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W4214860712 abstract "Free Access Endrin [MAK Value Documentation, 2002] 2002. Documentations and Methods First published: 31 January 2012 https://doi.org/10.1002/3527600418.mb7220e0018 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Published in the series Occupational Toxicants, Vol. 18 (2002) The article contains sections titled: Toxic Effects and Mode of Action Mechanism of Action Toxicokinetics and Metabolism Effects in Man Single exposures Repeated exposures Genotoxicity Carcinogenicity Animal Experiments and in vitro Studies Acute toxicity Inhalation Ingestion Dermal absorption Subacute, subchronic and chronic toxicity Inhalation Ingestion Dermal absorption Local effects on skin and mucous membranes Reproductive and developmental toxicity Multigeneration studies Fertility Developmental toxicity Genotoxicity In vitro In vivo Carcinogenicity Short-term studies Long-term studies Manifesto (MAK value/classification) MAK value (1969) 0.1 mg/m3 I (inhalable aerosol fraction) Peak limitation (1983) Category III Absorption through the skin (1969) H Sensitization - Carcinogenicity - Prenatal toxicity (1998) Group C Germ cell mutagenicity - BAT value - Synonyms 1,2,3,4,10,10-hexachloro-6,7-epoxy- 1,4,4a,5,6,7,8,8a-octahydro-endo, endo-1,4:5,8-dimethanonaphthalene Chemical name (CAS) (1aα,2β,2aβ,3α,6α,6aβ,7β,7aα)-3,4,5, 6,9,9-hexachloro−1a,2,2a,3,6,6a,7, 7a-octahydro-2,7:3,6-dimethanonaphth[2,3-b]oxirene CAS number 72–20–8 Structural formula Molecular formula C12H8Cl6O Molecular weight 380.93 Melting point 226–230°C (decomposition at 245°C) Density at 25°C 1.64 g/cm3 logPow* 5.34 This documentation is based mainly on a published review of the toxicological data (WHO 1992), supplemented with more recent information relevant to the evaluation. 1 Toxic Effects and Mode of Action Endrin is a stereoisomer of dieldrin; both substances are used as pesticides. Endrin has been used since the 1950s as an insecticide and rodenticide, in particular in the growing of cotton, maize, rice and sugar cane. Its use is now banned in the EU and in numerous other countries. Technical grade endrin with a purity of 92 to 99 % can contain e.g. dieldrin (0.42 %), aldrin (0.03 %) and isodrin (0.73 %) as impurities. Endrin is of higher acute toxicity than dieldrin, but is metabolized and eliminated more rapidly; thus endrin accumulates less in adipose tissue than do dieldrin and other substances of similar chemical structure. Endrin is absorbed well via the gastrointestinal tract and skin, and can pass the placenta. Endrin and its metabolite 12-ketoendrin can be detected in foetal tissue. The main metabolite anti-12-hydroxyendrin and the metabolites syn-12-hydroxyendrin and 12-ketoendrin are of greater acute toxicity than endrin itself. In addition to unchanged endrin, the free metabolites and their conjugates are excreted via the faeces. The glucuronic acid and sulfate conjugates of the metabolites can also be eliminated with the urine. Endrin is highly toxic after oral and dermal uptake of single doses. In man, the severe neurotoxic effects of endrin rapidly result in symptoms such as nausea, vomiting, dizziness, stomach-ache, headache, sudden unconsciousness, convulsions and CNS depression. In animals, also paralysis, dyspnoea and cyanosis are observed. In addition to the effects on the central nervous system, the other main symptoms of acute and chronic toxicity are liver and kidney damage, probably the result of oxidative stress. After long-term exposure, a NOEL (no observed effect level) of 0.025 mg/kg body weight and day was found for the most sensitive species, the dog. Endrin does not have irritative or sensitizing effects on the skin. Endrin is not genotoxic or carcinogenic. In vivo, DNA single strand breaks are induced only by exposure to high levels of endrin, which at the same time results in marked lipid peroxidation and probably the production of reactive oxygen species. Lipid peroxidation and DNA single strand breaks are also detectable in foetal tissue. Endrin does not cause impairment of fertility. Foetotoxic effects occur only with highly maternally toxic doses or doses which are known to produce tissue damage in the dams as a result of oxidative stress after single or repeated administration. 