DIAZINON First draft prepared by E. Bosshard Federal Office of Public Health, Schwerzenbach, Switzerland EXPLANATION Diazinon was previously evaluated by the Joint Meeting in 1963, 1965, 1966 and 1970 (Annex I, references 2, 3, 6, 14). An ADI of 0- 0.002 mg/kg bw was allocated in 1966, based on a NOAEL of 0.02 mg/kg bw/day in human volunteers (Annex I, reference 7). The compound was reviewed at the present Meeting on the basis of the CCPR periodic review programme. This monograph summarizes the data received since the previous evaluation and contains relevant data from the previous monographs and monograph addenda. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOLOGICAL DATA Biochemical aspects The fate of diazinon in various animal species was studied after oral and topical applications using unlabelled and radiolabelled diazinon in chicken, rats, guinea-pigs, dogs, sheep, goats and cows. Additional studies were performed in vitro using tissue slices or cell fractions from different tissues and various species to investigate the biotransformation of the compound. A short summary on the metabolism of diazinon has been published (Miyamoto 1976). Absorption, distribution and excretion Oral studies Rats After the application of a single oral dose of 0.8 mg/rat (4 mg/kg bw) 14C-labelled diazinon (labels at 2-14C, 4-14C or ethoxy- 14C) to four male and two female Wistar rats, radioactivity was eliminated practically completely during the 168-hours observation period with either label. Excretion of applied radioactivity amounted to 65-80% in urine, and 16-24% in faeces. The excretion half-time was estimated to be 12 hours for the pyrimidine-labelled and 7 hours for the ethoxy-labelled compound. After the application of side-chain labelled material, about 6% of the applied dose was eliminated as 14CO2. The absence of radioactive CO2 in the expired air after application of ring-labelled diazinon shows that no cleavage of the pyrimidine ring occurred (Mücke et al., 1970). After feeding male rats during 10 days 0.1 mg/rat/day (0.5 mg/kg bw/day) of 2-14C-diazinon, 2.9% of the applied dose was found in the essential organs 6 hours after the final application, whereas 2 days after cessation of treatment the radioactivity was below the detection limit (< 0.1%). These results indicate that no accumulation of diazinon or its metabolites occurs in the body (Mücke et al., 1970; Annex I, reference 15). In a more recent study, two groups of rats (5/sex/dose) were treated with a single oral dose of 10 or 100 mg/kg bw 14C-diazinon. A third group was treated daily with unlabelled diazinon at a dose level of 10 mg/kg bw during 14 days, followed by the same dose of 14C-labelled diazinon on day 15. The elimination of the radioactivity was monitored over a seven-day period. 14C- elimination of radioactivity was rapid and occurred mainly via the urinary tract. In the low-dose group, 93% of the applied radioactivity was excreted in the urine in males and 86% in females within 24 hours. At the high-dose level, an average of 91% and 58% in males and females, respectively, was excreted in the first 24 hours. After preconditioning, about 90% of the 14C-dose was excreted within 24 hours in both sexes. The total amounts eliminated over the 7-day observation period did not differ between the various dosing regimens. Total urinary excretion amounted to 96%, and faecal elimination to 3%. These results suggest that complete absorption occurs following intragastric administration and supports the hypothesis that the small amount of faecal radioactivity found may be of biliary origin. Tissue concentrations of 14C-diazinon and metabolites seven days after dosing were mostly less than 0.05 ppm for low-dose and pre-conditioned animals. In high-dose animals, residue levels in different organs varied between 0.1 and 0.4 ppm (red blood cells) with female rats showing consistently slightly higher tissue residues than males. The 14C in the blood was associated primarily with the cellular fraction, suggesting that binding occurred (Capps et al., 1989; Craine 1989). Guinea-pigs 32P-Labelled diazinon was administered orally or subcutaneously to male guinea-pigs at a dose level of 45 mg/kg bw. After oral dosing, 80% of the applied radioactivity was excreted in the urine within 48 hours, whereas faecal excretion was 10% mostly eliminated within the first day. After subcutaneous dosing, urinary excretion was 53%, faecal excretion was minimal. Highest residues were found in the caecum corresponding to 36% and 5% of the radioactivity administered 16 hours after oral and subcutaneous dosing, respectively. About 1-2% of the radioactivity was found in the liver after 16 hours. During the 7-day observation period, over 87% of the dose was eliminated in the excreta, mainly in the urine, indicating that the large amounts found in the caecum after oral treatment ultimately left the body via the kidneys. The accumulation of radioactivity in the caecum also following subcutaneous injection indicates that this tissue may play a role in metabolism or elimination of diazinon and/or its metabolites in guinea-pigs (Kaplanis et al., 1962). Hens After oral administration of 14C-diazinon to 4 laying hens by capsule for 7 consecutive days at daily doses of 2.8 mg/animal corresponding to 25 ppm, 79% of the total dose applied was eliminated in the excreta and 0.1% was found in the tissues at sacrifice, about 24 hours after the final dose. Highest tissue levels of 0.15 ppm were found in the kidney. Maximum residues in eggs amounted to 0.07 ppm. The treatment caused some reduction in body weight in most animals but had no influence on the general health condition (Simoneaux, 1988b; Simoneaux et al., 1988; Burgener & Seim 1988). Dogs In an intravenous study, 14C-ethoxy-labelled diazinon was injected at a dose level of 0.2 mg/kg bw. After 24 hours, 58% of the applied radioactivity was recovered in urine (Iverson et al., 1975). Goats Two lactating goats were treated daily with 14C-diazinon by capsule for four consecutive days at a dose of 150 mg/animal (4 mg/kg bw). Urinary excretion amounted to 64% of the applied dose, whereas faeces contained an average of 10%. Highest residues of 2 ppm 14C were found in kidneys whereas the levels in the other tissues ranged from 0.2 to 1.2 ppm. Highest levels in milk were 0.5 ppm (Pickles & Seim 1988; Simoneaux, 1988a,c; Simoneaux et al., 1988). Cows A lactating cow was orally treated by capsule with a dose level of 20 mg/kg bw of 32P-labelled diazinon. About 74% of the applied dose was excreted in the urine within 36 hours and 6% in the faeces. The cumulative percentage of total dose in milk 36 hours after treatment was less than 0.08% (Robbins et al., 1957). In summary, diazinon is rapidly and almost completely absorbed and eliminated after oral application. Excretion occurs mainly via the kidney. Diazinon or its metabolites do not accumulate in the body. Dermal studies Rats Groups of 4 rats were dermally treated with dose levels of 1 or 10 mg/kg bw 14C-diazinon dissolved in tetrahydrofuran. Renal excretion ranged from 70-80% of the applied dose at both dose levels over the 6 days observation period; elimination in faeces was usually less than 10%. Most of the radioactivity was eliminated within 48 hours after application. After 72 hours, less than 1% of the applied dose was found on the skin. Highest tissue residues were