Reaction mass of 4,4'-isopropylidenediphenol and phenol

Endpoint summary

Description of key information

No experimental data are available for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol. However, based on the general principles of mixture toxicology, data on the main constituents of this multi-constituent substance are used as surrogate.

 

Bisphenol A:

Oral studies in rats and mice have shown that the repeated dose toxicity of Bisphenol A involves effects on bodyweight gain, liver and kidney. The starting point for the human risk assessment is a BMDL10 for mean relative kidney weight of 8.9 mg/kg/day for systemic toxicity. In rats exposed daily to airborne Bisphenol A for 13 weeks there was a NOAEC of 10 mg/m3, with mild olfactory epithelium inflammation at 50 and 150 mg/m3. There was no evidence of systemic toxicity in this study.

 

Phenol:

Oral exposure
NOAEL = 300 mg/kg bw/day, systemic effects in rats
In a two generation drinking water reproductive toxicity study no relevant effects were observed up to 300 mg/kg bw in rats exposed over approx. 13 weeks. The NOAEL from a long-term drinking water (2a) study is 370 mg/kg bw/d in mice. Lower NOEL from 13 weeks study was not considered for risk assessment, as it is related to secondary effects due to reduced water and/or food intake.
Dermal exposure
NOAEL =130 mg/kg bw/day systemic effects in rabbits
NOAEC = 2.37%, local effects in rabbits
In the dermal study conducted by Deichmann et al. (1950) rabbits showed local effects at a concentration of 3.56% and neurobehavioral effects (tremor) after repeated exposure to 260 mg/kg bw/day. The NOAEL was 130 mg/kg bw/day. The validity of this study concerning systemic effects is limited.
Inhalation exposure
NOAEC = 20 mg/m³, systemic effects in monkeys
In a continuous inhalation study with rhesus monkeys, rats and mice no significant pathological effects were reported at 5 ppm (20 mg/m³) for 90 d. No adverse effects were reported in a valid 14 day-inhalation study in rats (Hoffman et al., 2001). The NOAEC for local and systemic effects was 96 mg/m³.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol can be predicted by studies conducted with the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol, because the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol contains phenol (40-45%, typical concentration ca. 40%) and 4,4’-isopropylidenediphenol (BPA) (20-40%, typical concentration ca. 33%) as main constituents. Both constituents are data rich substances with distinct hazard properties, so that mainly data on the constituents have been applied to characterize the Reaction mass of phenol and 4,4’-isopropylidenediphenol. Since this is a common approach in mixture hazard assessment, is reasonable to apply it also to multi-constituent substances.
Additionally, some data from a structurally related substance (2-acetone, polymer with phenol) containing the same constituents/impurities at different concentrations are available, which are applied to characterize the environmental fate and ecotoxicity of the impurities present in the Reaction mass of phenol and 4,4’-isopropylidenediphenol.

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol are predicted to be similar to those of the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol.

Therefore, read-across from the available studies with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
please refer to justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
please refer to justification for read-across attached to Iuclid section 13

4. DATA MATRIX
please refer to justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks:

Phenol

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: rat

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks:

Phenol

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: mouse

Critical effects observed:

no

Conclusions:

No experimental data are available for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol. However, based on the general principles of mixture toxicology, data on the main constituents of this multi-constituent substance are used as surrogate.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol can be predicted by studies conducted with the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol, because the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol contains phenol (40-45%, typical concentration ca. 40%) and 4,4’-isopropylidenediphenol (BPA) (20-40%, typical concentration ca. 33%) as main constituents. Both constituents are data rich substances with distinct hazard properties, so that mainly data on the constituents have been applied to characterize the Reaction mass of phenol and 4,4’-isopropylidenediphenol. Since this is a common approach in mixture hazard assessment, is reasonable to apply it also to multi-constituent substances.
Additionally, some data from a structurally related substance (2-acetone, polymer with phenol) containing the same constituents/impurities at different concentrations are available, which are applied to characterize the environmental fate and ecotoxicity of the impurities present in the Reaction mass of phenol and 4,4’-isopropylidenediphenol.

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol are predicted to be similar to those of the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol.

