Reaction mass of 4,4'-isopropylidenediphenol and phenol

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

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.

BPA

SCOEL Recommendation 2014 concluded concerning potential low-dose effects:
“Even though there are some concerns related to the long-term effects of Bisphenol A at exposure levels lower than 5 mg/kg bw after exposure during the foetal and early postnatal period, the results of these studies are controversial and there is no clear support for these effects at low dose levels from good quality animal studies (including the recent study by Delcloset al2014). Therefore, at present SCOEL did not consider them relevant for deriving the recommended OEL.”

EFSA Opinion 2015 concluded concerning potential Non-Monotonic-Dose-Resopnses (NMDR):
“The CEF Panel developed criteria for nonmonotonic dose-responses (NMDRs) and reviewed studies reporting a NMDR for Bisphenol A. None of the studies fulfil these criteria. Overall the CEF Panel concluded that the available data do not provide evidence that Bisphenol A exhibits a NMDR for the endpoints considered (reproductive/developmental toxicity, neurotoxicity/behavioural effects, metabolic effects, proliferative changes in mammary gland).“

 

Phenol:

Reported effects in a two generation reproduction toxicity study were considered secondary to water avoidance due to an flavour aversion to phenol. The NOAEL of phenol in drinking water is 1000 mg/l (70 mg/kg bw/day for males and 93 mg/kg bw/day for females), the LOAEL is 5000 mg/l. No impairment of reproductive capability and fertility was found at 5000 mg/l. There is no need for classification and labelling.

"

The NOELs for effects on fertility were higher than those of general systemic toxicity so that they will not be taken into account in the CSA.

Link to relevant study records

Reference

Endpoint:

multi-generation reproductive toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

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

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

other: overall effects

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Based on reduced testes weights and delay in acquisition of puberty in males

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional 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. A justification for read-across is attached to Iuclid section 13.

 

Studies with Phenol:

Phenol was investigated for effects on reproductive performance and fertility in a valid two generation reproductive toxicity study in Sprague-Dawley rats (Ryan et al., 2001). P1 and F1 rats were exposed via the drinking water to 0, 200, 1000, 5000 mg/l (calculated to be 0, 14, 70, and 310 mg/kg bw/day for males and 0, 20, 93, and 350 mg/kg bw/day for females in both generations). At 5000 mg/l, a dose level which led to reduced water intake and consequently decreased body weight and body weight gain in the animals, no impairment of reproductive capability and fertility was detected. However, postnatal litter survival and offspring body weights at birth and during the period of lactation were reduced at 5000 mg/l in F1 and F2 generation. Furthermore, signs of impaired offspring development were observed in F1 like delay in sexual maturation. However, all effects in progeny were found at a dose level that clearly indicated systemic toxicity in parental animals. From the findings of reduced water intake (which is considered secondary to an aversion to the flavour of phenol), body weight and organ weight impairment in the P0 and F1 generation at 5000 mg/l a NOAEL for general, systemic toxicity of 1000 mg/l (corresponding to 70 mg/kg bw/day for males and 93 mg/kg bw/day for females) can be derived. The observed impairment of development at the higher concentration levels may be considered to be secondary to the overall reduced state of health at 5000 mg/l.

Phenol is not classified as toxic to reproduction.

 

Studies with Bisphenol A:

The 2003 EU RAR concluded:

"No human data on reproductive toxicity of Bisphenol A are available. Bisphenol A has been shown to have endocrine modulating activity in a number of screening assays, with a potency that generally ranged from 3 to 5 orders of magnitude less than that of oestradiol. The effects of Bisphenol A on fertility and reproductive performance have been investigated in two-generation and multi-generation studies in the rat and a continuous breeding study in mice. Effects were seen in both species at approximately the same dose level and it is considered that the NOAEL of 50 mg/kg/day identified in the rat multi-generation study is also likely to produce no adverse effects in mice for which there is only a LOAEL of 300 mg/kg/day for a small decrease in epididymal weight in F1 males. The NOAEL of 50 mg/kg/day from the multi-generation study will be used for risk characterisation purposes, in relation to effects on fertility."

