4,4'-isopropylidenediphenol

Endpoint summary

Description of key information

Bisphenol A is of low acute toxicity by all routes of exposure relevant to human health. Oral LD₅₀ values beyond 2,000 mg/kg are reported in rodents, and dermal LD₅₀ values above 2,000 mg/kg are indicated in the rabbit. For inhalation, a 6-hour exposure to 170 mg/m³ (the highest attainable concentration) produced no death in rats; slight and transient slight nasal tract epithelial damage was observed. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Conducted under OECD Guidelines

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 6-10 weeks.
- Housing: Animals were housed in groups of 5 by sex in grid floor stainless steel cages.
- Diet: Ad libitum, with the exception of an overnight fast prior to dosing. Food was re-introduced 3-4 hours after treatment. SQC Rat and Mouse Maintenance Diet No. 1, Expanded (Special Diets Services, Ltd., Stepfield, Witham, Essex, England). Food was considered to not contain any contaminant at a level that might have affected the objectives or integrity of the study.
- Water: Water was provided at all times and dispensed from glass water bottles. Water was considered to not contain any contaminant at a level that might have affected the objectives or integrity of the study.
- Acclimation period: At least 3 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 degrees C
- Humidity: 40-70%
- Photoperiod: 12 hours light/12 hours dark

Route of administration:

oral: gavage

Vehicle:

other: 1% methylcellulose

Details on oral exposure:

Suspensions of BPA in 1% methylcellulose vehicle were administered once to each animal by oral gavage using a metal stomach tube attached to a disposable plastic syringe.

Doses:

5000 mg/kg and 2000 mg/kg

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

no

Details on study design:

A single oral dose of 5000 mg/kg BPA was administered by gavage to 5 male and 5 female Sprague Dawley rats after an overnight fast. At the request of the study sponsor, a second group of 10 animals (5 males, 5 females) was treated with a single oral dose of 2000 mg/kg. Animals were observed for overt signs of toxicity or behavioural changes at 1 and 4 hours after treatment and subsequently once daily for 14 days. Body weights were recorded on the day before treatment (day -1), the day of treatment (day 0), days 7 and 14, and at death. All animals were subjected to gross necropsy examination.

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 2 000 - <= 5 000 mg/kg bw

Mortality:

At 2000 mg/kg BPA, no animals died.
At 5000 mg/kg BPA, 1 male and 5 females died within 1-2 days after treatment.

Clinical signs:

other: At 5000 mg/kg BPA, major signs of toxicity noted on the day of dosing were lethargy, prostration, hunched posture, and piloerection. Three surviving animals were prostrate on the morning of day 1 and were found dead at afternoon death check approximately

Gross pathology:

Common findings at necropsy of animals that died during the study were associated with the liver and gastrointestinal tract. All animals necropsied at study termination were unremarkable.

Conclusions:

The acute oral median lethal dose of BPA in the rat was confirmed to be in excess of 2000 mg/kg and was approximately 5000 mg/kg.

Executive summary:

A single oral dose of 5000 mg/kg BPA was administered by gavage to 5 male and 5 female Sprague Dawley rats after an overnight fast. At the request of the study sponsor, a second group of 10 animals (5 males, 5 females) was treated with a single oral dose of 2000 mg/kg. Animals were observed for overt signs of toxicity or behavioural changes at 1 and 4 hours after treatment and subsequently once daily for 14 days. Body weights were recorded on the day before treatment (day -1), the day of treatment, days 7 and 14, and at death. All animals were subjected to gross necropsy examination. At 5000 mg/kg BPA, 1 male and 5 females died within 1-2 days after treatment. Major signs of toxicity noted on the day of dosing were lethargy, prostration, hunched posture, and piloerection. Three surviving animals were prostrate on the morning of day 1 and were found dead at afternoon death check approximately 30 hours after dosing. At 2000 mg/kg BPA, no animals died, but all animals were lethargic or prostrate on the day of dosing. Occasional signs of chromodacryorrhoea and salivation were noted on the day of dosing and on day 1. All surviving animals from both dose groups showed gains in body weight at study termination. Common findings at necropsy of animals that died during the study were associated with the liver and gastrointestinal tract. All animals necropsied at study termination were unremarkable. The authors concluded that the acute oral median lethal dose of BPA in the rat was in excess of 2000 mg/kg and was approximately 5000 mg/kg.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study discussed in the EU RAR 2003

Qualifier:

no guideline followed

Principles of method if other than guideline:

This was an acute oral toxicity test within a larger carcinogenesis bioassay of Bisphenol A. Single doses of Bisphenol A (1470, 2150, 3160, 4640, 6810, or 10000 mg/kg) with 1.5% acacia as the vehicle were administered via gavage to groups of B6C3F1 mice (5 males/5 females per dose group, except the 2150 mg/kg dose was not administered to males and the 10000 mg/kg dose was not administered to females). All surviving animals were sacrificed on day 15 and LD50 values were calculated.