measured 8 hours after treatment varying between 0.1 and 0.4 ppm in the low-dose animals. Residues in the high-dose animals were correspondingly higher. These results show that diazinon is easily absorbed through the skin (Ballantine et al., 1984). Sheep Two sheep were dermally exposed for 3 days to diazinon at a daily dose of 40 mg/kg bw. The sheep were sacrificed six hours after the final application. Radiolabelled residues were observed in all tissues at levels ranging from 2.2 to the highest value of 13 ppm in kidney. Because the study was designed to allow the identification of metabolites in sheep tissue after topical application of 14C-diazinon, no results were presented with respect to elimination of the compound (Capps et al., 1990; Pickles & Seim 1990). Biotransformation In vitro studies Diazinon was incubated with liver microsomes from different avian species, rat, guinea-pig, pig, sheep and cow. Metabolites identified included hydroxydiazinon, isohydroxydiazinon, dehydroxydiazinon, their oxons and diazoxon. Yields and rates of production of these metabolites varied between the different species (Machin et al., 1975). In vitro studies using microsomal preparations from rat liver showed that diazinon was converted rapidly to water-soluble metabolites (Dahm, 1970). The oxidation of diazinon by the microsomal enzyme system fortified with NADPH or NADH occurred through hydroxylation of the ring alkyl side chain, desulfuration, and cleavage of the arylphosphate bound. The major metabolic products of diazinon were hydroxydiazinon, diazoxon and hydroxydiazoxon. Other metabolites identified were 2-isopropyl-4- methyl-6-hydroxypyrimidine, 2-(2'-hydroxy-2'-propyl)-4-methyl-6- hydroxypyrimidine, diethyl-phosphorothioic acid and diethylphosphoric acid, which were all produced by the cleavage of the arylphosphate bound (Shishido et al., 1972a). Diazoxon, the active toxicant, formed by the oxidation of diazinon through desulfuration was degraded mainly by hydrolysis resulting in the two metabolites diethylphosphoric acid and 2-isopropyl-4-methyl-6- hydroxypyrimidine (Shishido & Fukami 1972). A glutathione conjugate S-(2-isopropyl-4-methyl-6-pyrimidinyl) glutathione was also identified. This compound was formed by conjugation of reduced glutathione and the pyrimidinyl moiety of diazinon with the simultaneous cleavage of the phosphate ester bound (Shishido et al., 1972b). In insects, diazoxon is degraded slowly by the microsomal mixed function oxidase system, while no diazoxon- hydrolyzing enzyme was found (Shishido & Fukami 1972; Yang et al., 1971). In vivo studies Biotransformation of diazinon has been extensively studied in numerous mammalian species and also in hens. Considerable breakdown occurs in all species studied. Rats Metabolic studies in rats treated with 14C-labelled diazinon (2-14C, 4-14C or ethoxy-14C labels) by the oral route (4 mg/kg bw) showed that the parent compound is degraded rapidly yielding the 3 pyrimidinols, 2-isopropyl-6-methyl-4(1H)-pyrimidinone, 2-(alpha- hydroxyisopropyl)-6-methyl-4(1H)-pyrimidinone and its beta isomer as main urinary metabolites. A number of polar unidentified substances was also found. In addition to small amounts of unchanged diazinon the same metabolites were also found in faeces. Diazoxon as a labile and transient intermediate was absent in the extracts of urine and faeces. The absence of radiolabelled CO2 indicated that no cleavage of the pyrimidine ring took place. The intravenous application of these main metabolites revealed that the pyrimidinols are further degraded yielding some unidentified polar metabolites (Mücke et al., 1970). In a more recent study, rats were treated with single oral doses of 10 or 100 mg/kg bw of 14C-labelled diazinon. Another group was preconditioned for 14 days with unlabelled diazinon and then dosed with 10 mg/kg bw of 14C-labelled diazinon. A similar metabolic pattern as in the above-mentioned study was found. In urine, the 3 pyrimidinols accounted for 65% of the applied radioactivity, whereas 15% consisted of polar non-identified metabolites and trace amounts of diazinon (0.11%), hydroxydiazinon (0.12%) and diazoxon (0.14%) (Capps et al., 1989). Dogs Metabolic studies in dogs were performed after oral and intravenous administration of ring-labelled and ethoxy-labelled diazinon, respectively. After i.v. application the 14C-ethoxy- labelled diazinon, diethyl phosphoric acid (DEP) and diethyl phosphorothioic acid (DETP) were detected in urine, whereas after the oral dosing with the 14C-ring-labelled diazinon, the pyrimidinols 2-isopropyl-6-methyl-4(1H)-pyrimidinone and 2-(alpha- hydroxyisopropyl)-6-methyl-4(1H)-pyrimidinone could be identified. In contrast to the results of an in vitro study (Shishido & Fukami 1972) no evidence was given from this dog study that the cleavage of the ester bond was glutathione-mediated (Iverson et al., 1975). Cows In a metabolic study with cows treated with an oral dose of 20 mg/kg bw 32P-labelled diazinon, DEP and DETP were found as urinary end products of diazinon metabolism (Robbins et al., 1957). The pyrimidinols were also identified as the major metabolites in urine and tissues of dermally treated sheep (Capps et al., 1990) and orally treated goats and hens (Simoneaux 1988c,d; Simoneaux et al., 1988). The respective glucuronides were also identified in these species (Sachsse & Bathe, 1976; Simoneaux 1988c,d; Simoneaux et al., 1989; Capps et al., 1990). In summary, diazinon was found to be readily degraded and the metabolites formed were mainly eliminated via the kidneys. The main degradative pathway of diazinon in mammals includes the oxidase/hydrolase-mediated cleavage of the ester bond leading directly and via diazoxon to the pyrimidinol derivative 2-isopropyl- 6-methyl-4(1H)-pyrimidinone, which is further oxidized at the isopropyl substituent resulting in the hydroxy pyrimidinols either excreted as such or further degraded to more polar metabolites. Metabolites with an intact pyrimidinyl phosphorus ester bond such as hydroxydiazinon, diazoxon and its hydroxy derivative are only transient products which are ultimately cleaved to their corresponding pyrimidine analogs. The uncleaved products were found only in in vitro studies (Hagenbuch & Mücke 1985). Figure 1 presents the proposed metabolic pathway of diazinon in mammals. Toxicological studies Acute toxicity studies The results of the acute studies are summarized in Table 1. Clinical signs of acute toxicity are consistent with those caused by organophosphates including decrease of spontaneous activity, sedation, dyspnea, ataxia, tremors, convulsions, lacrimation and diarrhoea. The symptoms were reversible in surviving animals. The studies on the acute toxicity of diazinon were conducted with technical grade material of 95.7-97.1% purity. Samples tested before 1979 show a much higher acute toxicity particularly due to the content of the highly toxic by-product tetraethyl-pyrrophosphate (TEPP). Improvements in the manufacturing of diazinon did reduce the content of toxic by-products (Annex I, reference 15, Ciba-Geigy 1992). WHO has classified diazinon as moderately hazardous (WHO, 1992). Table 1. Acute toxicity of diazinon (technical material) Species Sex Route LD50/LC50* Purity Reference (mg/kg bw)/(mg/l) % Mouse M,F oral 187 ? Bathe, 1972a Rat M,F oral 422 97.1 Bathe & Gfeller, 1980 M,F oral 1250 ? Kuhn, 1989a M,F oral 300 