 

The 2008 updated EU RAR concluded:

"A new two-generation study in mice by Tyl et al. (published in 2008) provides a comprehensive and definitive investigation on the effects of Bisphenol A on reproduction at exposure levels spanning the low (ug/kg/day) to high (mg/kg/day) ranges. This study showed that Bisphenol A causes adverse effects on pregnancy and the offspring at 600 mg/kg/day, an exposure level that also caused mild parental toxicity. Fertility was not affected by Bisphenol A exposure. A NOAEL for reproductive toxicity of 50 mg/kg/day was identified and should be used in the risk assessment."

 

SCOEL Recommendation 2014 concluded concerning potential low-dose effects:

“Even though there are some concerns related to the long-term effects of Bisphenol A at exposure levels lower than 5 mg/kg bw after exposure during the foetal and early postnatal period, the results of these studies are controversial and there is no clear support for these effects at low dose levels from good quality animal studies (including the recent study by Delclos et al 2014). Therefore, at present SCOEL did not consider them relevant for deriving the recommended OEL.”

 

SCOEL Recommendation 2014 concluded on reproductive and developmental toxicity:

"Overall, in standard reproductive and developmental studies in rodents, effects on reproduction have been seen only at high doses showing also other toxic effects. Even though several non-guideline studies suggest effects on reproductive and developmental parameters at lower dose levels (< 5 mg/kg bw), the data are contradictory and are not supported by the recent FDA/NTCR study with a wide-dose range (Delclos et al 2014). In humans, based on Chinese epidemiological studies, there is some concern for impaired sperm quality but, for example, the effect of other concurrent exposures cannot be excluded. In addition, there are some concerns on the potential developmental neurotoxicity of Bisphenol A based on animal studies suggesting effects on memory and learning and anxiety-like behaviour. However, since the data are very inconsistent it is difficult to conclude on the relevance of these findings."

 

EFSA Opinion 2015 concluded concerning potential Non-Monotonic-Dose-Responses (NMDR):

“The CEF Panel developed criteria for nonmonotonic dose-responses (NMDRs) and reviewed studies reporting a NMDR for Bisphenol A. None of the studies fulfil these criteria. Overall, the CEF Panel concluded that the available data do not provide evidence that Bisphenol A exhibits a NMDR for the endpoints considered (reproductive/developmental toxicity, neurotoxicity/behavioural effects, metabolic effects, proliferative changes in mammary gland). “

 

EFSA Opinion 2015 concluded on reproductive and developmental toxicity:

Overall, the better powered, better conducted studies in animals found few consistent effects of in-utero exposure to Bisphenol A on reproductive development at dose levels at or below 3.6 mg Bisphenol A/kg/day HED. On balance, the evidence remains contradictory and highly variable between studies. The CEF Panel noted that there is some evidence for effects of Bisphenol A exposure on several parameters indicative for changes in the reproductive system in adult male animals at dose levels below 3.6 mg/kg bw per day, although these effects were modest. It is not possible to conclude that these changes are reflective of changes in reproductive performance, since the studies rarely included a forced/continuous breeding phase in adulthood to establish reduced fertility. However, in several multigenerational studies no effects were observed at dose levels as low as 3mg/kg bw per day up to at least 50 mg/kg bw per day.

Using a WoE approach, the CEF Panel assigned a likelihood level of “as likely as not” to reproductive and developmental effects of Bisphenol A at low doses (below the HED of 3.6 mg/kg bw per day). Since the likelihood level for this endpoint is less than "likely" (see Appendix A), this endpoint was not taken forward for assessing the toxicological reference point,but was taken into account in the evaluation of uncertainty for hazard characterisation and risk characterisation (Section 4.3)."

 

For Bisphenol A, a harmonised classification for reproductive toxicity (Repr. 1B) has been adopted for fertility effects.

 

Conclusion:

Based on the available data, including the harmonised classification for reproductive toxicity (Repr. 1B) for the constituent Bisphenol A, the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol is also classified as reproductive toxicant (repro 1 B).

 

 

 

Effects on developmental toxicity

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.