Therefore, read-across from the available studies with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
please refer to justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
please refer to justification for read-across attached to Iuclid section 13

4. DATA MATRIX
please refer to justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks:

Phenol

Sex:

male

Basis for effect level:

immunology

Remarks on result:

other: only males tested

Dose descriptor:

LOAEL

Effect level:

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

Based on:

test mat.

Remarks:

Phenol

Sex:

male

Basis for effect level:

haematology

Remarks on result:

other: only males tested

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks:

BPA

Sex:

male/female

Basis for effect level:

body weight and weight gain

mortality

other: increased duration of diestrous cycle in females

Critical effects observed:

not specified

Conclusions:

No experimental data are available for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol. However, based on the general principles of mixture toxicology, data on the main constituents of this multi-constituent substance are used as surrogate.

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol can be predicted by studies conducted with the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol, because the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol contains phenol (40-45%, typical concentration ca. 40%) and 4,4’-isopropylidenediphenol (BPA) (20-40%, typical concentration ca. 33%) as main constituents. Both constituents are data rich substances with distinct hazard properties, so that mainly data on the constituents have been applied to characterize the Reaction mass of phenol and 4,4’-isopropylidenediphenol. Since this is a common approach in mixture hazard assessment, is reasonable to apply it also to multi-constituent substances.
Additionally, some data from a structurally related substance (2-acetone, polymer with phenol) containing the same constituents/impurities at different concentrations are available, which are applied to characterize the environmental fate and ecotoxicity of the impurities present in the Reaction mass of phenol and 4,4’-isopropylidenediphenol.

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol are predicted to be similar to those of the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol.

Therefore, read-across from the available studies with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
please refer to justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
please refer to justification for read-across attached to Iuclid section 13

4. DATA MATRIX
please refer to justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOEL

Effect level:

200 ppm

Based on:

test mat.

Remarks:

Phenol

Sex:

male/female

Basis for effect level:

water consumption and compound intake

Remarks on result:

other: 18 and 25 mg/kg bw/day for males and females

Dose descriptor:

BMDL10

Effect level:

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

Based on:

test mat.

Remarks:

BPA

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

Remarks on result:

other: mouse

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

BMDL10

8.9 mg/kg bw/day

Study duration:

subchronic

Species:

mouse

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol can be predicted by studies conducted with the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol, because the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol contains phenol (40-45%, typical concentration ca. 40%) and 4,4’-isopropylidenediphenol (BPA) (20-40%, typical concentration ca. 33%) as main constituents. Both constituents are data rich substances with distinct hazard properties, so that mainly data on the constituents have been applied to characterize the Reaction mass of phenol and 4,4’-isopropylidenediphenol. Since this is a common approach in mixture hazard assessment, is reasonable to apply it also to multi-constituent substances.
Additionally, some data from a structurally related substance (2-acetone, polymer with phenol) containing the same constituents/impurities at different concentrations are available, which are applied to characterize the environmental fate and ecotoxicity of the impurities present in the Reaction mass of phenol and 4,4’-isopropylidenediphenol.

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol are predicted to be similar to those of the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol.

Therefore, read-across from the available studies with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
please refer to justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
please refer to justification for read-across attached to Iuclid section 13

4. DATA MATRIX
please refer to justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEC

Effect level:

5 ppm

Based on:

test mat.

Remarks:

Phenol

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: only male monkeys tested

Dose descriptor:

LOEC

Effect level:

10 mg/m³ air (analytical)

Based on:

test mat.

Remarks:

BPA

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: systemic effects

Dose descriptor:

NOEC

Effect level:

10 mg/m³ air (analytical)

Based on:

test mat.

Remarks:

BPA

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: local effects

Critical effects observed:

not specified

Conclusions:

No experimental data are available for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol. However, based on the general principles of mixture toxicology, data on the main constituents of this multi-constituent substance are used as surrogate.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

10 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol can be predicted by studies conducted with the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol, because the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol contains phenol (40-45%, typical concentration ca. 40%) and 4,4’-isopropylidenediphenol (BPA) (20-40%, typical concentration ca. 33%) as main constituents. Both constituents are data rich substances with distinct hazard properties, so that mainly data on the constituents have been applied to characterize the Reaction mass of phenol and 4,4’-isopropylidenediphenol. Since this is a common approach in mixture hazard assessment, is reasonable to apply it also to multi-constituent substances.
Additionally, some data from a structurally related substance (2-acetone, polymer with phenol) containing the same constituents/impurities at different concentrations are available, which are applied to characterize the environmental fate and ecotoxicity of the impurities present in the Reaction mass of phenol and 4,4’-isopropylidenediphenol.