95.7 Piccirillo, 1978 M,F oral 1012 96.1 Schoch & Gfeller, 1985 Rat M,F dermal > 2150 ? Bathe, 1972b Rat M,F inhalation 2.3* ? Holbert, 1989 Rabbit M,F dermal > 2020 ? Kuhn, 1989d Irritation, sensitization Diazinon (tech.) was evaluated for irritation potential in rabbit eyes (Kuhn, 1989b) and skin (Kuhn, 1989c). The compound was not considered as an irritant. In a skin sensitization study in guinea-pigs, diazinon did not reveal a sensitizing potential (Kuhn, 1989e). Potentiation studies Potentiation studies were conducted with chlordimeform, jodfenphos, methacrifos and profenofos. No potentiation was observed after combined application of equitoxic doses (Sachsse & Bathe, 1975, 1976, 1977, 1978). A marked decrease of the acute toxicity during the degradation of diazinon was demonstrated by the studies on the pyrimidinol metabolites 2-isopropyl-6-methyl-4(1H)-pyrimidinone and 2-(alpha- hydroxyisopropyl)-6-methyl-4(1H)-pyrimidinone (Mücke et al., 1970; Annex I, reference 15).Short-term toxicity studies Although reported in the summaries of the following studies, the inhibition of plasma cholinesterase was not utilized as a criterion for the NOAEL, whereas inhibition of the erythrocyte cholinesterase activity may be taken as an indicator of an adverse effect of anticholinesterase pesticides. An inhibition of > 20% compared to the control activity is regarded as significant (Dressel et al., 1980; WHO, 1990). Rats Two short-term inhalation studies were conducted in rats. In a first study groups of rats (9/sex/group) were exposed to an aerosol of diazinon (purity 97.1%; droplet size < 1 µm 30-40%, 1-7 µm 50%) for 6 hours a day, 5 days per week for three weeks. Only the animals' snouts were exposed to the aerosol. The mean concentrations were 0, 151, 245 or 559 mg/m3. The treatment did not cause changes in the mortality rate, in haematology, macroscopical and histopathological findings or organ weights that were attributable to the inhalation of diazinon. Exophthalmus and diarrhoea were observed in animals at all dose levels and tonic- clonic muscle spasms occurred in the high-dose animals. The symptoms were reversible. Food intake at the highest dose level was reduced at the beginning of the treatment period. Body-weight gain was reduced in male rats at 245 and 559 mg/m3, and in female rats at 559 mg/m3. Plasma cholinesterase was inhibited at the intermediate and high levels, resulting in values corresponding to 56% and 37% of the activity in control animals, respectively. Erythrocyte cholinesterase was inhibited only at the highest dose level (34% of the control activity). Brain cholinesterase activity was dose-dependently reduced at all dose levels resulting in activities of 81, 56 and 37% of the control activity in both sexes at the low-, medium- and high-dose levels, respectively. The cholinesterase values returned to normal at the end of the 25-day recovery period. The NOAEL in this study was < 151 mg/m3 (corresponding to an estimated dose of 55 mg/kg bw/day), based on lack of significant brain cholinesterase inhibition at the lowest dose level (Zak et al., 1973). In a more recent 21-day inhalation study, diazinon (purity 88%; particle diameter 0.7-1.4 µm) was administered in a nose-only exposure system in rats (10/sex/group). The intended aerosol concentrations were 0, 0.1, 0.3, 1 or 10 mg/m3 (actual: 0, 0.05, 0.46, 1.57, 11.6 mg/m3). The animals were exposed during 6 hours a day, 5 days per week for 3 weeks. The treatment did not adversely affect body-weight gain, food consumption, haematological parameters, organ weights, macroscopy and histopathological findings. At 1 and 10 mg/m3, plasma cholinesterase activity was reduced in females by 70% and 50% compared to control animals, respectively. Erythrocyte cholinesterase was inhibited to 60% of the control activity at 10 mg/m3 in both sexes, whereas the activity of the brain cholinesterase was reduced in females only to 80% of the control activity at 1 mg/m3, and to 60% in the high-dose animals. The increase of the relative lung weight observed in females at 0.3 and 1 mg/m3 but not at the high dose was not considered biologically significant. The NOAEL in this study was 0.46 mg/m3 (corresponding to an estimated dose of 0.2 mg/kg bw/day), based on inhibition of brain cholinesterase at higher dose levels (Hartmann, 1990). Four groups of rats (Sprague-Dawley; Crl: VAF/Plus CD(SD)Br.; 15/sex/group) were orally treated with diazinon (purity 87.7%) at dietary concentrations of 0, 0.5, 5, 250 or 2500 ppm for 90 days. The treatment had no effect on mortality, water consumption, ophthalmoscopy or urinalysis. Treatment-related occurrence of soft faeces, hypersensitivity to touch and sound and in some male animals aggressiveness were observed at the 2500 ppm dose level. Moreover, hyperactivity was observed in several animals of the high-dose group at the end of the study. Body-weight gain was reduced at 2500 ppm by 6% in males and 13% in females compared to control animals. Food consumption was reduced at 2500 ppm sporadically on single days in both sexes. Haematological and biochemical investigations were performed in the last study week. In the highest dose females, slight reductions in haemoglobin and haematocrit values, as well as an increase of the white blood cell count and reticulocyte count were observed. A dose-dependent decrease in the mean serum cholinesterase activity was observed in females and males at 5 ppm (22% and 74%, respectively, of activity in control group), at 250 ppm (3% and 12% of the control activity, respectively) and at 2500 ppm (2% and 4% of the control activity, respectively). Erythrocyte cholinesterase activity was reduced to 73% and 59% of control activity at 250 and 2500 ppm in males and females, respectively. A reduction in brain cholinesterase activity was found at 250 ppm in females only (59%) and at 2500 ppm in both sexes resulting in activities of 40%-50% of the control activity. An increase in female liver and kidney weights was observed at 2500 ppm. Microscopic evidence of centrolobular hepatocellular hypertrophy was observed in single females at 250 ppm and in most females at 2500 ppm. The NOAEL in this study was 5 ppm, equal to 0.4 mg/kg bw/day, based on erythrocyte and brain cholinesterase inhibition at 250 ppm and higher (Singh et al., 1988). Rabbits In a dermal toxicity study, groups of albino rabbits (5/sex/group) received dermal applications of 0, 1, 5 or 100 mg/kg bw diazinon (purity 97.1%; 50% aqueous suspension in PEG 300), 5 days a week during a 3-week period. Because of high mortality in males at 100 mg/kg bw (4/5 animals died between study days 3 and 6), this dose level was reduced to 50 mg/kg bw on day 8 of the study. In high-dose animals, signs of toxicity included anorexia, ataxia, tremors, diarrhoea, hypoactivity, hypotonia and salivation. Body- weight gain and food consumption tended to be higher in treated animals compared to control animals. Serum cholinesterase was inhibited in both sexes at 100/50 mg/kg bw resulting in values of about 37% of the control group activity. At 5 mg/kg bw, activities were 77% and 65% of the control activity in males and females, respectively. At 1 mg/kg bw, inhibition was only found in females resulting in an activity of 68%. Erythrocyte acetylcholinesterase was inhibited only at 100/50 mg/kg bw resulting in 61% and 68% of the control activity in males and