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Key value for chemical safety assessment

Effects on fertility

Additional information

The reaction mass of phenol and 4,4'-isopropylidenediphenol (BPA) contains phenol and BPA.

For considerations on the analogue approach used please refer to the reporting form attached to section 13 of the IUCLID.

The properties of both constituents will be taken into account for hazard characterisation.

Phenol

In the phenol EU-RAR (2006) toxicity to reproduction was documented in Section 4.1.2.9. Data on fertility impairment (page 128ff) indicated no impairment of reproductive capability (but systemic toxicity in parenteral animals) even at a dose of 5000 mg/l in a drinking water study. 

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. 

BPA

The 2003 BPA EU RAR concluded that no human data on reproductive toxicity of BPA are available. BPA 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 estradiol. The effects of BPA 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 2008 updated EU RAR concluded that a new two-generation study in mice by Tyl et al. (published in 2008) provides a comprehensive and definitive investigation on the effects of BPA on reproduction at exposure levels spanning the low (ug/kg/day) to high (mg/kg/day) ranges. This study showed that BPA 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 BPA exposure.

There is no significant new information on the reproductive or developmental toxicity of BPA that was not discussed in the 2003 or 2008 EU RARs.


Short description of key information:
The reaction mass of phenol and 4,4'-isopropylidenediphenol (BPA) contains phenol and BPA.
No impairment of reproductive capability and fertility by phenol was found at 5000 mg/l in a two-generation study. Reported effects 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.

The 2008 updated EU RAR on BPA 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 BPA on reproduction at exposure levels spanning the low (ug/kg/day) to high (mg/kg/day) ranges. This study showed that BPA 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 BPA exposure. "

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.

Effects on developmental toxicity

Description of key information
The reaction mass of phenol and 4,4'-isopropylidenediphenol (BPA) contains phenol and BPA. 
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.
The 2003 BPA EU RAR concluded that in standard developmental studies in rodents, there is no convincing evidence that BPA is a developmental toxicant. Available and apparently conflicting data from studies conducted using low doses raise uncertainties that the Competent Authorities required to be resolved through further testing. A provisional NOAEL of 50 mg/kg/day for developmental effects, derived from a rat multi-generation study, should be used in the risk characterisation in the interim while awaiting the outcome of further testing.
The NOELs for effects on development were higher than those of general systemic toxicity so that they will not be taken into account in the CSA.
Additional information

The reaction mass of phenol and 4,4'-isopropylidenediphenol (BPA) contains phenol and BPA.

From the assessment of the data from the phenol 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) 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 (Procter&Gamble, 1997)

 

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.

BPA:

The 2003 BPA EU RAR concluded that in standard developmental studies in rodents, there is no convincing evidence that BPA is a developmental toxicant. Available and apparently conflicting data from studies conducted using low doses raise uncertainties that the Competent Authorities required to be resolved through further testing. A provisional NOAEL of 50 mg/kg/day for developmental effects, derived from a rat multi-generation study, should be used in the risk characterisation in the interim while awaiting the outcome of further testing.

The 2008 updated EU RAR concluded that no conclusions could be drawn from new developmental toxicity studies or from a human study investigating recurrent miscarriage and BPA exposure, so these studies do not influence the conclusions of the original risk assessment report.

There is no significant new information on the reproductive or developmental toxicity of BPA that was not discussed in the 2003 or 2008 EU RARs.

Justification for classification or non-classification

Due to the official classification of the constituent BPA, the reaction mass will be classified as

Repro Cat 3; R62 according to DSD

Repro Cat 2 (H361f) according to CLP.

Additional information