PESTICIDE RESIDUES IN FOOD - 1979 Sponsored jointly by FAO and WHO EVALUATIONS 1979 Joint meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues Geneva, 3-12 December 1979 ALDICARB IDENTITY Chemical Name 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime Synonyms TemikR, UC 21149, OMS 771 Structural Formula CH3 O H ' " ' CH3 - S - C - CH = N - O - C - N - CH3 ' CH3 C7H14N2O2S Other Information on Identity and Properties Molecular weight: 190.3 State: White, crystalline solid Odor: Slight sulfurous odor M.P.: 98-100°C S.G.: 1.195 @ 25°C B.P.: Decomposes above 100°C V.P.: 0°C 1 × 10-5 mm Hg 25°C 1 × 10-4 mm Hg 50°C 7 × 10-4 mm Hg 75°C 4 × 10-3 mm Eg Stability: Heat sensitive, relatively unstable chemical; stable in acidic media; unstable, decomposes rapidly in alkaline media. Solubility: Percent Solubility at: 10°C 20°C 30°C 50°C Water 0.4 0.6 0.9 1.4 Acetone 28 40 43 67 Benzene 9 24 49 Carbon tetrachloride 2 5 25 Chloroform 38 35 44 53 Methyl isobutyl ketone 13 24 42 Toluene 10 10 12 33 Ethanol 25 Isopropanol 20 Vapour Pressure of Aldicarb and Metabolites V.P. (mm Hg) at: Chemical 0°C 25°C 50°C 75°C Aldicarb 1 x 10-5 1 x 10-4 7 x 10-4 4 x 10-3 Aldicarb Sulfoxide 1 x 10-5 7 x 10-5 5 x 10-4 2 x 10-3 Aldicarb Sulfone 8 x 10-6 9 x 10-5 6 x 10-4 3 x 10-3 Aldicarb in relatively non-volatile and the major toxic metabolites are less volatile than aldicarb. Purity of Technical Product The Meeting noted that the technical product normally contains from 94.7 to 97.7% aldicarb and considered the likely impurities. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, Distribution and Excretion Aldicarb is readily absorbed, distributed widely in the body and excreted rapidly in mammals. Radiolabeled aldicarb (the 14C radiolabel was present in one of three positions in the molecule, S-methyl, tert-butyl or N-methyl) was administered orally to male rats and residue were analyzed over a 14-day period. Excretion was essentially complete within 4 days (greater than 95% of the administered dose). The major concentrations of metabolites were observed to have been excreted within 24 hours of dosing. Four days following acute oral dosing residues were not detected in animal tissues (Knaak et al., 1966). Following oral administration (0.4 mg/kg), aldicarb was rapidly eliminated predominantly in the urine 80%) and faeces (5%) within 24 hours. Low levels of radioactive metabolite were noted in a variety of tissues in the first days after treatment. Within four days there were essentially no residues which could be suggestive of (selective) storage of residues in the body. By the fifth day following acute treatment, tissues were free of detectable residues (Andrawes, et al., 1967). Aldicarb sulfone, a minor carbamate metabolite, was administered orally to rats and also found to be rapidly absorbed and excreted in a manner similar to that noted with aldicarb. Within 4 days from 90 to 95% of the orally administered dose was excreted predominantly in urine. In two analytical studies, performed at 7 or 11 days after treatment, tissue residues were absent (Sullivan, 1968c; Andrawes 1977). In dogs, the excretion pattern of aldicarb administered subacutely was similar to that noted following acute administration in other species. Aldicarb was administered to dogs at a dose of 0.75 mg/dog/day in the diet for 20 days. On the 21st day, a single radiolabeled dose of aldicarb was administered in the place of the non-radiolabeled chemical. Dogs were thereafter maintained for an additional ten days on a diet containing aldicarb. The daily excretion pattern was examined in urine. Approximately 90% of the recovered urinary radioactivity was observed to have been excreted within the first 24 hours of the administration time of the radio-labelled dose. Thus, the elimination via the urine of aldicarb from dogs equilibrated for up to three weeks showed an excretion pattern similar to that noted with animals administered aldicarb in a single acute dosage (Sullivan, 1968a). A similar urinary excretion pattern was observed when aldicarb sulfone (Sullivan, 1968b; Andrawes 1977) and aldicarb nitrile (Sullivan and Carpenter, 1974) were orally or dietarily administered to lactating dairy cows either alone or in combination with one or more aldicarb metabolites. Following a single acute administration of aldicarb, approximately 83% of the dosage was eliminated in the urines within 24 hours. A minor quantity of residue was eliminated in the faeces and small residues were observed in milk (less than 3% of the administered dose was observed in milk over a 5-day interval) (Dorough and Ivie, 1968). Increasing the number of days of treatment from one to 14 did not change the magnitude or the elimination pattern of aldicarb in milk or excretory products. Approximately 1% of the administered dose was secreted in milk with 95% of the administered dose eliminated by the other routes. Small levels of residues were observed in tissues with the liver showing the major terminal residue. Continuous exposure of cows to aldicarb in the diet did not significantly alter its absorption and excretion patterns (Dorough, et al., 1970). In an additional subchronic study a 1:1 mixture of aldicarb sulfoxide and aldicarb sulfone was administered to cows to 32 to 46 days. Milk residues were found to be approximately 0.1% of the administered aldicarb metabolites. In these studies there was no apparent build-up of residues in milk or animal tissues from continuous administration of aldicarb and/or its carbamate metabolites (Romine, 1973). Aldicarb and/or aldicarb sulfone administered as a single oral dose to laying hens was rapidly excreted in the faeces. Minute quantities of terminal residues were observed in eggs on the first day after treatment but the residue level declined rapidly. Tissue residues were maximal within 6 hours of treatment after which a rapid decline was observed. Continuous administration of aldicarb for 21 days did not change the pattern of rapid excretion or of terminal residues in eggs or tissues (Hicks, et al., 1972). Biotransformation The metabolic fate of aldicarb has been studied in a variety of vertebrate and invertebrate species. Minor biotransformation differences have been found to occur with respect to quantities of individual metabolites. The basic metabolic profile of aldicarb in all species examined appears to be the same and is shown in figure 1. Aldicarb is rapidly oxidized to aldicarb sulfoxide, a relatively stable metabolite. Aldicarb sulfoxide in slowly degraded by both oxidative and hydrolytic mechanisms yielding the corresponding aldicarb sulfone and sulfoxide oxime. In rats, urinary metabolites include aldicarb sulfoxide (40%), the sulfoxide oxime (30%) and a variety of more polar, relatively acidic, metabolites. Aldicarb was noted in urine only in trace quantities (Knaak, et al., 1966; Andrawes, et al., 1967). Results of in vitro studies have shown that aldicarb was completely metabolized rapidly through oxidative and/or hydrolytic mechanisms yielding the same profile of metabolites noted in Figure 1. Further studies of the metabolic fate of aldicarb sulfoxide and aldicarb sulfone have confirmed the metabolic pattern of these components as shown in Figure 1 (Andrawes et al., 1967; Andrawes, 1977). Approximately one-half of the administered dose of aldicarb sulfoxide was rapidly degraded through cleavage of the ester carbonyl and eliminated as hydrolytic products in the urine. Aldicarb sulfone was identified as a very minor metabolite following administration of aldicarb sulfoxide. In contrast to the rapid cleavage of the carbamate ester and urinary elimination following aldicarb sulfoxide treatment, administration of aldicarb sulfone to rats resulted in approximately 80% of the urinary metabolites as the unchanged aldicarb sulfone. Conjugation mechanisms for elimination of aldicarb from the body appeared to be minor reactions possibly because of the polar nature of the metabolites themselves. Studies using enzyme or acid hydrolysis of polar urinary metabolites have resulted in the characterization of the aldicarb, alcohol and aldehyde derivatives shown in Figure 1a. These represent a very small portion of the degradation mechanism noted for aldicarb. In dogs, the identification of a similar urinary metabolic pattern was reported (Sullivan, 1968a). The major urinary metabolites were aldicarb sulfoxide and sulfoxide oxime. Further characterizations of the sulfone, sulfone oxime and nitrile were reported. The metabolic fate of aldicarb in dairy animals was reported to be the same as those metabolite species detected in urine with the principal products being aldicarb sulfoxide, sulfoxide oxime and sulfoxide nitrile (Dorough and Ivie, 1968). Characterization of aldicarb metabolites in milk of cows fed for 14 consecutive days showed a slightly different metabolic profile than animals receiving an acute single administration of aldicarb. In animals treated for 14 days, the major milk metabolic component was found to be aldicarb sulfone and its corresponding nitrile derivative. Small quantities of aldicarb sulfoxide and larger quantities of the sulfoxide oxime suggested that an increased level of oxidative and/or hydrolytic metabolism would be expected following subacute, continuous dietary administration as opposed to that pattern noted with the single acute exposure (Dorough, et al., 1970). The metabolic fate of aldicarb in hens (Hicks, et al., 1972), insects (Metcalf, et al., 1966; Bull, et al., 1967) and plants (Metcalf, et al., 1966) appears to follow the same pattern as noted in mammalian species with oxidation of the sulfur atom predominating, yielding primarily aldicarb sulfoxide and to a lesser extent, aldicarb sulfone which are further degraded to the hydrolytic oximes and corresponding nitriles. In rats, aldicarb nitrile was rapidly degraded to the sulfoxide nitrile. This was identified as a major component in urine with the sulfone nitrile and further degradation products also noted (Sullivan and Carpenter, 1974). Effects on Enzymes and Other Biochemical Parameters As noted with other N-methylcarbamate esters aldicarb in an inhibitor of cholinesterase activity (Chin & Sullivan, 1968). Aldicarb is a readily reversible cholinesterase inhibitor and in vitro studies have shown that cholinesterase inhibition, induced by aldicarb and its oxidative metabolites (aldicarb sulfoxide and aldicarb sulfone) can be readily reversed by simple dilution. Aldicarb sulfoxide in a more active cholinesterase agent than aldicarb or the corresponding sulfone. Aldicarb sulfoxide was 47 and 25 times more effective in inhibiting cholinesterase than aldicarb and aldicarb sulfone respectively with an insect-enzyme preparation and 23 and 60 times more effective respectively when using a red blood cell preparation obtained from cows (Bull, et al., 1967; Metcalf, et al., 1966). Aldicarb sulfoxide and aldicarb sulfone were administered to rats in the diet for periods of time varying from 1 to 56 days after which the animals were sacrificed for plasma, erythrocyte and brain cholinesterase determinations. Groups of 5 male and 5 female rats were administered aldicarb sulfoxide in the diet at dosage levels of 0, 0.3 and 1.0 mg/kg/day and aldicarb sulfone was administered at dietary levels of 0, 2.4 and 16.2 mg/kg/day. Animals were sacrificed at 1, 3, 7, 14, 28 and 56 days for cholinesterase analyses. Plasma and erythrocyte cholinesterase activity was measured at the first three time intervals. At the last three time intervals, plasma, erythrocyte and brain cholinesterase activity was examined. Over the course of the of the growth was recorded routinely. There was no mortality and growth, as evidenced by body weight, was depressed at the highest dose levels with both the sulfoxide and sulfone. Rats administered aldicarb sulfoxide at 1.0 mg/kg body weight had a slight but significant cholinesterase depression during the study. There were no effects noted at 0.3 mg/kg. Cholinesterase depression was marked with the aldicarb sulfone consistently throughout the study at the highest dose level, 16.2 mg/kg. Although there were no clinical signs of poisoning and no deaths during the 56 days of treatment, plasma erythrocyte and brain cholinesterase were consistently depressed below control values (Weil and Cox, 1975).FIGURE 1a;V079PR02.BMP TOXICOLOGICAL STUDIES Acute Toxicity The acute toxicity of aldicarb and its metabolites has been studied in a variety of mammalian species. A summary of acute toxicity data for aldicarb in shown in Table 1 and for the metabolites, in Table 2. Antidotal studies Following acute oral administration to rats, aldicarb has been shown to induce a strong muscarinic action at excretory, bronchial and cardiac nerve sites. A nicotinic effect was also shown to occur at myoneural junctions. The parasympathetic signs of poisoning were readily reduced following atropine administration (Johnson and Sullivan, 1968a). Administration of combinations of atropine and 2-PAM alone, or in combination, showed that while atropine was a more effective antidote, 2-PAM was also active (Johnson and Sullivan, 1968b). While it has been shown that aldicarb elicits a strong muscarinic action as well as nicotinic action at myoneural sites, the control of signs of poisoning from both mechanisms appears to be somewhat difficult to achieve. Atropine has been shown to be an effective antidote to block the nicotinic effects but decamethonium, commonly used to block the nicotinic effects, has been shown to be somewhat ineffective. Additional studies to influence the nicotinic action by such drugs as tubocurare also failed to completely eliminate