females, respectively. Brain acetylcholinesterase was also inhibited only at the highest dose level of 100/50 mg/kg bw resulting in values corresponding to 72% and 57% of the control activity in males and females, respectively. The only change in organ weights was a decrease in kidney weight in females at 100/50 mg/kg bw. No treatment-related macroscopic or microscopic alterations were observed with the exception of slight erythema at the application sites. Histologically a slight hyperkeratosis was observed in treated skin of high-dose animals The results of this study indicate a marked percutaneous absorption and are thus in agreement with the results of other studies. The NOAEL in this study was 5 mg/kg bw dermal, based on erythrocyte and brain cholinesterase inhibition at 100/50 mg/kg bw (Ballantine et al., 1984; Tai & Katz 1984). Dogs In a 90-day feeding study, diazinon (purity 87.7%) was administered to groups of beagle dogs (4/sex/group) at dietary concentrations of 0, 0.1, 0.5, 150 or 300 ppm (adjusted for purity). No treatment-related mortalities occurred. The treatment did not adversely affect food consumption, ophthalmoscopy, haematology, urinalysis, organ weights or macroscopic findings. Clinical signs such as emesis or bloody faeces were sporadically observed in males at 300 ppm and in females at 150 ppm. Reduced body-weight gain was observed in females at 150 ppm and at 300 ppm in both sexes. In males, inhibition of serum cholinesterase was observed resulting in activities of 70%, 20% and 15% of that measured in control animals at the end of the study at 0.5, 150 and 300 ppm, respectively. Erythrocytes activities corresponding to 75% and 69% of control activity were measured at 150 and 300 ppm, whereas in brain the acetyl cholinesterase inhibition resulted in 69% and 58% of control activity at 150 and 300 ppm, respectively. In females a reduction in acetylcholinesterase activity was observed at 150 and 300 ppm. The inhibition of serum and erythrocyte cholinesterase resulted in an activity of about 18% and 70% of control activity, respectively, at both dose levels, and brain cholinesterase inhibition resulted in 70% and 55% of control activity at 150 and 300 ppm, respectively. Other changes of biochemical parameters consisted of a decrease in total protein at 300 ppm in males. The only microscopic alteration that might be compound-related was atrophy of the pancreatic acini in one male dog of the highest dose group. The NOAEL in this study was 0.5 ppm, equal to 0.02 mg/kg bw/day, based on erythrocyte and brain cholinesterase inhibition at 150 ppm and above (Barnes et al., 1988). Diazinon has been reported to produce pancreatic acinar lesions in dogs at 75 mg/kg bw/day (Frick et al., 1987). In a 52-week oral toxicity study, groups of beagle dogs (4/sex/group) were fed diazinon (purity 87.7%) at dietary concentrations of 0, 0.1, 0.5, 150 or 300 ppm (adjusted for purity). Due to lack of body-weight gain the dietary concentration of 300 ppm was reduced to 225 ppm after 14 weeks of treatment (dose 300/225 ppm). Mortality was not increased by treatment and haematology, urinalysis, gross pathology and histopathology revealed no changes attributable to treatment. Overt clinical signs of dehydration and emaciation became evident in one male at 300/225 ppm. The symptoms remained even though the initial dose was reduced. Reductions in body-weight gain were observed at 150 ppm and higher in males and at 300/225 ppm in females. However, no clear-cut dose-response relationship was evident and the differences attained statistical significance compared to the control group at only some observation times. Food consumption was reduced at 150 ppm and higher, again without a clear dose-response relationship, most probably due to reduced palatability of the feed admixtures. Treatment-related decreases in acetylcholinesterase activity at dose levels of 0.5 ppm and higher were found: serum cholinesterase was reduced at 0.5 ppm and higher in males and at 150 ppm and higher in females, resulting in activities of about 20% of the activity in the control group at 150 and 300/225 ppm in both sexes. Erythrocyte cholinesterase activity was also reduced at 150 and 300/225 ppm, where activities corresponding to about 70% of the control activity were measured in both sexes. Brain cholinesterase was inhibited at 150 ppm to 75% of control activity in females and at 300/225 ppm to 65% and 75% of control activity in females and males, respectively. The NOAEL in this study was 0.5 ppm, equal to 0.02 mg/kg bw/day, based on erythrocyte and brain cholinesterase inhibition at 150 ppm and above (Rudzki et al., 1991). Long-term toxicity/carcinogenicity studies Mice Groups of mice (B6C3F1 Hybrid; 50 (control 25)/sex/group) were administered diazinon (purity 98%) at 0, 100 or 200 ppm over 103 weeks. Survival, body weight, clinical signs and pathology were investigated. The treatment had no effect on survival or body- weight development. An increased incidence of hepatocellular carcinomas was observed in the low-dose males only. The incidences of hepatocellular carcinomas were 19, 43 and 21% in the control, low and high-dose males, respectively, whereas the incidence of liver adenomas was not increased in treated animals compared to control animals. The mean incidences of hepatocellular carcinomas in historical controls of this mouse strain (18 studies) were reported to be 14% (max. 27%) for males and 3% (max. 10%) for females. Concerning the total incidence of carcinomas and adenomas, incidences of 29% (max. 58%) and 11% (max. 34%) in males and females were reported (personal communication from Ciba Geigy to WHO, 1993). Thus the incidence of hepatocellular carcinomas found in males of the low-dose group markedly exceeded the range of historical control incidences. Because no dose-response relationship was evident, the result was most probably fortuitous and could not be interpreted as providing evidence for a carcinogenic potential of diazinon in mice (NCI, 1976). Rats Groups of rats (Fischer F344; 50 (control 25)/sex/group) were fed diazinon (purity 98%) at dietary concentrations of 0, 400 or 800 ppm for 103 weeks. Survival, body weight, clinical signs and pathology were the parameters investigated. There was no dose- related reduction of survival and the body-weight development was similar in control and treatment groups. Clinical signs of hyperactivity were observed in treated males in both dose groups and in high-dose females. The incidence of leukaemia was increased in low-dose males (50%) compared to the incidence in the concurrent control (20%) and high-dose males (24%). The leukaemias were of the type usually seen in aging F344 rats. In females, the incidences of leukaemia were also higher (12% at 400 ppm and 10% at 800 ppm) compared to the concurrent controls (4%). Historical control incidences of leukaemia were reported to be 48% for males (range 32- 62%) and 27% for females (range 14-15%). Because of the lack of a dose-response relationship, the increase in tumour incidence was considered of questionable significance and the results therefore could not be interpreted as providing evidence for a tumorigenic potential of diazinon in rats (NCI, 1976; NIEHS, 1991). Diazinon (purity 87.7%) was administered as feed admixture to groups of rats (Sprague-Dawley; 30-40/sex/dose) at concentrations of 0, 0.1, 1.5, 125 or 250 