis of multi-generation studies by EFSA (2015) is taken forward for hazard assessment of the UVCB substance.

Link to relevant study records

Reference

Reference 1

Endpoint:

fertility, other

Remarks:

subchronic repeated dose toxicity study

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2015 - 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD TG 408

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2015-05-30
- Expiration date of the lot/batch: 2016-05-20
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: analytically confirmed
- Solubility and stability of the test substance in the solvent/vehicle: analytically confirmed
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: none
Stability for at least 5 hours at room temperature and for at least 8 days in the refrigerator in the dark is
confirmed over the concentration range 1 to 200 mg/mL, Test Facility Study No. 510051.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The substance 2-Acetone, condensation product with phenol was filled at 130 °C into plastic covered Duran glass bottles. During the cooling down a vacuum was build which tightens the cap. Therefore, the bottles need to be heated up to 60°C in a cabinet heater before the cap could be loosed. Decanting was not possible at this temperature. Therefore, the bottles need to be heated up to 100-120 °C in a cabinet heating with loosed cap. Then decanting was possible in a fume
cupboard with appropriate heat protection gloves.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approximately 6 weeks
- Fasting period before study: no
- Housing: 5 animals per sex in Macrolon cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days before start of treatment
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C
- Humidity (%): 40-70%
- Air changes (per hr): at least 10 air changes/hours
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

IN-LIFE DATES: From 2015-09-30 to 2016-02-26 (including dose range finding study)

Route of administration:

oral: gavage

Vehicle:

other: polyethylene glycol 400, specific gravity 1.125

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at Charles River Den Bosch and on information from the sponsor.
- Amount of vehicle (if gavage): 5 mL/kg bw
METHOD of FORMULATION:
Formulations (w/w) were prepared within 8 days prior to dosing and were homogenized to visually acceptable levels. The formulations were heated on the day of formulation to a maximum of 80±5°C for at least 15 minutes to obtain visual homogeneity. Formulations were released for dosing when they had obtained a temperature of 40°C or lower. Adjustment was made for specific gravity of the vehicle. No correction was made for purity/composition of the test item.

Details on mating procedure:

not applicable because it is a subchronic study

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability measurements were conducted as part of the method development and validation study (ABL Pr oject 15273). The stability of the test item in the vehicle was assured prior to the start of the main study.
Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations, in Weeks 1, 7 and 13).
The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration for solutions. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%.

RESULTS:
No test item was detected in the control group formulations.
The concentrations analysed in the formulations of Group 2, 3 and 4 were in agreement with the target concentrations (i.e. mean accuracies between 90% and 110%).
The formulations of Group 2 and Group 4 were homogeneous in all groups analysed (i.e. coefficient of variation ≤ 10%).

Duration of treatment / exposure:

at least 90 days

Frequency of treatment:

once daily

Dose / conc.:

10 mg/kg bw/day (actual dose received)

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Dose / conc.:

250 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10/sex/dose
control female 50 was replaced at day 8 due to an accidental death on day 7 and treated one week less with the vehicle

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
Dose levels are based on results of a 28-day oral range finding study with 2-Acetone, condensation product with phenol by daily gavage in the rat (Test Facility Study No. 509883).

Positive control:

not adequate

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily
Once prior to start of treatment and at weekly intervals, this was also performed outside the home cag e in a standard arena (collected under Test Facility Study No. 510847 for logistic reasons and reported
under Test Facility Study No. 509882). The time of onset, grade and duration of any observed signs were recorded. Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were
coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption: weekly

WATER CONSUMPTION:
Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical signs were predominantly noted for the animals at 250 mg/kg bw/day and consisted of rales, hunched posture, piloerection and/or labored respiration in three males and three females. At low i ncidence hunched posture, piloerection and/or rales were noted at 50 mg/kg bw/day in one male and one female. These clinical signs were not noted for the animals at 10 mg/kg bw/day.

Description (incidence):

There was one unscheduled death. Male no. 31 (250 mg/kg bw/day) was sacrificed moribund condition at Day 77. During two weeks prior to death this animal showed, hunched posture, laboured respiration and
rales. In addition swelling of the abdomen and lean appearance were noted in this animal on the last two days prior to death.
At macroscopic examination the male was emaciated, showed a gastro-intestinal tract distended with gas, tan discoloration of the thymus and a reduced size of the thymus, mesenteric lymph node and seminal vesicles. Relevant microscopic findings consisted of atrophy (up to moderate degree) of thymus, mesenteric lymph node and seminal vesicles correlating with the reduced size of these organs. Since this unscheduled death was incidental and histopathological findings were unique in nature and/or severity in this study, a relation to treatment was doubted but could not be excluded.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced body weight gain was noted in males at 250 mg/kg bw/day, achieving a statistically significant difference in from week 5 onwards. Statistical significance was also achieved for the lower body weights in males from week 9 onwards.
Body weights and body weight gain of female animals remained in the same range as controls over the study period.

