4,4'-isopropylidenediphenol

Endpoint summary

Description of key information

Bisphenol A has neither a sensitizing potential after dermal application nor any UV-A irradiation-dependent immunostimulating (photosensitizing) potential after epicutaneous application in mice. However, according to the EU-RAR Update (2003 & 2008)"Overall the new information does not confirm the previously reported evidence of a skin sensitisation potential of Bisphenol A. While the data do not exclude a skin sensitising activity of Bisphenol A at high concentrations (>30%), there is no evidence that this is a concern for workers in current Bisphenol A manufacturing plants (such workers are believed to represent the group most likely to be exposed to Bisphenol A in dust)."

Based on the EU-RAR Bisphenol A is allocated to the moderate hazard band.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Remarks:

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 406 (Skin Sensitisation)

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2600 (Skin Sensitisation)

GLP compliance:

yes

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

NMRI

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Animal strain: Specific pathogen-free female NMRI mice of the strain Hsd Win:NMRI were obtained from Harlan Winkelmann GmbH, 33176 Borchen, Germany.
- Housing: During the adaptation period, animals were housed in conventional Makrolon type III cages with up to 10 mice per cage. During the study period, animals were housed in type II cages with one mouse per cage. The cages were changed at least twice a week. Low-dust wood granulate type S 8/15 from J. Rettenmaier & Sohne Fullstoff-Fabriken, 7092 Ellwangen-Holzmuhle, was used as bedding. The wood granulate was analysed at random for contaminants.
-Diet: Ad libitum. Feed was PROVIMI KLIBA SA 3883 maintenance diet for rats and mice (from Provimi Kliba SA, CH-4303 Kaiseraugst, Switzerland). Contaminant content and nutritive composition was analysed routinely in random samples.
-Drinking water. Ad libitum. Tap water of drinking water quality was provided in polycarbonate bottles.
-Acclimation period: At least 7 days, during which the state of health of the animals was monitored.

ENVIRONMENTAL CONDITIONS
-Temperature: 20-24 degrees C
-Relative humidity: About 30%
-Photoperiod: 12 hours light/12 hours dark

Vehicle:

other: DAE 433

Concentration:

25 µl of a 0%, 3%, 10%, or 30% solution of BPA in DAE 433

No. of animals per dose:

6

Details on study design:

Female NMRI mice were treated epicutaneously on the dorsal part of both ears with 25 µl per ear of a solution containing 0%, 3%, 10%, or 30% BPA in DAE 433 (6 animals per dose group). Treatments were given once per day for three consecutive days (day 0, day 1, and day 2). On day 0 and day 3 (one day after last application), the ear swelling of the animals was measured using a spring-loaded micrometer and mean ear swelling was calculated. Ear weight was measured on day 3 using a punch to cut off a piece of each ear with an 8 mm diameter. Also on day 3, animals were sacrificed by inhalation of carbon dioxide and lymphatic organs (the auricular lymph nodes) were transferred to PBS. Lymph nodes (LNs) were weighed and then crushed through a plastic sieve into 12-well plates and cell counts per ml were determined using a Coulter counter. The stimulation index was calculated by dividing the absolute number of the weight or cell counts of the treated lymph nodes by the vehicle lymph nodes.

Statistics:

When statistically reasonable, the values from treated groups were compared with those from controls by the Mann-Whitney or the Wilcoxon significance test (Rank Sum Test or One-Way ANOVA or Kruskal-Wallis ANOVA) at significance levels of 5% (one-tailed for LLNA/ear swelling). Outlying values in the LN/ear weights or LN cell counts were eliminated at a probability level of 99% by Nalimov's method. For the LLNA/ear swelling, the smallest significant differences in the means were calculated by Scheffe's method. For indices, only the standard deviations between groups and difference analysis of the mean values (Scheffe's method) were used in the evaluation of the biological relevance.

Positive control results:

No positive control was used.

Parameter:

SI

Remarks:

Lymph node weight index

Value:

1

Test group / Remarks:

6 animals, 0% BPA in DAE 433

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling.

Parameter:

SI

Remarks:

Lymph node weight index

Value:

0.85

Test group / Remarks:

6 animals, 3% BPA in DAE 433

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling.

Parameter:

SI

Remarks:

Lymph node weight index

Value:

1.07

Test group / Remarks:

6 animals, 10% BPA in DAE 433

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling.

Parameter:

SI

Remarks:

Lymph node weight index

Value:

0.93

Test group / Remarks:

6 animals, 30% BPA in DAE 433

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling.

