4,4'-isopropylidenediphenol

Endpoint summary

Description of key information

In animal studies Bisphenol A is not irritating to the skin but irritating to the eye with effects persisted until the end of the study (day 28 post instillation), consequently, Bisphenol A has the potential to cause serious damage to the eyes. In inhalation studies slight and transient nasal tract epithelial damage was observed in rats exposed to Bisphenol A dust at 170 mg/m³ for 6 hours. Slight local inflammatory effects in the upper respiratory tract were observed in rats exposed to 50 mg/m³ and 150 mg/m³ of Bisphenol A in 2 and 13 week repeat inhalation studies, but were not observed at 10 mg/m³ in the same studies.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Conducted under OECD guidelines, OECD Good Laboratory Practices

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

Himalayan

Details on test animals or test system and environmental conditions:

TEST ANIMALS
-General information: Three male animals approximately 5-10 months of age with initial body weights of 2.4-2.6 kg were used.
-Diet: Ad libitum before and after the exposure period. Standard rabbit diet of Altromin 2023 (ALTROMIN GmbH, D-32791 Lage/Lippe). Food was analysed at least twice per year for contaminants.
-Drinking water: Water was offered ad libitum before and after the exposure period. Water samples were analysed twice per year for contaminants and once per year for a bacteriological investigation.
-Housing: Before and after the exposure period, animals were kept singly in cages measuring 425 mm x 600 mm x 380 mm (manufacturer: Dipl. Ing. W. EHRET GmbH, D-16352 Schonwalde). During the exposure period, animals were kept singly in restrainers which allowed free movement of the head but prevented a complete body turn. The cages excluded irritation of the skin by excrement and urine.
-Acclimation period: At least 20 days.

ENVIRONMENTAL CONDITIONS
-Temperature: 17-23 degrees C
-Humidity: 30-70%
-Photoperiod: 12 hours light (150 lux at approximately 1.5 meter room height)/12 hours dark

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

no

Amount / concentration applied:

500 mg BPA per animal. 4000 mg of the test compound was mixed with 2 ml water and 750 mg of this paste was applied per animal.

Duration of treatment / exposure:

Four hours.

Observation period:

72 hours.

Number of animals:

Three male animals.

Details on study design:

Three male Himalayan rabbits were shaved on the dorsal trunk area. Only animals with healthy, intact skin were used. Approximately 24 hours after shaving, a dose of 500 mg BPA per animal was applied to the test site (approximate area of 6 square cm) and covered with a gauze patch that was held in place with non-irritating tape for the duration of the exposure period. The surrounding untreated skin served as a control. The exposure time was four hours. After exposure, the patch was removed and the scores of the resulting reactions were taken 60 minutes, 24, 48, and 72 hours after patch removal.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 60 minutes

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 60 minutes

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 60 minutes

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

48 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

48 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

48 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

72 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

72 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

72 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: 60 minutes

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: 60 minutes

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: 60 minutes

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #1

Time point:

48 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #2

Time point:

48 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #3

Time point:

48 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #1

Time point:

72 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #2

Time point:

72 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritation parameter:

edema score

Basis:

animal #3

Time point:

72 h

Score:

0

Reversibility:

other: No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Irritant / corrosive response data:

No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Other effects:

There were no systemic intolerance reactions.

Conclusions:

The authors concluded that there were no substance-related lesions from the acute skin irritation test with BPA.

Executive summary:

Three male Himalayan rabbits were shaved in the dorsal trunk area and 24 hours later, 500 mg BPA per animal was applied to the test site. The surrounding untreated skin served as a control. The exposure period was four hours, after which the patch was removed and the resulting reactions were examined and scored at 60 minutes, 24, 48, and 72 hours after patch removal. The skin irritation scores for each animal were zero for erythema and edema at all time points. The authors concluded that there were no BPA-related lesions at any time point and there were no systemic intolerance reactions.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Conducted under OECD guidelines, OECD Good Laboratory Practices