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

The following statistically significant changes in clinical biochemistry parameters distinguished treated from control animals:
- Higher alanine aminotransferase in males at 250 mg/kg bw/day
- Higher alkaline phosphatase in females at 250 mg/kg bw/day
- Lower albumin in females at 50 and 250 mg/kg bw/day
- Higher urea in females at 250 mg/kg bw/day (non-statistically significant at 50 mg/kg bw/day)
- Lower cholesterol in both sexes at 50 and 250 mg/kg bw/day (not statistically significant in males at 50 mg/kg bw/day)
- Higher inorganic phosphates in both sexes 250 mg/kg bw/day

Any other statistically significant changes in clinical biochemistry parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopic findings which were considered to be related to the treatment with the test item were noted at 250 mg/kg bw/day in the liver of both sexes. These findings consisted of hepatocellular hypertrophy (minimal) to 3/9 in males and 6/10 in females.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Some slight clinical biochemistry changes were found in the high dose group (such as higher alanine aminotransferase, alkaline phosphatase, urea and/or inorganic phosphates and lower albumin and cholesterol levels).

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects on reproductive organs or tissues seen after oral dosing for 90 days

Remarks on result:

other:

Critical effects observed:

no

Reproductive effects observed:

not specified

Conclusions:

No adverse effects on reproductive organs or tissues were observed in a subchronic oral study with rats up to and including 250 mg/kg and bw.

Executive summary:

In a 90 -day repeated dose toxicity study in rats (Wistar, OECD TG 408) the substance was administered via gavage to 10 rats/sex/dose at 0, 10, 50, 250 mg/kg bw in PEG 400 for 13 weeks. Up to and including the highest tested dose of 250 mg/kg bw neither gross pathological nor histopathological changes of the male and female reproductive organs (testes, epididymides, prostate, seminal vesicles incl. coagulation glands, ovaries with oviducts, uterus with cervix, vagina, mammary glands) were reported. Overall, based on the subchronic toxicity study there is no indication of a reproductive toxicity potential of the substance and the NOAEL for reproductive effects for male and female rats can be considered as 250 mg/kg bw.

Reference 2

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Justification for type of information:

IUCLID READ-ACROSS: Justification for type of information
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The registered UVCB substance 2-acetone, condensation product with phenol mainly, in the following referred to as UVCB substance, consists of 4,4’-isopropylidenediphenol (Bisphenol A, CAS-No. 80-05-7, typical concentration about 40%). Consequently, 4,4’isopropylidenediphenol has major influence on the potential of 2-acetone, condensation product with phenol with regard to human health effects. .
For the assessment of human health toxicity of the UVCB substance two approaches were followed:
1) Data generation for the UVCB substance itself and toxicological assessment on the basis of the gained results, supplemented with
2) Read-across based on toxicological data for the main component of the UVCB substance, i.e. 4,4’-isopropylidenediphenol (Bisphenol A, CAS-No. 80-05-7).

2. SOURCE AND TARGET CHEMICAL(S)
Source: 4,4’-isopropylidenediphenol (Bisphenol A, EC No. 201-254-8)
Target: 2-acetone, condensation product with phenol (EC No. 931-252-8), consisting of about 40% 4,4’-isopropylidenediphenol
A separate document is attached for the description of the approach, called Information on Read-Across and DNEL Derivation for REACH Registration of 2-acetone, condensation product with phenol (EC Inventory No. 931-252-8)

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 416 (Two-Generation Reproduction Toxicity Study) TG 416 Enhanced

Species:

mouse

Strain:

CD-1

Sex:

male/female

Remarks:

Doses / Concentrations:
0, 0.018, 0.18, 1.8, 30, 300, and 3500 ppm (0, 0.003, 0.03, 0.3, 5, 50, 600 mg/kg body weight)
Basis:
nominal in diet

No. of animals per sex per dose:

28

Dose descriptor:

NOEL

Remarks:

Systemic

Effect level:

30 ppm (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Based on centrilobular hypertrophy in adult males at 300 ppm

Remarks on result:

other: Generation: F0 and F1 (migrated information)

Dose descriptor:

NOAEL

Remarks:

Systemic

Effect level:

300 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The EU RAR 2003 concluded that the NOAEL is 300 ppm based on reduced body weight and effects on liver and kidney weight and histopathology at 3500 ppm

Remarks on result:

other: Generation: F0 and F1 (migrated information)

Dose descriptor:

NOEL

Remarks:

fertility

Effect level:

3 500 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on fertility, reproductive organ weights and histopathology or sperm production were observed at any dose tested

Remarks on result:

other: Generation: F0 and F1 (migrated information)

Critical effects observed:

yes

Lowest effective dose / conc.:

3 500 ppm

System:

other: reduced body weight and effects on liver and kidney weight and histopathology

Organ:

kidney

liver

Treatment related:

yes

Dose response relationship:

yes

Dose descriptor:

NOAEL

Remarks:

reproductive

Generation:

other: F1 and F2

Effect level:

3 500 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reduced F1/F2 weanling body weight, reduced weanling spleen and testes weight

Critical effects observed:

yes

Lowest effective dose / conc.:

3 500 ppm

System:

other: reduced F1/F2 weanling body weight, reduced weanling spleen and testes weight

Treatment related:

yes

Dose response relationship:

yes

Reproductive effects observed:

yes

Lowest effective dose / conc.:

3 500 ppm

Treatment related:

yes

Relation to other toxic effects:

reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects

Dose response relationship:

yes

Conclusions:

The authors concluded that BPA is not a selective reproductive or developmental toxicant in mice.

