4,4'-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]diphenol; bisphenol AF

Specific investigations: other studies

Description of key information

This section is covering IUCLID section 7.9.3, which does not permit entry of endpoint summary;

The main adverse finding for this endpoint included increase organ weight i.e. uterus and glans penis weight, abnormal estrous cycles, high adrenal weight in males, atrophy of mammary glands.

Dose related accumulation of the testate in the testes, decline in genes and protein involved in cholesterol biosynthesis, transport and steroid biosynthesis.

Decreased testicular mRNA levels of inhibin B, estrogen receptor (ER) and luteinizing hormone receptor (LHR).

The NOAEL <8 mg/kg bw/day from uterotrophic and Hershberger repeat dose study due to signifigant increase in the uterus weight in the 8 and 40 mg/kg bw/day dose group.

It can be concluded that this substance may be considered an endocrine disruptor.

Additional information

In a subacute toxicity study conducted on rats in accordance with OECD 407 under GLP (Umano et al., 2012), The substance was administered to 30 male and 30 female Sprague-Dawley rats by oral gavage at dose levels of 10, 30 and 100 mg/kg bw/day for up to 28 consecutive days.  Although there was no recovery phase, this is not a guideline requirement.  The key findings in this study were lower body weight gain at 100 mg/kg/day for males and at 30 and 100 mg/kg/day for females; lower white cell counts in males at 100 mg/kg/day; lower cholesterol levels in both sexes at 100 mg/kg/day; lower cholinesterase and higher bilirubin levels in females at 100 mg/kg/day; longer oestrous cycles in females at 100 mg/kg/day; lower absolute and relative prostate and seminal vesicles weights at 100 mg/kg/day, possibly reflecting the lower body weight; higher adrenal weight in males at 100 mg/kg/day; Leydig cell atrophy at 100 mg/kg/day in 5/10 males; hypertrophy of the adrenal zona fasciculata at 100 mg/kg/day in 8/10 males, 2/10 females; atrophy of mammary glands in 3/10 males at 100 mg/kg/day; decreased haematopoiesis in bone marrow and extramedullary haematopoiesis in spleen at 100 mg/kg/day in 4/10 and 2/10 males, respectively.  Many findings were related to endocrine effects, but had not considered that some may have been secondary to the lower body weights.  Without having the individual data, it is not possible to comment further.  In conclusion, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was 10 mg/kg bw/day due to findings of reduced body weight gain and abnormal estrous cycles in the female rat treated at 30 mg/kg bw/day.

In an uterotrophic and Hershberger repeated dose test (Yamasaki et al., 2003), the test item was administered to rats via subcutaneous injections and oral garage at dose levels of 8, 40 and 100 mg/kg bw/day and 50, 200 and 600 mg/kg bw/day respectively. Test item related effects were noted in both female and male individuals in their respective tests at the tested concentrations, significant reduction in weight increase and significant increase glans penis weight observed in the 200 and 600 mg/kg bw/day male treatment groups. Mortality of two individuals was also observed in the male Hershberger test at the highest dose group.  There was also significant increase in relative uterus weight in the 8 and 40 mg/kg bw/day dose groups. The NOAEL for male and female rats was < 8 mg/kg bw/day based on histopathology results, where a significant increase in organ weight (uterus) was observed in female individuals, there is an implication that the test item has estrogen agonistic properties.

In another study (Li et al., 2016), the endocrine -mediated effect of BPAF was assessed in gestational, lactating and pups following exposure to 100 mg/kg bw/day from gestational day (GD) 3 to postnatal day (PD 19). Free and total BPAF levels in testis was detected in all treatment groups with bioacumalation observed in offspring testes. there was also increased testis testosterone level and decreased testis inhibin B (INHB) levels. Furthermore, there was increase levels of steroidogenesis genes (P450scc and StAR) in the male rat testis. These results indicate that gestational and loctational exposure to BPAF in the mother can impair reproductive function in male offspring.

In another sub-chronic study (Feng et al., 2012), Bisphenol AF was administered to 30 Sprague-Dawley male rats by gavage at dose levels of 2, 10, 50 and 100 mg/kg bw/day along with a vehicle control group for 14 days. Key finding included, decreased total serum cholesterol at dose of 50 and 200 mg/kg/day, reduced serum testosterone and increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were observed in rats in the higher dose groups. Dose related accumulation of the testate in the testes, decline in genes and protein involved in cholesterol biosynthesis, transport and steroid biosynthesis. Similarly, the testicular mRNA levels of inhibin B, estrogen receptor (ER) and luteinizing hormone receptor (LHR) also decreased in rats given a dosage of 200 mg/kg/d. The NOEAL for bisphenol-AF for male Sprague-Dawley rats was < 10 mg/kg/bw/day.