ppm (adjusted for purity) for up to 98-99 weeks. An additional vehicle control group was included in this study. The animals of this dose group were treated with epoxidized soybean oil. Up to 10 rats/sex/group were used for the interim sacrifice after at least 52 weeks of treatment. Another number of up to 10 rats/sex from the control and high-dose group were placed on a four-week recovery period and sacrificed thereafter. The study was terminated after 98-99 weeks because of decreased survivability in the 0.1 ppm male group only, which was unrelated to treatment and associated with age-related changes (e.g., senile nephropathy and/or pituitary adenoma, both considered to be the result of senescence in this rat strain). This earlier termination was not considered to have affected the quality or integrity of the study because a sufficient number of animals were at risk in the other treatment groups for the development of tumours. The treatment did not cause increased mortality, and did not affect ophthalmological or haematological findings, urinalysis or organ weights. Body-weight gain was increased in males at dose levels of 0.1 ppm and higher and in some instances in females at 125 ppm and higher compared to the untreated control animals. Because the body-weight gain in the vehicle control group also showed an increase compared to the untreated controls, the increases in body-weight may reflect an increased palatability of the feed admixtures containing the epoxidized soybean oil. In fact the increases in mean body-weight gain generally coincided with increases in mean food consumption in these dose groups. Decreases in serum cholinesterase activities were observed at concentrations of 1.5 ppm and higher in both sexes, resulting in values of about 50% of the control activity at the end of the study. A dose-dependent reduction of erythrocyte cholinesterase activity was observed at 125 and 250 ppm resulting in activities of 80% and 75% of the control activity in males and females, respectively, at either dose level at the end of the study. Brain cholinesterase activity was also inhibited to 76% and 71% of the control activity in males and females, respectively, at 125 ppm, and to 58% and 52% of the control activity at 250 ppm in males and females, respectively. Similar inhibition was observed after the first year of the study. A slight reduction of less than 9% was still found after the 4-week recovery period in erythrocyte and brain cholinesterase activity at 250 ppm. Gross and microscopic pathology examinations did not give evidence of any compound-related lesions. The NOAEL in this study was 1.5 ppm, equal to 0.07 mg/kg bw/day, based on inhibition of erythrocyte and brain cholinesterase at 125 ppm and above (Kirchner et al., 1991). Reproduction studies Rats Diazinon (purity 94.9%) was administered in the diet to groups of rats (Sprague-Dawley CRCD; 30/sex/group) over two parental generations (F0, F1) and up to weaning of the F2 pups at concentrations of 0, 10, 100 or 500 ppm. Treatment-related clinical symptoms and deaths were observed in a few high-dose females. They consisted of tremors (3/30) and dystocia (2/30) followed by death or sacrifice in the F0 generation. In the F1 generation, a few high- dose females showed tremors as only compound-related signs. Food consumption was increased in females of the 500 ppm group in the F0 generation, whereas in the F1 generation, a dose-related reduction of food consumption was observed at 100 and 500 ppm in males only. Body-weight gain was lower in F0 females at 500 ppm during gestation. In the F1 generation, reduced body-weight gain was observed at 100 and 500 ppm in males and at 500 ppm in females. There were no treatment-related effects on mating behaviour and the reproductive parameters (including mating, fertility, gestation indices, number of viable pups, and number of stillborn pups) were comparable in control and treatment groups in the F0 generation and at the low and intermediate dose level of the F1 generation. At 500 ppm, a greater proportion of females showed a prolonged gestation duration at both generations. A decrease in the number of pregnancies and viable pups as well as reduced fertility and mating indices were observed in high-dose females of the F1 generation. A dose-related reduction in survival of F1 pups was observed at 100 ppm and 500 ppm and in F2 at 500 ppm. Weights of F0 pups were reduced in the 100 and 500 ppm groups, and in F2 pups at 500 ppm. No treatment-related malformations were found in the pups. The NOAEL in this study was 10 ppm, equivalent to 0.5 mg/kg bw/day, based on reduced parental body-weight gain and reduced viability of pups and pup weights at 100 ppm and higher (Giknis 1989). Special studies on embryotoxicity/teratogenicity Mice Groups of mice (6 females/dose) were given oral daily doses of 0, 0.18 or 9 mg/kg bw diazinon throughout gestation. Treated animals gained less weight during gestation compared to control animals. Weight gain of pups born to mothers receiving 9 mg/kg bw/day was reduced. Daily testing for physiological and behavioural development of the pups revealed some evidence of retarded development among the offspring of high-dose animals (e.g., retardation of eye and ear opening). Measures of endurance and coordination also gave some evidence of impairment (e.g., increased rod cling endurance in both groups, reduced rotarod endurance, impaired running performance in a maze inclined plane test). Impaired reactions were sometimes observed at both dose levels but without a clear dose-effect relationship. Examination of brain tissue of only 8 of a total number of 132 offspring at the high-dose level revealed morphological abnormalities in the forebrain. The relationship of these findings to the observed behavioural changes is unknown (Spyker & Avery 1977). The evidence for morphological effects of diazinon on the developing brain was considered insufficient by an expert (Krinke, 1991). Rats In a teratogenicity study in Sprague-Dawley rats at dose levels of 0, 15, 50 or 100 mg/kg bw/day administered orally on days 6 through 15 of gestation, dams at the 100 mg/kg bw/day dose level showed a marked decrease in food consumption correlating with weight loss at the beginning of the treatment period. Skeletal assessment showed a slightly higher incidence of incomplete ossification at different sites in the fetuses at 100 mg/kg bw/day. Visceral examination revealed a dystopia cordis in association with hypoplasia of lungs in 1/105 fetuses at 100 mg/kg bw/day. This anomaly has been reported to occur spontaneously in control animals. Because of the single occurrence this anomaly was not considered to be due to a direct action of diazinon but to be secondary to maternal toxicity (Fritz, 1974). In a later study, groups of rats (Charles River Crl. COBS CD(SD)(BR); 27 females/group) were treated with doses of diazinon (purity 97.4%) at 0, 10, 20 or 100 mg/kg bw/day by gavage during gestational days 6 through 15. The treatment had no effect on the mortality of the dams. During the first half of the dosing period, the dams lost weight and food consumption was reduced at 100 mg/kg bw/day. No compound-related clinical signs and no abnormal gross pathological findings were observed in the dams. At 100 mg/kg bw/day some reproductive parameters differed from the control values but no statistical significance