Executive summary:

There were no BPA-related effects on adult mating, fertility or gestational indices, ovarian primordial follicle counts, estrous cyclicity, precoital interval, offspring sex ratios or postnatal survival, sperm parameters, or reproductive organ weights or histopathology (including the testes and prostate). Adult systemic effects: at 300 ppm, only centrilobular hepatocyte hypertrophy; at 3500 ppm, reduced body weight, increased kidney and liver weights, centrilobular hepatocyte hypertrophy, and renal nephropathy in males. At 3500 ppm, BPA also reduced F1/F2 weanling body weight, reduced weanling spleen and testes weights (with seminiferous tubule hypoplasia), slightly delayed PPS, and apparently increased the incidence of treatment-related, undescended testes only in weanlings, which did not result in adverse effects on adult reproductive structures or functions; this last finding is considered a developmental delay in the normal process of testes descent. It is likely that these transient effects were secondary to (and caused by) systemic toxicity. Gestational length was increased by 0.3 days in F1/F2 generations; the toxicological significance, if any, of this marginal difference is unknown. At lower doses (0.018 - 30 ppm), there were no treatment-related effects and no evidence of non-monotonic dose response curves for any parameter. The systemic NOEL was 30 ppm BPA (approximately 5 mg/kg-day); the reproductive/developmental NOEL was 300 ppm (approximately 50 mg/kg-day).

Reference 3

Endpoint:

three-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Justification for type of information:

IUCLID READ-ACROSS: Justification for type of information
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The registered UVCB substance 2-acetone, condensation product with phenol mainly, in the following referred to as UVCB substance, consists of 4,4’-isopropylidenediphenol (Bisphenol A, CAS-No. 80-05-7, typical concentration about 40%). Consequently, 4,4’isopropylidenediphenol has major influence on the potential of 2-acetone, condensation product with phenol with regard to human health effects. .
For the assessment of human health toxicity of the UVCB substance two approaches were followed:
1) Data generation for the UVCB substance itself and toxicological assessment on the basis of the gained results, supplemented with
2) Read-across based on toxicological data for the main component of the UVCB substance, i.e. 4,4’-isopropylidenediphenol (Bisphenol A, CAS-No. 80-05-7).

2. SOURCE AND TARGET CHEMICAL(S)
Source: 4,4’-isopropylidenediphenol (Bisphenol A, EC No. 201-254-8)
Target: 2-acetone, condensation product with phenol (EC No. 931-252-8), consisting of about 40% 4,4’-isopropylidenediphenol
A separate document is attached for the description of the approach, called Information on Read-Across and DNEL Derivation for REACH Registration of 2-acetone, condensation product with phenol (EC Inventory No. 931-252-8)

Reason / purpose for cross-reference:

read-across source

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: feed

Remarks:

Doses / Concentrations:
0, 0.015, 0.3, 4.5, 75, 750, and 7500 ppm (0, 0.001, 0.02, 0.3, 5, 50, 500 mg/kg body weight)
Basis:
nominal in diet

No. of animals per sex per dose:

30 males/30 females per dose group

Dose descriptor:

NOEL

Remarks:

systemic

Effect level:

75 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Based on body weight reduction in adult females at 750 ppm

Remarks on result:

other: Generation: F0, F1, F2 (migrated information)

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The EU RAR 2003 concluded that the NOAEL for systemic toxicity in this study is 50 mg/kg/day, based on consistent and significant reductions in body weight gain in both sexes and renal tubule degeneration in females only at 7500 ppm

Remarks on result:

other: Generation: F0, F1 and F2 (migrated information)

Dose descriptor:

NOAEL

Remarks:

reproductive

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD)

Remarks on result:

other: Generation: F1 and F2 (migrated information)

Critical effects observed:

yes

Lowest effective dose / conc.:

7 500 ppm

System:

other: reduced body weight gain and renal tubule degeneration in females at 7500 ppm (about 500 mg/kg bw/day)

Organ:

other: kidney in females

Treatment related:

yes

Dose descriptor:

NOAEL

Remarks:

reproductive

Generation:

other: F1 and F2

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD)

Critical effects observed:

yes

Lowest effective dose / conc.:

7 500 ppm

System:

other: pup weight

Organ:

other: Total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD)

Treatment related:

yes

Reproductive effects observed:

yes

Lowest effective dose / conc.:

7 500 ppm

Treatment related:

yes

Relation to other toxic effects:

reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects

Dose response relationship:

yes

Conclusions:

The authors concluded that based on the results of this study, BPA should not be considered a selective reproductive toxicant.