nicotinic activity. Further studies confirmed the therapeutic effects of a variety of oximes (P2S and obidoxime) in reducing the acute toxic signs of poisoning associated with aldicarb (Natoff and Reiff, 1973). Signs of Poisoning Aldicarb is an extremely toxic chemical by any route of administration. Severe anticholinesterase signs of poisoning appear almost immediately following poisoning. These signs of poisoning, standard parasympathomimetic responses seen with other carbamates and anti-cholinesterase organophosphate esters, include: tremors, salivation, lacrimation, urination, diarrhea, convulsions, laboured respiration, myosis, piloerection, ataxia, pinpoint pupils and death. Table 1. Acute Toxicity - Aldicarb Species Sex Route Vehicle1 LD50 Reference (mg/kg) Rat M Oral Corn oil 0.93 Striegel and Carpenter, 1962 M Oral Corn oil 0.67-1.23 Carpenter, 1963; Nycum and Carpenter, 1968b F Oral Corn oil 0.62-1.07 Carpenter, 1963; Nycum and Carpenter, 1968b F Oral Glycerol formal: 1.0 WHO, 1966 ethanol (9:1) F ip Corn oil 0.71 Carpenter, 1963 M&F ip Corn oil 0.44 Carpenter, 1963 M ip PEG 0.37-0.44 Weil and Carpenter, 1970a M ip Ethanol 0.57 Johnson and Carpenter, 1966b M iv Water 0.47 Weil and Carpenter, 1970a F Dermal DMP 3.2-7.0 (24 hr) WHO, 1966 M Dermal Dry 3952 (4 hr) Weil and Carpenter, 1970b Dermal Water 38.1-44.9 (24 hr) Weil and Carpenter, 1968a Mouse M Oral Corn oil 0.382 Weil and Carpenter, 1972b M Oral Corn oil 0.50 Weil and Carpenter, 1972c F Oral Cotton seed oil 1.5 Dorough, 1970 F ip Cotton seed oil 0.3 Dorough, 1970 Rabbit M Dermal PEG 5.0 Striegel and Carpenter, 1962 M&F Dermal Water 32-502 West and Carpenter, 1966b; Carpenter and Smyth 1966; M Dermal Dry 141 - >200 Weil and Carpenter, 1968a Chicken M Oral 9 West and Carpenter, 1965, 1 PEG = polyethylene glycol DMP = dimethyl phthalate 2 Wettable powder formulation Table 2. Acute Toxicity - Metabolites LD50 Chemical Species Route1 (mg/kg) Reference Aldicarb Rat Oral 0.84 West and Carpenter, 1966b Aldicarb nitrile Rat Oral 570 West and Carpenter, 1966b Aldicarb sulfoxide Rat (M) Oral (C.O.) 0.49-1.13 Weil and Carpenter, 1970a; Nycum and Carpenter, 1968b Aldicarb sulfone Rat (M) Oral (C.O.) 20-25 Weil and Carpenter, 1970a; Nycum and Carpenter, 1968b Aldicarb sulfoxide Rat (M) ip (Water) 0.47 Weil and Carpenter, 1970a Aldicarb sulfone Rat (M) ip (PEG) 21.2 Weil and Carpenter, 1970a Aldicarb sulfoxide Rat (M) iv (Water) 0.47 Weil and Carpenter, 1970a Aldicarb sulfone Rat (M) iv (Water) 14.9 Weil and Carpenter, 1970a Aldicarb sulfoxide Rabbit Dermal (Water) >20 mg/kg West and Carpenter, 1969b Aldicarb suifone Rabbit Dermal (Water) >20 mg/kg West and Carpenter, 1969b 2-Methy]-2-(methyl sulfinyl) propanol-1 Rat Oral 11,000 mg/kg Weil and Carpenter, 1969d Hydroxymethyl aldicarb Rat Oral 42.9 Carpenter, 1969 Aldicarb sulfoxide oxime Rat (M) Oral 8060 Nycum and Carpenter, 1968a Aldicarb sulfone oxime Rat (M) Oral 1590 Nycum and Carpenter, 1968a Aldicarb sulfoxide nitrile Rat (M) Oral 4000 Nycum and Carpenter, 1968a Aldicarb sulfone nitrile Rat (M) Oral 350 Nycum and Carpenter, 1968a 1 C.O. = corn oil PEG = polyethylene glycol Special Studies on Acute Toxicity Administration of aldicarb to the conjunctival sac of rabbits did not produce ocular irritation or corneal damage. Ocular irritation studies were performed at doses that were lethal without indication of ocular damage (Striegel and Carpenter, 1962). There was no evidence of dermal irritation when aldicarb was applied to the shaved, abraded backs of rabbits (Striegel and Carpenter, 1962). Penetration of aldicarb through the skin was observed to be rapid, especially when the skin was moistened, simulating perspiration. When dry, aldicarb did not penetrate the skin as rapidly as evidenced by a substantial increase in toxicity when using a wet versus the dry preparation (Carpenter and Smyth, 1965; Weil and Carpenter, 1969a). There was no indication of a sensitization reaction induced by aldicarb. Male guinea pigs were administered aldicarb by multiple subdermal applications (0.7 mg/kg body-weight) and re-administered aldicarb three weeks later by a similar interderal administration. There was no suggestion of sensitization in any of the animals tested (Pozzani and Carpenter, 1968a). Aldicarb is extremely toxic when administered by the inhalation route (Striegel and Carpenter, 1962). Exposure of rats, mice and guinea pigs to a dust formulation at a concentration of 200 mg/m3 for five minutes resulted in the death of all animals. Exposure of female rats to a dust formulation at concentrations of 6.7 mg/m3 for 15 minutes was not lethal to any of the animals tested. When exposed for 30 minutes, 5 of 6 animals died. However, aldicarb is not volatile and studies on the exposure of rats to aldicarb vapours emanating from technical or granular formulations for 8 hours resulted in no mortality (Pozzani and Carpenter, 1968b; Carpenter, 1963). Groups of male rabbits (5 rabbits/group) were administered aldicarb dermally for 15 days with a daily exposure of 6 hours per day. Four groups of rabbits with abraded skin were administered aldicarb at dose levels of 0, 5, 10 and 20 mg/kg/day. Water was added periodically during the exposure time to the dressing containing the aldicarb treatment, simulating a condition of excess perspiration. One additional group was administered 20 mg/kg per day to intact, unbraded skin with no water added to the dressing. The animals were administered aldicarb 5 days per week with a 2-day interval of non-treatment. One 3-day period of no treatment was reported, during the third week of the study. Those animals treated with aldicarb under a dry condition with unabraded skin showed normal weight gains and no apparent effects as a result of the treatment. During the interim where dermal treatment was not applied, recovery of growth was extremely rapid, attesting to the transient toxic nature of dermally-applied aldicarb. The administration of aldicarb under conditions where the dressing was wet and the skin abraded resulted in reduced body-weight reflecting rapid absorption and an adverse effect at a dermal dosage of 5 mg/kg. Plasma cholinesterase activity was inhibited at the two highest dose levels. There were no adverse effects on haematology or clinical chemical parameters or on gross weights of liver and kidney observed at the conclusion of the study. Microscopic examination of several major tissues showed no pathological events to attributable to aldicarb (Carpenter and Smyth, 1966). In a similar study, application of 10 mg/kg aldicarb and above when administered to abraded rat skin in the presence of water, again severely depressed body-weight. The 5 mg/kg dosage also depressed body weight, but to a lesser extent. No deaths were noted over the 14 day interval. When administered dry, aldicarb at 20 mg/kg (the highest dose level) was without effect (Weil and Carpenter, 1968a). Special Study on Behaviour The effects of acute administration of aldicarb and aldicarb sulfoxide on avoidance behaviour in rats, was compared to a variety of other carbamate esters. Rats were trained and evaluated for their ability to avoid electrical shock in standard avoidance behaviour tests. Aldicarb and aldicarb sulfoxide were administered by intraperitoneal injection and the rats were evaluated for their ability to avoid shocks over a 6-hour period following administration. The effects of aldicarb and its sulfoxide were compared with 3 other carbamate esters. The lowest behaviourally effective dose was found to be 0.266 mg/kg body weight which, when compared to the acute IP LD50 value, was noted to have a smaller ratio of behaviour effects to acute LD50 than any of the other carbamates tested. These data suggest that the level of aldicarb needed to produce measurable avoidance in greater (closer to a fatal dose and less likely to be achieved at the suggested use level) than the chemicals to which it was compared. Additionally, the activity over the 6 hour period was seen to rapidly decline again attesting to the transient nature of the cholinesterase inhibition (Johnson and Carpenter, 1966b). Special Studies on Potentiation Aldicarb was administered orally to male rats alone and in combination with a series of 8 organophosphate esters or 1 carbamate ester, all anticholinesterase agents, to examine the potential interactive or additive effect. Results of the study, using proportions of the acute lethal dose of each material alone and in combination with aldicarb, showed a simple additive effect with all materials tested. Aldicarb was not found to potentiate the acute oral toxicity of other anticholinesterase agents (West and Carpenter, 1966a). Further studies were reported on the potential interaction of aldicarb with alpha-naphthol, aldicarb sulfoxide with aldicarb sulfone and aldicarb sulfone with parathion administered orally and aldicarb with alpha-naphthol or with carbaryl administered by the interperitoneal route. In no case were any interactions greater than the predicted additive effects (Weil and Carpenter, 1970a). Special Studies on Reproduction Groups of rats (8 male and 16 female rats per group) were administered aldicarb in the diet at concentrations of 0, 0.05 and 0.1 mg/kg body weight in their diet for approximately 90 days and mated to initiate a 3 generation reproduction study. The offspring from the first generation were mated to produce the second generation in the one litter per generation reproduction study. In addition to the reproduction indices (fertility, gestation, viability and lactation) the F3 generation was maintained for an additional period and tissues from these animals were histologically examined at either weaning or at 90 days of age. In all animal groups, the reproduction indices from the aldicarb-tested animals were statistically similar to the mean values of the control groups. Body weights of both male and female pups at weaning were statistically similar to control values as were results of gross and microscopic examinations of tissues and organs in the F3 weanling and 90-old animals. In all three generations, with all criteria examined, there were no effects of aldicarb on reproduction at a dosage level of 0.1 mg/kg body weight (Weil and Carpenter, 1964). Groups of rats (10 male and 20 female per group) were administered aldicarb in the diet at dosage levels of 0, 0.2, 0.3 and 0.7 mg/kg body weight for 100 days and mated to initiate an additional 3 generation (1 litter per generation) reproduction study. A larger group was used for the F2 generation (15 male and 25 female rate) as male pups of this generation were maintained on aldicarb-diets for 148 days and subjected to a (modified) dominant lethal (mutagenesis) bioassay where they were mated with groups of untreated virgin females for a period of 10 weeks. Each female in the group was mated with 2 treated males and allowed to maintain pregnancy until day 12 when they were sacrificed and examined. There was some mortality over the course of the study which was associated with lung infection and not as a result of aldicarb in the diet. A significant difference from control values was noted in the second generation pups with respect to body weight at the highest dose level fed. At this dose level, body weights of both male and female were lower than the control values. Overall, there were no effects on any of the reproduction indices (fertility, gestation, viability or lactation). Gross and microscopic examinations of the parents and pups of the high level and control groups showed no effects attributable to aldicarb. The dietary dominant lethal mutagenesis bioassay showed no statistical differences between the aldicarb-treated rats and controls with respect to early or late fetal death or any other parameter examined (Weil and Carpenter, 1974a). Special Studies on Teratogenicity Using a test protocol where both the reproductive and teratologic potential of aldicarb was evaluated, groups of pregnant rats were administered aldicarb in the diet at dosage levels of 0, 0.04, 0.2 and 1.0 mg/kg body weight. Five or six females from each of the dietary groups were assigned to one of three treatment groups: (1) aldicarb administered in the diet throughout pregnancy or until pups were weaned; (2) aldicarb administered in the diet from day 0 to day 7 of gestation; (3) aldicarb administered in the diet from day 5 to day 15 of gestation. Five or six females from each group were sacrificed and examined on day 20 of pregnancy and a similar number of females were allowed to bear, nurse and wean the pups. Qualitative data were recorded with respect to fertility, gestation, viability and lactation, the indices of a standard reproduction study. There were neither gross manifestations of teratogenesis in any of the pups carried by females administered aldicarb at dosage levels of up to 1 mg/kg body weight nor was there apparent interference with the reproductive process by any of the dosing regimens used in this study. The administration of aldicarb at dosage levels up to and including 1.0 mg/kg body weight had no apparent effect on the growth of pregnant females during the course of the study. There were no anomalies observed in the animals sacrificed just prior to term nor in the animals undergoing natural birth and allowed to be maintained until weaning. Aldicarb, at levels of 1 mg/kg body weight, administered to rats during sensitive stages of gestation, did not induce a teratogenic effect (Weil and Carpenter, 1966a). Special Studies for Mutagenesis Rat-Dominant Lethal Study Groups of virgin female rats (15 rats per group) were mated with male rats that had been administered aldicarb (in the diet at dose