was achieved (e.g., increase in number of resorptions, percent pre- and post-implantation loss, reduction in number of live fetuses). On gross observation, 3/262 (1%) fetuses from 3 litters showed external malformations (single occurrences of a umbilical hernia, filament tail, sublingual extraneous soft tissue), whereas in the concurrent controls no similar effects were observed. Umbilical hernia and tail abnormalities however are reported to be spontaneous malformations observed routinely in this rat strain. Concerning skeletal variations, an increased incidence in rudimentary ribs (T-14) was observed in all treatment groups attaining statistical significance in the high-dose group (5% versus 0%). Because of the single occurrences of the different malformations observed and because the malformations also occur in control animals they were considered to be a consequence of the marked maternotoxicity at this dose level, and not due to a teratogenic effect of the test compound. The increased incidence of the skeletal variation observed at the top dose level was considered to be related to maternotoxicity at this dose level. The NOAEL in this study was 20 mg/kg bw/day based on maternotoxicity and fetotoxicity at the higher dose level (Infurna & Arthur, 1985). Rabbits Diazinon (purity 89.2%) was administered to groups of pregnant rabbits (New Zeeland white; 18-22 females/group) by gavage at dose levels of 0, 7, 25 or 100 mg/kg bw/day from days 6-18 of gestation. An increase in maternal mortality was observed at 100 mg/kg bw/day (41% vs 0% in all other groups). Overt clinical signs of maternal toxicity at 100 mg/kg bw/day included tremors, convulsions, hypoactivity and anorexia. Reduced body-weight gain was found at the highest dose level. The treatment did not influence the number of corpora lutea, number of implantation sites, live fetuses per litter or fetal weight. The incidence of visceral and skeletal malformations and variations showed no differences between the groups that could be attributed to treatment. The study therefore gave no evidence for an embryotoxic or teratogenic activity of diazinon. The NOAEL in this study was 25 mg/kg bw/day based on materno-toxicity at the highest dose level (Harris & Holson, 1981). Chickens The teratogenic effects of some anticholinesterase insecticides (organophosphates and methylcarbamates) on chicken embryos have been known for some time. In a first study, eggs were injected with diazinon to explore some of the biochemical variables that might be involved in producing micromelia, beak and feather deformities (type I signs) in avian embryos that are known to be caused by OP insecticides. The results of this study confirm the assumption that a tryptophan deficiency (tryptophan plays an important role in the developing embryo) may cause the abnormalities observed (Kushaba- Rugaaju & Kitos, 1985). Another study was conducted to investigate the involvement of cholinergic functions in OP-induced teratogenesis in chick embryos by examining the effects of diazinon on the developmental pattern of AChE and ChAT activities in hindlimb, wing and brain. The results of this study confirmed that type II teratogenesis (wry neck, short neck, arthrogryposis and muscular hypoplasia of legs) may be mediated via cholinergic nicotinic receptors. Cholinergic dysfunction including decreased activity of AChE and ChAT was not correlated with diazinon-induced type I teratogenesis (micromelia, abnormal feathering) (Misawa et al., 1981). Cattle As part of a survey to determine the causes of abortion in dairy cattle in Wisconsin, the potential role of pesticides was examined. Diazinon in the form of wettable powder was orally administered to two pregnant cows at a daily dose level of 6.6 mg/kg bw. The continuous treatment started in the 5th and 6th month of pregnancy (abortion commonly affects cows in the 5th to 8th month of pregnancy) and was maintained until parturition. No diazinon residues were detected in the tissues examined (fat, liver, kidney) nor in milk. The treatment failed to reveal any abortions (Macklin & Ribelin 1971). Special studies on genotoxicity Diazinon has been adequately tested in a series of genotoxicity assays. The results are summarized in Table 2. Special study of effects on the pancreas A study was conducted using a canine model to investigate the induction of pancreatic ductal hypertension following cholinesterase inhibitor intoxication known to be an important triggering mechanism in the pathogenesis of acute and chronic pancreatitis. Diazinon was intravenously administered (25 mg/kg bw) to the pancreatic ampulla of dogs and the tissue cholinesterase activity of the canine pancreatic sphincters was determined. Two enzymes are responsible for the total cholinesterase activity of whole blood: a membrane- bound AChE associated with the erythrocyte membrane, and a soluble enzyme, pseudocholinesterase or butyrylcholinesterase (BChE) in the serum. In tissues, which also contain the two forms of cholinesterase, AChE is important in the regulation of neuromuscular activity and parasympathetic ganglion transmission, while the role of BChE is unknown. The observation of the negative correlation between serum BChE activity and intraductal pancreatic pressure supports the hypothesis that the pancreatic ductal hypertension which occurs following cholinesterase inhibitor intoxication is due to a selective reduction in pancreatic BChE activity (Dressel et al., 1980). The induction of acute pancreatitis by OPs found in dogs was confirmed in guinea-pigs but not in cats. These results may reflect species-related differences in the distribution of pancreatic BChE (Frick et al., 1987). Special studies on antidotes Previous reports with respect to the usefulness of PAM and other oxine reactivators against this organophosphate have been published (Sanderson & Edson, 1959; Wills, 1959). A recent study was undertaken to provide information on the antidotal effectiveness of pyridine-2-aldoxime methochloride (2-PAM) against diazinon poisoning in animals. The administration of atropine (16 mg/ kg bw; i.m.) or 2-PAM (30 mg/kg bw; i.v.) alone 10 minutes after poisoning rats with doses of 235 mg/kg bw corresponding to the approximate oral LD50 or higher provided little or no protection. Best protection was achieved when the oxime was given orally in conjunction with atropine (i.m.) or followed by a subsequent dose of 2-PAM orally or i.v. Administration of 2-PAM to diazinon-poisoned rabbits (1600 mg/kg bw) resulted in reactivation of inhibited blood ChE activity concurrent with a decrease in signs of poisoning. Within 2 hours, however, the animals were again weak and ataxic and blood ChE showed renewed inhibition. The authors suggested that effective therapy of diazinon intoxication requires repeated doses of oxime to maintain effective antidote levels in the body (Harris et al., 1969). In dogs and guinea-pigs, pretreatment with atropine protected the animals against diazinon-induced pancreatitis (Frick et al., 1987). Special study on delayed neurotoxicity Hens An oral dose of 28 mg/kg bw/day of diazinon technical (87% purity) was administered to a group of 18 hens (the target dose of 13 mg/kg bw/day as the approximate LD50 was doubled due to a preparation error). The schedule to protect the hens from acute cholinergic effects of diazinon consisted of a 10 mg/kg bw atropine