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol are predicted to be similar to those of the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol.

Therefore, read-across from the available studies with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
please refer to justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
please refer to justification for read-across attached to Iuclid section 13

4. DATA MATRIX
please refer to justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Species:

rabbit

Duration of treatment / exposure:

18 days

Frequency of treatment:

5 h per day, 5 days per week for totally 18 days

Dose descriptor:

NOAEL

Effect level:

130 mg/kg bw/day

Sex:

not specified

Basis for effect level:

other: systemic effects

Dose descriptor:

LOAEL

Effect level:

260 mg/kg bw/day

Sex:

not specified

Basis for effect level:

other: systemic effects (e.g. tremor)

Dose descriptor:

conc. level: NOAEC

Effect level:

2.37 other: % in vehicle

Sex:

not specified

Basis for effect level:

other: no local effects

Dose descriptor:

conc. level: LOAEC

Effect level:

3.56 other: % in vehicle

Sex:

not specified

Basis for effect level:

other: local effects (hyperemia)

Critical effects observed:

not specified

Conclusions:

No experimental data are available for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol. However, based on the general principles of mixture toxicology, data on the main constituents of this multi-constituent substance are used as surrogate.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

3.8 mg/kg bw/day

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

EPS RDT

 

 

 

No experimental data are available for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol. However, based on the general principles of mixture toxicology, data on the main constituents of this multi-constituent substance are used as surrogate. A justification for read-across is attached to Iuclid section 13.

 

Studies with PHENOL:

ORAL EXPOSURE

In long-term drinking water studies (NIH, 1980; robust study summary in IUCLID Section 7.7), 50 animals/sex/group of F344 rats and B6C3F1 mice were administered 2500 or 5000 mg/l (equivalent to 200 and 450 mg/kg bw/day for rats and 280 and 370 mg/kg bw/day for mice) for 103 weeks. Parameters on haematology, clinical biochemistry and urinanalysis were not investigated.
In both treatment groups of the rat study the water consumption was decreased (80% and 90% of control value, respectively) and in the high dose groups the body weight was reduced. No clinical signs of toxicity were recorded. No treatment related effects were detected in histopathological evaluation of non-neoplastic effects. Neoplastic effects were discussed in Section 7.7.
The reduction of body weight gain was attributed to the reduced water consumption, the NOAEL in rats is 450 mg/kg bw/day.
In mice of the low and high dose groups the body weight was reduced and water consumption was suppressed (75% and 50 -60% of control value, respectively). No clinical signs of toxicity were recorded except a reduced tendency to fight in treated males (no data about dose) . No treatment related effects were detected in histopathological evaluation of non-neoplastic and neoplastic effects. The reduction of body weight gain was attributed to the reduced water consumption, the NOAEL in mice is 370 mg/kg bw/day. 

 

In a two generation drinking water reproductive toxicity study (Ryan et al., 2001) a subset of male Sprague-Dawley rats were administered concentrations of 0, 200, 1000 or 5000 mg/l (corresponding to 0, 15, 71 and 300 mg/kg bw/day) for approximately 13 weeks prior to assessing clinical chemistry, haematology and immunological parameters. In contrast to the concurrent positive control no significant effects were observed on spleen weight, cellularity (cells/spleen), or antibody-forming cells (no. of antibody producing plasma cells per spleen or per 10E6 cells) for any of the treated groups compared to the control group. No relevant effects were detected in haematology and clinical chemistry. For the parameters examined, the NOAEL was considered to be 300 mg/kg bw/day. 

