4-hydroxybenzophenone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Urine concentrations in male humans were negatively associated with fecundability (Louis et al., American Journal of Epidemiology, 2014, Vol. 180, No. 12).

4OH-BP was detected in human urine. No significant semen quality endpoint associations (odd ratio) were observed for urinary concentrations of 4OH-BP in humans (Louis et al., Fertil Steril 2015, 104:989–96).

There were no statistically significant differences (Spearman correlation) between human children malformation cases and controls in the median placenta concentration of 4-OH-BP (Fernandez et al., Reproductive Toxicology 59, 2016, 89–95)

4-OH-BP was detectable in human urine, amniotic fluid and cord blood samples but not in paired fetal blood (Krause et al., Environment International 110, 2018, 51-60).

None of the 15 tested human milk samples showed detectable levels of 4-OH-BP (Lopez et al., J Matern Fetal Neonatal Med, 2016; 29(S1): 1–317 and also in Lopez et al., Eur J Pediatr, 2016, 175:1393–1880).

4-OH-BP was detected in human seminal plasma and urine. There was no association between 4-OH-BP levels and couple fecundability observed (Louis et al.,Environmental Research 163, 2018, 64-70).

Read-across data captured from published Benzophenone registration dossier:

Oral OECD rats two gen (Guideline 416): No reproductive toxicity was found and effects on the offspring (inhibition of body weights) were observed at the highest dose only. LOAEL: 6 mg/kg bw based on the dose-dependent histopathological findings in liver of adult rats (Hoshino et al., 2005, J Toxicol Sci 30, 5-20).

Oral rabbits (OECD Guideline 414) and OPPTS 870.3700 rabbits prenatal development studies: Developmental toxicity was noted only in the presence of well-defined maternal toxicity. There was no evidence for selective susceptibility of the conceptus relative to the pregnant dam.

Receptor binding/estrogenicity/uterotrophic assay

4-HO-BP has a weak androgen receptor binding affinity (Receptor binding assay) (Fang et al., Chem. Res. Toxicol. 2003, 16, 1338-1358)

4-HO-BP has a strong estrogen activity (Yeast two hybrid assay) (Kawamura et. al, Journal of Health Science,49(3) 205-212 (2003))

4-HO-BP has no/very weak androgen receptor activity (hAR Mediated Reporter Gene Agonist Assay), estrogenic activity (hERα Mediated reporter gene agonist assay). Kawamura et al. (Journal of Health Science, 51(1) 48-54 (2005).

Estrogenicity was measured colormetrically as ß-galactosidase activity. 4-HO-BP exhibited weak ß-galactosidase activity (Schultz, Environmental Toxicology and Chemistry, Vol. 19, No. 2, pp. 301-304. 2000)

4-HO-BP exhibited estrogenic activity in the estrogen screening assay. No androgenic activity of 4-HO-BP was observed in the concentration range of 10^-7to 10^-4M in vitro (Suzuki et al., Toxicology and Applied Pharmacology 203, 2005, 9 – 17).

4OH-BP showed potent estrogenic activity inducing a response from 10^-6M in CXCL-testing, a cell proliferation test (Hebauzit et al., Chemosphere 173 (2017) 253-260)

Administration (s.c.) of 100-400 mg/kg bw 4-HO-BP elicited an increase in absolute and relative uterine weights in a dose dependent manner accompanied by an increase in luminal epithelial height and stromal cells in the uterus and an increase in thickness of vaginal epithelial cell layers with cornification in juvenile female rats (21-days old, administration for 3 days) (Nagakawa, Arch Toxicol (2001) 75: 74-79)

4-HO-BP was positive in the reporter gene assay for ER-alpha agonists. Uterine blotted weight decreased significantly in rats given 200 mg/kg bw 4-HO-BP plus ethinyl-estradiol in an uterotrophic assay (Yamasaki et al., Toxicology Letters 142, 2003, 119-131)

4-HO-BP exerted both estrogen agonistic effect and reduced the estrogenic effect of ethinylestradiol in the uterotrophic assay (Yamasaki et al., Toxicology 183, 2003, 93-115)

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

4-HO-BP gave positive results in several uterotrophic and receptor binding assays. Nevertheless, there was no indication for reproductive toxicity in several epidemiological studies. Also the read across data from a 2-generation study with benzophenone as test compound gave no indication for reproductive toxicity. It must be considered, that the high dose of the 2-generation study (150 mg/kg bw/d) was below the effective concentration in uterotrophic assays with benzophenone as test compound (300 mg/kg bw/d). Additionally, since benzophenone was administered via the feed, likely no peak concentrations of its metabolite 4 -OH-BP occured in this study.

Consequently, the RA data is insufficient to exclude an estrogenic potential of hydroxybenzophenone, nevertheless the available data is insufficient for reproductive toxicity classification purposes under Regulation (EC) No 1272/2008, as amended for the seventh time in Regulation (EU) No 2015/1221.