Executive summary:

Bisphenol A (BPA) was administered at concentrations of 0, 0.015, 0.3, 4.5, 75, 750, and 7500 ppm (approximately 0.001, 0.02, 0.3, 5, 50, and 500 mg/kg-day) in the diet ad libitum to 30 CD Sprague Dawley rats/sex/dose for 3 offspring generations, 1 litter/generation, through F3 adults. Adult systemic toxicity at 750 and 7500 ppm in all generations included: reduced body weights and body weight gains, reduced absolute and increased relative weanling and adult organ weights (liver, kidneys, adrenals, spleen, pituitary, and brain), and female slight/mild renal and hepatic pathology at 7500 ppm. Reproductive organ histopathology and function were unaffected. Ovarian weights as well as total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD). Mating, fertility, gestational indices; ovarian primordial follicle counts; estrous cyclicity; precoital interval; gestational length; offspring sex ratios; postnatal survival; nipple/areolae retention in preweanling males; epididymal sperm number, motility, morphology; daily sperm production (DSP), and efficiency of DSP were all unaffected. At 7500 ppm, vaginal patency (VP) and preputial separation (PPS) were delayed in F1, F2, and F3 offspring, associated with reduced body weights. Anogenital distance (AGD) on PND 0 was unaffected for F2 and F3 males and F3 females (F2 female AGD was increased at some doses, not at 7500 ppm, and was considered not biologically or toxicologically relevant). Adult systemic no observed adverse effect level (NOAEL)= 75 ppm (5 mg/kg-day); reproductive and postnatal NOAELs = 750 ppm (50 mg/kg-day). There were no treatment-related effects in the low-dose region (0.001-5 mg/kg-day) on any parameters and no evidence of nonmonotonic dose-response curves across generations for either sex. BPA should not be considered a selective reproductive toxicant, based on the results of this study.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

BMDL10

8.9 mg/kg bw/day

Study duration:

subchronic

Species:

other: rat and mouse

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

In a developmental toxicity study on rats a NOAEL of 60 mg/kg bw/day for developmental toxicity (slight reduction of fetal weight; no visceral or skeletal effects) was obtained for the UVCB substance (deRaaf-Beekhuizen, 2016). For the main constituent Bisphenol A a comparable NOAEL of 50 mg/kg bw/day (300 ppm) for developmental toxicity (reduced offspring body weight at 3500 ppm) was obtained in a multi-generation study on mice (Tyl, 2008). In a multi-generation study on rats a comparable NOAEL was obtained for Bisphenol A.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

(2001)

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2015-05-30
- Expiration date of the lot/batch: 2016-05-20

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: analytically confirmed
- Solubility and stability of the test substance in the solvent/vehicle: analytically confirmed - Reactivity of the test substance with the solvent/vehicle of the cell culture medium: none
Stability for at least 5 hours at room temperature and for at least 8 days in the refrigerator in the dark is confirmed over the concentration range 1 to 200 mg/mL, Test Facility Study No. 510051.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The substance 2-Acetone, condensation product with phenol was filled at 130 °C into plastic covered Duran glass bottles. During the cooling down a vacuum was build which tightens the cap. Therefore, the bottles need to be heated up to 60°C in a cabinet heater before the cap could be loosed. Decanting was not possible at this temperature. Therefore, the bottles need to be heated up to 100-120 °C in a cabinet heating with loosed cap. Then decanting was possible in a fume cupboard with appropriate heat protection gloves.

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Crl:WI(Han) (outbred, SPF-Quality)
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at delivery: 10-14 weeks
- Housing: individually in Makrolon cages (MIII type) on sterilized sawdust as bedding material.
- Diet and water: ad libitum
- Acclimation period: at least 5 days prior to treatment


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24°C
- Humidity (%): approximately 40-70 %
- Air changes (per hr): > 10 per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 2015-11-18 to 2016-02-11 (including dose range finding study)

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

specific gravity 1.125

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at Charles River Den Bosch and on information from the sponsor.
- Amount of vehicle (if gavage): 5 mL/kg bw

METHOD of FORMULATION:
Formulations (w/w) were prepared within 8 days prior to dosing and were homogenized to visually acceptable levels. The formulations were heated on the day of formulation to a maximum of 80±5°C for at least 15 minutes to obtain visual homogeneity. Formulations were released for dosing when they had obtained a temperature of 40°C or lower. Adjustment was made for specific gravity of the vehicle. No correction was made for purity/composition of the test item.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability measurements were conducted as part of the method development and validation study (ABL Pr oject 15273). The stability of the test item in the vehicle was assured prior to the start of the main study.
Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations, in Weeks 1, 7 and 13).
The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration for solutions. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%.

RESULTS:
No test item was detected in the control group formulations.
The concentrations analysed in the formulations of Group 2, 3 and 4 were in agreement with the target concentrations (i.e. mean accuracies between 90% and 110%).
The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%).