In a drinking water study related to neurotoxic effects (CMA, 1998) 15 rats per dose per sex were exposed to 0, 200, 1000, or 5000 ppm for 13 weeks. Five rats/sex/group were used for the following phases of the study: perfusion after 13 weeks of treatment, perfusion at the end of the recovery period of 4 weeks, and necropsy at the end of the recovery period of 4 weeks.
At a concentration of 5000 ppm lower body weight, reduced food and water consumption and abnormal clinical signs including dehydrated appearance was reported; one female was sacrificed due to poor condition. At 1000 ppm, decreased water intake and on occasion dehydrated appearance were seen. Marked improvements were noted following recovery. No effects were noted for any parameters at 200 ppm. Neurobehavioral evaluations (functional observation battery) did not reveal any findings of neurotoxicological significance at any concentration following treatment or recovery. Observations of altered motor activity (females only) were noted, however, these findings were considered to be secondary to the reduction in water and/or food intake. No gross or histopathological lesions in nervous tissue attributed to treatment with phenol were detected. Based on these findings, a NOAEL for neurotoxicity under the conditions of this study was 5000 ppm (308 and 360 mg/kg bw/day for males and females, respectively). The overall study NOEL under the conditions of this study was 200 ppm (18 and 25 mg/kg bw/day for males and females, respectively). Conclusion: In male and female rats the NOAEL for neurotoxic effects was 5000 ppm in a 13 week drinking water study. The NOEL concerning overall effects was 200 ppm. However, this NOEL was not used for risk assessment, as it is related to secondary effects from reduced water and food intake.

In a subacute gavage study (Berman et al., 1995; see IUCLID Section 7.5.1; limited validity; 0, 4, 12, 40, and 120 mg/kg bw/day for 14 days) in female F344 rats it has been shown that the effect level (NOAEL presumably 4 mg/kg bw/day; 120 mg/kg bw/day was lethal for all rats) is clearly lower than in drinking water studies which might be related to the bolus effect. 

 

In a subacute study (Hsieh et al., 1992) male CD-1 mice were continuously exposed to 0, 4.7, 19.5, and 95.2 mg phenol/l drinking water (corresponding to 0, 1.8, 6.2, 33.6 mg/kg bw/day) for 4 weeks. In summary, hematological and neurochemical parameters were altered in male mice even at the lowest dose of 1.8 mg/kg bw/day, the toxicological relevance of the neurochemical effects are not clear; immunological parameters were affected at >= 6.2 mg/kg bw/day. LOAEL = 1.8 mg/kg bw/day. According to SCOEL (2003) the significance of these findings for human health is questionable, particularly as the surrounding database on repeated exposure studies by the inhalation or oral routes does not provide consistent and convincing evidence of appreciable immunotoxicity or neurotoxicity. 

 

DERMAL EXPOSURE

In a subacute dermal study in rabbits (Deichmann et al., 1950; limited validity) 4 albino rabbits per dose level received repeated dermal application 5 days per week for 18 days. The daily exposure duration was 5 hours. The phenol concentrations of test solutions were 1.18, 2.37, 3.56, 4.75, 5.93, and 7.12% in water corresponding to systemic dose levels of 130, 260, 390, 520, 650, and 780 mg/kg bw/day. Systemic effects like tremor were detected at 260 mg/kg bw/day, mild irritant effects at a concentration of 3.56% and severe local effects at 4.75%. Mortality (presumably due to systemic effects) was reported at 780 mg/kg bw/day. For systemic effects, the NOAEL was 130 mg/kg bw/day (LOAEL 260 mg/kg bw/day). The LOAEC for local effects was 3.56% aqueous solution and the NOAEL 2.37%.

There are no further valid data for the dermal route.

 

INHALATION EXPOSURE

Studies in experimental animals 

In relation to the effects of long-term exposure, continuous inhalation exposure of rhesus monkeys, rats and mice to 5 ppm (20 mg/m³) phenol for 90 days resulted in no significant pathological effects (Sandage, 1961). Although this was a well-designed and wide-ranging study, SCOEL felt that limited reporting of results, especially regarding irritation of the upper respiratory tract, was a difficulty. However, no significant systemic toxicity seems to have been produced in any of the three species at this level. 

 

In a 14 day-inhalation study male and female F344 rats (n=20 per dose per sex; CMA, 1998 & Hoffman et al., 2001) were exposed to phenol vapour by nose-only exposures for 10 exposures (5 days/week, 6 hours/day) at target concentrations of 0, 0.5, 5.0 and 25 ppm (0, 1.9, 19, 96 mg/m³). 10 rats/sex/group were sacrificed after 10 exposures, and after a 14-day recovery time for the remaining animals. No signs of toxicity in clinical observations (including neurological signs), body weights, food consumption, clinical chemistry, haematology, organ weights, macroscopic pathology or microscopic pathology were seen during the exposures or at either sacrifice interval. The NOAEC for local or systemic effects is 96 mg/m³. The study supported the finding of Sandage et al. (1961) of no effects at 20 mg/m3). 