pretreatment (i.m.). At the time of diazinon dosing, 2-PAM at an i.m. dose of 50 mg/kg bw was administered. Post-treatment consisted of concurrent doses of atropine and 2-PAM one and five hours following dosing. Since there were no neurotoxic responses in the test group in the three weeks following the treatment they were again treated with 13 mg/kg bw of diazinon on day 21. One test group hen was found dead on day 5 after the first dosing, and one hen six hours after the second treatment. One hen exhibited a slight unsteadiness in walking only on day 41. No neurotoxic signs became apparent during the three-week observation period after the second treatment. Histopathological examination revealed no lesions in the brain, spinal cord or peripheral nerves in diazinon-treated animals, whereas animals of the positive control (TOCP treatment) showed multiple lesions (axonal degeneration) consistent with peripheral neuropathy (Jenkins, 1988). Observations in humans Numerous reports of intentional and accidental intake of diazinon and other OPs have been published describing the clinical manifestations of organophosphate toxicity and the usefulness of erythrocyte and serum cholinesterase activity assays for diagnosis as well as the efficacy of supportive and specific therapies (Kabrawala et al., 1965; Payot, 1966; Banerjee, 1967; Gupta & Patel, 1968; Zwiener & Ginsburg, 1988). A case of acute diazinon poisoning complicated by pericarditis and pneumonia followed by recovery has been reported. The intoxication caused the occurrence of cyanosis, tracheobronchial congestion, pulmonary edema and pneumonia. The treatment included the intramuscular injection of atropine (Banerjee, 1967). Another complication reported following accidental ingestion of diazinon consisted of severe pancreatitis and a pseudocyst (Dressel et al., 1979). The induction of pancreatitis was reproduced in dogs treated intravenously with a dose of 5 mg/kg bw diazinon. Pancreatitis may be the result of hypersecretion and ductal obstruction (Dressel et al., 1980). Table 2. Results of genotoxicity assays on diazinon Test system Test object Concentration/dose Purity Results Reference Non-activated Activated In vitro Ames test S. typhimurium 313-5000 µg/0.1 ml 88.0% negative negative Geleick & Arni, 1990 TA 98, 100, 1535, 1537 DMSO E. coli WP2uvrA Ames test S. typhimurium in DMSO >50-1000 ? negative negative Marshall et al., 1976 TA 1535, 1536, 1537, 1538 µg/plate Mouse lymphoma Mouse lymphoma cell 1. 6 to 60 µg/ml with 97.2% negative negative Dollenmeier & Müller, assay L5178Y/TK+/- activation 1986 2. 12 to 120 µg/ml without activation Mouse lymphoma Mouse lymphoma cell up to 100 µg/ml ? positive positive McGregor et al., 1989 assay L5178Y TK+/- Sister chromatid Chinese hamster cells 10, 20 and 40 µg/ml 99.2% negative Chen et al., 1981 exchange study (V79) 99.2% in DMSO Chromosomal Chinese hamster lung 0.1 mg/ml ? cytotoxic positive Matsuoka et al., 1979 aberration test cells Sister chromatid Human lymphoid cells 0.02, 0.2, 2.0 and ? negative negative1 Sobti et al., 1982 exchange study (LAZ-007) 200 µg/ml in Ethanol (< 0.1%) Sister chromatid Human lymphoid cells 12.5, 25, 50, 100 and 87.5% negative negative Strasser & Arni, 1988 exchange study (CCL-156) 200 µg/ml in DMSO Table 2 (contd) Test system Test object Concentration/dose Purity Results Reference Non-activated Activated Sister chromatid Whole blood human 1. 0.0668 to 2000 µg/ml 88.0% equivocal equivocal2 Murli & Haworth, 1990a exchange study lymphocytes in DMSO (± activation) 2. 0.668 to 20 µg/ml (non-activation) 3. 2-66.8 µg/ml (activated) Autoradiographic Rat hepatocytes 1.1 to 120 µg/ml in 88.0% negative Hertner & Arni, 1990 DNA repair test DMSO In vivo Micronucleus test Mouse 1. 120 mg/kg bw oral 87.5% negative Ceresa, 1988 in vivo 2. 30, 60, and 120 mg/kg bw oral Dominant lethal Mouse oral dose of 14 and 45 95% negative Fritz, 1975 study mg/kg bw Chromosome studies Mouse a) daily oral doses of ? negative a) Hool & Müller, 1981c in male germinal a) spermatogonia 10.5, 21 and 63 mg/kg b) Hool & Müller, 1981b epithelium b) spermatocytes bw for five days, or b) 5 treatments with the same doses over a period of 10 days Sister chromatid Bone marrow cells single oral doses of 88.0% negative Murli & Haworth, 1990b exchange study of mice 10, 50 and 100 in vivo mg/kg bw Table 2 (contd) Test system Test object Concentration/dose Purity Results Reference Non-activated Activated Sister chromatid Chinese hamster bone oral gavage of 6.5 ? negative Hool & Müller, 1981a exchange study marrow cell to 26 mg/kg bw Nucleus anomaly Chinese hamster bone oral gavage of ? negative Hool & Müller, 1981d test marrow cells 6.5, 13 and 26 mg/kg bw/day for two days 1 Cyotoxicity at a concentration of 20 µg/ml. The increased frequency of sister chromatid exchanges at 20 µg/ml with metabolic activation did not show a doubling of the control frequency and was therefore not considered positive. 2 Two independent trials: Cytotoxicity at concentrations of 66.8 µg/ml (with activation) respectively. Increases in the SCE frequency (just doubling) observed only in the first assay without metabolic activation at dose levels of 0.668 µg/ml to 20 µg/ml, but without a dose-relationship. Increases observed after activation in both trials did not show doubling and again no dose-response. Thus the results of these studies are not considered positive. A study of 60 poisoning cases with diazinon has been reported. The most common clinical manifestations were vomiting, giddiness, constricted pupils and signs of bronchoconstriction with pulmonary congestion. The amount of poison ingested varied from 4 ml to 15 ml with an average of 7.5 ml (% active ingredient not specified in publication). This was ingested by 55 patients with suicidal intention, whereas in 5 patients the compound was taken accidentally. Atropine injections were administered repeatedly (up to a total dose of 22.4 g over 42 hours). Five patients died in spite of intensive atropine therapy initiated more than 8 hours after ingestion. Other cases who had ingested the same amount of poison as the fatal cases received treatment within three hours of ingestion. These findings emphasize the importance of early treatment in diazinon poisoning (Gupta & Patel, 1968). In addition, these results are in agreement with an earlier observation that the combination of diazinon with cholinesterase occurs in two stages, an early reversible stage and a late irreversible stage (Grob, 1956). In another study, cases of organophosphate and carbamate poisoning in 37 infants and children were reported, only 5 of which were associated with diazinon. Miosis, excessive salivation, muscle weakness, respiratory distress, lethargy and tachycardia were the most common clinical findings. Erythrocyte cholinesterase activities were determined from 24 patients showing erythrocyte cholinesterase activities that were less than 50% of the lower limit of the normal range. There were no differences between the erythrocyte and serum cholinesterase activity in 20/24 patients from whom both tests were obtained, whereas in the remaining 4 cases either the erythrocyte or the serum activity was decreased. A combined atropine/pralidoxime therapy is recommended in case of organophosphate toxicity. Although the recommended dose for atropine in infants is 0.01-0.02 mg/kg bw, the dose is generally insufficient