 

Phenol

In gavage studies phenol was evaluated for maternal and developmental toxicity in valid teratology studies with rats and mice. Data on developmental toxicity are also available from a 2 generation drinking water study. Oral exposure to phenol resulted in growth retardation of the offspring and impaired postnatal viability and growth. However, these effects were found at dose levels that were also toxic to the dams. Therefore, phenol is not considered to have specific embryo- or fetotoxic effects. The NOAEL for developmental toxicity is 93 mg/kg bw/day. There is no need for classification and labelling

 

BPA

SCOEL Recommendation 2014 concluded concerning potential low-dose effects:
“Even though there are some concerns related to the long-term effects of Bisphenol A at exposure levels lower than 5 mg/kg bw after exposure during the foetal and early postnatal period, the results of these studies are controversial and there is no clear support for these effects at low dose levels from good quality animal studies (including the recent study by Delcloset al2014). Therefore, at present SCOEL did not consider them relevant for deriving the recommended OEL.”
EFSA Opinion 2015 concluded concerning potential Non-Monotonic-Dose-Responses (NMDR):
“The CEF Panel developed criteria for nonmonotonic dose-responses (NMDRs) and reviewed studies reporting a NMDR for Bisphenol A. None of the studies fulfil these criteria. Overall the CEF Panel concluded that the available data do not provide evidence that Bisphenol A exhibits a NMDR for the endpoints considered (reproductive/developmental toxicity, neurotoxicity/behavioural effects, metabolic effects, proliferative changes in mammary gland).“

 

 

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

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

Species:

mouse

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
ORGAN WEIGHTS: There was a statistically significant increase in liver and kidney weights at 3500 ppm.

Dose descriptor:

NOEL

Remarks:

Systemic

Effect level:

300 ppm (nominal)

Based on:

act. ingr.

Basis for effect level:

organ weights and organ / body weight ratios

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

300 ppm

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

changes in postnatal survival

other: Sexual maturation

Abnormalities:

not specified

Developmental effects observed:

not specified

Reference 2

Endpoint:

developmental toxicity

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

Reason / purpose for cross-reference:

read-across source

Species:

rat

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

other: no adverse effects

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male/female

Basis for effect level:

other: no adverse effects

Abnormalities:

no effects observed

Developmental effects observed:

no

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional 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. A justification for read-across is attached to Iuclid section 13.

 

Studies with Phenol:

From the assessment of the data from the teratology studies with mice and rats it was concluded in the EU-RAR (2006; page 131ff) that phenol does not seem to have any specific embryotoxic or teratogenic properties.

In a valid developmental study (Jones-Price et al., 1983; see robust study summary in IUCLID Section 7.8.2) CD-1 mice received via gavage 0, 70, 140, and 280 mg/kg bw daily during gestation days (GD) 6 -15. Maternal toxicity was observed at the high dose level including increased mortality, reduced body weight and reduced weight gain as well as clinical signs like tremor and ataxia. No effects were detected on prenatal mortality or the incidence of teratogenic effects in any of the dosed groups, except for an increase in cleft palate at the highest dose level, a malformation for which the CD-1 mouse is predisposed under conditions of maternal stress. At 280 mg phenol/kg bw the mean gravid uterine weight and the average fetal body weight per litter was statistically significantly reduced. In this study development effects were detected at dosages of 280 mg/kg bw/day that also led to maternal toxicity. The NOAEL for developmental and maternal effects is 140 mg/kg bw/day.

 

Pregnant Sprague-Dawley rats received on gestation day 6 -15 via gavage 0, 60, 120, 360 mg/kg bw. Dams of the high dose group revealed excess salivation and respiratory distress (tachypnea) as well as significantly reduced maternal body weight and body weight gain at 360 mg/kg bw/day. At 120 mg/kg bw/day also statistically significant effects on body weight gain were detected. No maternal effects were recorded in the low dose group. No developmental effects were reported except slight (but significant) reduction of fetal body weight and delayed ossifications (in metatarsals) at 360 mg/kg bw/day. From the results of this study the NOAEL for maternal toxicity is 60 mg/kg bw/day and the NOAEL for developmental toxicity is 120 mg/kg bw/day (Proctor&Gamble, 1997; see robust study summary in IUCLID Section 7.8.2).

 

In the 2 generation reproduction study described above (Ryan et al., 2001; see also IUCLID Section 7.8.1) pre- and postnatal developmental effects as well as maternal toxicity have been reported at 5000 mg/l, the NOAEL was 1000 mg/l corresponding to mean daily intake of 93 mg/kg bw/day for the dams.

