Mammalian epoxide hydrolases in xenobiotic metabolism and signalling

Epoxide hydrolases catalyse the hydrolysis of electrophilic—and therefore potentially genotoxic—epoxides to the corresponding less reactive vicinal diols, which explains the classification of epoxide hydrolases as typical detoxifying enzymes. The best example is mammalian microsomal epoxide hydrolase (mEH)—an enzyme prone to detoxification—due to a high expression level in the liver, a broad substrate selectivity, as well as inducibility by foreign compounds. The mEH is capable of inactivating a large number of structurally different, highly reactive epoxides and hence is an important part of the enzymatic defence of our organism against adverse effects of foreign compounds. Furthermore, evidence is accumulating that mammalian epoxide hydrolases play physiological roles other than detoxification, particularly through involvement in signalling processes. This certainly holds true for soluble epoxide hydrolase (sEH) whose main function seems to be the turnover of lipid derived epoxides, which are signalling lipids with diverse functions in regulatory processes, such as control of blood pressure, inflammatory processes, cell proliferation and nociception. In recent years, the sEH has attracted attention as a promising target for pharmacological inhibition to treat hypertension and possibly other diseases. Recently, new hitherto uncharacterised epoxide hydrolases could be identified in mammals by genome analysis. The expression pattern and substrate selectivity of these new epoxide hydrolases suggests their participation in signalling processes rather than a role in detoxification. Taken together, epoxide hydrolases (1) play a central role in the detoxification of genotoxic epoxides and (2) have an important function in the regulation of physiological processes by the control of signalling molecules with an epoxide structur

Chlordan

Chlordane [57-74-9] is used as an insecticide but is no longer approved in the European Union. The previous MAK value documentation and supplement do not reflect the current data situation of the substance. The MAK Commission decided that a new evaluation is not of high priority. The MAK value and the other classifications are therefore suspended and the substance is listed in the Section II c of the List of MAK and BAT Values for substances no longer evaluated

Aldrin

Aldrin [309-00-2] is used as an insecticide but is no longer approved in the European Union. The previous MAK value documentation and supplement do not reflect the current data situation of the substance. The MAK Commission decided that a new evaluation is not of high priority. The MAK value and the other classifications are therefore suspended and the substance is listed in the Section II c of the List of MAK and BAT Values for substances no longer evaluated

Sodium pyrithione

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated sodium pyrithione [3811-73-2; 15922-78-8] considering all toxicological end points. Available publications and unpublished study reports are described in detail. Sodium pyrithione is neurotoxic in rats and rabbits, but not in monkeys. As there is no sufficient mechanistic explanation for the observed differences between the species, the rat as the most sensitive species is used for the derivation of a maximum concentration at the workplace (MAK value). The NOAEC in a 90-day inhalation study with rats is 1.1 mg/m3. In a chronic feeding study with rats, a NAEL of 0.16 mg/kg body weight and day is derived from the LOAEL of 0.5 mg/kg body weight and day. Both the NOAEC and the NAEL correspond to a MAK value of 0.2 mg/m3 for the inhalable fraction. As a systemic effect is critical, the substance remains classified in the Limitation Category II. As the initial half-life of sodium pyrithione is in the range of up to 2.8 hours, an excursion factor of 2 is assigned. In developmental toxicity studies, the most critical effects of sodium pyrithione are skeletal anomalies in rats. NOAELs for developmental effects are 2 mg/kg body weight and day after oral treatment of rats as well as 3 and 5 mg/kg body weight and day after dermal application to rats and rabbits, respectively. The differences between the NOAELs for rats and rabbits scaled to an inhalation concentration at the workplace and the MAK value are considered sufficient. Therefore, damage to the embryo or foetus is unlikely when the MAK value is not exceeded and sodium pyrithione is assigned to Pregnancy Risk Group C. Sodium pyrithione is still regarded as a non-genotoxic and non-carcinogenic substance. Skin contact may contribute significantly to systemic toxicity and sodium pyrithione remains designated with an “H” notation. Sensitization is not expected based on the limited data available