GLP compliance:

not specified

Test type:

standard acute method

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: 1.5% acacia

Preliminary study:

The LD50 values were 5200 mg/kg for male mice and 4100 mg/kg for female mice.

Sex:

male

Dose descriptor:

LD50

Effect level:

5 200 mg/kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

4 100 mg/kg bw

Mortality:

At 1470 mg/kg BPA, one female and no males died.
At 2150 mg/kg BPA, no females died (males were not tested).
At 3160 mg/kg BPA, no males or females died.
At 4640 mg/kg BPA, one male and four females died.
At 6810 mg/kg BPA, all males and all females died.
At 10000 mg/kg BPA all males died (females were not tested).

Executive summary:

This was an acute oral toxicity test within a larger carcinogenesis bioassay of Bisphenol A. Single doses of Bisphenol A (1470, 2150, 3160, 4640, 6810, or 10000 mg/kg) with 1.5% acacia as the vehicle were administered via gavage to groups of B6C3F1 mice (5 males/5 females per dose group, except the 2150 mg/kg dose was not administered to males and the 10000 mg/kg dose was not administered to females). All surviving animals were sacrificed on day 15 and LD50 values were calculated. The LC50 value for male mice was 5200 mg/kg Bisphenol A and for female mice was 4100 mg/kg Bisphenol A.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

4 100 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Conducted in compliance with FDA and EPA good laboratory practices

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 10 male and 10 female Fischer 344 rats were exposed by inhalation to 0 or 170 mg/cubic meter Bisphenol A for 6 hours. The mass median aerodynamic diameter (MMAD) for the Bisphenol A aerosol was 3.9 µm (geometric standard deviation = 3.5). Body weights were obtained on the first day after exposure and approximately twice per week during a 14-day post-exposure period. Necropsies of 5 males and 5 females from each group were performed the day after exposure. All other rats were submitted for a gross necropsy examination at the end of the 14-day post-exposure period.

GLP compliance:

yes

Test type:

standard acute method

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 7-9 weeks
- Housing: Animals were housed in groups in stainless steel cages during the acclimation period and were housed singly during exposure and the 14-day post-exposure period.
- Diet: Ad libitum (except during exposure). Certified Rodent Chow (Ralston Purina Co., St. Louis, Missouri, United States).
- Water: Ad libitum (except during exposure). Municipal tap water analysed by the City of Midland, Michigan, United States.
- Acclimation period: At least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature: 72 degrees F
- Humidity: 50%
- Photoperiod: 12 hours light/12 hours dark

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Polycarbonate grade BPA was aerosolised using a modified Marple dust generator. Approximately 90 liters/min of dry, compressed air was used to aerosolise the particles in the dust generator. The remaining air supplied to the chamber was controlled to maintain a temperature of 70 degrees F and relative humidity of 50%. The control chamber also had approximately 90 liters/min of dry, compressed air added to the chamber airstream. Whole-body exposures were conducted using stainless steel and glass 1000 liter Rochester-type chambers. The airflow was maintained at approximately 200 liters/min. Groups of animals were exposed to room air or 170 mg/cubic meter BPA for 6 hours.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The mass concentration of aerosol present in the chamber was determined gravimetrically at least 3 times on pre-weighed Teflon (TE36) filters during the 6-hour exposure period. Particle size of BPA was determined aerodynamically twice during the exposure.

Duration of exposure:

6 h

Concentrations:

170 mg/cubic meter

No. of animals per sex per dose:

10 males and 10 females

Control animals:

yes

Details on study design:

Groups of 10 male and 10 female Fischer 344 rats were exposed by inhalation to 0 or 170 mg/cubic meter BPA (the highest attainable concentration)for 6 hours. The mass median aerodynamic diameter (MMAD) for the BPA aerosol was 3.9 µm (geometric standard deviation = 3.5). Body weights were obtained on the first day after exposure and approximately twice per week during a 14-day post-exposure period. Necropsies of 5 males and 5 females from each group were performed the day after exposure. All other rats were submitted for a gross necropsy examination at the end of the 14-day post-exposure period.

Sex:

male/female

Dose descriptor:

other: reversible nasal inflammation; reversible ulceration of incisive ducts

Effect level:

170 mg/m³ air

Exp. duration:

6 h

Mortality:

There were no deaths during the exposure period or 14-day recovery period.

Body weight:

Body weight gains of males exposed to BPA were slightly decreased from control values on the day after exposure, but were comparable to control values within 3 days following exposure. Body weights of females were comparable to control values.

Gross pathology:

Soiling of the face and forelimb in males and females and soiling of the perineal region in females was observed one day after exposure.

Other findings:

Histopathological changes were observed in the anterior portion of the nasal tissue. Acute inflammation of the external nares and ulceration of the incisive ducts were observed one day after exposure, but these changes were reversible within the 14-day recovery period. No evidence for systemic toxicity was observed throughout the study.