Parameter:

SI

Remarks:

LN cell count index

Value:

1

Test group / Remarks:

6 animals, 0% BPA in DAE 433

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling.

Parameter:

SI

Remarks:

LN cell count index

Value:

1.25

Test group / Remarks:

6 animals, 3% BPA in DAE 433

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling.

Parameter:

SI

Remarks:

LN cell count index

Value:

1.35

Test group / Remarks:

6 animals, 10% BPA in DAE 433

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling.

Parameter:

SI

Remarks:

LN cell count index

Value:

1.24

Test group / Remarks:

6 animals, 30% BPA in DAE 433

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling.

Parameter:

SI

Remarks:

Ear swelling index on day 3

Value:

1

Test group / Remarks:

6 animals, 0% BPA in DAE 433

Parameter:

SI

Remarks:

Ear swelling index on day 3

Value:

1.02

Test group / Remarks:

6 animals, 3% BPA in DAE 433

Parameter:

SI

Remarks:

Ear swelling index on day 3

Value:

1.04

Test group / Remarks:

6 animals, 10% BPA in DAE 433

Parameter:

SI

Remarks:

Ear swelling index on day 3

Value:

0.99

Test group / Remarks:

6 animals, 30% BPA in DAE 433

Parameter:

other: disintegrations per minute (DPM)

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling, as authorised in OECD Guideline No. 429.

The authors stated that compared to vehicle-treated animals, none of the measured parameters reached or exceeded the "positive levels" defined for the assay.

Interpretation of results:

not sensitising

Remarks:

Migrated information

Conclusions:

The authors concluded that BPA has neither an irritating nor a sensitising potential in mice after dermal application.

Executive summary:

Female NMRI mice were treated epicutaneously on the dorsal part of both ears with 25 µl per ear of a solution containing 0%, 3%, 10%, or 30% BPA in DAE 433 (6 animals per dose group). Treatments were given once per day for three consecutive days (day 0, day 1, and day 2). On day 0 and day 3 (one day after last application), the ear swelling of the animals was measured using a spring-loaded micrometer and mean ear swelling was calculated. Ear weight was measured on day 3 using a punch to cut off a piece of each ear with an 8 mm diameter. Also on day 3, animals were sacrificed by inhalation of carbon dioxide and lymphatic organs (the auricular lymph nodes) were transferred to PBS. Lymph nodes (LNs) were weighed and then crushed through a plastic sieve into 12-well plates and cell counts per ml were determined using a Coulter counter. The stimulation index was calculated by dividing the absolute number of the weight or cell counts of the treated lymph nodes by the vehicle lymph nodes. Compared to vehicle-treated animals, none of the measured parameters reached or exceeded the "positive levels" defined for the assay. The authors concluded that BPA has neither an irritating nor a sensitising potential in mice after dermal application.

Reference 2

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Conducted under OECD Guidelines and OECD Good Laboratory Practices

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2600 (Skin Sensitisation)

GLP compliance:

yes

Type of study:

other: Photoreactive local lymph node assay to investigate UV dependent activation of BP

Species:

mouse

Strain:

NMRI

Sex:

female

Vehicle:

other: DAE 433

Concentration:

25 µl of a 0%, 3%, 10%, or 30% BPA solution in DAE 433 with UV-A irradiation and 30% BPA solution in DAE 433 without UV-A irradiation.

No. of animals per dose:

6

Details on study design:

Female NMRI mice were treated epicutaneously on the dorsal part of both ears with 25 µl per ear of a solution containing 0%, 3%, 10%, or 30% BPA in DAE 433 (6 animals per dose group). Treatments were given once per day for three consecutive days (day 1, day 2, and day 3). Except for one group receiving 30% BPA, the animals were irradiated with UV light (20 J UV-A/cm squared) immediately after BPA application. On day 1 and day 4 (one day after last application), the ear swelling of the animals was measured using a spring-loaded micrometer and mean ear swelling was calculated. Ear weight was measured on day 4 using a punch to cut off a piece of each ear with an 8 mm diameter. Also on day 4, animals were sacrificed by inhalation of carbon dioxide and lymphatic organs (the auricular lymph nodes) were transferred to PBS. Lymph nodes (LNs) were weighed and then cut up with broad forceps and cell counts per ml were determined using a Coulter counter. The stimulation index was calculated by dividing the absolute number of the weight or cell counts of the treated lymph nodes by the vehicle lymph nodes.