 

In a subchronic study (Deichmann et al., 1944; limited validity) 15 rats were exposed 7 hours per day, 5 days per week for 74 day to 100 -200 mg/m³ (analytically verified). No clinical signs were observed during exposure period. No effects were detected at necropsy and in histopathological examination of liver, lung, kidney and heart. In summary, in this inhalation study of limited validity no adverse effects were found in rats exposed to 100-200 mg/m³. These data supported the results in the 2 -week inhalation study by Hoffman et al.(2001).

  

Human data

In the study of Shamy et al. (1994; see IUCLID Section 7.10.1 for details) 20 workers were exposed to phenol alone; the time weighted average exposure was 5.4 ppm (21 mg/m³) and the mean duration of exposure was 13.2 +-6.6 (SD) years. The reference group (n=30) had the same demographic characters like age, educational status and socioeconomic status. In summary, workers exposed to a time weighted average of 21 mg/m³ showed significantly altered parameters in clinical chemistry and haematology along with a significantly increased amount of phenol excreted via the urine. These data suggested systemic hepatotoxic effects, the LOAEC is 21 mg/m³. According to SCOEL (2003) the study has some shortcomings, as only 20 workers were examined, it is not clear whether the exposure was only to phenol and how the exposure was measured.

 

Studies with Bisphenol A 

The 2003 EU RAR for BPA concluded that no useful information on the effects of repeated exposure to BPA in humans is available, but experimental studies in rats, mice, and dogs are available. In rat inhalation studies, the principal effect of repeated exposure was the same as observed following a single exposure: slight upper respiratory tract epithelium inflammation, with a NOAEC of 10 mg/m3and a LOAEC of 50 mg/m3. Dietary studies in rats have reported reductions in reproductive organ weights and testicular toxicity at 235 mg/kg and a NOAEL of 74 mg/kg was established in a two-year study based on marginal effects on body weight gain at the next dose level of 148 mg/kg. In mice, the LOAELs of 120 mg/kg in males for multinuclear giant hepatocytes and 650 mg/kg in females for a reduction in body weight gain of unknown magnitude were identifed in a two-year study. There are no animal data available for repeated dermal exposure.

 

The 2008 updated EU RAR concluded: "Oral studies in rats and mice have shown that the repeated dose toxicity of BPA involve[s] effects on bodyweight gain, liver and kidney. A NOAEL of 50 mg/kg/day has been identified in a recent 2 -generation study in mice for these effects. This NOAEL rather than the original NOAEL of 120 mg/kg/day for liver effects from the published report is taken forward to the risk characterisation."

 

In 2014 SCOEL published a Recommendation on Bisphenol A:

“To establish a recommended occupational exposure limit (OEL), SCOEL began by considering the available data relating to inhalation exposure. In rats exposed daily to airborne Bisphenol A for 13 weeks there was a NOAEC of 10 mg/m3, with mild olfactory epithelium inflammation at 50 and 150 mg/m3. There was no evidence of systemic toxicity in this study (Nitschke 1988).”

 

EFSA reevaluated Bisphenol A and published a Scientific Opinion in 2015:

“Bisphenol A was found to affect kidney and liver weight in parental animals and in all the generations of rats and mice examined in multi-generation studies. These effects were considered by EFSA (2006, 2010) as relevant systemic effects for the identification of a NOAEL. In mice the increased kidney weight was associated with nephropathy at the highest Bisphenol A dose. Liver weight was increased in rats (relative weight) and mice (both absolute and relative weight). The latter species also showed hepatocellular hypertrophy. The CEF Panel considered the endpoint “general toxicity” for hazard characterisation, using a reference point from the two-generation study in mice, which provided a BMDL10 for mean relative kidney weight of 8 960 μg/kg bw per day in male mice of the F0 generation.”

 

 

Conclusion

The BMDL10 of 8.9 mg/kg bw/d obtained for Bisphenol A in a two generation toxicity study in mice is considered to be the overall dose descriptor for eth endpoint repeated dose toxicity.

Justification for classification or non-classification

Based on the hazard profile/classification of phenol, the following classification will be assigned to the reaction mass:

STOT RE 2 (H373)