levels of 0, 0.2, 0.3 or 0.7 mg/kg body weight) prenatally through gestation, through weaning and thereafter for up to 148 days of age. The males, part of a 3-generation reproduction study were mated with virgin untreated females at weekly intervals for a total of 10 consecutive weeks. At the initiation of the dominant lethal study, the males were fed control diets (having been exposed to aldicarb prenatally and for 148 days prior to mating). Each female was mated with 2 treated males and allowed to develop for 12 days of gestation. At 12 days of gestation each female was sacrificed and examined for pregnancy, implantation sites and for viable fetuses. Data from all of the ten mating periods, at all of the dosage levels, were compared to control values. There were no significant differences with respect to any of the parameters of mating, pregnancy and fetal deaths at any dose levels in the study. In this slightly modified dominant lethal mutagenic study, aldicarb did not induce adverse or mutagenic effects in males as evidenced by sperm abnormalities (Weil and Carpenter, 1974a). Special Study on Carcinogenicity Mice Groups of C3H/HeJ male mice were administered aldicarb, dissolved in acetone, dermally 3 times a week for 28 months. Aldicarb was administered by applying a brush full of an acetone solution to the shaved back of the mice. Aldicarb was administered for the first two weeks at the rate of 3 times a week using a 0.25% solution in acetone. After two weeks this was reduced to a twice-weekly application. This dosing regimen was maintained for two months and further reduced thereafter to a concentration of 0.125% which was maintained for the remainder of the study. While there was some aldicarb-induced mortality noted over the course of the study, this mortality was not substantially different from that noted with control applications. There were no substantial differences with respect to the incidence or onset of tumors. Two growths, a hemangioma and a thymoma, were noted in the animals administered aldicarb. Neither of these internal growths was accompanied by cutaneous papillomas or carcinomas and were considered to be spontaneous growths unrelated to treatment. Aldicarb, administered dermally to this sensitive species, did not induce any incidence of malignancy (Weil and Carpenter, 1966b). Special Studies on Delayed Neurotoxicity Groups of 6 adult chickens were administered aldicarb as a single oral dose of 4.5 mg/kg body weight or as daily oral doses of 0, 2.25 or 4.5 mg/kg body weight for 30 days. A positive control, treated with 100 mg of TOCP, was used to produce typical delayed neurotoxic signs of poisoning. While there was some weight loss, which was correlated with the dose of aldicarb administered, the only neurological effects attributable to aldicarb were acute signs of poisoning noted in the first two or three days of treatment. Neither ataxia nor hind limb paralysis were noted over the course of the study. Aldicarb does not induce a delayed neurotoxic syndrome similar to that induced by certain organophosphate esters (Johnson and Carpenter, 1966a). Short Term Studies Rat-Aldicarb Groups of rats (5 male and 5 female rats per group, 6-week old rats) were fed aldicarb in the diet for 7 days at dosage levels of 0, 4, 8 and 16 mg/kg body weight. Animals were observed for acute signs of toxicity and were weighed three times during the course of the week's study. Mortality was noted predominantly at the highest dose level, at which all males and 2 of 5 females died. One of 5 males also died at the 8 mg/kg dose level. There were substantial body weight changes noted at all dose levels. In males, kidney weight was significantly reduced at 8 mg/kg and liver weight was depressed at the 4 and 8 mg/kg dose levels. In females, both liver and kidney weight was significantly depressed at all dose levels in the study (Weil and Carpenter, 1970c). Groups of young rats (5 male and 5 female rats per group, 7 weeks of age) were fed aldicarb in the diet at dose levels of 0, 0.8, 1.6 and 3.2 mg/kg body weight for 7 days. Animals were weighed three times during the week and observed for clinical signs of toxicity. At the conclusion of the study, animals were sacrificed and brain, red blood cell and plasma cholinesterase activity was measured. Growth was depressed during the one week study at dosage levels of 1.6 mg/kg and above. There was no apparent mortality in the study attributable to aldicarb. Slight effects were noted on both liver and kidney weight. In males, liver weight and liver to body weight ratios were depressed in all treatment groups. In females, liver weight was affected only at the highest dose level, but the liver to body weight ratio was reduced at 1.6 mg/kg and above. Kidney weight was reduced in males at all dose levels and in females only at the highest dose level. Cholinesterase depression, measured on day after the conclusion of feeding, was normal at the highest dose level tested with the exception of plasma cholinesterase which was slightly reduced at the highest level (Weil and Carpenter, 1969b). Groups of rats (5 male and 5 female rats per group) were fed diets containing aldicarb, at dosage levels of 0, 0.4, 0.8, 1.6 and 3.2 mg/kg body weight, or aldicarb sulfoxide, at dosage levels of 0, 0.4 and 0.8 mg/kg body weight, or aldicarb sulfone, at dosage levels of 0, 0.4, 1.0, 2.5, 5.0 and 20.0 mg/kg body weight, for 7 days. With aldicarb (as with its two major carbamate metabolites) there was a significant growth (body weight) depression at the highest dose level. There were no effects noted with respect to gross liver or kidney weight at the conclusion of the study. Erythrocyte and plasma cholinesterase activity was depressed by aldicarb at the highest dose level; with aldicarb sulfoxide, erythrocyte-cholinesterase activity was also depressed at the highest dose level; with aldicarb sulfone, plasma and erythrocyte cholinesterase activity was also depressed at the two highest dose levels, while brain cholinesterase was inhibited, in both males and females only at the highest dose level (20 mg/kg). The erythrocyte cholinesterase appeared to be the most sensitive parameter with all three materials tested. A no-effect level based on erythrocyte-cholinesterase depression or decreased body weight over the 7-day interval was suggested to be: aldicarb - 0.8 mg/kg; aldicarb sulfoxide - 0.4 mg/kg; and aldicarb sulfone - 2.5 mg/kg (Nycum and Carpenter, 1968b). Aldicarb/Aldicarb Metabolites Groups of rats (5 male and 5 female rats per group, 7 weeks of age) were fed dietary levels of aldicarb (0.3 mg/kg body weight), aldicarb sulfoxide (0.4, 0.8 and 1.6 mg/kg body weight), aldicarb sulfone (0.6, 5.0 and 20 mg/kg body weight), a 1:1 mixture of aldicarb sulfoxide and aldicarb sulfone (1.2 mg/kg body weight) or a control diet. Animals were weighed three times during the course of the study and were examined daily for clinical signs of toxic reaction. At the end of the seven days of feeding, animals were placed on control diets for one day after which they were sacrificed for cholinesterase determination and for examination for liver and kidney toxicity. A second one-week feeding trial was performed to compare the data with other strains of rats. Aldicarb sulfoxide was fed to groups of 5 male rats at dosage levels of 0, 0.4, 0.8 or 1.6 mg/kg body weight. Aldicarb sulfone was also fed to male rats at dosage levels of 0, 5.0 or 20 mg/kg body weight. In the initial study, aldicarb did not affect growth in males but did reduce female growth substantially (during the course of the one week study. Aldicarb sulfoxide substantially reduced growth at 0.8 mg/kg and above in males and females. Aldicarb sulfone reduced growth at 5 mg/kg and above in males and at 0.6 mg/kg and above (all dose levels in females). The combination of the sulfoxide and sulfone reduced growth only in females and only at the least measurement interval. In males, aldicarb did not appear to affect liver or kidney weight while in females there was a slight but significant decrease in liver weight at the conclusion of the study. Aldicarb sulfoxide reduced both liver and kidney weight in males and females at the highest dose level. Aldicarb sulfone in both males and females reduced kidney and liver weight over the course of the study at the highest dose level tested. The 1:1 combination of the sulfoxide and sulfone in males and females had no adverse affect on liver and kidney. As might be expected with the protocol followed in the study, cholinesterase depression was not observed in either plasma, erythrocyte or brain at the conclusion of the study. The second trial using both the same and a different strain of rats was performed in an effort to explain a slight but non-significant inhibition of erythrocyte cholinesterase activity measured in the initial study. Over the course of this study, there were no effects noted on erythrocyte cholinesterase activity. With aldicarb sulfoxide, growth was slightly reduced at the two highest dose levels (0.8 and 1.6 mg/kg) in both strains and at 5 mg/kg body weight and above with aldicarb sulfone. Liver and kidney weight were unaffected by aldicarb sulfoxide but were slightly reduced with aldicarb sulfone at the highest dose level (Weil and Carpenter, 1970d). Aldicarb Sulfoxide Groups of rats (15 male and 15 female rats/group) were fed aldicarb sulfoxide in the diet at dose levels of 0, 0.125, 0.25, 0.5 and 1.0 mg/kg body weight for 6 months. Animals were sacrificed at 3 months and at the conclusion of the study for cholinesterase determinations and for gross and microscopic examination of liver and kidney. There was no mortality noted during the course of the study, although growth, especially in males, at 0.25 mg/kg and above was reduced. In females growth was depressed only at the highest dose level. Cholinesterase activity was substantially reduced at the three highest dose levels, especially in plasma and erythrocytes of males. In females, erythrocyte and plasma cholinesterase depression was noted at the two highest dose levels. Gross examination of liver and kidney revealed no abnormalities attributable to aldicarb. In an attempt to resolve the question of cholinesterase depression and rapid recovery, groups of rats (5 male and 5 female rats per group) were administered aldicarb sulfoxide for one week or one week plus one day of control diets at a dietary level of 1 mg/kg body weight. When the study was concluded (within one week), animals were sacrificed at 0 and 24 hours after the dietary feeding interval (the 24 hour animals were fed control diets). Cholinesterase depression was noted at the 0 hour sacrifice in erythrocyte and plasma preparations. Administration of a control diet for one day (24 hour sacrifice) completely reversed the cholinesterase depression noted when animals were sacrificed without any recovery interval. Groups of 5 male and 5 female rats were also fed aldicarb sulfoxide in the diet at dosage levels of 0, 0.0625, 0.125, 0.25, 0.50 and 1.0 mg/kg body weight for 3 and 6 months after which some of the animals were sacrificed immediately and others were placed on a control diet for 24 hours prior to sacrifice and cholinesterase analyses. Cholinesterase activity in the brain was unaffected by aldicarb sulfoxide. Plasma and erythrocyte cholinesterase was substantially reduced at the 0 hour sacrifice in both males and females. Males were slightly more sensitive with depression being noted at 0.25 mg/kg and above, while with females depression was noted at 0.5 mg/kg and above. There was no cholinesterase depression noted in any of the animals treated for either 3 months or 6 months when the animals were allowed to recover from cholinesterase depression for a one-day recovery interval. Depression of cholinesterase activity, of as much as 89% of control values, was completely reversed within one day on a control diet. A no-effect level of 0.125 mg/kg body weight was observed (Weil and Carpenter, 1968b). Aldicarb Sulfone In a series of studies similar to those reported with aldicarb sulfoxide, groups of rats (15 male and 15 female rats per group) were administered aldicarb sulfone in the diet at dosage levels of 0, 0.2, 0.6, 1.8, 5.4 and 15.2 mg/kg body weight for 6 months. Animals were sacrificed at 3 and 6 months for examination of liver and kidney abnormalities and for evaluation of cholinesterase activity. Cholinesterase determinations were made at the end of 3 and 6 month intervals with rats fed continuously until sacrifice for analysis. Additional rat studies using 5 male and 5 female rats per group were performed for one week or for 3 months on diets containing aldicarb sulfone at dose levels comparable to the levels reported above. In these studies, animals were either sacrificed at the end of the feeding regimen or were allowed to consume a control diet for 24 hours prior to sacrifice and determination of cholinesterase activity. There was no mortality over the course of the study. A transient but significant growth depression was noted at the highest level in the 6-month feeding study. There were no effects noted with respect to diet consumption or on gross and microscopic examinations of liver and kidney. Plasma, erythrocyte and brain cholinesterase were significantly depressed at 5.4 mg/kg dose level and above. Erythrocyte cholinesterase depression was also noted at 1.8 mg/kg. There was no cholinesterase depression noted at 0.6 mg/kg in any of the tissues examined. In the study to evaluate recovery of cholinesterase activity, aldicarb sulfone was fed for 7 days at a dosage of 5.4 mg/kg body weight. At the conclusion of dosing, significant depression of cholinesterase (plasma, erythrocyte and brain) was noted. When animals were allowed to equilibrate for 1 day on control diets, all depressed cholinesterase values returned to normal. A similar study was run for 3 months and 3 months and 1 day at dietary levels of 0, 0.2, 0.6, 1.2, 1.8, 5.4 and 16.2 mg/kg. The data showed that extensive cholinesterase depression, noted at the conclusion of the feeding trial was completely recovered within one day of feeding control diets. In this 3-month trial there was a substantial depression of plasma cholinesterase activity at 1.8 mg/kg erythrocyte activity at 5.4 mg/kg and brain activity at 16.2 mg/kg. At 1.2 mg/kg cholinesterase was not substantially depressed (Weil and Carpenter, 1968c). Aldicarb Oxime Groups of rats (the number of males and females per group was not stated) were administered aldicarb oxime in the diet at dose levels of 0, 31.25, 62.5, 125, 250, 500 and 1000 mg/kg body weight for 7 days. There was no mortality over the course of the study. Growth was slightly reduced at the initiation of the study at dose levels of 125 mg/kg and above, but at the end of one week only the two highest dose levels appeared to show a retardation in growth. Gross changes were noted in both liver and kidney at the two highest dose levels in both males and females. A dietary dosage level without substantial effect appeared to range between 62.5 and 250 mg/kg body weight over the course of this short term trial (Weil and Carpenter, 1974b). 