 

Studies with Bisphenol A

The 2003 EU RAR concluded:

"No human data on reproductive toxicity of Bisphenol A are available. Bisphenol A has been shown to have endocrine modulating activity in a number of screening assays, with a potency that generally ranged from 3 to 5 orders of magnitude less than that of oestradiol. The effects of Bisphenol A on fertility and reproductive performance have been investigated in two-generation and multi-generation studies in the rat and a continuous breeding study in mice. Effects were seen in both species at approximately the same dose level, and it is considered that the NOAEL of 50 mg/kg/day identified in the rat multi-generation study is also likely to produce no adverse effects in mice for which there is only a LOAEL of 300 mg/kg/day for a small decrease in epididymal weight in F1 males. The NOAEL of 50 mg/kg/day from the multi-generation study will be used for risk characterisation purposes, in relation to effects on fertility."

 

The 2008 updated EU RAR concluded:

"A new two-generation study in mice by Tyl et al. (published in 2008) provides a comprehensive and definitive investigation on the effects of Bispheol A on reproduction at exposure levels spanning the low (ug/kg/day) to high (mg/kg/day) ranges. This study showed that Bisphenol A causes adverse effects on pregnancy and the offspring at 600 mg/kg/day, an exposure level that also caused mild parental toxicity. Fertility was not affected by Bisphenol A exposure. A NOAEL for reproductive toxicity of 50 mg/kd/day was identified and should be used in the risk assessment."

 

SCOEL Recommendation 2014 concluded concerning potential low-dose effects:

“Even though there are some concerns related to the long-term effects of Bisphenol A at exposure levels lower than 5 mg/kg bw after exposure during the foetal and early postnatal period, the results of these studies are controversial and there is no clear support for these effects at low dose levels from good quality animal studies (including the recent study by Delcloset al2014). Therefore, at present SCOEL did not consider them relevant for deriving the recommended OEL.”

SCOEL Recommendation 2014 concluded on reproductive and developmental toxicity:

"Overall, in standard reproductive and developmental studies in rodents, effects on reproduction have been seen only at high doses showing also other toxic effects. Even though several non-guideline studies suggest effects on reproductive and developmental parameters at lower dose levels (< 5 mg/kg bw), the data are contradictory and are not supported by the recent FDA/NTCR study with a wide-dose range (Delclos et al 2014). In humans, based on Chinese epidemiological studies, there is some concern for impaired sperm quality but, for example, the effect of other concurrent exposures cannot be excluded. In addition, there are some concerns on the potential developmental neurotoxicity of Bisphenol A based on animal studies suggesting effects on memory and learning and anxiety-like behaviour. However, since the data are very inconsistent it is difficult to conclude on the relevance of these findings."

 

EFSA Opinion 2015 concluded concerning potential Non-Monotonic-Dose-Responses (NMDR):

“The CEF Panel developed criteria for nonmonotonic dose-responses (NMDRs) and reviewed studies reporting a NMDR for Bisphenol A. None of the studies fulfil these criteria. Overall the CEF Panel concluded that the available data do not provide evidence that Bisphenol A exhibits a NMDR for the endpoints considered (reproductive/developmental toxicity, neurotoxicity/behavioural effects, metabolic effects, proliferative changes in mammary gland). “

 

EFSA Opinion 2015 concluded on reproductive and developmental toxicity:

Overall, the better powered, better conducted studies in animals found few consistent effects of in-utero exposure to Bisphenol A on reproductive development at dose levels at or below 3.6 mg Bisphenol A/kg/day HED. On balance, the evidence remains contradictory and highly variable between studies. The CEF Panel noted that there is some evidence for effects of Bisphenol A exposure on several parameters indicative for changes in the reproductive system in adult male animals at dose levels below 3.6 mg/kg bw per day, although these effects were modest. It is not possible to conclude that these changes are reflective of changes in reproductive performance, since the studies rarely included a forced/continuous breeding phase in adulthood to establish reduced fertility. However, in several multigenerational studies no effects were observed at dose levels as low as 3mg/kg bw per day up to at least 50 mg/kg bw per day.

Using a WoE approach, the CEF Panel assigned a likelihood level of “as likely as not” to reproductive and developmental effects of Bisphenol A at low doses (below the HED of 3.6 mg/kg bw per day). Since the likelihood level for this endpoint is less than "likely" (see Appendix A), this endpoint was not taken forward for assessing the toxicological reference point, but was taken into account in the evaluation of uncertainty for hazard characterisation and risk characterisation (Section 4.3)."

 

 

Justification for classification or non-classification

Due to the harmonised classification of the constituent BPA, the reaction mass will be classified as Repro Cat 1B (H361F) according to CLP.