2 Mechanism of Action The neurotoxic effects (see Sections 5 and 6) of endrin and its metabolite 12-ketoendrin are the result of disturbances in nerve conduction following interaction with the γ-aminobutyric acid (GABA) neurotransmitter system, which has an inhibiting effect on the central nervous system. The probably non-competitive binding to an allosteric binding site of the γ-aminobutyric acid receptor of the chloride ion channels causes blocking of the chloride channels in cell membranes of the central nervous system and thus a decrease in the chloride ion flow. This facilitates synaptic transmission, which in turn leads to overstimulation of the nervous system which is associated with changes in EEG activity and the triggering of convulsions (Narahashi et al. 1992, WHO 1992). It is also conceivable that inhibition of the calmodulin-dependent calcium pump in the neurons is involved in the neurotoxic effects (WHO 1992). Endrin causes the induction of cytochrome P450-dependent monooxygenases (WHO 1992). Oxidative stress probably plays a decisive role in the tissue-damaging, foetotoxic and lethal effects of endrin. Lipid peroxidation has been observed in various organs such as the liver, kidneys, brain, placenta and in foetal tissue (Bagchi et al. 1992a, 1992b, 1995, Hassan et al. 1991, Hassoun and Stohs 1996a, 1996b, Hassoun et al. 1996, Numan et al. 1990; see Section 6.1.2). Pretreatment with antioxidants led to the complete inhibition of lipid peroxidation and of the effects in the liver and kidneys (Hassan et al. 1991, Numan et al. 1990). It is still unclear whether the lipid peroxidation is initiated by a reactive metabolite or free radicals. Therefore oxidative damage to the central nervous system could also be involved in the neurotoxic effects of endrin. 3 Toxicokinetics and Metabolism Endrin is absorbed via the gastrointestinal tract and the skin. There are no data available for absorption rates. The toxicokinetics of endrin differ in different species and sexes. In rats endrin was stored mainly in adipose tissue and skin. In male rats which were fed endrin at a level of 1.5 mg/kg body weight and day for 8 days, the concentrations in adipose tissue reached 3 to 4 µg/g. Beagle dogs were given endrin in the diet at a level of 0.1 mg/kg body weight and day for 128 days. From day 9 the concentration in blood remained constant at 4 µg/l. 7 days after the end of exposure, concentrations less than 0.2 µg/g were found in 8 tissues and up to 0.8 µg/g in adipose tissue. Endrin persists in the body of female rats for longer and in higher concentrations than in males. After oral doses of up to 0.064 mg/kg body weight, the elimination half-time was about 2 days. Elimination was slower with a half-time of about 6 days after a higher dose of 0.128 mg/kg body weight. After intravenous administration of 0.200 mg/kg body weight, the half-life of endrin in male rats was 2.5 to 3 days, in female rats 4 days. While rats excreted up to about 90 % of the dose with the faeces mainly in metabolized form, rabbits excreted about half of the dose in the urine (only metabolites) over several days and in the faeces (unchanged endrin) within 24 hours. Because the molecular weight thresholds for biliary elimination are higher in rabbits than in rats, rabbits can excrete conjugates of endrin metabolites with the urine while rats cannot (WHO 1992). Endrin can pass the placenta. After oral exposure of pregnant rats to endrin doses of 0.45 mg/kg body weight and day from days 7 to 20 of gestation, endrin concentrations of 0.327 µg/g were found in the livers of the dams and of 0.027 µg/g in the tissue of the foetuses. In hamsters exposed to higher endrin doses of 1.5 and 2.5 mg/kg body weight and day from days 5 to 14 of gestation, tissue concentrations of 1.45 and 2.55 µg/g were reached in the livers of the dams, in foetal tissue concentrations of 0.021 and 0.075 µg/g. The tissue concentrations of 12-ketoendrin were not determined quantitatively. In hamster foetuses there is much more 12-ketoendrin present than endrin (ratio