2-Methyl-2-(methylsulfinyl)propanol-1 Groups of rats (5 male and 5 female rats per group, 6 weeks of age) were fed the hydrolytic metabolite of aldicarb (2-methyl-2-(methylsulfinyl)propanol-1) in the diet for 7 days at dosage levels of 0, 500 and 1000 mg/kg body weight. Growth was depressed at both dosage levels fed to males but only at the highest dosage level in females. In females, while growth was depressed within one day of treatment, the animals appeared to recover during the rest of the week. There was no apparent effect on major organs, although, in females at the high dosage level, kidney weight was slightly depressed. Cholinesterase was not measured (Weil and Carpenter, 1969c). Mice Aldicarb/Aldicarb Metabolites Groups of mice (5 males and 5 females per group) were fed aldicarb in the diet at dosage levels of 0, 0.1, 0.3, 0.6 and 1.2 mg/kg body weight for 7 days. Mortality was noted in both males and females at the high dose level. Growth was not affected over the course of the study. Liver and kidney weight were also unaffected. In this one week study, an actual dosage level of aldicarb, based on food consumption data varying from 0.65 mg/kg body weight for females to 0.75 mg/kg body weight for males was without substantial acute effects (Weil and Carpenter, 1970f). Groups of mice (3 male and 5 female mice per group) were fed a mixture of aldicarb and aldicarb sulfone (1:1) in the diet at dosage levels of 0, 2, 6, 18, and 36 mg/kg body weight for 7 days. Growth was measured three times during the course of the study, and animals were observed daily for any signs of abnormality. No mortality was noted at any dosage level. Severe cholinergic signs of poisoning were observed at the high dose level in males. Depression of growth, observed at the two highest dose levels, was statistically significant in both males and females. Reduced body weights were, however, observed in all animals on the study at all dosage levels. Kidney weight was depressed at the highest dose level within one week in both males and females. No effects on the kidney were noted at dose levels of 18 mg/kg and below. Liver weight was reduced substantially at dosage levels of 6 mg/kg and above in both males and females. Significant liver reduction was observed at the two highest dose levels in males and at the highest dose level in females (Weil and Carpenter, 1970e). Dog-Aldicarb Groups of beagle dogs (2 male and 2 female dogs per group) were fed dietary levels of aldicarb at dosage levels of 0, 0.2, 0.3 and 0.7 mg/kg body weight for 7 days. Dogs were weighed three times during the week and observed daily for clinical signs of poisoning. At the end of 7 days of feeding, 24 hours after being placed on control diets, the dogs were sacrificed for cholinesterase examinations and for gross examinations of kidney and liver. There was no mortality over the course of the one-week study. Plasma, erythrocyte and brain cholinesterase activity, measured one day after conclusion of the dietary treatment, was normal. Gross liver and kidney weight and organ-to-body weight ratios were unaffected by aldicarb in the diet (Weil and Carpenter, 1973). Groups of beagle dogs (4 male and 4 female dogs per group) were fed aldicarb in the diet for five days per week at dosage levels of 0, 0.2, 0.3 and 0.7 mg/kg body weight for 99-100 days. Clinical chemistry (including plasma and erythrocyte cholinesterase) and haematology parameters were examined prior to the initiation of feeding and at two intervals during the course of the study. At the conclusion of the study, a final clinical chemistry and haematology evaluation and gross and microscopic examinations of tissues and organs were performed. At the conclusion of the study, brain cholinesterase activity was also measured. There was no mortality over the course of the study. Growth was comparable within all dosage groups. At the conclusion of the study, organ weight and organ-to-body weight ratios were slightly affected only at the highest level of aldicarb. A slightly decreased testes weight was observed in all treated groups with a significant effect noted only at the highest level. A slight increase in adrenal weight was also noted at this level. There were no effects in females on any of the tissues and organs examined. Microscopic analysis did not suggest any abnormalities including tissues where gross changes had been seen to occur. Cholinesterase values, as well as other clinical chemistry and haematology parameters were unaffected by the presence of aldicarb in the diet. As the animals had been removed from aldicarb exposure for 24 to 48 hours prior to cholinesterase analyses, and considering the reversibility of inhibition, this parameter was not useful in this study in defining an effect of aldicarb. A no-effect level in the study is 0.3 mg/kg body weight (Weil and Carpenter, 1974c). Aldicarb Metabolites Groups of dogs (3 male and 3 female dogs/group) were fed aldicarb sulfoxide in the diet at dosage levels of 0, 0.0625, 0.125, 0.25 and 0.5 mg/kg body weight five days per week for three months. There was no mortality over the course of the study. Slight body weight changes were noted in many of the dogs at the highest dose level within the first week of treatment and thereafter the body weight changes were similar to, but lower than, control values. No effects on haematologic and blood chemistry were observed. Cholinesterase depression measured 24-48 hours after the final exposure was not observed in plasma, erythrocytes or brain of any of the animals at the conclusion of the study. Gross and microscopic examination of tissues and organs did not show any adverse effect attributable to the presence of aldicarb. A no-effect level based on somatic effects is 0.25 mg/kg body weight (Weil and Carpenter 1968b). Groups of dogs (3 male and 3 female dogs per group) were fed aldicarb sulfone in the diet at dosage levels of 0, 0.2, 0.6, 1.8 and 5.4 mg/kg five days per week for 90 days. Prior to the study and at 1, 2 and 3-month intervals, plasma and erythrocyte cholinesterase were examined. In addition, at the beginning and end of the study, blood chemistry and haematologic values were examined. At the conclusion of the study, gross and microscopic examination of a variety of tissues and organs was performed. There was no mortality over the course of the study. Slight body weight depression was noted at the highest dose level, although the body weight was not statistically lower than control levels. There were no effects noted with respect to biochemical and haematologic parameters and gross and microscopic examination of tissues and organs revealed no effects attributable to the presence of aldicarb sulfone in the diet. Cholinesterase depression was not noted over the course of the study. Based upon available information, a no-effect level of 5.4 mg/kg for dogs was observed (Weil and Carpenter, 1968). In all of the three previous dog studies, cholinesterase activity is not a significant parameter to be considered in a toxicological evaluation because the animals were not administered aldicarb continuously, but were removed from dietary treatment for 1-2 days before the enzyme activity was measured. Long-Term Studies Rat Groups of rats (20 male and 20 female rats per group) were fed aldicarb in the diet for 2 years at dosage levels of 0, 0.005, 0.025, 0.05 and 0.1 mg/kg body weight. Additional groups of 16 of each sex were maintained for serial sacrifices at 6 and 12 months. There was no mortality over the course of the study attributable to the presence of aldicarb in the diet. Growth was normal at all dosage levels, as was consumption of food, and behavioural characteristics. Results of gross examination of liver and kidney weight at 6 months and at one year did not differ from control values. Haematologic values, including cholinesterase analyses, were normal. (Haematologic data included red blood cell or haematocrit determinations in the highest dosage level and control groups.) Blood and brain cholinesterase activity, measured at 6 and 12 months, were normal. Microscopic examination of tissues and organs for histopathologic occurrences and neoplasms showed the incidence of lesions to be similar in aldicarb-treated and in control groups. An apparent no-effect level in the study is 0.1 mg/kg body weight (2 ppm) in the diet (Weil and Carpenter, 1965). Groups of rats (20 male and 20 female rats per group) were fed aldicarb in the diet at dosage levels of 0 and 0.3 mg/kg body weight. In addition, groups of rats were fed aldicarb sulfoxide (0.3 and 0.6 mg/kg body weight). There was no significant mortality observed over the course of the study with any of the individual chemicals or the mixture of sulfoxide and sulfone. In the initial phases of the study, there was a slightly higher mortality noted in the high dosage level of aldicarb sulfoxide and in the group receiving the combined aldicarb sulfoxide and aldicarb sulfone. A slight increase in mortality was also noted at the latter part of the study with aldicarb sulfoxide. Growth was slightly depressed at the high dose level of the sulfoxide:sulfone mixture, primarily in males. There were no apparent effects on growth with respect to the aldicarb, aldicarb sulfoxide or aldicarb sulfone administered alone. Hemocrit values observed at various intervals over the course of the study did not differ from controls. Cholinesterase determinations were made periodically over the course of the study (6, 12 and 24 months). Plasma, erythrocyte and brain cholinesterase were examined only at a 24-hour interval after animals were removed from test diets. There was a slight depression of plasma cholinesterase noted in males administered the high dose level of the combination aldicarb sulfoxide and sulfone at the 24-month interval. A repeat of the data within the final week of the study showed slight depression in all chemical groups with respect to plasma cholinesterase. There were no effects noted at any interval with respect to red blood cell or brain cholinesterase. The plasma cholinesterase depression noted at the 24-month interval was limited to male rats. An evaluation of the incidence of tumors suggested that there was no statistical difference between treated and control groups. Gross and microscopic examination of tissues and organs at various periods over the two-year test interval showed that these sporadically distributed lesions were not considered to be indicative of damage induced by aldicarb, its major metabolites, or the combination of the sulfoxides and sulfone (Weil and Carpenter, 1972a). Groups of rats (50 male and 50 female F344 rats per group, 25 of each sex were used as controls) were administered aldicarb in the diet at dosage levels of 0, 2 and 6 ppm for 103 weeks. A preliminary dietary study used 10 male and 10 female rats fed dietary levels of aldicarb (0, 5, 10, 20, 40, 80, 160 and 320 ppm) for 13 weeks. Microscopic examinations performed on male and female rats of the 0 and 80 ppm dosage levels at the conclusion of the preliminary trial showed no significant somatic effects. In the long-term carcinogenicity study, there was no mortality noted attributable to aldicarb in the diet. A variety of benign and malignant tumors occurring at different sites in both control and aldicarb treated rats were not unusual for this strain of rat and were evaluated to be independent of the administration of aldicarb. Gross and microscopic examination of tissues, organs and all gross lesions was performed and it was concluded that aldicarb was not carcinogenic for the F344 strain of rat of either sex (NIH, 1979). Dog Groups of beagle dogs (3 male and 3 female dogs per group) were fed aldicarb in the diet at dose levels of 0, 0.025, 0.05 and 0.1 mg/kg body weight for 2 years. Aldicarb was administered in a moistened diet and the concentration was adjusted monthly to correspond to the mean body weight and diet consumed. The dogs, 8 to 20 months of age at the initiation of the study, were administered aldicarb in the diet 5 days per week for the two-year test interval. There was no mortality over the course of the study and growth and food consumption data