Details on mating procedure:

Untreated females were mated at the Supplier, and were at Day 0 or 1 post-coitum on arrival at the Test Facility (Day 0 post-coitum is the day of
successful mating; confirmed by vaginal plug).

Duration of treatment / exposure:

Days 6 - 20 post-coitum, inclusive

Frequency of treatment:

Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.

Duration of test:

from day 0 to necropsy at day 21 p.c.

Dose / conc.:

20 mg/kg bw/day (actual dose received)

Dose / conc.:

60 mg/kg bw/day (actual dose received)

Dose / conc.:

150 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

22 pregnant females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: In order to set the dose levels for the main teratology study, a dose range finding study was performed. Four groups of 6 pregnant females were exposed to 60, 1500, or 300 mg/kg bw/day for Days 6 to 20 post-coitum inclusive by oral gavage. These dose levels were based on (interim) a 28-day dose-range finding study in which male and female rats received the test substance by oral gavage at dose levels of 0, 100, 250, 500, and 1000 mg/kg bw/day.
One animal treated at 300 mg/kg bw/day (No. 23) showed signs of ill health towards the end of the study, including lethargy, hunched posture, laboured and shallow respiration and rales, piloerection and chromodacryorrhoea. Body weight and food consumption were severely reduced for this animal
and at necropsy a Gi-tractus distended with gas, several black-brown foci on the glandular mucosa of the stomach and reduced spleen and thymus were noted.
Overall, body weight and food consumption were decreased at 150 and 300 mg/kg bw/day.
At necropsy, gelatinous mandibular lymph nodes and salivary glands were observed in two animals treated at 150 mg/kg bw/day, Gi-tractus distended with gas noted for one animal in Group 3 and one in Group 4. Furthermore, a small spleen and thymus were also noted for one animal treated at 150
mg/kg bw/day, for another animal in this group a reduced size and greenish discolouration of the papillary process of the liver was observed. No treatment related effect on absolute or relative liver and kidney weights was observed.
The percentage of post-implantation loss was slightly increased at 150 and 300 mg/kg bw/day.

Fetal findings
Litter sizes were within normal limits for all groups.
The male : female ratios were equal in litters of all groups.
Combined fetal body weights were decreased in the 150 and 300 mg/kg bw/day dose group compared to the vehicle control group (3.6, 4.6 and 5.2 grams, respectively). At 60 mg/kg bw/day, combined fetal weights were within the normal range (5.5 grams).
No external abnormalities were noted for any of the fetuses in any of the groups.

Based on the results of the dose range finding study, selected dose levels for the main study were 20, 60 and 150 mg/kg bw/day.

Maternal examinations:

CLINICAL EXAMINATIONS: Yes
- Time schedule: At least once daily from Day 2 post-coitum onwards up to the day prior to necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: Days 2, 6, 9, 12, 15, 18 and 21 post-coitum.

FOOD CONSUMPTION: Yes
- Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum.

WATER CONSUMPTION: Yes
- Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.

POST-MORTEM EXAMINATIONS: Yes
- All animals surviving to the end of the observation period and the animal showing premature delivery were deeply anaesthetized using isoflurane and subsequently exsanguinated and subjected to an external, thoracic and abdominal examination, with
special attention being paid to the reproductive organs.


The liver and kidneys (and the animal identification marks) were collected from all females at necropsy and fixed in 10% buffered formalin (neutral phosphate buffered 4% formaldehyde solution). No histotechnology or histopathology on these organs was performed.
Based on target organs (in female rats) identified in a 28-day dose range finding study toxicity study (WIL Research Project 509883) with the test substance, the terminal body weight and the weights of the liver and kidneys were recorded for all females surviving to the planned day of necropsy.

Ovaries and uterine content:

Each ovary and uterine horn of animals surviving to planned necropsy was dissected and examined as quickly as possible to determine:
- The number of corpora lutea.
- The weight of the (gravid) uterus.
- The number and distribution of live and dead fetuses.
- The number and distribution of embryo-fetal deaths (early and late resorptions).
- The weight of each fetus.
- The sex of each fetus from the ano-genital distance (during necropsy) and also from gonadal
inspections (during further fetal examination).
- Externally visible macroscopic fetal abnormalities.

One animal that was sacrificed before planned necropsy was subjected to relevant examinations of the ovaries and uterine horns.
In case implantations were not macroscopically visible, the uterus was stained using the Salewski technique in order to determine any former implantation sites.