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

Himalayan

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
-General information: Three male animals approximately 7-9 months of age with initial body weights of 2.3-2.4 kg were used.
-Diet: Ad libitum before and after the exposure period. Standard rabbit diet of Altromin 2023 (ALTROMIN GmbH, D-32791 Lage/Lippe). Food was analysed at least twice per year for contaminants.
-Drinking water: Water was offered ad libitum before and after the exposure period. Water samples were analysed twice per year for contaminants and once per year for a bacteriological investigation.
-Housing: Before the exposure period and 8 hours after the exposure period, animals were kept singly in cages measuring 425 mm x 600 mm x 380 mm (manufacturer: Dipl. Ing. W. EHRET GmbH, D-16352 Schonwalde). During the exposure period and for 8 hours afterwards, animals were kept singly in restrainers which allowed free movement of the head but prevented a complete body turn and wiping of the eyes by the paws and excluded irritation of the eye by excrement and urine.
-Acclimation period: At least 20 days.

ENVIRONMENTAL CONDITIONS
-Temperature: 17-23 degrees C
-Humidity: 30-70%
-Photoperiod: 12 hours light (150 lux at approximately 1.5 meter room height)/12 hours dark

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

The test material was ground to a fine dust and 100 mg was used per animal.

Duration of treatment / exposure:

Single instillation into the conjunctival sac, after which the lids were gently held together for one second.

Observation period (in vivo):

28 days.

Number of animals or in vitro replicates:

Three males.

Details on study design:

Three male Himalayan rabbits were treated with 100 mg BPA by a single instillation into the conjunctival sac of the right eye. The eye lids were then gently held together for one second to prevent loss of the material. The left eye, which remained untreated, served as a control. The eyes of the animals were not rinsed. The eyes were examined ophthalmoscopically with a slit lamp prior to the administration and 1, 24, 48, and 72 hours and 4 to 28 days after administration. The eye reactions were observed and registered. At 24 hours, 7, 14, and 28 days after administration, the eyes were treated with Fluorescein SE Thilo eye drops (Alcon Pharma GmbH, D-79108, Freiburg, Germany) and examined.

Irritation parameter:

cornea opacity score

Remarks:

opacity

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Reversibility:

not specified

Remarks on result:

other: Corneal opacity (grade 1) was observed in all three animals 1 hour to 9 days after instillation

Irritation parameter:

cornea opacity score

Remarks:

opacity

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Reversibility:

not specified

Remarks on result:

other: Corneal opacity (grade 1) was observed 1 hour to 13 days after instillation

Irritation parameter:

cornea opacity score

Remarks:

opacity

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Reversibility:

not specified

Remarks on result:

other: Corneal opacity (grade 1) was observed 1 hour to 28 days after instillation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Reversibility:

not specified

Remarks on result:

other: An irritation of the iris (grade 1) was observed one hour to 9 days after instillation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Reversibility:

not specified

Remarks on result:

other: An irritation of the iris (grade 1) was observed one hour to 11 days after instillation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Reversibility:

not specified

Remarks on result:

other: An irritation of the iris (grade 1) was observed one hour to 28 days after instillation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24 h

Score:

1

Reversibility:

not specified

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24 h

Score:

1

Reversibility:

not specified

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24 h

Score:

1

Reversibility:

not specified

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Reversibility:

not specified

Remarks on result:

other: Redness was abserved until 4 days after instillation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Reversibility:

not specified

Remarks on result:

other: Redness was abserved until 6 days after instillation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24 h

Score:

1

Reversibility:

not specified

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24 h

Score:

1

Reversibility:

not specified

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Reversibility:

not specified

Remarks on result:

other: Conjunctival chemosis (grade 2) was observed one hour to 4 days after instillation.

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

other: 5 and 6 days

Score:

1

Reversibility:

not specified

Remarks on result:

other: Conjunctival chemosis (grade 1) was observed 5 and 6 days (grade 1) after instillation.