were comparable to control values. Haematology parameters and clinical chemistry values evaluated at five intervals over the course of the study were normal. Plasma and erythrocyte cholinesterase, evaluated over the course of the study, did not differ from control values. At the conclusion of the study brain cholinesterase, while somewhat lower at the high dosage level, was not statistically different from controls. Gross and microscopic examination of tissues and organs showed no lesions which could be attributable to the presence of aldicarb in the diet at dosage levels up to and including 0.1 mg/kg/day (Weil and Carpenter, 1966c). Mouse Groups of male mice (50 male and 50 female B6C3F1 mice per group, 25 of each sex were used as controls) were administered aldicarb in the diet at dosage levels of 0, 2 and 6 ppm for 103 weeks in a carcinogenicity bioassay. A preliminary dietary study used 10 male and 10 female mice fed dietary levels of aldicarb (0, 0.5, 1.0, 2.5, 5.0, 10, 20 and 40 ppm) for 13 weeks. Microscopic examinations, performed on male and female mice of the 0, 20 and 40 ppm dose levels at the conclusion of the preliminary trial showed no significant somatic effects. In the long-term carcinogenicity study there was no mortality noted attributable to aldicarb in the diet. A variety of benign and malignant tumors occurring at different sites in both control and aldicarb-treated mice were not unusual for this strain of mice and were evaluated to be independent of the administration of aldicarb. Gross and microscopic examination of tissues, organs and all gross lesions was performed and it was concluded that aldicarb was not carcinogenic for the B63F1 strain of mice of either sex (NIH, 1979). Groups of mice (44 male and 44 female CD-1 mice per group) were fed aldicarb in the diet at dosage levels of 0, 0.1, 0.2, 0.4 and 0.7 mg/kg body weight for 18 mouths (539 days or 77 weeks or 17.8 months of actual dosing). Gross and microscopic examinations were performed on all surviving animals and on those mice that died during the course of the study. Mortality was evident in males at the two highest dosage levels and in females at the three highest dosage levels during the first two and one-half months of the study. Following this period, aldicarb was mixed with the diet in a different manner which appeared to eliminate its acutely toxic effects. (In the early parts of the study, aldicarb was mixed in a dry fashion using a finely ground aldicarb preparation. At the 2.5 month interval, aldicarb was dissolved in acetone and the acetone-aldicarb solution was dispersed in the diet at a more uniform rate. It was assumed that consumption of small crystalline particles of aldicarb may have led to the high mortality during the initial phases of the study.) At the high dosage level in males there was a statistically significant increase in hepatomas found predominantly in the survivors at the termination of the study and an increase in lymphoid neoplasias which occurred in the mice that died. None of the male mice surviving at the end of the study were found to have lymphoid neoplasias. There were no significant increases in any other types of tumors at dosage levels of 0.4 mg/kg and below (Weil and Carpenter, 1972c). Groups of 50 male CD-1 mice were fed aldicarb in the diet at dosage levels of 0, 0.1, 0.3 and 0.7 mg/kg body weight in an effort to verify the results of the previous mouse carcinogenicity bioassay. A group of 150 mice were used as concurrent controls with a mouse being sacrificed for each treated animal that died during the course of the study. Diets were prepared by dissolving aldicarb in acetone and mixing the solution with the diet. The aldicarb was the same sample as used in the previous study and the duration of the study was approximately the same as in the previous trial. There was no mortality observed in the study an a result of aldicarb in the diet. At the end of 18 months cumulative mortality at all dosage levels was the same as noted in controls. There was no effect of aldicarb on growth in any of the groups. An examination of the animals that died during the course of the study and those that were sacrificed at the end of 18 months was made and the data compared with control values. There was no significant association between aldicarb in the diet and the formation of tumors, particularly with respect to the incidence of hepatomas, lung adenomas, and lymphoid neoplasias. The data were evaluated with respect to the mice that died, those that survived the test and the total of all animals. It was concluded that the administration of aldicarb at levels up to and including 0.7 mg/kg body weight for approximately 18 months did not result in a higher than normal incidence of tumors and the inclusion of aldicarb in the diet of CD-1 mice did not result in an increased incidence of carcinogenic response (Weil and Carpenter, 1974d). Observations in Humans Groups of 4 adult male volunteers were administered aldicarb orally in aqueous solution at dosage levels of 0.025, 0.05 and 0.1 mg/kg body weight. Clinical signs of poisoning were recorded and whole blood cholinesterase activity was measured up to six hours after administration of the sample. Total urine voided was collected and aldicarb-excretion patterns for the initial eight hours after dosing were evaluated. In addition, spot samples were taken at 12 and 24 hours. Acute signs of poisoning, typical of anticholinesterase agents, were observed at the high dose level within one hour after administration of aldicarb. There were no signs of poisoning observed at the 0.05 mg/kg body weight dose level. Cholinesterase depression was observed in all volunteers predominantly within 1-2 hours after treatment. Within the first six hours of treatment almost all cholinesterase depression and clinical signs of poisoning were diminished. Examination of urinary excretion patterns showed that approximately 10% of the administered dose was excreted as carbamates (toxic residues) within the first eight-hour interval. Cholinesterase analyses confirmed the same rapid inhibition and recovery pattern with man as had been observed in experimental animals (Haines, 1971). In another study, two additional subjects were administered aldicarb in water solution at dosage levels of 0.05 and 0.26 mg/kg body weight. Acute signs of poisoning were recorded at the higher dose level and atropine was administered to aid recovery. No signs of poisoning were recorded with the lower dose level. Urinary excretion of carbamate residues within 24 hours accounted for approximately 10% of the administered dose (Cope and Romine, 1973). A series of human exposure episodes was reported occurring as a result of a variety of field and glasshouse conditions in an effort to assess the potential for human harm from exposure under actual occupational conditions. In several instances, slight blood cholinesterase depression attested to the actual exposure situation. Exposure data, as indicated by cholinesterase depression or urinary excretion, suggested that there was no change in the general health of workers exposed under any of the working conditions. Although there were acute clinical signs of poisoning there was no indication that the workers exposed were harmed once removed from exposure situation (Williams, 1966; Burrows, et al., 1970; Wakefield, et al., 1973; Shrivastava, 1975; Pandey, 1977). From 1966 to 1979, 133 cases of apparent overexposure to aldicarb formulations were reported (Abdalla, 1977; 1979). Of these cases, 40 were confirmed aldicarb poisoning episodes where clinical diagnosis and/or urinalysis for aldicarb and its metabolites were performed. There have been no confirmed deaths resulting from (predominantly occupational) overexposure, and, as has been the case with other carbamate insecticides, the acute signs of toxicity are rapidly dissipated, although atropine therapy and hospitalization have been useful therapeutic regimens. California, which has one of the best pesticide reporting systems for accidental overexposure, reported that in 1974, 75 & 76 a total of 10, 14 and 13 cases of human illnesses were reported respectively for the three years (Peoples, et al., 1977). In these incidents, people were directly exposed to aldicarb and illness was brought on by dermal, inhalation and in one instance, ocular exposure. While most illnesses resulted from aldicarb exposure in loading or applying the formulated pesticide, some illness has been reported from the handling of plants and soils treated with aldicarb (Abdalla, 1977; 1979). COMMENTS Aldicarb is an N-methyl carbamate ester of an aliphatic oxime currently used as an insecticide in agriculture. Aldicarb has been, and is currently formulated as, a granular preparation for use as a soil treatment having systematic activity in plants against a variety of insect, mite and nematode pests. Aldicarb in extremely toxic with an extremely low LD50 value in a wide variety of mammalian species. The onset of acute signs of poisoning appears to be due to reversible cholinesterase inhibition resulting in parasympathomimetic signs of poisoning. The acute signs of poisoning are alleviated rapidly usually without treatment, and frequently within hours, but always within 1-2 days of exposure. Aldicarb is rapidly absorbed, widely distributed in the body and rapidly excreted. Bioaccumulation does not appear to be a factor with aldicarb. Aldicarb metabolism has been widely studied in a variety of organisms and appears to be similar in all species examined. Aldicarb is rapidly metabolized through oxidation of the sulfur atom to produce a toxic, relatively stable metabolite, aldicarb sulfoxide. Aldicarb sulfoxide in slowly converted by hydrolytic and/or oxidative mechanisms to aldicarb sulfone and related oxime and other degradation products. A wide variety of special studies have been performed to evaluate the toxicological hazard associated with the use of aldicarb. Aldicarb does not affect reproduction, is not teratogenic or carcinogenic in mammals and there is no evidence of a delayed neurotoxic potential. Cholinesterase depression is the most significant parameter of exposure that can be evaluated with respect to the toxicology of aldicarb. Considerable attention was paid to the analytical methodology used to develop cholinesterase depression data. Short-term and long-term dietary studies were conducted with aldicarb and aldicarb metabolites both alone and in combination, and no-effect levels were noted. In some of these studies, there was a discontinuation of feeding of aldicarb or its metabolites for short periods prior to the evaluation of cholinesterase activity. This practice served to point to the rapid reversibility of cholinesterase depression, although in the toxicological evaluation, continuous exposure prior to analysis of cholinesterase activity was thought to be very important. Erythrocyte and plasma cholinesterase were the most sensitive parameters of exposure. In a short-term study in rats with aldicarb sulfoxide, cholinesterase depression served as the basis for evaluating a dietary no-effect level. Cholinesterase depression in plasma and erythrocytes, measured through the use of an acceptable analytical procedure, was not observed at 0.125 mg/kg body weight. Studies on dogs have been performed with aldicarb, aldicarb sulfoxide and sulfone for various time intervals up to and including two years. Cholinesterase depression was not noted in the dog studies because of interrupted treatment. An appropriate short-term cholinesterase study in dogs would be desirable to allow further evaluations to be made. Currently, standardized tests for mutagenicity have not been reported, although a dominant lethal assay in mice suggested no potential for mutagenic events. Microbial mutagenicity tests were considered to be desirable. Human volunteer studies show that man reacts in a similar manner to experimental animals. Data on the rapid onset and diminution of signs of poisoning and depression and recovery of cholinesterase activity parallel those observed in animal bioassays. As the slope of the acute toxicity curve is so steep, an additional margin of safety reflected the high acute toxicity of aldicarb. The rapid reversibility of cholinesterase depression, the lack of long-term pathological events and the lack of effects in a wide variety of toxicological parameters were all reassuring in estimating an acceptable daily intake for man. TOXICOLOGICAL EVALUATION Level Causing No Toxicological Effects Rat: 2.5 ppm in the diet, equivalent to 0.125 mg/kg body weight Dog: 0.25 mg/kg body weight Estimate of Acceptable Daily Intake for Man 0-0.001 mg/kg body weight RESIDUES IN FOOD AND THEIR EVALUATION USE PATTERN Pre-harvest treatments Aldicarb is employed as a systemic pesticide to control insect, mite and nematode pests in plants. Technical aldicarb is so extremely toxic to man that it has never been commercially available in conventional wettable powder, emulsifiable or solution form. The inventor and sole manufacturer, Union Carbide Corporation, markets aldicarb only as granular products containing 5 to 15 percent active ingredient. This formulation allows the product to be handled and applied with minimal hazard to man. The granular products employ ground corn cobs, gypsum, or ground charcoal as substrates. Granular particle size range is 16 to 60 mesh, or about 0.25 to 1.5 mm diameter. Technical aldicarb is produced in acetone or methylene chloride solution, impregnated into granules and the solvent in removed by evaporation. One percent of water-soluble resin is added as a bonding agent to hold the aldicarb on