of peak heights 3.2:1), while in rat foetuses more endrin is present than 12-ketoendrin (peak height ratio 1:0.4) (Chernoff et al. 1979, Kavlock et al. 1981). Rats metabolize endrin mainly via anti-12-hydroxyendrin to form the sulfate and glucuronic acid conjugate. In lower concentrations syn-12-hydroxyendrin, 3-hydroxyendrin, 12-ketoendrin and 4,5-trans-dihydroisodrindiol and their conjugates are formed (metabolic pathways from WHO 1992). The transformation of endrin to anti-12-hydroxyendrin and of syn-12-hydroxyendrin to 12-ketoendrin by monooxygenases takes place rapidly. Male animals form more anti-12-hydroxyendrin and excrete this via the faeces, while female animals excrete this mainly as anti-12-hydroxyendrin sulfate in urine. In the male animals 12-ketoendrin was the main urinary metabolite. In the tissues mainly endrin and 12-ketoendrin are found; in male animals in the ratio 1:8, in female animals in the ratio 2:1. In the liver and kidneys of male animals more 12-ketoendrin is therefore found, in the kidneys of female animals, however, more endrin. In rabbits mainly anti-12-hydroxyendrin is formed and excreted in the urine as anti-12-hydroxyendrin sulfate in addition to syn-12-hydroxyendrin sulfate and the glucuronic acid conjugates of 3-hydroxyendrin and 4,5-trans-dihydroisodrindiol. syn-12-Hydroxyendrin does not seem to be oxidized to 12-ketoendrin. In the urine of workers exposed to endrin (level of exposure not specified), anti-12-hydroxyendrin was identified (up to 0.36 mg/g creatinine; decrease over the weekend) and in the faeces its glucuronic acid conjugate. In another study, endrin and anti-12-hydroxyendrin were found in the faeces of workers, and the glucuronic acid conjugate of anti-12-hydroxyendrin (up to 0.14 mg/l, expressed as anti-12-hydroxyendrin) in all urine samples. 4 Effects in Man 4.1 Single exposures Repeatedly in the past there have been cases of intoxication as a result of the ingestion of accidentally contaminated food and also after dermal exposure. The main symptoms reported were nausea, vomiting, dizziness, stomach-ache, headache, sudden unconsciousness, seizures and CNS depression, which began 0.5 to 10 hours after uptake of endrin. Respiratory depression was occasionally fatal. Generally the condition of the patients improved within hours or days (Ferrer and Cabral 1991, 1995, WHO 1992). Changes in the EEG were still registered after several weeks and were attributed to brain stem irritation. It was not possible to deduce the exact dose-response relationship for effects in man, as the doses absorbed were not known. Estimated doses from cases of accidental intoxication are available, but the values differ greatly. Oral doses of about 0.25 and 1 mg/kg body weight are said to cause single and repeated seizures, respectively, and 10 mg/kg body weight to be lethal. In other reports, however, doses of 5 to 50 mg/kg body weight are given as toxic and a total dose of about 6 g (about 100 mg/kg body weight) as lethal (WHO 1992). After higher-level short-term inhalation exposure (no details of exposure level), a worker from an endrin formulation plant suffered seizures, while two workers who accidentally spilt the substance on their skin had no symptoms of intoxication. For these workers a half-life of the substance in blood of about 24 hours was estimated and a LOEL (lowest observed effect level) for symptoms of intoxication of 50 to 100 µg/l blood (WHO 1992). 4.2 Repeated exposures In several studies with workers exposed to endrin (average exposure duration 12 to 24 years, level of exposure and number of persons exposed not specified), liver function tests and determination of urine and blood parameters did not yield any unusual findings. The workers exposed to endrin were not off sick any more often than other workers. Endrin was not detectable in plasma or adipose tissue (detection limit 3 µg/l, 0.03 µg/g), presumably because little accumulation of endrin took place because of rapid metabolism and elimination (see Section 4). Significant induction of microsomal enzyme systems was observed after exposure to endrin; the exposure level was not determined. Increased excretion of the metabolite anti-12-hydroxyendrin was used as an indicator of enzyme induction; a urinary anti-12-hydroxyendrin level of 0.130 µg/g creatinine was given as the LOEL; no NOEL was given (WHO 1992). The associated air concentrations were, however, not determined. It is not clear from the reports how inhalation and dermal absorption contribute to the body burden during exposure at the workplace. Nor are air concentrations or daily exposure durations described; thus a MAK value cannot be derived from these studies. 