Tetrabromobisphenol A: MAK Value Documentation - Translation of the German version from 2023.

After repeated administration by gavage, the target organs were the endocrine system in male and female rats with a decrease in the total T4 concentration, and the kidneys in male mice with cytoplasmic changes in the tubules. Tetrabromobisphenol A induced uterine tumours in female Wistar Han rats as well as hepatoblastomas and haemangiosarcomas in male B6C3F1/N mice. MAK value and peak limitation.  Studies with test persons or epidemiological studies are not available. A NOAEL of 50 mg/kg body weight and day was derived for the most sensitive end point, a decrease in the T4 concentration at doses of 100 mg/kg body weight and day and above, from a 14-week study with gavage administration in male and female F344/NTac rats (NTP 2014 ). The cytoplasmic changes found in the renal tubules at doses of 500 mg/kg body weight and day and above were identified as the critical end point of the 14-week gavage study with male B6C3F1/N mice. The NOAEL was 100 mg/kg body weight and day (NTP 2014 ). A NOAEL for effects on the uterus was not derived for Wistar Han rats from the findings of the 2-year study, only a LOAEL of 250 mg/kg body weight and day for atypical hyperplasia (Dunnick et al. 2015 ; NTP 2014 ). Histological examination of the uterus did not reveal any effects up to a dose of 1000 mg/kg body weight and day in rat studies with shorter periods of exposure of up to 14 weeks or in the carcinogenicity study in Wistar Han rats at interim necropsy after 3 months (Cope et al. 2015 ; NTP 2014 ; Osimitz et al. 2016 ). Furthermore, no NOAEL for effects on the liver was derived from the long-term study in mice, only a LOAEL of 250 mg/kg body weight and day for eosinophilic foci (Dunnick et al. 2015 ; NTP 2014 ). A NOAEL of 100 mg/kg body weight and day was the lowest NOAEL derived from short-term studies for effects on the liver. This NOAEL was determined by a 14-week study for an increase in liver weights in male mice (an increase of less than 20% is not adverse) (LOAEL 500 mg/kg body weight and day; NTP 2014 ). Histological examination of the liver did not reveal any unusual findings up to a dose of 1000 mg/kg body weight and day, the highest dose tested, in short-term studies and in the long-term study at interim necropsy (NTP 2014 ). The following toxicokinetic data are taken into consideration for the extrapolation of the NOAELs of 50 mg/kg body weight and day for rats (T4 concentration) and 100 mg/kg body weight and day for mice (kidneys) to a concentration in workplace air: the corresponding species-specific correction values for the rat and mouse (1:4 and 1:7, respectively), the experimentally determined oral absorption (72%; Hakk et al. 2000 ), the body weight (70 kg), the respiratory volume (10 m 3 ) of the person and the assumed 100% absorption by inhalation. Other factors that are taken into consideration are the extrapolation of the data from animal studies to humans (1:2), no time-extrapolation for the reduced T4 concentrations and the study duration of 14 weeks (1:2) for the effects on the kidneys because the effects in the 2-year study occurred at the lowest dose of 250 mg/kg body weight and day and above (NTP 2014 ). On this basis, a concentration in air of 32 mg/m 3 has been calculated using the data from rats and of 18 mg/m 3 using the data from mice, which would result in a limit value in air for the inhalable fraction of tetrabromobisphenol A of 10 mg/m 3 . However, the adenocarcinomas of the uterus and their precursors must likewise be taken into consideration. The very low effect concentrations in vitro at possible cellular points of action, the inhibition of the SULT1E1 sulfotransferase that metabolizes oestradiol (IC 50 12 to 33 nM; Hamers et al. 2006 ; Kester et al. 2002 ) and the possible proliferative effects via GPER at 10 nM (Hoffmann et al. 2017 b ) suggest that tetrabromobisphenol A may already induce effects in vivo at concentrations below 10 mg/m 3 . There are no in vivo correlates for these mechanisms. A NOAEL is not available for the development of preneoplastic lesions (atypical hyperplasias) that were observed in Wistar Han rats at doses of 250 mg/kg body weight and day and above (Dunnick et al. 2015 ; NTP 2014 ). The course of the dose–response curve is not known. The extrapolation of the LOAEL of 250 mg/kg body weight and day for atypical endometrial hyperplasias to a concentration in air results in a value of 157 mg/m 3 based on the same assumptions as used above. In view of the severity of the effects (preneoplastic lesions), the margin between the LOAEL and the concentration in air of 10 mg/m 3 is not considered adequate. As a result, and because of the uncertainties relating to the dose–response curve, a MAK value has not been derived based on the LOAEL for atypical hyperplasia. A MAK value cannot be derived because the data needed to establish a NOAEL for atypical hyperplasia are not available and it is neither possible to clarify whether the uterine tumours are strain-specific effects nor to characterize the mechanism of action of tumour formation in greater detail. As a MAK value has not been derived, peak limitation does not apply. Prenatal toxicity.  In a prenatal developmental toxicity study carried out according to OECD Test Guideline 414 with gavage administration in rats from gestation days 0 to 19, developmental and maternal toxicity were not observed up to the highest dose tested of 1000 mg/kg body weight and day. The NOAEL for developmental toxicity was 1000 mg/kg body weight and day, the highest dose (Cope et al. 2015 ; MPI Research 2001 ). A NOAEL of 1000 mg/kg body weight and day, the highest dose, was derived for perinatal toxicity from the findings of a 2-generation study with gavage administration in rats (Cope et al. 2015 ). As no MAK value has been derived, the substance has not been classified in a pregnancy risk group. Carcinogenicity.  