the granule. Various antistatic or colouring agents may be added in small amounts. The finished granular products are clean, free-flowing, and stable in storage for at least two years. Aldicarb is marketed worldwide in waterproof dispensers, bags or cartons containing 1.5 or 10 kg of granular product. The pesticide is most commonly applied by mechanical tractor-mounted applicators which deliver the granules 2.5 to 5 cm beneath the soil surface. For field crops like cotton, sugar beets, and potatoes, granules are applied in the seed furrow, adjacent to the seed, or alongside the row after crop emergence. In some cases, surface application followed by immediate rototilling to incorporate the granules into the soil is recommended. In glasshouse usage for treating commercially grown ornamental plants, smaller hand-held applicators spread the granules over beds, benches, or pots and the aldicarb is watered into the soil. Rate of use range from one to three kg/ha for row crops. As much as 5 kg ai/ha may be used in potatoes against the golden nematode. Citrus and some ornamentals require higher rates, up to 11 kg ai/ha. Usually, only one application is made per crop either at planting or within six weeks after emergence. In bananas, 2.5 to 3 g ai/mat/6 mos is applied. Aldicarb is also used as a seedling treatment for coconut and cacao. For most food crops, a 90-120 day pre-harvest interval is required for residues to be reduced below acceptable levels. There are no post-harvest uses. Aldicarb is used on numerous crops in many countries. Registered usages include potatoes, coffee, sugar beets, cotton, soybeans, dry beans, bananas, oranges, sugarcane, peanuts, sweet potatoes, pecans and ornamentals. In 1979, Temik 15G was tke major product used in the USA for aphids, golden nematode, and Colorado potato beetle on potatoes; for early season insects and nematodes on cotton; and for aphids, maggots, and nematodes on sugar beets. The USA consumes 70% of world production; Pan America, 15%; Europe, 10%; and other areas, 5%. RESIDUES RESULTING FROM SUPERVISED TRIALS Extensive data provided by the manufacturer on residues of aldicarb and its toxic metabolites are the basis for the following discussions. Cotton During 1966 through 1968 with aldicarb applied at planting time, as sidedress treatment, and a combination of the two treatments, 75% of 244 samples showed no residues above the sensitivity of the method; 90% less than 0.07 mg/kg and 1% more than 0.1 mg/kg. Aldicarb itself was not detected in any sample, but the sulfone formed the main portion of the residue. Potatoes Residue data was collected in the United States for nine consecutive crop years (1964 through 1972). There was a total of 342 samples from 21 states in the USA, representing all the potato growing areas. Samples were also collected from Quebec and Ontario. Growth dilution is the important factor as regards residues in tubers. In the period from 70 to 90 days after planting, the tuber is growing rapidly with much increase in bulk. The uptake of new pesticide apparently cannot match the dilution by new tissue, and there is a rapid decrease in residue concentration. From 90-110 days, residues are still increasing at a slowing rate, an average decrease of about 40 percent, and after 110 days, the tuber residue changes very little. Aldicarb itself has not been found as a residue in potato tubers. The toxic tuber residue consists entirely of aldicarb sulfoxide and aldicarb sulfone. At harvest, a ratio of 78 percent aldicarb sulfoxide and 22 percent aldicarb sulfone has been found. There was considerable variation in tuber residue even for those seemingly grown under identical cultural practices and climatic conditions, pointing to the need to rely on the determined values rather than general assumptions. Samples collected from Maine, USA for potatoes treated at the rate of 0.5 to 1.5 kg in-furrow ranged from 0.01 to 0.5 mg/kg after 107 days. Of the 248 samples from recommended at-planting treatments, only two show residues which might exceed one mg/kg at harvest assuming a pre-harvest interval of 90 days. Sidedressing after an application at planting time did not add significantly to tuber residues. In South Africa measurements of residues in potatoes, at periods ranging from 90 to 180 days after treatment in eight sites and at the registered application rate of 7.5 kg ai/ha, show that the recommended 120 days PHI could accommodate the national limit of 1 mg/kg. (As the PHI is normally extended up to 150-170 days, the evidence indicates that this figure would not generally be exceeded.) In New Zealand single pre-planting applications at 10 kg ai/ha gave ca. 0.1 mg/kg aldicarb at harvest 118 days later (New Zealand, 1979). In the Netherlands, trials in several localities with aldicarb applied 90-160 days before harvest at the 5 kg ai/ha application rate gave levels mainly in the 0.06 - 0.5 mg/kg range. Only one sample out of 52 had residues in the 0.6 - 1 mg/kg range. At the normally recommended application rate of 3 kg ai/ha, the maximum residues occurred in the 0.06 - 0.1 mg/kg range. Peanuts Aldicarb is generally applied at 1 to 2 lbs ai/A in-furrow at planting. In the samples of harvest peanuts from at-planting treatments of up to 4 lbs. ai/A, the range of residues were as follows: Residue Range in Whole Nuts (mg/kg) No. Samples in Range % >0.2 0 - 0.1 - 0.2 1 2 0.05 - 0.1 5 11 0.01 - 0.05 20 43.5 <0.01 20 43.5 Whole nut residues were concentrated primarily in the hull and peanut kernels generally contained less than 0.02 mg/kg aldicarb. Citrus Analysis of over 200 samples of oranges treated at rates of 2.3 to 22 kg ai/ha showed that the maximum residues in ripe oranges was 0.2 mg/kg. Residues are higher in immature green fruit than in ripe fruit and residues in peel are higher than in edible pulp, averaging about 4:1 peel-pulp in both green and ripe fruits. The maximum residue found in ripe orange pulp was 0.1 mg/kg in a Valencia, 30 days after a treatment of 11 kg ai/ha. The peel residue was 0.5 mg/kg, resulting in a calculated whole fruit residue of 0.2 mg/kg. Fruits becoming ripe six to seven months after the ripe fruit cited above continued to show whole fruit residues of 0.1 - 0.2 mg/kg. When aldicarb was applied to the soil around orange trees at rates of 0.09, 0.45, and 2.26 g ai/929 cm2, analysis of the orange peel and pulp at approximately 100 days after treatment did not detect the presence of aldicarb. The aldicarb sulfoxide residues in the peel from the three treatments were 0.06, 1.4, and 12.8 mg/kg, while the residues in the pulp were 0.03, 0.4, and 2.6 mg/kg. The aldicarb sulfoxide residues in the peel from the three treatments were 0.06, 1.4, and 12.8 mg/kg, while the residues in the pulp were 0.01, 0.1 and 0.6 mg/kg. Iwata et al. (1977) detected 0.03 - 0.05 mg/kg residues in orange pulp 28 days after treatment with 22 kg ai/ha, but not at 11 kg ai/ha. Bananas Samples were obtained from Ecuador, Peru, Philippines and Costa Rica. The maximum residue found in whole bananas treated either at or near the recommended rate of three g ai/mat (i.e. ca. m2) is 0.2 mg/kg. The data are summarized in Table 3. Measurements in Ecuador, Peru, the Philippines and S. Africa of residues in fruit at known periods after application show that peak levels are reached in 40 to 100 days. This is illustrated in Table 4 (S. Africa). The variation in time after treatment when peak residues occur is probably a combined effect of differences in moisture, plant size, soils, temperature and growth dilution. Apparently, residues in harvest fruit are not additive nor accumulative from multiple treatments at six months intervals. Analysis of the pulp and peel showed that there is no significant difference in residues and that the whole fruit data could represent the edible pulp residues as well. There is also no discernible difference in the residue content of the top, middle and bottom hands on the stem. The first application resulted in residues in some samples slightly higher than the proposed MRL; but the Meeting viewed the more extensive residues data from Ecuador, Peru, Philippines and Costa Rica, the traditional banana suppliers of the world, as being more indicative of the residues situation. Dry Beans About 75 dry beans seed samples have been analyzed. Aldicarb was applied at a maximum treatment rate of 22 kg ai/ha in-furrow at planting time. The maximum residue found at normal harvest was 0.07 mg/kg after application of the highest rate tested, 3.3 kg ai/ha at planting. At normal rates, the maximum residues was 0.02 mg/kg. The type of application at planting did not influence residues at harvest. Each sample was a composite of green ripe fruit from bottom, middle and top of bunch. Bean (Dry) forage The highest residue found in dry bean forage was 2.8 mg/kg in a sample of straw after an at-planting application of 3.3 kg ai/ha. Harvest residues in other samples from this application, timing and use rate ranged from 0.2 to 1.2 mg/kg. Residues in green forage may approach 30 mg/kg at recommended use rates, but decline as the plants mature, lose some of their leaves and become dry toward harvest. Dry bean straw, green forage, and hay are restricted from use by directions to the label. Aldicarb was applied at 0.8 to 3.3 kg ai/ha at planting. Forty-eight soybean seed samples and 44 forage samples were collected. No detectable residues (0.02 mg/kg) were found in any soybean seed at harvest, regardless of the application rate or type of application. Low level aldicarb residues were found in some immature seeds but these residues quickly diminished as the seed matured to become non-detectable at harvest. The highest residue found in any soybean seed was 0.15 mg/kg in very immature seed 58 days before threshing. Three weeks later (still 36 days before normal harvest) the residues diminished to non-detectable (0.02 mg/kg) and remained so at harvest). Table 3. Maximum Residues of Aldicarb (mg/kg) in Bananas Collected from Different Countries Rate (ai/mat/treatment) Location 21 3 4 6 7-8 Ecuador 0.04 0.09 0.1 Peru - 0.2 0.2 - 0.6 Philippines 1973 - 0.1 - - - 1975 0.05 0.09 - - 0.8 Costa Rica - - 0.3 - - 1 Application to the nearest gram. (mat similar or equal to sq.m) Table 4. Aldicarb Residues in Bananas at Different Periods after Application (South Africa) Residues of Aldicarb (mg/kg) Days After First Treatment Treatment 6 Months Later Application A-3g ai/m2 A-6g ai/m2 B-3g ai/m2 B-6g ai/m2 15 0.04 0.05 0.04 0.2 30 0.2 0.4 0.03 0.04 45 0.3 0.7 0.06 0.1 60 0.4 0.7 0.1 0.2 90 0.4 0.6 0.2 0.2 120 0.4 0.5 0.3 0.05 180 0.1 0.4 0.2 0.4 Soybean forage and straw At-harvest residues in soybean straw are generally quite low and do not exceed 0.1 mg/kg. Aldicarb residues in green soybean forage may exceed 5 mg/kg at the proposed treatment rates two months before harvest and younger plants would contain even higher residues. Use of soybean forage or hay as animal feed is not recommended. Soybean oil and meal Soybean seeds do not contain detectable residues (<0.01 mg/kg) when treated up to two to three times the recommended rates; higher rates are generally phytotoxic to soybeans. Just the same, soybeans from fields treated at 1× and 2× the recommendations were composited and fractionated by procedures closely paralleling the commercial solvent extraction process to yield oil and meal. No residues were found in either the oil or meal components. The procedure applied would have detected residues at 0.005 mg/kg in soybean oil and 0.01 mg/kg in the meal. Coffee Only 6 of the 47 samples of green coffee analyzed show analytically significant residues at a method sensitivity of 0.02 mg/kg. These samples include exaggerated treatment rates (up to 2×) as well as multiple treatments (1-3) and preharvest intervals from 15 days to 274 days. Aldicarb residues seem to preferentially concentrate in the hulls of the dry coffee berry as shown below: Hulls 0.01 mg/kg Parchment 0.05 mg/kg Green coffee 0.04 mg/kg The higher residue level in hulls is logical since more water is lost from the pulpy hull on drying than from either the parchment or seeds. Strawberry From the results of supervised trials undertaken in Finland, it was noted that quite high residues could be found after application of aldicarb to strawberries (Finland, 1979). It was also noted that use on this crop has not been recommended. Sugarcane Applications of 5.5 kg ai/ha at planting time into the furrows and to ratoon canes resulted in residues shown in Table 5 (South Africa, 1979). Aldicarb appears to be concentrated in the leaves. Table 5. Residues of Aldicarb in Sugarcane following application of 5.5 kg ai/ha at Planting Time (An extract from results received from South Africa) Treatment Application intervals (days) 18 25 32 46 60 75 (Residues in mg/kg) I. Plant cane Site A. T1 18.3 5.7 5.1 4.3(L) 0.9 0 6(L) 21 5.5 5.1 4.0(L) 1.0 0:6(L) 1.0(S) 0.3(S) 0.9(S) 0.3(S) Site A. T3 12.8 4.0 4.7 3.9(L) 1.1 0.8(L) 11.1 3.4 3.9 3.6(L) 1.2 0.8(L) 0.8(S) 0.3(S) 0.9(S) 0.3(S) II. Ratoon cane Site A. 15 29 54 91 5.1 12.3 4.7 0.01 5.4 11.6 4.5 0.01 Site B. 7 13 20 28 7.3 2.1 0.4 0.2 7.5 2.0 0.5 0.2 L = leaves S = stalk Sugarbeet fodder It is seen below that aldicarb is concentrated on the sugarbeet tops (Denmark, 1979). Low level residues occurred 135 and 180 days after application at dosage rates of 0.7 and 1.4 kg ai/ha. The numbers refer to mg/kg aldicarb sulfone. 