Fetal examinations:

External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural
anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).
External:
Each viable fetus was examined in detail, weighed and sexed. All live fetuses were euthanized by administration of approximately 0.05 mL (=10mg) of sodium pentobarbital into the oral cavity using a small flexible plastic or metal feeding tube.
Nonviable fetuses (the degree of autolysis was minimal or absent) were examined and weighed. For late resorptions a gross external examination performed (if possible).
Visceral (Internal):
Approximately one-half of the fetuses (live and dead) in each litter (all groups)were examined for visceral anomalies by dissection in the fresh (non-fixed) state. The thoracic and abdominal cavities were opened and dissected using a technique described by Stuckhardt and Poppe (Ref. 2). This
examination included the heart and major vessels. Fetal kidneys were examined and graded for renal papillae development as described by Woo and Hoar (Ref. 3). The sex of all fetuses was confirmed by internal examination.
The heads were removed from these fetuses and placed in Bouin's solution. Tissues were then transferred to a 70% aqueous ethanol solution for subsequent processing and soft-tissue examination of all groups using the Wilson sectioning technique. After examination, the tissues were stored in 10% buffered formalin. Any remaining tissues (from the fetuses used for fresh visceral examination) was discarded. The carcasses were processed and stained with Alizarin Red S (as described below), but not examined in first instance.
Skeletal:
From the other one-half of the fetuses (live and dead) in each litter (all groups), the sex was confirmed by internal examination. All fetuses were eviscerated, fixed in 96% aqueous ethanol, macerated in potassium hydroxide and stained with Alizarin Red S by a method similar to that described by Dawson (Ref. 5). Skeletal examination was done for one-half of the fetuses (i.e. the fetuses with heads). The specimens were archived in glycerin with bronopol as preservative. A few bones were not available for skeletal examination because they were accidentally damaged or lost during processing. The missing bones were listed in the raw data; evaluation by the fetal pathologist and study director determined there was no influence on the outcome of the individual or overall skeletal examinations, or on the integrity of the study as a whole.

Statistics:

The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control group.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- The Mann Whitney test was used to compare mean litter proportions (percent of litter) of the number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and postimplantation loss, and sex distribution.
- Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test was used to compare the compound-treated groups to the control group.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.
Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations might be rounded off before printing. Therefore, two groups might display the same printed means for a given parameter, yet display different test statistics values.
No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and post-implantation loss.

Indices:

For each litter the following calculations were performed:
Percent Pre-implantation loss, percent Post-implantation loss
The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a
mean litter proportion on a total group basis, i.e. percent Viable fetuses affected/litter
The following definitions were applicable for implantation data:
- Fetal (late) resorptions were defined as a dead fetus with external degenerative changes and presence of distinguishable features such as head or limbs.
- Embryonic (early) resorptions were defined as evidence of implantation without presence of distinguishable features such as head or limbs.
- Dead fetus was defined as a non-viable fetus without external degenerative changes and presence of distinguishable features such as head or limbs.
- Post-implantation loss included embryonic (early) resorptions, fetal (late) resorptions and dead fetuses.

Historical control data:

yes, historical data on fetal morphology are part of the report

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

No treatment related effects were observed in animals treated at 20 mg/kg bw/day. Although the incidence and persistence of salivation showed a dose related increase, no correlated findings were noted. Therefore, the salivation is likely attributed to the taste of the test item and of no toxicological relevance.
At 60 mg/kg bw/day, piloerection was observed in 3/22 females. As the piloerecton was limited to three animals this finding was considered to be of no toxicological relevance.
At 150 mg/kg bw hunched posture was noted for 3/22 animals and piloerection for 5/22 females. Together with reduced body weight gain and food comsumption this effect was considered as treatment related and adverse.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At 60 mg/kg bw/day a significantly reduced body weight gain with concurrent decreased food consumption was observed at Day 9 post-coitum. As the body weight gain and food consumption recovered from Day 12 post-coitum onwards, these findings were considered to be of no toxicological relevance.
At 150 mg/kg bw/day body weight was significantly reduced between day 9 and day 15 post-coitum. Together with the reduced food consumption and the clinical signs in some animals of this group these findings were considered to be treatment related and adverse.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

At start of treatment, food consumption was significantly decreased from Day 6-9 post-coitum at 60 mg/kg bw/day and from Day 6-12 at 150 mg/kg bw/day. Additionally, at the end of treatment food consumption was slightly decreased in animals treated at 150 mg/kg bw/day compared to the vehicle controls.
Food consumption at 20 mg/kg bw/day remained within the same range as the control group.

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The weight of the liver was slightly increased in animals treated at 150 mg/kg bw/day. The approximately 7% increase was significant when corrected for body weight.
Absolute kidney weights were slightly, but significantly decreased in the 150 mg/kg bw/day Group. As considered to be of toxicological relevance.
Liver and kidney weights were unaffected by treatment at 20 and 60 mg/kg bw/day.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The presence of scab formation and alopecia were confirmed at necropsy for female No. 3 (Control) and 52 (60 mg/kg bw/day), respectively.
The contents of the stomach of the female that delivered early on Day 21 post-coitum was found to be reddish. This is most likely the result of cleaning of the litter after birth.

Neuropathological findings:

not examined

Number of abortions:

no effects observed

Pre- and post-implantation loss:

effects observed, non-treatment-related

Description (incidence and severity):

At 60 mg/kg bw/day, a significant increase in pre-implantation loss was observed (12.2% compared to 6.0% in the control group). Treatment was started on Day 6 post-coitum, after implantation has occurred, therefore this finding is considered not to be related to treatment. Moreover, no dose response relationship was noted.