4.3 Genotoxicity In peripheral lymphocytes from 8 male workers exposed to endrin (exposure level not specified) no increase in the incidence of chromosomal aberrations was observed (WHO 1992). 4.4 Carcinogenicity Mortality and the causes of death of 232 workers exposed for 4 to 27 years (on average 11 years) to endrin were followed over a period of 4 to 29 years (on average 24 years); mortality and tumour incidence were not increased relative to the values for the general population. At the beginning of employment, the workers were exposed to high levels of endrin; there are, however, no data available for the levels of exposure (WHO 1992). 5 Animal Experiments and in vitro Studies 5.1 Acute toxicity 5.1.1 Inhalation Exposure for 1 hour of groups of 10 rats to an endrin concentration of about 2000 mg/m3 (“mist of an emulsifiable concentrate in xylene” or “25 % and 30 % endrin dust concentrates of endrin”) led to the death of 3/10, and 5/10 and 3/10 animals (WHO 1992). These studies from the 1950s cannot be used in the present evaluation because the exposure atmosphere (particle size not specified) and conditions were insufficiently characterized. 5.1.2 Ingestion Single oral doses of endrin are highly toxic. The LD50 values for technical grade endrin are given as 4.0 to 17.8 mg/kg body weight for rats and mice, 7 to 10 mg/kg body weight for rabbits and 16 to 36 mg/kg body weight for guinea pigs; female animals were much more sensitive. Cats and monkeys were also found to be more sensitive, with lethal doses for the cat of 3 to 6 mg/kg body weight and LD50 values for the monkey of 3 to 12 mg/kg body weight. With LD50 values of 0.8 to 2.8 mg/kg body weight, the endrin metabolites anti-12-hydroxyendrin, syn-12-hydroxyendrin and 12-ketoendrin, administered orally to rats, are more toxic than endrin itself. The symptoms of intoxication included overexcit-ability, tremor followed by tonic-clonic cramps, paralysis, ataxia, dyspnoea, wheezing and cyanosis. In animals that survived, these effects were completely reversible. In addition to the neurotoxic effects of endrin, the main other effect is tissue damage, in particular of the liver and kidneys, and is probably the result of oxidative stress (see Section 3). After oral administration of endrin doses of 1.5 to 6.0 mg/kg body weight to Sprague-Dawley rats, a dose-dependent increase in lipid peroxidation (excretion of formaldehyde, malondialdehyde, acetaldehyde and acetone with the urine) was observed over a period of 12 to 72 hours after administration (maximum 24 hours after administration) (Bagchi et al. 1992b). A similar course was observed after doses of 3 to 6 mg/kg body weight with evidence of oxidation products and changed membrane structures in liver mitochondria and liver microsomes (increased membrane viscosity and reduced membrane fluidity) (Bagchi et al. 1992a). After administration of two endrin doses of 2.25 mg/kg body weight (0.25 times the LD50) 21 hours apart to rats, lipid peroxidation was detected 3 hours after the last dose, not only in liver homogenates but also in brain homogenates (Bagchi et al. 1995). In liver and kidney tissue, lipid peroxidation and decreased glutathione levels were found 24 hours after the administration of endrin doses of 4.0 mg/kg body weight (Numan et al. 1990). The extent of lipid peroxidation decreased in the following order: in the liver, rat > mouse > guinea pig (no significant increase in the hamster), in the kidneys, rat > mouse > hamster (no increase in the guinea pig) (Hassan et al. 1991). When endrin was administered after pre-treatment of the animals with antioxidants, the level of lipid peroxidation was found to be