135 days 180 days root top root top 0.7 kg ai/ha 0.007 1.0 n.d. 0.05 0.007 1.0 n.d. 0.08 1.5 kg ai/ha 0.009 1.4 n.d. 0.2 0.02 2.9 n.d. 0.3 Onions Residue trials in the Netherlands showed residues less than the 0.05 mg/kg limit of detection after application of 1.5 kg ai/ha as row treatment, 150-168 days after application (Netherlands, 1979). FATE OF RESIDUES General The common metabolic pathway for aldicarb in plants, animals, insects and soils is shown in Figure 2. The consistency of aldicarb metabolism in plants has been illustrated with cotton, potatoes, spearmint, lettuce, sugarbeets, peanuts and tobacco. Following soil treatment, aldicarb is readily absorbed by the plant with subsequent translocation. Within the plant, the initial step is thioether oxidation to aldicarb sulfoxide. This biochemical conversion occurs rapidly since no parent aldicarb is found in the plant after a few weeks. Aldicarb sulfoxide is subsequently metabolized primarily by hydrolysis to yield the sulfoxide oxime. It also produces aldicarb sulfone through slow thioether oxidation. Both the sulfoxide and the sulfone suffer extensive degradation through hydrolysis elimination, oxidation, reduction and conjugation reactions. Such products include the oximes and the resulting alcohols and their glycoside conjugates, the amides, the nitriles and the carbonic acids. Essentially, these are of no toxicological significance. There has been no evidence of conjugated carbamate metabolites in plants resulting from aldicarb treatment. Consequently, the only significant terminal carbamate containing residues in plants following aldicarb treatment are the aldicarb sulfoxide and aldicarb sulfone, and depending on the harvesting time, a minor residue of parent aldicarb. There is essentially no retention of aldicarb and its carbamate metabolites in tissues, milk and eggs. Residues can be detected in milk only when cows were fed with exaggerated dosages. At residue levels normally resulting from aldicarb usage, no residues can be detected in milk. Excretion is mainly through the urine. In laying hens, excretion of aldicarb sulfoxide and sulfone is rapid for both single oral and continuous feeding for up to 10 days. About 75 percent of the doses are in the faeces by 24 hours and a large portion of the metabolites are water-soluble materials. Only minute quantities of the toxic carbamate compounds were observed. A positive correlation exists between temperature and moisture and the rate of loss of aldicarb in soils. Aldicarb is very susceptible to alkaline hydrolysis and is presumably unstable at higher soil pH. Upward movement is observed with most soils with aldicarb apparently leaving the soil surface entrained with water vapour. Only in pure sand is downward movement readily achieved through water action so that aldicarb does not pose a hazard through ground water contamination. Aldicarb is degraded by micro-organisms and the catalytic action of clays and other inorganic soil constituents. No hazard from carryover residues is expected. Bacteria or fungi do not appear to be susceptible to the toxic action of aldicarb and the compound could even serve as a carbon source for some micro-organisms. In animals (see Biochemical Aspects). In plants Metcalf et al. (1966) demonstrated that aldicarb was completely oxidized to aldicarb sulfoxide in cotton foliage within four to nine days. Further hydrolysis yielded the sulfoxide oxime, and oxidation of the aldicarb sulfoxide to aldicarb sulfone occurred. Coppedge et al. (1967) confirmed these findings, and identified the sulfoxide nitrile as a definite metabolite in cotton. Once formed, aldicarb sulfone is not reduced to provide a secondary source of aldicarb sulfoxide, nor could evidence of oxidative N-demethylation be found. The total radioactivity in the cotton plant in reduced with time through volatilization and dilution by plant growth. Field-grown cotton was treated with radioactive aldicarb by in-furrow at planting and by side-dressed applications (Andrawes and Bagley, 1968c). The residues were identified, quantitated, and the rates of decline determined. The metabolic pattern of aldicarb in vivo was in agreement with that described by earlier investigators. A second field study employed petiole injection and obtained similar results (Bull, 1968). A complete distribution of radioactivity in the cotton plant was described and the residue in the maturing fruit was characterized. After four weeks no toxic residues were present in the bolls. Bartley, et al. (1970) showed that sulfoxide oxime in further transformed to a mixture of water-soluble products. These consist primarily of sugar conjugates of sulfoxide alcohol, as well as smaller quantities of sulfoxide and sulfone acids and sulfone amide. There is no evidence for the presence of N-methylol or N-demethyl derivatives as sugar conjugates. After gaining entrance into the potato plant, aldicarb residues move primarily by xylem transport with highest concentrations appearing in the foliage. Stem injection studies have shown that only limited quantities of aldicarb and its metabolites move downward into the tuber. The toxic carbamate residues appearing in the tuber do not persist, but are actively degraded to non toxic water-soluble products similar to those formed in the foliage (Andrawes and Bagley, 1968b; Andrawes et al., 1971b). Systemic movement and concomitant metabolism of aldicarb resulted in a preferential accumulation of the residues in peanut foliage (Andrawes,l972). A small fraction of the observed radioactivity was found in the fruits. Translocation of residues to the forming fruit is facilitated by the polar nature of the metabolic products present in the maturing plants. These water-soluble metabolites were the predominant component of the terminal residues in the foliage and constituted 90 to 95 percent of the recovered radioactivity in the kernels. Aldicarb sulfoxide, aldicarb sulfone, and the non-toxic water soluble metabolites constituted the major portion of the residual C14 materials in sugar beets (Andrawes et al., 1970). Most of the absorbed radioactivity was found in the foliar portion of the plant throughout the growing season. At maturity (140 days after treatment) total C14 residues were 27.2 mg/kg in the foliage and 2.5 mg/kg in the roots. The corresponding values for total toxic residues was 11.0 mg/kg in the foliage and 0.6 mg/kg in the roots. In soil The chemical changes that occur in soil are essentially the same as for plants, animals and insects. Series of parallel experiments have been performed under the same environmental conditions with single factors varied to assess the roles in controlling the persistence of aldicarb in the soil. These factors include soil types, moisture, pH, and temperature (Coppedge, et al., 1967; Bull, 1968; Romine et al., 1968; Bull et al., 1970; Quraishi, 1972; Supak, 1972; Gawaad et al., 1971). A positive correlation exists between temperature moisture and rate loss from soil. Changes in pH in the 6 to 8 range do not appear to adversely affect aldicarb although the compound in is very susceptible to alkaline hydrolysis so that it is anticipated that it would be unstable in high soil pH. Under greenhouse and field conditions, aldicarb and its breakdown products leave the soil with unexpected rapidity; a half-life of seven days was observed (Bull et al., 1968). This emission is definitely linked to the degree of soil moisture and consists primarily of an upward movement. This phenomenon has been studied in an elaborate series of percolation experiments with different soil types in assorted sizes of columns (Bull et al., 1968; Romine et al., 1968) and under field conditions (Bull, 1968; Bull et al., 1968). Only in pure sand is downward movement readily achieved through water action. Aldicarb and related compounds probably leave the soil entrained with water vapour as little movement has been noted in dry soils. The dissipation of aldicarb in the soil is sufficiently rapid and complete that recommended rates will offer no hazard of contamination of subsequent crops in a treated area (Andrawes and Bagley, 1968; Andrawes et al., 1971a; Quraishi, 1972). Predictably, discing or other soil manipulations will serve to disperse and dilute aldicarb that has been placed in-furrow. Tomatoes transplanted into fields 90 days after a 3.3 kg/ha application of radioactive aldicarb showed no detectable radioactivity when analyzed seven days later. Bioassays of volunteer potato plants taken from fields treated the previous year with 6.6 kg/ha active ingredient were completely non-toxic to the highly sensitive Colorado potato beetle (Clarkson, 1968). Extensive laboratory screening tests in which high concentrations of aldicarb and its metabolites were incorporated into various nutrient media and then inoculated with bacteria or fungi suggest that the pesticide has no toxic effect on microorganisms (Spurr and Chancey, 1968; Spurr and Sousa, 1974; Anderson, 1971). Gawaad et al., (1972) also found no effect on the nodulation rate of Rhizobium phaseoli and R. trifolii in broad beans and Egyptian clover. Soil enrichment experiments even demonstrated that aldicarb could serve as a carbon source for certain microbes (Spurr and Chancey, 1968). Aldicarb was however very toxic to oribatid mites while it was less toxic than several other materials to earthworms, enchytraeids, predatory mites and collembola (Heungens, 1970). Since aldicarb does not readily move downward through different soil types by leaching action except in sandy soil, resultant contamination of ground water from surface-treated fields is unlikely. Clarkson et al. (1968a) treated a graded 0.2 ha with 4.5 kg of aldicarb. They did not find any significant movement of the pesticide during the 30-day test period and over 20 cm of rainfall. On the other hand, Gawaad et al. (1971) showed that aldicarb had leaching rates of 47.12, 42.3 and 56.14 percent from sand, loam and sandy clay loam soils respectively. Lateral movement of aldicarb is low (Woodham et al., 1973). Kearby et al. (1970) in a study of the distribution and persistence of residues in a Pennsylvania tree farm soil, wherein aldicarb was applied at 0.23 and 0.45 kg trees, found no apparent chemical residues in soil samples taken at depths of 15 and 30 cm, 36 and 63 days after treatment. The half-lives of aldicarb and its major metabolites were estimated to be 15 days. In Water The disappearance of aldicarb was determined over a 30-day period in distilled water at pH 6, 7 and 8, and in pond water and lake water, the latter two in the presence and absence of their respective bottom material (Moorefield, 1974). The initial concentration of aldicarb in all samples was 0.5 mg/kg. There was little or no degradation of aldicarb carbamates in the distilled water, or in the pond and lake water in the absence of bottom material. In the pond water with about 5% mud (percent by weight, dry basis) present, the aldicarb carbamate residue degraded to a concentration of 0.02 mg/kg in 20 days, the half-life being about 5 days. After 20 days, the bottom mud contained less than 0.01 mg/kg aldicarb carbamates. In lake water in the presence of bottom silt, aldicarb carbamates degraded to a concentration of 0.03 mg/kg in 25 days; half-life is about 6 days. Moorefield (1974) further reported on a field study in which a farm pond was treated with aldicarb at an initial concentration of 3 mg/kg. Samples of water and bottom and were taken periodically. Aldicarb carbamate residues in the pond water declined to 1.1 mg/kg after 2 weeks; 0.26 mg/kg after 4 weeks; 0.06 mg/kg (the limit of sensitivity of the method) after 6 weeks. The half-life was about 7 to 10 days. The maximum concentration of aldicarb carbamate residues in the bottom mud was 0.09 mg/kg at 4 weeks. The dissipation of aldicarb carbamate residues on this farm pond was rapid and complete, without residue buildup in pond sediment. Quraishi (1972) studied the persistence of aldicarb in water collected from fields. Treatment at 100 mg/kg of aldicarb resulted in residues of aldicarb and metabolites at 0.4 mg/kg after 11 months. In storage and processing Cotton Processed cotton meal from seed treated at 0.1 mg/kg contained only a fraction of the residue present in the whole seed and no detectable residues (<0.003 mg/kg) were found in refined cottonseed oil. Potatoes The processing of potatoes into potato chips, potato flakes and the process of baking, boiling, making into french fries, hash browning and canning of potatoes was investigated for their effect on residues in raw tubers. In the case of potato chips, 95 percent of the residue in raw tubers is lost during the manufacturing. However, since up to 5 lbs. of tubers are required to produce kg × kg of chips, the concentrative effect results in chips having an apparent loss of only 69 percent. The maximum residues found in potato chips was 0.2 mg/kg and resulted from tubers having 0.45 mg/kg residues. The rest shows residue of 0.1 mg/kg or less. In potato flakes, the maximum residues found from harvest tubers treated at recommended rates was 0.12 mg/kg. Aldicarb residues destroyed in the other processes were: baking, 65 percent; boiling, 60 percent; french frying, 36 percent; hash browning, 72 percent; canning, 65 percent. This in an average destruction of about 60 percent of the raw tuber residue for these commonly used cooking procedures. Smelt et al. (1975) found in five samples of peeled potatoes and peelings that the contents in the peelings were on the average 11% higher than in the peeled potatoes. Hence, peeling does not lead to a significant decrease of the residue. On boiling with 2% NaCl solution for 20-24 minutes 42-52% lower residues were observed than before cooking. Only about 2.5 -8.1% of the initial residue was found in the water drained off potatoes. Storage of potatoes at 20°C for two months also resulted in 42-55% lower