Conclusions:

Exposure of rats to 170 mg/cubic meter BPA resulted in inflammation in the anterior portion of the nose and ulceration in the incisive ducts. These changes were reversible within the 14-day recovery period. No evidence for systemic toxicity was observed throughout the study.

Executive summary:

Groups of 10 male and 10 female Fischer 344 rats were exposed by inhalation to 0 or 170 mg/cubic meter Bisphenol A (the highest attainable concentration) for 6 hours. The mass median aerodynamic diameter (MMAD) for the Bisphenol A aerosol was 3.9 µm (geometric standard deviation = 3.5). Body weights were obtained on the first day after exposure and approximately twice per week during a 14-day post-exposure period. Necropsies of 5 males and 5 females from each group were performed the day after exposure. All other rats were submitted for a gross necropsy examination at the end of the 14-day post-exposure period. There were no deaths during the exposure period or 14-day recovery period. Body weight gains of males exposed to Bisphenol A were slightly decreased from control values on the day after exposure, but were comparable to control values within 3 days following exposure. Body weights of females were comparable to control values. Soiling of the face and forelimb in males and females and soiling of the perineal region in females was observed one day after exposure. Acute inflammation of the external nares and ulceration of the incisive ducts were observed one day after exposure, but these changes were reversible within the 14-day recovery period. No evidence for systemic toxicity was observed throughout the study.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

discriminating conc.

Value:

170 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study discussed in the EU RAR 2003

Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute toxicity by skin penetration (exact site not reported) was determined in 15 rabbits. Rabbits were treated with a 2 g/kg dose of Bisphenol A (administered as a 20 ml/kg dose of a 10% suspension of Bisphenol A in propylene glycol) and the LD50 was estimated.

GLP compliance:

no

Test type:

standard acute method

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

propylene glycol

Sex:

not specified

Dose descriptor:

LD50

Effect level:

ca. 3 000 mg/kg bw

Remarks on result:

other: 3/15 rabbits died and the authors concluded that the LD50 would be close to 3000 mg/kg

Mortality:

Three of 15 rabbits died after treatment.

Executive summary:

Acute toxicity by skin penetration (exact site not reported) was determined in 15 rabbits. Rabbits were treated with a 2 g/kg dose of Bisphenol A (administered as a 20 ml/kg dose of a 10% suspension of Bisphenol A in propylene glycol) and the LD50 was estimated. Three of 15 rabbits died after treatment and the estimated LD50 was close to 3000 mg/kg.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study discussed in the EU RAR 2003

Qualifier:

no guideline followed

Principles of method if other than guideline:

Four male New Zealand albino rabbits, 3 to 5 months of age, were exposed to 6.4 g/kg Bisphenol A under impervious sheeting on the clipped intact skin of the trunk for 24 hours. Excess fluid was removed to prevent ingestion and the maximum dosage that could be retained in contact with the skin of the trunk was determined.

GLP compliance:

no

Test type:

standard acute method

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Type of coverage:

occlusive

Vehicle:

DMSO

Sex:

male

Dose descriptor:

other: maximum dosage that can be retained

Effect level:

ca. 6 400 mg/kg bw

Mortality:

One of the 4 animals died two days after exposure.

Executive summary:

Four male New Zealand albino rabbits, 3 to 5 months of age, were exposed to 6.4 g/kg Bisphenol A (16 ml/kg of a 40% Bisphenol A solution in dimethylsulfoxide) under impervious sheeting on the clipped intact skin of the trunk for 24 hours. Excess fluid was removed to prevent ingestion and the maximum dosage that could be retained in contact with the skin of the trunk was determined. One of the 4 animals died two days after exposure. The authors concluded that the dose of 6.4 g/kg represents the maximum amount of Bisphenol A solution that can be retained in contact with the skin of the trunk beneath an impervious covering.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 000 mg/kg bw

Additional information

The 2003 EU RAR concluded:

"No useful information is available on the effects of single exposure to Bisphenol A in humans. Oral LD50 values beyond 2,000 mg/kg are indicated in the rat and mouse, and dermal LD50 values above 2,000 mg/kg are indicated in the rabbit. Few details exist of the toxic signs observed or of target organs. For inhalation, a 6-hour exposure to 170 mg/m³ (the highest attainable concentration) produced no death in rats; slight and transient slight nasal tract epithelial damage was observed. These data indicate that Bisphenol A is of low acute toxicity by all routes of exposure relevant to human health."

There is no reliable and significant new information on the acute toxicity of Bisphenol A in the updated 2008 EU RAR or elsewhere.

Justification for selection of acute toxicity – oral endpoint
Jones 1985 reported LD₅₀ >2000; NTP reported 4100 mg/kg as the lowest LD₅₀.

Justification for classification or non-classification

Bisphenol A is included in Annex VI of Regulation (EC) No 1272/2008. 

No classification regarding acute toxicity is required.