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

One female (No. 30; 60 mg/kg bw/day) delivered early on Day 21 postcoitum.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

All females at scheduled necropsy were pregnant except for one female (No. 20; Control) and had litters with viable fetuses.

Dose descriptor:

NOAEL

Effect level:

60 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: no adverse effects at this dose

Dose descriptor:

LOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

Abnormalities:

effects observed, treatment-related

Localisation:

other: general maternal toxicity

Description (incidence and severity):

slight at 150 mg/kg bw

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Combined fetal body weights were significantly reduced at 150 mg/kg bw/day compared to the Control group (4.9 grams versus 5.3 grams, respectively).
Mean fetal body weights were unaffected at 20 and 60 mg/kg bw/day.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

There were no treatment related effects on external morphology following treatment up to 150 mg/kg bw/day.
Five fetuses in this study were externally malformed. One in the 20 mg/kg bw/day Group (A039-09), three at 60 mg/kg bw/day (A046-04, A049-09, A057-12) and one at 150 mg/kg bw/day (A081-05). The nature of malformations observed in these respective fetuses (generalized subcutaneous edema, small lower jaw, hyperextended limb, small eye bulge and omphalocele) and single occurrence does not suggest a relation to treatment and therefore all were considered to be chance findings.
There were no other external malformations, and external variations were not seen in any group.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

There were no treatment related effects on skeletal morphology following treatment up to 150 mg/kg bw/day.
Skeletal malformations were observed in 4 (2), 1 (1), 5 (3) and 2 (2) fetuses (litters) in Groups 1, 2, 3 and 4, respectively. The ones noted at 150 mg/kg bw/day, vertebral anomaly with or without associated rib anomaly (fetus A077-03) and bent limb bones (fetus A088-10) were also noted in respectively the control group (fetus A008-06 and A011-07) and at 20 mg/kg bw/day (fetus A031-07) and are as such not considered to have a relation to treatment.
At 60 mg/kg bw/day, fetuses A047-05 and -09 had a rib anomaly which was also observed in control fetuses A008-08 and -12. The other skeletally malformed fetuses in this group either had sternoschisis (fetus A046-08) or a vertebral centra anomaly (fetus A046-04 and A055-06). These two malformations did not occur in other groups, but at the low incidence observed were considered to be chance findings. Moreover, all three malformations in the 60 mg/kg bw/day Group were also noted previously in historical control fetuses.
Skeletal variations occurred at an incidence of 80.2%, 69.3%, 72.1% and 83.1% per litter in Groups 1, 2, 3 and 4, respectively. All the variations noted, were not considered treatment related as they occurred in the absence of a dose-dependent relationship, infrequently and/or at frequencies that were within the range of available historical control data.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

There were no treatment related effects on visceral morphology following treatment up to 150 mg/kg bw/day.
Apart from a fetus in the 60 mg/kg bw/day Group (A045-10), which had a small eye that was observed at soft tissue cephalic examination, there were no other viscerally malformed fetuses. The externally noted small eye bulge in 60 mg/kg bw/day Group fetus A057-12 should be mentioned here as well, but the presence of two of the same eye findings at the mid-dose level only, does not indicate a treatment related effect.
The variations that were noted in this study were small supernumerary lobe(s) and appendix of the liver, convoluted and dilated ureter(s), small renal papilla, retroesophageal right subclavian artery and abnormal lung lobation. These variations occurred at low incidences, in the absence of a dose-related incidence trend and/or in control fetuses only and therefore were not considered to be treatment related.

Dose descriptor:

NOAEL

Effect level:

60 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects at this dose

Dose descriptor:

LOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Abnormalities:

no effects observed

Developmental effects observed:

no

Executive summary:

In a prenatal developmental toxicity study performed according to OECD TG 414 mated female Wistar rats were assigned to four dose groups, each containing twenty-two animals. The test item was administered once daily by gavage from Day 6 to 20 post-coitum at doses of 20, 60 and 150 mg/kg bw/day. The rats of the control group received the vehicle, Polyethylene glycol 400, alone.

With regard to maternal toxicity no treatment related effects were observed in animals treated at 20 mg/kg bw/day. Although the incidence and persistence of salivation showed a dose related increase, no correlated findings were noted. Therefore, the salivation is likely attributed to the taste of the test item and of no toxicological relevance. At 60 mg/kg bw/day, piloerection was observed in 3/22 females. Additionally, a significantly reduced body weight gain with concurrent decreased food consumption was observed at Day 9 post-coitum. As the piloerecton was limited to three animals and the body weight gain and food consumption recovered from Day 12 post-coitum onwards, these findings were considered to be of no toxicological relevance. In females treated at 150 mg/kg bw/day, the weight of the liver was slightly increased compared to the concurrent controls. The approximately 7% increase was significant when corrected for body weight. Although this effect is likely the result of treatment, it is only minor (<10%) and therefore not considered adverse. Furthermore, in the 150 mg/kg bw/day Group hunched posture was noted for 3/22 animals and piloerection for 5/22 females. Body weight gain was significantly reduced between Day 9 and Day 15 post-coitum. Additionally, overall food consumption was reduced in these animals. Taken together these findings were considered to be treatment related and adverse.

