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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

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 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)."

 


Short description of key information:
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).“

Effects on developmental toxicity

Description of key information
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).“
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
640 mg/kg bw/day
Study duration:
subacute
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

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)."

Toxicity to reproduction: other studies

Additional information

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).“

Justification for classification or non-classification

Harmonised classification - Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation).

ATP Updated: CLP00/ATP09: Repr. 1B (H360F)

--------------------

General Information

The ECHA Risk Assessment Committee (RAC) recently proposed to strengthen the reproductive toxicity classification of Bisphenol A to a category 1B (H360 May damage fertility) reproductive toxicant. This conclusion is based on high-dose effects in the comprehensive studies. RAC (ECHA/RAC/RES-O-0000001412-86-56/F) concluded:“Based on the available studies, RAC considers that there is evidence of effects of Bisphenol A exposure on several parameters indicative of changes in the reproductive system. The multi-generation studies (Tyl et al. 2008 and 2002, NTP 1985, EMA et al. 2001) and a subchronic study (Delclos et al. 2014, also referred to as US FDA/NCTR 2013) were the basis of the CLP classification for fertility by RAC (2014). RAC’s opinion (RAC 2014) was based on adverse effects, such as disturbances in the oestrous cycle, at a dose of 600 mg/kg bw/day (Tyl et al. 2008) and at a dose of 100 mg/kg bw/day (Delclos et al. 2014). The ovarian toxicity reported in Tyl et al. (2002) included reduced absolute and relative ovarian weight at the two highest doses of 50 and 500 mg/kg bw/day and in Delclos et al. (2014) an increase in ovarian follicular cysts was observed at 300 mg/kg bw/day. In Delclos et al. (2014), an increase in cystic endometrial hyperplasia was observed in the uterus at the highest dose of 300 mg/kg bw/day.”

The above mentioned guideline generation studies in rats and mice show that Bisphenol A is not a selective reproductive toxicant.

• NOAEL for systemic toxicity 5 mg/kg bw/day in rats and mice; LOAEL >= 50 mg/kg bw/day.

• In rats no adverse effects on oestrus cycle, fertility, litter sizes, pre- and post-natal survival, growth and development at doses at doses up to ca. 200 mg/kg bw/day. With 500 mg/kg bw/day reduced litter size (at systemic toxic dose) in the Three Generation Reproduction Study.

• In mice no adverse effects on fertility, litter sizes, pre- and post-natal survival at doses up to ca. 600 mg/kg bw/day. With 600 mg/kg bw/day delayed offspring development in the Two Generation Reproduction Study. As the studies discussed in this chapter show, effects on animal fertility only occur at high doses of Bisphenol A and are a consequence of systemic toxicity.