The uterus was the target organ of carcinogenicity in Wistar Han rats. The incidence of adenocarcinomas was increased in the 2-year carcinogenicity study at 500 mg/kg body weight and day and above. In addition, malignant mixed Müllerian tumours, a very rare form of tumour, occurred in isolated cases and uterine tumour metastases were found in several organs. Atypical endometrial hyperplasia, a preneoplastic lesion, was observed at the lowest dose of 250 mg/kg body weight and day and above. No carcinogenic effects were found in male rats (Dunnick et al. 2015 ; NTP 2014 ). In the 2-year carcinogenicity study, the incidence of hepatoblastomas and the combined incidence of hepatocellular carcinomas and hepatoblastomas were increased with statistical significance in male B6C3F1/N mice at 250 mg/kg body weight and day, but not at 500 mg/kg body weight and day. At both doses, the incidences for hepatoblastomas were higher than those of the historical controls. In male mice, the incidence of haemangiosarcomas (all organs) and the combined incidence of haemangiomas and haemangiosarcomas were increased at 500 mg/kg body weight and day with a significant trend. However, the incidences were within the range of those of the historical controls of the laboratory. The incidence of tumours in female mice was not increased (NTP 2014 ). Tetrabromobisphenol A was carcinogenic in female Wistar Han rats and in male B6C3F1/N mice. There is no evidence to suggest that the substance is genotoxic (see below). Non-genotoxic mechanisms are responsible for tumour formation. The development of uterine tumours in Wistar Han rats is attributed to oestrogenic and non-oestrogenic effects. A gene expression study in female Wistar Han rats demonstrated that tetrabromobisphenol A disrupts oestrogen homeostasis; this is not mediated by an agonist effect on the oestrogen receptors ERα and ERβ (Sanders et al. 2016 ). The proliferative effects on the endometrium are attributed to oestrogen (NTP 2014 ). The non-oestrogenic effects include immunosuppressive effects. As there is no evidence that the uterine tumours are specific to a certain strain, the tumours have been included in the evaluation in compliance with the procedure established by the Commission (Laube et al. 2019 ). In the B6C3F1/N mouse strain, hepatoblastomas are known to develop in male mice via a CAR/PXR induction mechanism. The eosinophilic foci are indirect precursors that lead to hepatoblastomas via hepatocellular carcinomas. The Commission assumes that the tumour is relevant to humans, but that humans are much less susceptible (Felter et al. 2018 ). It is postulated that, besides PPARγ agonistic effects, the development of haemangiosarcomas in male B6C3F1/N mice is associated with the comparably higher basal proliferation rate of endothelial cells in this strain of mouse in comparison with the rates found in F344 rats and humans. There is no evidence that the effects are species-specific; the Commission therefore assumes that the tumour is relevant to humans. Due to the non-genotoxic mechanism of action, it is assumed that a NAEL (no adverse effect level) can be established for the carcinogenic effects. For this reason, it would be possible to classify tetrabromobisphenol A in Carcinogen Category 4. As the available data are not sufficient to allow for the derivation of a MAK value (see above), the substance has been classified in Carcinogen Category 2 according to the procedure currently followed by the Commission (Hartwig and MAK Commission 2022 ) and bears the footnote “Prerequisite for Category 4 in principle fulfilled, but insufficient data available for the establishment of a MAK or BAT value”. Germ cell mutagenicity.  No studies with germ cells are available. Tetrabromobisphenol A was not mutagenic in numerous bacterial gene mutation tests (EU 2006 ; Litton Bionetics Inc. 1976 , pp. 214–223, 1977 , pp. 21–32; MHLW 2019 b ,  e ; Mortelmans et al. 1986 ; NTP 2014 ; SRI 1976 a , b ). Tetrabromobisphenol A did not cause clastogenicity or polyploidy in 2 tests for chromosomal aberrations in mammalian cells (BioReliance 2001 , pp. 340–378; MHLW 2019 c ). Oxidative stress in the kidneys and testes of male juvenile Sprague Dawley rats was observed at a tetrabromobisphenol A dose of 500 mg/kg body weight and day (Choi et al. 2011 ). Tetrabromobisphenol A was not clastogenic in male and female B6C3F1/N mice after exposure for 3 months to doses up to 1000 mg/kg body weight and day (NTP 2014 ). According to the available data, tetrabromobisphenol A is not genotoxic. For this reason, the substance has not been classified in a category for germ cell mutagens. Absorption through the skin.  Tetrabromobisphenol A causes low acute toxicity after dermal application. Data from in vitro and in vivo studies are available for the absorption of tetrabromobisphenol A through the skin. In vitro studies carried out by Knudsen et al. ( 2015 ) demonstrated that the barrier properties of human skin are markedly better than those of rat skin. Three in vivo studies investigated the penetration of tetrabromobisphenol A through the rat skin. On the basis of the penetration data reported by the studies of Yu et al. ( 2016 , 2017 ) and Knudsen et al. ( 2015 ), 0.3 mg to 361.9 mg of tetrabromobisphenol A would be absorbed after 1-hour exposure of 2000 cm 2 of skin. The amount is dependent on the dose and sex. Data from in vivo studies suggest that relevant amounts of the substance are absorbed through the skin. As a result, the substance has been provisionally designated with an “H” (for substances which can be absorbed through the skin in toxicologically relevant amounts) because it is classified as a Category 2 carcinogen, but there is currently no known threshold for the carcinogenic effects. Sensitization.  There are no findings of sensitizing effects in humans and no positive results from experimental studies with animals or in vitro studies. Therefore, tetrabromobisphenol A has not been designated with “Sh” or “Sa” (for substances which cause sensitization of the skin or airways).