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

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

Chlorothalonil

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has reviewed an unpublished inhalation study of chlorothalonil [1897 456] to evaluate whether its findings can be used to derive a maximum concentration at the workplace (MAK value). As described in the 2018 supplement, chlorothalonil is corrosive to the eyes of rabbits. Workers reported irritation of the eyes, nose and throat at exposure concentrations of 0.3 to 1.2 mg/m3. An unpublished 2 week inhalation study with exposure of rats to chlorothalonil aerosol concentrations of 0,1.1, 2.9, 9.6 or 14.3 mg/m3 has been made available to the MAK Commission. Squamous metaplasia and necrosis in the U shaped cartilage of the larynx were observed in all 10 exposed animals at the low concentration of 1.1 mg/m3 and above; higher concentrations induced additional effects in the larynx, lungs and respiratory tract. It is still not possible to derive a MAK value and chlorothalonil remains assigned to Section II b of the List of MAK and BAT Values. No other end points were re evaluated

Paraquatdichlorid

Paraquat dichloride [1910-42-5] is used as a herbicide but is no longer approved in the European Union. The previous MAK Value documentations and supplements 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

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

Fettsäuren, C14–18-gesättigt und C16–18-ungesättigt

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated fatty acids, C14–18 saturated and C16–18 unsaturated [67701-06-8], considering all toxicological end points. It is a UVCB substance (substances of Unknown or Variable composition, Complex reaction products or Biological materials). There are no data for humans or from repeated dose studies in animals for fatty acids, C14–18 saturated and C16–18 unsaturated, that can be used to derive a maximum concentration at the workplace (MAK value). No data are available for the irritation potential of the UVCB substance. The systemic oral NOAEL of behenic acid (C22), a structurally similar fatty acid, was found to be 1000 mg/kg body weight and day in a study carried out in rats according to OECD Test Guideline 422. The fatty acids, C14–18 saturated and C16–18 unsaturated, are non-ionic surfactants; therefore, effects on the pulmonary surfactant are likely to occur. A MAK value cannot be established because no data for inhalation toxicity are available. In vitro studies of the fatty acids, C14–18 saturated and C16–18 unsaturated, or acids of similar length and similar degree of unsaturation showed no genotoxic potential. No in vivo genotoxicity studies and no carcinogenicity studies have been carried out with the fatty acids, C14–18 saturated and C16–18 unsaturated. Limited studies of fatty acids of similar length and similar degree of saturation did not find effects of developmental toxicity. A sensitizing potential is not expected based on the available data. The substance does not penetrate the skin in toxicologically relevant amounts

N′-(3-Aminopropyl)-N′-dodecylpropane-1,3- diamine

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated N′-(3-aminopropyl)-N′-dodecylpropane-1,3-diamine [2372-82-9] to derive a maximum concentration at the workplace (MAK value), considering all toxicological end points. Available unpublished study reports and publications are described in detail. Critical effects are degeneration of heart muscle cells and lympho-histiocytic infiltrations in the skeletal muscles of male rats. No NOAEL could be derived for these effects. The LOAEL is 4 mg/kg body weight. A NAEL of 1.3 mg/kg body weight was extrapolated and a MAK value of 0.05 mg/m3 for the inhalable fraction could be derived. The derivation of the MAK value is conservative because the determined oral absorption is very low and for the inhalative absorption a default value of 100% is assumed due to a lack of experimental data. N′-(3-Aminopropyl)-N′-dodecylpropane-1,3-diamine is basic and therefore corrosive to rabbit skin, hence an irritation potential for the respiratory tract has to be assumed. No inhalation studies are available. Compared to several primary, secondary and tertiary amines which have MAK values between 1 and 13 mg/m3, the basicity of N′-(3-aminopropyl)-N′-dodecylpropane-1,3-diamine is almost the same or less. Therefore, a MAK value of 0.05 mg/m3 should protect against local irritating effects. As the critical effect is systemic, the substance has been classified in Peak Limitation Category II. An excursion factor of 8 is set as the half-life in blood is at least 28.5 hours. The NOAELs for developmental toxicity in rats and rabbits are 22.5 and 9 mg/kg body weight and day, respectively, which can be scaled to concentrations of 1 and 0.66 mg/m3 at the workplace. Thus, there is no reason to fear damage to the embryo or foetus when the MAK value is observed and the substance is classified in Pregnancy Risk Group C. N′-(3-Aminopropyl)-N′-dodecylpropane-1,3-diamine is not genotoxic or carcinogenic. The potential of contact sensitization in humans cannot be definitely assessed because of the corrosive character. The substance is not a contact sensitizer in guinea pigs. Skin contact is not expected to contribute significantly to systemic toxicity

Schwefelhexafluorid

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated sulfur hexafluoride [2551-62-4] considering all toxicological end points. This supplement evaluates only pure sulfur hexafluoride. Reaction products that are highly toxic for humans can form during its use as an insulating gas in high voltage switchgear. Under normal conditions, the reactivity of sulfur hexafluoride gas is comparable to that of helium or nitrogen. Therefore, systemic or local effects were not observed in studies carried out in compliance with OECD test guidelines with exposure of rats to the gas at concentrations up to 20 052 ml/m3 for 13 weeks. Acute exposure to 550 000 ml/m3 (55%) induced sleepiness and analgesia in humans. On the basis of the NOAEC of 20 052 ml/m3, a maximum concentration at the workplace (MAK value) of 5000 ml/m3 has been set. As significant effects were not observed in humans up to 390 000 ml/m3, Peak Limitation Category II and the excursion factor of 8 have been retained. Sulfur hexafluoride showed no genotoxic potential. Carcinogenicity studies have not been carried out. Sulfur hexafluoride was not teratogenic in a developmental toxicity study in concentrations up to 19 100 ml/m3, but led to a transient delay in foetal development. After consideration of all data as well as the fact that sulfur hexafluoride is inert under normal conditions, it has been assigned to Pregnancy Risk Group C. There are no data for the sensitizing potential of sulfur hexafluoride. Skin contact is not expected to contribute significantly to systemic toxicity