for treatment of signs and symptoms secondary to organophosphate poisoning (Zwiener & Ginsburg, 1988). Neurobehavioural effects of short-term, low-level exposure to diazinon were investigated in 99 pest control workers. A computer assisted neuro-behavioural test battery (including attention, vigilance, hand-eye coordination, visual perception, verbal ability) was used before and after their work shift. The diazinon metabolite diethyl-thiophosphate (DETP) was measured in urine samples collected from 46 diazinon applicators and 56 non-applicators. Post-shift DETP values were 24 and 3 ppb for applicators and non-applicators, respectively. The study failed to demonstrate any behavioral effects of diazinon under the conditions of this study (Maizlish et al., 1987). The results of the following old study have been reported in an earlier monograph (Annex I, reference 7). Because of certain inaccuracies in that monograph, the study was reviewed again and summarized below. A subacute oral toxicity study was conducted in four male volunteers. Diazinon (different batches, purity 95.4-95.7%) was administered in capsules at dose levels of 2-2.5 mg per day per person, equal to a dose of 0.025 mg/kg bw/day. The test period lasted 42 days with an interruption in treatment from the 5th to 10th day in two volunteers and for 34 consecutive days in the other two volunteers. Plasma cholinesterase activity was markedly depressed the first 6 days of treatment in 2/4 subjects (no plasma cholinesterase activity measurable). Therefore treatment was interrupted for 6 days to enable recovery. Subsequent treatment at the same dose level did not reveal inhibitory effects on plasma cholinesterase. The fluctuations observed during the treatment period were similar to those observed during the pre-test period. In no instance was the erythrocyte acetylcholinesterase depressed compared to the pre-test values. Other parameters investigated included haematology and blood chemistry, urinalyses and symptomatology. No changes were observed that could be attributed to the treatment. The NOAEL in this study was 0.025 mg/kg bw/day based on transitory depression of plasma cholinesterase activity as the only effect observed at this dose level (Payot, 1966). COMMENTS Following oral administration to rats, diazinon was almost completely absorbed and eliminated, mainly in the urine. The main degradative pathway includes the oxidase/hydrolase- mediated cleavage of the ester bond leading to the pyrimidinol derivative 2-isopropyl-6-methyl-4(1H)-pyrimidinone, which is further oxidized to more polar metabolites. Diazinon has moderate acute oral toxicity to mice and rats. The clinical signs observed were consistent with cholinesterase inhibition and included sedation, tremors, convulsions and ataxia. It has been classified by WHO as moderately hazardous. In an oral 90-day feeding study in rats at dietary concentrations of 0, 0.5, 5, 250 or 2500 ppm, the NOAEL was 5 ppm (equal to 0.4 mg/kg bw/day), based on erythrocyte and brain cholinesterase inhibition at 250 ppm and higher. In short-term studies in dogs, diazinon was administered at dietary concentrations of 0, 0.1, 0.5, 150 or 300 ppm for either 90 days or 52 weeks. In both studies, the NOAEL was 0.5 ppm, equal to 0.02 mg/kg bw/day based on erythrocyte and brain cholinesterase inhibition at 150 ppm and above. In a carcinogenicity study in mice, diazinon was administered at dietary concentrations of 0, 100 or 200 ppm over 103 weeks. There was no evidence of carcinogenicity. In a carcinogenicity study in rats diazinon was administered at dietary concentrations of 0, 400 or 800 ppm for 103 weeks. There was no evidence of carcinogenicity. In a long-term toxicity/carcinogenicity study, rats were maintained on a diet containing diazinon at concentrations of 0, 0.1, 1.5, 125 or 250 ppm for up to 99 weeks. The NOAEL was 1.5 ppm, equal to 0.07 mg/kg bw/day, based on inhibition of erythrocyte and brain cholinesterase at 125 ppm and above. There was no evidence of carcinogenicity. A multigeneration study was conducted in rats using dietary concentrations of 0, 10, 100 or 500 ppm. The NOAEL was 10 ppm (equivalent to 0.5 mg/kg bw/day), based on a reduction in parental body-weight gain in the F1 generation and a reduced survival rate and reduced body weight of F1 pups at 100 ppm. In a teratogenicity study in rats, diazinon was orally administered at dose levels of 0, 10, 20 or 100 mg/kg bw/day. Maternal toxicity, indicated by weight loss correlating with reduced food consumption, became evident at 100 mg/kg bw/day. Effects on the fetuses at this dose level consisted of retarded ossification and an increased incidence of rudimentary ribs. The NOAEL was 20 mg/kg bw/day based on maternotoxicity and fetotoxicity. There was no evidence of teratogenicity. A teratogenicity study in rabbits conducted with oral dose levels of 0, 7, 25 or 100 mg/kg bw/day revealed clinical signs of maternotoxicity, increased mortality and reduced body-weight gain at 100 mg/kg bw/day. The NOAEL was 25 mg/kg bw/day. There was no evidence of teratogenicity. A neurotoxicity study performed with hens treated at dose levels of 13 or 28 mg/kg bw/day (protected by atropine pre- treatment) did not reveal evidence of delayed neurotoxicity. Diazinon has been adequately tested in a series of genotoxicity assays. Chromosomal aberrations were induced in cultured mammalian cells, but there were no other indications of genotoxicity. The Meeting concluded that diazinon was not genotoxic. Diazinon was evaluated in four human male volunteers who received 0.025 mg/kg bw/day of diazinon in capsules for 34-36 days. There were no consistent treatment-related effects on plasma or erythrocyte cholinesterase activity, blood chemistry or urinalysis. No clinical effects were reported. The NOAEL was 0.025 mg/kg bw/day. The ADI of 0-0.002 mg/kg bw, which was based on the NOAEL of 0.025 mg/kg bw/day in the study in humans using a 10-fold safety factor, was maintained. TOXICOLOGICAL EVALUATION Level causing no toxicological effect Rat: 5 ppm, equal to 0.4 mg/kg bw/day (90-day study) 1.5 ppm, equal to 0.07 mg/kg bw/day (99-week study) 10 ppm, equivalent to 0.5 mg/kg bw/day (reproduction study) 20 mg/kg bw/day (maternotoxicity in teratogenicity study) Rabbit: 25 mg/kg bw/day (maternotoxicity in teratogenicity study) Dog: 0.5 ppm, equal to 0.02 mg/kg bw/day (one-year study) Human: 0.025 mg/kg bw/day (34-36-day study) Estimate of acceptable daily intake for humans 0-0.002 mg/kg bw Studies which will provide information valuable in the continued evaluation of the compound Further observations in humans. REFERENCES Ballantine, L., Marco, G.J. & Williams, S.C. (1984) Percutaneous absorption of 2 delta - 14C - Diazinon in Rats. Numbers ABR-84011, 302950. Unpublished Report Prepared by Ciba-Geigy Corp., Greensboro, NC. Banerjee, D. (1967) Pericarditis in acute diazinon poisoning. A case report. Armed Forces Med. J. (India), 23: 187-190. 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See Also: Toxicological Abbreviations Diazinon (EHC 198, 1998) Diazinon (ICSC) Diazinon (FAO Meeting Report PL/1965/10/1) Diazinon (FAO/PL:CP/15) Diazinon (FAO/PL:1967/M/11/1) Diazinon (FAO/PL:1968/M/9/1) Diazinon (AGP:1970/M/12/1) Diazinon (WHO Pesticide Residues Series 5) Diazinon (Pesticide residues in food: 1979 evaluations) Diazinon (JMPR Evaluations 2001 Part II Toxicological)