the same as in untreated animals or even lower; histological examination did not reveal any unusual findings in the liver or kidneys and mortality after an otherwise lethal endrin dose was greatly reduced (Hassan et al. 1991, Numan et al. 1990). Effects on the organs were dose-dependent and time-dependent increases in relative liver and spleen weights and decreases in the relative thymus weight from doses of 3 mg/kg body weight, as for lipid peroxidation (Bagchi et al. 1992a, 1992b). Histopathological examination of the hepatotoxic and nephrotoxic effects in the various species 24 hours after administration of oral endrin doses of 4 mg/kg body weight was carried out with Sprague-Dawley rats, Swiss-Webster mice, hamsters and guinea pigs. Liver damage was found in all species in the form of apoptosis and focal necrosis (changes in the cell nucleus, cytoplasm and membrane fragmentation), inflammatory reactions (leukocyte infiltration and congestion), interstitial oedema, hyperplasia of Kupffer's cells and green-brown pigments. In the rats, the species which reacted most sensitively, there was also fat accumulation and bile stasis. In the kidney tubules of rats, mice and hamsters, endrin caused cell necrosis, cloudy swelling, accumulation of hyaline droplets (only rat and hamster) and narrowing of the lumen, in the interstitium oedema and infiltration of inflammatory cells (only rats and mice). The most severe effects were found in rats, the least changes (only cloudy swelling and narrowing of the tubule lumen) in guinea pigs. 5.1.3 Dermal absorption Dermal application of technical grade endrin dissolved in a hydrophobic solvent or in oil revealed an LD50 of 5 to 20 mg/kg body weight for the rat; thus the acute toxicity of the substance is similar after dermal and oral application (WHO 1992). After dermal exposure to the solid, the toxicity of a minimum lethal dose of 94 mg/kg body weight was found to be much lower when rabbits were exposed for 24 hours occlusively than after oral administration (Treon et al. 1955). 5.2 Subacute, subchronic and chronic toxicity 5.2.1 Inhalation In an inhalation study from the 1950s, 3 mice, 3 rats, 2 guinea pigs, 2 hamsters, 4 rabbits and one cat were exposed via inhalation to endrin concentrations of 5.44 mg/m3, 7 hours a day, 5 days a week for up to 26 weeks. The exposure atmosphere contained endrin vapour, which, according to the authors, was produced by sublimation. In rabbits and mice, deaths occurred from the 22nd exposure (2/4 and 1/3, respectively), seizures were not observed (Treon et al. 1955). As a result of the unclear exposure conditions and small number of animals, this study does not meet present-day standards and therefore cannot be included in the evaluation. 5.2.2 Ingestion The numerous studies with mice, rats and rabbits and up to life-long exposure to endrin are listed in Table 1. They were carried out between 1955 and 1980. From what is known today of the mechanism of toxicity after short-term exposure (see Sections 3 and 5) it is clear, however, that in the studies with repeated exposure the most sensitive parameters of toxic effects were not always investigated and neurotoxic symptoms not always described. Accordingly, high doses were without effect in some studies but not in others, and there are considerable differences between the NOELs (see Table 1). Table 1. Toxicity after repeated oral administration of endrin Species Duration of administration, dose Results References mouse 6 weeks treatment, body weights unaffected NTP 1979, B6C3F1 2 weeks follow-up from 0.75 mg/kg: over-excitability in ♂ (LOEL) WHO 1992 5 ♂ and 5 ♀ 2.5–20 mg/kg diet from 1.5 mg/kg: mortality increased in both sexes (0.375–3 mg/kg body weight and day) NOEL: 0.375 mg/kg body weight and day mouse 80 weeks treatment, 10–11 weeks follow-up body weights, histology unaffected; NTP 1979, B6C3F1 50 ♂ and 50 ♀; endrin (purity 97 %) ♂: average dose: 1.6, 3.2 mg/kg diet from 0.24 mg/kg: clinical symptoms: e.g. over-excitability as evidence of neurotoxic effects (LOEL); WHO 1992 matched controls: groups of 10; (0.24, 0.48 mg/kg body weight and day); weeks 1–25: 2.5, 5 mg/kg diet (0.375, ♂: 0.24 mg/kg: accidental overdose in week 66, therefore mortality could not be evaluated; pooled controls: 0.75 mg/kg body weight and day); dose 0.48 mg/kg: ♂: mortality increased groups of 50 reduction: weeks 26–80: 1.2, 2.5 mg/kg diet (0.19, 0.375 mg/kg body weight and day) up to 0.75 mg/kg: ♀: mortality not increased, therefore ♂ much more sensitive ♀: weeks 1–80: 2.5, 5 mg/kg diet (0.375, 0.75 mg/kg body weight and day) NOEL could not be determined mouse C57B 1/6 J 117 weeks endrin (purity 99 %) mortality, body weight gains, food consumption, haematology unaffected Shell 1970 100 ♂ and 100 ♀, controls: 200 ♂ 0.3, 3 mg/kg diet (0.045, 0.45 mg/kg body weight and day) 0.45 mg/kg: at the beginning of the study occasional seizures, effects reversible; histology: liver damage typical of chlorinated insecticides and 200 ♀ NOEL: 0.045 mg/kg body weight and day mouse C32F1/J ♂: 117 weeks; ♀: 78 weeks, without follow-up mortality, body weight gains, food consumption, haematology unaffected Shell 1970 100 ♂ and 100 ♀, controls: 200 ♂ endrin (purity 99 %) 0.3, 3 mg/kg diet 0.45 mg/kg: at the beginning of the study occasional seizures, effects reversible; histology: liver damage typical of chlorinated insecticides and 200 ♀ (0.045, 0.45 mg/kg body weight and day) ♀: experiment terminated after 78 weeks because of high incidence of spontaneous fibroadenomas of the mamma NOEL: 0.045 mg/kg body weight and day rat 6 weeks treatment, 2 weeks follow-up body weights unaffected NTP 1979, Osborne-Mendel endrin (purity 97 %) from 1 mg/kg: mortality increased WHO 1992 5 ♂ and 5 ♀ 2.5–80 mg/kg diet (0.125–4.0 mg/kg body weight and day) NOEL: 0.5 mg/kg body weight and day rat Sprague-Dawley 16 weeks technical grade endrin from 0.05 mg/kg: dose-dependent decrease in body weights with reduced food consumption; alkaline phosphatase increased WHO 1992 5 ♂ and 5 ♀ 1, 5, 25, 50, 100 mg/kg diet (0.05, 0.25, 1.25, 2.5, 5 mg/kg body weight from 0.25 mg/kg: mortality increased in ♂, ♂ much more sensitive than ♀ and day) from 1.25 mg/kg: over-sensitivity to external stimuli; seizures; mortality increased in ♀ study from 1956 NOAEL: marginal effects at 0.05 mg/kg body weight and day rat 29 months mortality, body weight gains, relative liver weights unaffected; Deichmann Osborne-Mendel 50 ♂ and 50 ♀ endrin (purity 98 %) 2, 6, 12 mg/kg diet (0.1, 0.3, 0.6 mg/kg body weight and day) from 0.1 mg/kg: dose-dependent symptoms of intoxication; histology: et moderate, not dose-dependent, cloudy swellings in liver and kidney tubules; lungs: congestion and focal haemorrhage moderately increased al. 1970 NOEL could not be determined rat 80 weeks treatment, 31–34 weeks follow-up body weights and mortality unaffected NTP 1979, Osborne-Mendel endrin (purity 97 %) from 0.125 mg/kg: clinical symptoms as evidence of neurotoxic effects WHO 1992 50 ♂ and 50 ♀ ♂: 2.5, 5 mg/kg diet from 0.25 mg/kg: not tolerated by ♀, dose reduced as a result matched controls: groups of 10; pooled controls: groups of 50 (0.125, 0.25 mg/kg body weight and day); ♀: average dose: 3, 6 mg/kg diet (0.15, 0.30 mg/kg body weight and day); weeks 1–9: 5, 10 mg/kg diet (0.25, 0.5 mg/kg body weight and day); dose reduction: weeks 10–80: 2.5, 5 mg/kg diet) (0.125, 0.25 mg/kg body weight and day) NOEL could not be determined rat 104 weeks mortality unaffected; no other details Reuber 1978 Osborne-Mendel 15–23 ♂ and 15- endrin (purity 99 %) 0.1, 1.0, 5, 10, 25 mg/kg diet from 0.005 mg/kg: liver: increase in hyperplasia and hyperplastic nodules, not dose-dependent 23 ♀ (0.005, 0.05, 0.25, 0.5, 1.25 mg/kg body weight and day) 0.05 and 1.25 mg/kg: nephritis increased only in ♂, not dose- dependent NOEL could not be determined rat Carworth 2 years endrin (purity not specified) from 0.25 mg/kg: ♂: delayed body weight gains during the first 40 weeks; relative liver weights increased Treon et al. 1955 20 ♂ and 20 ♀ 1, 5, 25, 50, 100 mg/kg diet (0.05, 0.25, 1.25, 2.5, 5 mg/kg body weight and day) from 1.25 mg/kg: mortality increased (♀ reacted more sensitively); in animals that died: diffuse degenerative changes in the liver, kidneys, adrenal glands and brain; in ♀: relative liver weights increased from 2.5 mg/kg: also in