With regard to developmental findings up to 60 mg/kg bw/day, no developmental toxicity was observed. At 150 mg/kg bw/day, fetal body weights were significantly decreased. As maternal body weights were also decreased at this dose level, this was likely related to maternal toxicity.

In conclusion and based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for 2-Acetone, condensation product with phenol was established as being 60 mg/kg bw/day.

Reference 2

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Justification for type of information:

IUCLID READ-ACROSS: Justification for type of information
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The registered UVCB substance 2-acetone, condensation product with phenol mainly, in the following referred to as UVCB substance, consists of 4,4’-isopropylidenediphenol (Bisphenol A, CAS-No. 80-05-7, typical concentration about 40%). Consequently, 4,4’isopropylidenediphenol has major influence on the potential of 2-acetone, condensation product with phenol with regard to human health effects. .
For the assessment of human health toxicity of the UVCB substance two approaches were followed:
1) Data generation for the UVCB substance itself and toxicological assessment on the basis of the gained results, supplemented with
2) Read-across based on toxicological data for the main component of the UVCB substance, i.e. 4,4’-isopropylidenediphenol (Bisphenol A, CAS-No. 80-05-7).

2. SOURCE AND TARGET CHEMICAL(S)
Source: 4,4’-isopropylidenediphenol (Bisphenol A, EC No. 201-254-8)
Target: 2-acetone, condensation product with phenol (EC No. 931-252-8), consisting of about 40% 4,4’-isopropylidenediphenol
A separate document is attached for the description of the approach, called Information on Read-Across and DNEL Derivation for REACH Registration of 2-acetone, condensation product with phenol (EC Inventory No. 931-252-8)

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 416 (Two-Generation Reproduction Toxicity Study) TG 416 Enhanced

Species:

mouse

Strain:

CD-1

Route of administration:

oral: feed

No. of animals per sex per dose:

28

Dose descriptor:

NOEL

Effect level:

30 ppm

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Remarks:

Systemic

Effect level:

300 ppm

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Remarks:

Developmental

Effect level:

300 ppm

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Abnormalities:

effects observed, treatment-related

Localisation:

other: reduced body weight gain and effects on liver and kidney

Dose descriptor:

NOAEL

Remarks:

developmental

Effect level:

300 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on reduced offspring body weight, spleen and testes weights and delay in acquisition of puberty in males at 3500 ppm

Abnormalities:

effects observed, treatment-related

Localisation:

other: reduced offspring body weight, spleen and testes weights and delay in acquisition of puberty in males

Developmental effects observed:

yes

Lowest effective dose / conc.:

3 500 ppm

Treatment related:

yes

Relation to maternal toxicity:

developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Conclusions:

The authors concluded that BPA is not a selective developmental toxicant in mice.

Executive summary:

There were no BPA-related effects on adult mating, fertility or gestational indices, ovarian primordial follicle counts, estrous cyclicity, precoital interval, offspring sex ratios or postnatal survival, or reproductive organ weights or histopathology. Maternal systemic effects were increased liver and kidney weight at 3500 ppm. At 3500 ppm, BPA also reduced F1/F2 weanling body weight, reduced weanling spleen and testes weights, slightly delayed PPS, and apparently increased the incidence of treatment-related, undescended testes only in weanlings, which did not result in adverse effects on adult reproductive structures or functions; this last finding is considered a developmental delay in the normal process of testes descent. It is likely that these transient effects were secondary to (and caused by) systemic toxicity. Gestational length was increased by 0.3 days in F1/F2 generations; the toxicological significance, if any, of this marginal difference is unknown. At lower doses (0.018 -30 ppm), there were no treatment-related effects and no evidence of non-monotonic dose-response curves for any parameter. The systemic NOEL and developmental NOEL were 300 ppm BPA (approximately 50 mg/kg-day).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

other: rat and mouse

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

The UVCB substance did not affect the reproductive organs of male and female rats in a 90-day repeated dose toxicity study (Beerens-Heijnen, 2016). No specific reproductive toxicity study is available for the UVCB substance. However, due to an existing legal classification for Bisphenol A for reproductive toxicity (fertility) with Cat. 1B (new entry: change from Repr. Cat 2 to Cat 1B see Commission Regulation (EU) 2016/1179 of July 2016 amending Annex VI to Regulation (EC) 1272/2008; documentation on ECHA homepage not yet updated accordingly) this classification for reproductive toxicity is also applied to the UVCB substance as worst-case consideration.

No classification for developmental toxicity is warranted for the UVCB substance, based on a developmental toxicity study on rats with the substance itself and on Bisphenol A data on rats and mice.