Irritant / corrosive response data:

Corneal opacity (grade 1) was observed in all three animals 1 hour to 9 days after instillation; in animal #2 until 13 days; and in animal #3 until 28 days after instillation. The fluorescein test performed after 24 hours revealed corneal staining in all 3 rabbits (whole surface). The fluorescein test performed after 7 days revealed corneal staining in animal #1 and animal #2 (3/4 of the corneal surface) and in animal #3 (whole surface). The fluorescein tests performed after 14 and 21 days revealed corneal staining in animal #3 (1/2 of the corneal surface). An irritation of the iris (grade 1) was observed in all three animals one hour to 9 days after instillation, and in animal #2 until 11 days and in animal #3 until 28 days after instillation. Conjunctival redness (grade 1) was observed in all animals one to 24 hours after instillation, in animal #2 until 4 days and in animal #3 until 6 days after instillation. Conjunctival chemosis (grade 1) was observed in animal #1 and animal #2 24 hours after instillation and in animal #3 one hour to 4 days (grade 2) and 5 and 6 days (grade 1) after instillation. Whitish deposits in the conjunctival sac (probably pus) were observed in animal #2 and animal #3 from 72 hours to 5 days after instillation.

Other effects:

There were no systemic intolerance reactions.

Conclusions:

The authors concluded that BPA induced grade 1 corneal opacity, corneal staining, grade 1 iris irritation, grade 1 conjunctival redness, and grades 1 and 2 conjunctival chemosis.

Executive summary:

Three male Himalayan rabbits were treated with 100 mg BPA by a single instillation into the conjunctival sac of the right eye. The eye lids were then gently held together for one second to prevent loss of the material. The left eye, which remained untreated, served as a control. The eyes of the animals were not rinsed. The eyes were examined ophthalmoscopically with a slit lamp prior to the administration and 1, 24, 48, and 72 hours and 4 to 28 days after administration. The eye reactions were observed and registered. At 24 hours, 7, 14, and 28 days after administration, the eyes were treated with Fluorescein SE Thilo eye drops (Alcon Pharma GmbH, D-79108, Freiburg, Germany) and examined. Corneal opacity (grade 1) was observed in all three animals 1 hour to 9 days after instillation; in animal #2 until 13 days; and in animal #3 until 28 days after instillation. The fluorescein test performed after 24 hours revealed corneal staining in all 3 rabbits (whole surface). The fluorescein test performed after 7 days revealed corneal staining in animal #1 and animal #2 (3/4 of the corneal surface) and in animal #3 (whole surface). The fluorescein tests performed after 14 and 21 days revealed corneal staining in animal #3 (1/2 of the corneal surface). An irritation of the iris (grade 1) was observed in all three animals one hour to 9 days after instillation, and in animal #2 until 11 days and in animal #3 until 28 days after instillation. Conjunctival redness (grade 1) was observed in all animals one to 24 hours after instillation, in animal #2 until 4 days and in animal #3 until 6 days after instillation. Conjunctival chemosis (grade 1) was observed in animal #1 and animal #2 24 hours after instillation and in animal #3 one hour to 4 days (grade 2) and 5 and 6 days (grade 1) after instillation. Whitish deposits in the conjunctival sac (probably pus) were observed in animal #2 and animal #3 from 72 hours to 5 days after instillation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

The 2003 EU RAR concluded:

"Limited human anecdotal information of uncertain reliability is available from written industry correspondence suggesting that workers handling Bisphenol A have in the past experienced skin, eye and respiratory tract irritation. It cannot be determined whether the reported skin reactions were related to skin sensitisation or irritation. However, a recent well conducted animal study clearly shows that Bisphenol A is not a skin irritant. A recent well conducted animal study shows that Bisphenol A is an eye irritant; effects persisted until the end of the study (day 28 postinstillation) in 1 of 3 rabbits. Overall, taking into account the animal and human evidence, Bisphenol A has the potential to cause serious damage to the eyes. Slight and transient nasal tract epithelial damage was observed in rats exposed to Bisphenol A dust at 170 mg/m³ for 6 hours. Slight local inflammatory effects in the upper respiratory tract were observed in rats exposed to 50 mg/m³ and 150 mg/m³ of Bisphenol A in 2 and 13 week repeat inhalation studies, but were not observed at 10 mg/m³ in the same studies. Taken together with anecdotal human evidence, these data suggest Bisphenol A has a limited respiratory irritation potential."

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

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Bisphenol A is classified with Eye Dam. 1 (H318) and STOT SE 3 (H335) according to Annex VI of Regulation (EC) No 1272/2008.