surviving animals histopathological changes; over-sensitivity to external stimuli; seizures NOEL: 0.05 mg/kg body weight and day dog beagle 1–2 ♂ or 1–2 ♀ 18–47 days, 6 days/week endrin (purity not specified) 5, 10, 25, 50 mg/kg diet (about 0.20–0.27, 0.49–0.81, 1.21–2.20, 2.50–4.00 mg/kg body weight and day) from 0.20 mg/kg: lethal within 18–47 days, body weight gains delayed; symptoms of intoxication: vomiting of food, food refusal; lethargy, salivation; shortness of breath; tremor, seizures; histopathology: degenerative changes in the liver (fat vacuoles, cell necrosis), kidneys (necrosis of the convoluted kidney tubules), heart, brain; hyperaemia and oedema of the lungs Treon et al. 1955 from 0.49 mg/kg: weight loss NOEL could not be determined dog beagle 80 week, 6 days/week endrin (purity not specified) body weight gains, haematology unaffected; no evidence of intoxication Treon et al. 1955 2 ♂ and 2 ♀ 1, 3 mg/kg diet (0.045–0.12, 0.12–0.25 mg/kg body weight high dose: relative kidney and heart weights significantly increased; histopathological examination revealed no effects and day) NOEL: 0.045–0.12 mg/kg body weight and day dog beagle 2 years endrin (purity 99 %) body weights, food consumption, haematology, urinalysis, alkaline phosphatase, prothrombin time, clinico-chemical parameters unaffected Shell 1969 3 ♂ and 3 ♀ 0.1, 0.5, 1, 2, 4 mg/kg diet (about 0.0025, 0.0125, 0.025, 0.05, 0.10 mg/kg body weight and day) from 0.05 mg/kg: seizures; in ♀: liver weights slightly increased in some animals; histopathology: liver: slight to moderate vacuolation; kidneys: no effects NOEL: 0.025 mg/kg body weight and day For rats exposed for 16 weeks, a NOAEL (no observed adverse effect level) of 0.05 mg/kg body weight was found (reduced body weights with reduced food consumption, alkaline phosphate activity increased; WHO 1992) and in a 2-year study also a NOEL of 0.05 mg/kg body weight (Treon et al. 1955). The documentation of these studies from the 1950s is incomplete, but more recent studies do not yield a better-founded NOEL for the rat. A NOEL of 0.045 mg/kg body weight was determined after lifelong exposure of 2 strains of mouse to endrin. A dose of 0.45 mg/kg body weight led initially to seizures and in the long term to liver damage (Shell 1970). In dogs given endrin with the diet for 2 years, a LOEL of 0.05 mg/kg body weight was determined for seizures and liver changes, doses up to 0.025 mg/kg body weight had no effects (Shell 1969). Another study with dogs (Treon 1955) yielded similar threshold values for increased kidney and heart weights (without histopathological findings). In extensive studies, neurotoxic symptoms and histological changes in the liver were found to be the most sensitive parameters of the chronic toxicity of endrin in mice and dogs. Assuming the dog to be the most sensitive species, a NOEL of 0.025 mg/kg body weight and day can be deduced, and used to derive a MAK value. 5.2.3 Dermal absorption Dermal exposure of rabbits to endrin (solid) doses of 75 mg/animal and day for a period of up to 14 weeks, for 2 hours a day on 5 days a week, led to symptoms of intoxication such as seizures, tremor and facial twitching, and to death of 1 of 3 animals. All animals given doses of 150 mg/animal and day died within 5 weeks (Treon et al. 1955). 5.3 Local effects on skin and mucous membranes Single applications to the skin of endrin doses of up to 250 mg/kg body weight in the form of a dry powder did not lead to any gross pathological or microscopic findings in rabbits. Likewise, with repeated application (75 or 150 mg/animal, 2 hours daily, 5 days weekly, up to 70 applications) of dry endrin powder to the intact or scarified skin, irritative effects on the skin were not observed (Treon et al. 1955). There are no data available for the allergenic effects of endrin. 5.4 Reproductive and developmental toxicity 5.4.1 Multigeneration studies In a 3" @default.
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W4214860712 date "2012-01-31" @default.
W4214860712 modified "2023-10-16" @default.
W4214860712 title "Endrin [MAK Value Documentation, 2002]" @default.
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