residues. Peanuts Fractionation of peanuts containing 0.01 to 0.04 mg/kg residues on the whole dry nuts (equivalent to 0.002 to 0.02 mg/kg residues in the kernel) resulted in peanut oil with no detectable residues (<0.003 mg/kg), whether the oil was recovered by the screwpress or solvent extraction procedure. The peanut meal contains about the same level of residues as the kernels. Sugar beet In a simulated commercial processing operation for using roots of treated sugar beet, the residue was <0.005 mg/kg in all fractions except the diffusion juice which had a maximum of 0.02 mg/kg. When diffusion juice was fortified with lime water under conditions simulating plant processing, <0.005 mg/kg residue remained at the exaggerated fortification level of 13.0 mg/kg. No detectable residues were found in fortified beet pulp after simulating plant drying conditions. Therefore, there in no reasonable expectation of detectable residues in sugar, molasses or beet pulp. Oranges Aldicarb-treated oranges were processed as in a commercial operation and the different fractions were analyzed for residues. It is seen in Table 6 that the residues in the whole fresh fruit can be concentrated in the dried citrus pulp by a factor of 1.75%. The portion of the wet peel residues which do not survive the dried citrus pulp process are believed to be destroyed by the liming process prior to screw pressing and during the application of heat in the pulp drier. Orange juice residues are equal to fresh pulp residues. Concentrated orange juice (concentrated about 3×) shows residues greater then fresh juice and reconstitution prior to consumption would generate the original juice residue. The other by-products of commercial processing which were investigated, molasses oil, press liquor and oil water layer contain only low level residues, not exceeding 0.04 mg/kg. Table 6. Effect of Commercial Processing on Aldicarb Residues in Oranges Aldicarb Residues, mg/kg First Fractionation Second Fractionation Orange Fraction UCC1 UCR UCC UCR Whole fruit 0.22 - 0.07 0.1 Wet pulp 0.1 0.1 - - Wet peel 0.6 0.4 0.08 0.09 Dried citrus pulp 0.4 0.4 0.04 0.07 Dilute juice 0.1 0.2 0.06 0.09 Conc. juice - - 0.2 0.3 Press liquor - - 0.02 0.02 Molasses 0.04 0.04 0.04 0.02 Oil 0.02 0.02 0.03 0.02 1 Analyzed by UCC = Union Carbide Corp., UCR = University of California (Riverside) 2 The orange pulp is 75% by weight of the whole fruit and the wet peel 25%. The calculated whole fruit residue from the pulp and wet peal analysis in 0.24 mg/kg [(0.1 × 0.8) + (0.6 × 0.2) = 0.2]. Whole fruit containing 0.2 mg/kg aldicarb residues resulted in 0.4 mg/kg in the dried citrus pulp or a 1.75-fold concentration. Dry beans (cooking) Cooking as usually done in homes reduces dry beans residues by 85% after 1 hour and over 90 percent after 3 hours. Apparently, the residues are diluted by water absorption and resultant weight gain of the seed or diffuse from the dry seed into the water during the soaking process. This is reflected in 0.5 mg/kg residues in the dry seed becoming 0.2 mg/kg in the soaked seeds. Most of the residues are then destroyed during cooking at 100°c. EVIDENCE OF RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION Aldicarb in generally not yet included in pesticide monitoring programmes. Therefore no data were available to the Meeting. METHODS OF RESIDUE ANALYSIS The most widely-used procedure is that wherein aldicarb and aldicarb sulfoxide are converted to the sulfone by hydrogen peroxide-acetic acid oxidation and quantitated by GLC (Maitlen et al., 1968, 1969, 1970). The method is simple and rapid. Generally, aldicarb residues are extracted from the crop by blending the sample in a mixed solvent consisting of 75 percent acetone and 25 percent water. The aldicarb residues are oxidized to aldicarb sulfone by addition of peracetic acid to the extracting solvent. After clean-up on a Florisil column, the residues are determined with a flame photometric detector and reported as aldicarb. Alternatively, the metabolites may be separated by Florisil column chromatography prior to oxidation. Detection limits of 0.007 to 0.01 mg/kg have been obtained in apples alfalfa, bananas, beans, coffee, cucumbers, oranges, potatoes, soybeans and sugar beets. NATIONAL MRLs REPORTED TO THE MEETING The following were reported: Country Crop Limit mg/kg USA cattle (meat, fat, meat by-products) 0.01 citrus 0.3 citrus pulp, dried 0.6 cottonseed 0.1 cottonseed hulls 0.3 goats, hogs, horses, sheep (meat,fat, meat by-products) 0.01 milk 0.002 oranges 0.3 potatoes 1.0 peanut hulls 0.5 peanuts 0.05 sugar beets 0.05 sugar beet tops 1.0 sweet potatoes, sugar cane 0.02 Argentina cottonseed 0.1 peanuts 0.05 potatoes 1.0 sweet potatoes 0.02 Brazil cottonseed 0.1 peanuts 0.05 potatoes 1.0 sugarcane 0.02 Panama potatoes 1.0 Mexico cottonseed 0.1 peanuts 0.05 potatoes 1.0 sugarcane 0.02 National MRLs, Continued... Country Crop Limit mg/kg Netherlands onions, bulb 0.1 potatoes 0.3 sugar beets 0.02 other products of plant origin 0.01* Federal Rep. of Germany strawberries 0.05 sugar beets 0.05 East Germany (DDR) onions, bulb 0.1 Switzerland corn 0.02 sugar beets 0.05 Hungary sugar beets 0.05 sugar 0.01 South Africa potatoes 0.1 sugarcane 0.1 bananas 0.5 APPRAISAL Aldicarb is a very toxic systemic pesticide for the control of insects, mites and nematodes. It is sold only an the granular material containing 5 to 15 percent active ingredient. Among the crops for which aldicarb in registered are bananas, citrus, cotton, coffee, potatoes, peanuts, sugar beets, sugarcane, sweet potatoes, dry beans and soybeans. Application rate is generally from 1 to 3 kg/ha. For most food crops the use pattern involves a 90 day pre-harvest interval. There is a common metabolic pathway in plants, animals, insects and soils. The initial step in the rapid thioether oxidation to the sulfoxide followed by a slower conversion to sulfone. Both the sulfoxide and sulfone undergo extensive degradation; the primary metabolic step is hydrolysis to the corresponding oximes. Aldicarb, aldicarb sulfone and aldicarb sulfoxide are the toxicologically important residues, but aldicarb itself is seldom detected at harvest. Feeding studies with dairy cows at 0.12, 0.6 and 1.2 ppm for 14 days showed no apparent harmful effects. There were also no changes in blood cholinesterase levels, milk production, quantity of excretory * At or about the limit of detection. products, or food consumption. About 90 percent of the applied dose was excreted in the urine. At feeding levels above that normally encountered as a result of field treatment, no toxic carbamate residues could be detected in milk. Considerable residue data for potatoes, cottonseed, sugar beets, peanuts, coffee and bananas were reviewed. Residue levels were normally low following the long pre-harvest intervals prescribed. Processing further reduced the residue levels either due to dilution or to thermal degradation. The most widely-used analytical procedure requires the conversion of aldicarb and the sulfoxide to the sulfone and then quantitation by gas chromatography with a flame photometric detector in the sulfur mode. Residues are expressed as aldicarb. Alternatively, the three carbonate materials can be separated by column chromatography prior to oxidation. For a variety of crops limits of determination ranged from 0.007 to 0.01 mg/kg. RECOMMENDATIONS The following levels are recommended as MRLs which need not be exceeded when aldicarb is used according to good agricultural practice. They refer to aldicarb, aldicarb sulfoxide, and aldicarb sulfone determined as aldicarb sulfone and expressed as aldicarb. Pre-harvest intervals Limit on which recommendations Commodity mg/kg are based bananas 0.5 1 beans, dry 0.1 2 citrus fruits 0.2 90 cottonseed 0.1 90 meat 0.01* - milk 0.002* - peanuts 0.05* 90 potatoes 120 soybeans 0.02* 3 sugar beets 0.05* 90 sugar beet tops 120 coffee beans (green) 0.1 2 onions 0.05* 1 No PHI because of continuous harvesting 2 At planting time only. * at or about the limit of determination FURTHER WORK Desirable: 1. Studies on cholinesterase activity in dogs associated with short-term continuous dietary exposure. 2. Examination of the mutagenic potential of aldicarb using short-term microbial bioassays. 3. Data on use patterns and resultant residues in important crops in countries other than USA. REFERENCES Abdallah, N.A. Alleged Overexposure Cases Reported from Use of Temik Formulations - 1966 to 1976. (1977) Unpublished report from Union Carbide Corporation Alleged Human Overexposure Cases Reported from Use of Temik Formulations - 1976 to 1979. (1979) Unpublished report from Union Carbide Corporation Anderson, J.P.E. Factors influencing insecticide degradation by a soil fungus Mucor altermans. Diss. Abstr. Int. 32(6), 3114B-3115B Andrawes, N.R. Dorough, H.W. and Lindquist, D.A. Degradation and Elimination of Temik in Rats. J. Econ. Ent. 60(4):979-987 Andrawes, N.R. and Bagley, W.P. Fate of C14 Temik in cultivated soil. UCC Project Report 9218. May 24 (1968a), Unpublished. Degradation of 2-methyl-2-(methylthio) propionaldehyde-O-(methylcarbamoyl) oxime (Temik) in potato foliage. UCC Project Report 10495, Nov. 11 (1968b), Unpublished. Metabolism of C14 Temik in cotton plants under field conditions. UCC Project Report 10492, Nov. 13 (1968c), Unpublished. Degradation and carry-over properties of 2-methyl-2-(methylthio) propionaldehyde O-(methyl-carbamoyl) oxime (Temik) in soil. UCC Report 104949, Nov. 19 (1968d), Unpublished. Andrawes, N.R., Bagley, W.P. and Herrett, R.A. Metabolism of Temik aldicarb pesticide (2-methyl-2-(methylthio)-propionaldehyde O-(methyl-carbamoyl) oxime in sugar beets. UCC Project Report 12694 May 1 (1970), Unpublished. Fate and carryover properties of Temik aldicarb pesticides. J. Agr. Food Chem. 19(4), 727-730 Metabolism of 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) Oxime in potato plants. J. Agr. Food Chem. 19, 731 Andrawes, N.R. The metabolism and terminal residues of Temik aldicarb pesticide in peanut plants under field conditions. UCC Project Report 17613, Sept. 14 (1972), Unpublished. Andrawes, N.R. The metabolism of (UC 21865) Sulfocarb Pesticide in the Rat. 1977 Unpublished report from Union Carbide Corporation. Bartley, W.J., Andrawes, N.R., Chancey, E.L., Bagley, W.P. and Spurr, H.W. The metabolism of Temik aldicarb pesticide in the cotton plant. J. Agr. Food Chem. 18, 454 Bull, D.L., Lindquist, D.A. and Coppedge, J.R. Metabolism of 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (Temik US-21149) in Insects. J. Agr. Food Chem. 15(4): 610-616 Bull, D.L. Metabolism of UC 21149 (2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime in cotton plants and soil in the field. J. Econ. Entomol. 61, 1598 Bull, D.L., Coppedge, J.R. and Ridgway, R.L. Fate of Temik in soil with special reference to chemical changes, movement and volatization. USDA, College Station Project Report (1968), Unpublished. Bull, D,L., Stokes, R.A., Coppedge, J.R. and Ridgway, R.L. Further studies of the fate of aldicarb in soil. J. Econ. Entomol. 63(4), 1283-1289. Burrows, I.E., Haynes, G., and Roberts, N. Determination of Exposure Levels in Operators to Temik during Field Trials. (1970) Unpublished report from Huntingdon Research Centre submitted by UCC. Carpenter, C.P. Comparison of the Acute Toxicity of Compound 21149 with Several of its Analogues. 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Haines, R.G. Ingestion of Aldicarb by Human Volunteers: A controlled Study of the Effect of Aldicarb on Man. (1971) Unpublished report from UCC submitted by UCC. Heungers, A. The Influence of some pesticides in the soil fauna in Azalea culture. Ueded, Fac. Landbonwivet. Ryksuniv, Gent, 35(2), 717-729. Hicks B.W., Dorough, H.W. and Mehendale, H.M. Metabolism of Aldicarb Pesticide in Laying Hens. J. Agr. Food Chem. 20(l): 151-156. Iwata Y., Westlake, W.E., Barkley, J.H., Carman, G.E. and Gunther, F.A. Aldicarb residues in oranges, citrus by-products, orange leaves, and soil after an aldicarb soil-application in an orange grove. J. Agr. Food Chem. 25, 933. Johnson, H.E. and Carpenter, C.P. Temik (Technical Grade Compound 21149). Demyelination Potential in Chickens. (1966a) Unpublished report from Mellon Institute submitted by Union Carbide Corporation. Temik (Technical Grade Compound 21149). Comparative Behavioural effect in Rats. (1966b) Unpublished report from Mellon Institute submitted by UCC. Johnson, H.E., and Sullivan, L.J. Studies on an Effective Therapy for Overdoses of Temik, Temik Sulfoxide, and Temik Sulfone in the Rat. (1968a) Unpublished report from Mellon Institute submitted by UCC. Temik (UC 21149) Antidotal Therapy in Rats Following Administration of Multiple Lethal Doses. (1968b) Unpublished report from Mellon Institute submitted by UCC. Knaak. J.B., Tallant, M.J. and Sullivan, L.J. The Metabolism of 2-Methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime in the Rat. J. Agr. Food Chem. 14(6):573-578. Maitlen, J.C. McDonough, L.M. and Berosa, M. Determination of residues of 2-Methyl-2(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (UC 21149), Temik) and its sulfoxide and sulfone by gas chromatography. J. Agr. Food Chem. 16, 549. Rapid method for the extraction, cleanup and GC determination of toxic residues of Temik. J. Assoc. Official Anal. Chem. 52, 786. 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See Also: Toxicological Abbreviations Aldicarb (EHC 121, 1991) Aldicarb (HSG 64, 1991) Aldicarb (ICSC) Aldicarb (Pesticide residues in food: 1982 evaluations) Aldicarb (Pesticide residues in food: 1992 evaluations Part II Toxicology) Aldicarb (IARC Summary & Evaluation, Volume 53, 1991)