Triphenyl phosphate, isopropylated

he German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated triphenyl phosphate, isopropylated [68937-41-7] to derive a maximum concentration at the workplace (MAK value), considering all toxicity end points. Available unpublished study reports and publications are described in detail. Isopropylated triphenyl phosphate has no irritant effects on the skin of rats and rabbits, and is not, or at most minimally, irritating to the eyes of rabbits. It belongs to the group of organophosphates and shows the typical delayed organophosphate neurotoxicity (axonal degeneration). The neurotoxicity decreases with increasing isopropylation. However, the most sensitive toxicological end points following repeated exposures are histopathological changes in the adrenal gland and ovary. The LOAEC in 90-day inhalation studies in rats and in hamsters was 10 mg/m3, the lowest tested concentration. Oral studies according to OECD TG 422 and TG 408 have revealed a LOAEL of 25 mg/kg body weight and day in rats. Neurotoxicity tests in hens have yielded a NOAEL of 20 mg/kg body weight and day. After scaling these NOAELs to a concentration at the workplace, a MAK value of 1 mg/m3 is derived. As the systemic effect is critical, isopropylated triphenyl phosphate is assigned to Peak Limitation Category II with the default excursion factor of 2, as no specific toxicokinetic data are available. No developmental toxicity was observed at 260 mg isopropylated triphenyl phosphate/kg body weight and day. Therefore, no damage to the embryo or foetus has to be expected and isopropylated triphenyl phosphate is classified in Pregnancy Risk Group C. Isopropylated triphenyl phosphate is not genotoxic in vitro or in vivo nor does it have cell-transforming activity. No data on carcinogenicity are available. Overall, the available data do not indicate that the substance should be classified as a carcinogen or a germ cell mutagen. Sensitizing potential was not investigated with isopropylated triphenyl phosphate, and similar compounds have led to inconclusive results. Absorption through the skin is low and does not relevantly contribute to systemic toxicity

2-Butanethiol

MAK Value Documentation – Translation of the German version from 202

Tricresyl phosphate, isomers, “free of o-isomers”

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated tricresyl phosphate, isomers [1330-78-5], “free of o-isomers” considering all toxicological end points. The para and meta isomers do not cause severe effects on the CNS. In a 90-day inhalation study with rats, 300 mg/m3 did not induce neurotoxic effects. The critical effects of tricresyl phosphate, isomers, “free of o-isomers” in oral 2-year studies were higher grades of cytoplasmic vacuolation in the adrenal glands and hyperplasia of the interstitial cells of ovaries at 15 mg/kg body weight and day in female rats. The NOAELs were 13 mg/kg body weight and day for male rats (highest dose tested) and 7 mg/kg body weight and day for females. In male mice, the NOAEL was 7 mg/kg body weight and day based on ceroid pigmentation, foci and changes in the fat cells of the liver at 13 mg/kg body weight and day. In female mice, ceroid pigmentation in the adrenals occurred as from the lowest dose of 8 mg/kg bodyweight and day. Ceroid pigmentation in adrenals is common in older mice and therefore of questionable relevance for humans. A maximum concentration at the workplace (MAK value) of 5 mg/m3 was derived for the inhalable fraction based on the NOAEL of 7 mg/kg body weight and day determined in female rats and male mice. As a systemic effect is critical, Peak Limitation Category II and the default excursion factor of 2 are assigned. A NOAEL of 100 mg/kg body weight and day was found in a developmental toxicity study in rats and a NOAEL of 62.5 mg/kg body weight and day in a 1-generation study in mice. Workplace concentrations of 175 and 88 mg/m3 are calculated from these values. Therefore, damage to the embryo or foetus is unlikely when the MAK value is not exceeded and tricresyl phosphate, isomers, “free of o-isomers” are assigned to Pregnancy Risk Group C. Tricresyl phosphate, isomers, “free of o-isomers” were not mutagenic or clastogenic in vitro and did not increase tumour incidences in a 2-year study in rats or mice. Model calculations do not predict dermal uptake in toxicologically relevant amounts. There are no data that show that tricr

DDT (Dichlordiphenyltrichlorethan)

DDT [50-29-3] and DDT preparations are no longer approved in the European Union or in Germany. The previous documentation does not reflect the current data situation of the substance. The MAK Commission decided that a new evaluation is not of high priority. The MAK value and the other classifications are therefore suspended and the substance is listed in the Section II c of the List of MAK and BAT Values for substances no longer evaluated

Dieldrin

Dieldrin [60-57-1] is used as an insecticide but is no longer approved in the European Union. The previous MAK value documentation and supplement do not reflect the current data situation of the substance. The MAK Commission decided that a new evaluation is not of high priority. The MAK value and the other classifications are therefore suspended and the substance is listed in the Section II c of the List of MAK and BAT Values for substances no longer evaluated