Parameter:

SI

Remarks on result:

other: see Remark

Remarks:

Lymph node stimulation was measured by cell counts instead of radioactive labelling. Lymph node weight index at 0, 3%, 10%, 30%, and 30% without UV: 1.00, 0.81, 0.97, 0.91, and 0.93, respectively. LN cell count index at 0, 3%, 10%, 30%, and 30% without UV: 1.00, 0.66, 0.80, 0.78, and 0.74, respectively. Ear swelling index on day 4 at 0, 3%, 10%, 30%, and 30% without UV: 1.00, 0.98, 0.99, 1.00, and 0.97, respectively.

Parameter:

other: disintegrations per minute (DPM)

Remarks on result:

other: Lymph node stimulation was measured by cell counts instead of radioactive labelling, as authorised in OECD Guideline No. 429.

The mice did not show any UV-A-dependent effect with respect to the stimulation indices for cell counts or LN weights after application of BPA. The positive levels for the cell count index and for ear swelling were not exceeded in any BPA dose group. The body weights of the animals were not affected by any treatment.

Interpretation of results:

not sensitising

Remarks:

Migrated information

Executive summary:

Female NMRI mice were treated epicutaneously on the dorsal part of both ears with 25 µl per ear of a solution containing 0%, 3%, 10%, or 30% BPA in DAE 433 (6 animals per dose group). Treatments were given once per day for three consecutive days (day 1, day 2, and day 3). Except for one group receiving 30% BPA, the animals were irradiated with UV light (20 J UV-A/cm squared) immediately after BPA application. On day 1 and day 4 (one day after last application), the ear swelling of the animals was measured using a spring-loaded micrometer and mean ear swelling was calculated. Ear weight was measured on day 4 using a punch to cut off a piece of each ear with an 8 mm diameter. Also on day 4, animals were sacrificed by inhalation of carbon dioxide and lymphatic organs (the auricular lymph nodes) were transferred to PBS. Lymph nodes (LNs) were weighed and then cut up with broad forceps and cell counts per ml were determined using a Coulter counter. The stimulation index was calculated by dividing the absolute number of the weight or cell counts of the treated lymph nodes by the vehicle lymph nodes. The mice did not show any UV-A-dependent effect with respect to the stimulation indices for cell counts or LN weights after application of BPA. The positive levels for the cell count index and for ear swelling were not exceeded in any BPA dose group. The body weights of the animals were not affected by any treatment. The authors concluded that BPA does not show any UV-A irradiation-dependent immunostimulating (photosensitising) potential after epicutaneous application.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

The 2008 updated EU RAR concluded: 

"Overall the new information does not confirm the previously reported evidence of a skin sensitisation potential of Bisphenol A. While the data do not exclude a skin sensitising activity of Bisphenol A at high concentrations (>30%), there is no evidence that this is a concern for workers in current Bisphenol A manufacturing plants (such workers are believed to represent the group most likely to be exposed to Bisphenol A in dust)."  

 

The 2003 EU RAR concluded: 

"Based on the findings from the most robust animal study, Bisphenol A may possess a skin sensitisation potential, albeit a limited one, and that the available data suggest that Bisphenol A is considered capable of producing skin sensitisation responses in humans."  

  

  
Migrated from Short description of key information: 

The 2008 updated EU RAR reported that reliable and new animal studies do not confirm the previously reported evidence of a skin sensitisation potential of Bisphenol A and concluded: “While the data do not exclude a skin sensitising activity of Bisphenol A at high concentrations (>30%), there is no evidence that this is a concern for workers in current Bisphenol A manufacturing plants (such workers are believed to represent the group most likely to be exposed to Bisphenol A in dust)." 
 
Justification for selection of skin sensitisation endpoint: 

No sensitisation was observed in recent animal studies conducted according to guideline. 

 

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

The 2008 updated EU RAR came to the same conclusion but added: "However, based on the lack of reports of cases of respiratory sensitisation, there are no grounds for concern for this endpoint."

 

The 2003 EU RAR concluded that there are no data from which to evaluate the potential of Bisphenol A to be a respiratory sensitiser.

  

Migrated from Short description of key information:

According to the updated EU RAR 2008 "there are no grounds for concern for this endpoint." 

Justification for classification or non-classification

Bisphenol A is classified as Skin Sens. 1 according to Annex VI of Regulation (EC) No 1272/2008.

The 2008 updated EU RAR concluded:

"Overall the new information does not confirm the previously reported evidence of a skin sensitisation potential of Bisphenol A. While the data do not exclude a skin sensitising activity of Bisphenol A at high concentrations (>30%), there is no evidence that this is a concern for workers in current Bisphenol A manufacturing plants (such workers are believed to represent the group most likely to be exposed to Bisphenol A in dust)."

Based on the EU-RAR Bisphenol A is allocated to the moderate hazard band.