PHOSMET JMPR 1978 Explanation This compound was evaluated by the 1976 Meeting (FAO/WHO, 1977b) but no acceptable daily intake could be allocated in the absence of the required full toxicological data. Although available residue data were sufficient to allow some guideline levels to be recorded, more detailed data from supervised trials on fruit and forage crops were requested. The data received in response to these requests are reviewed in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, distribution and excretion Phosmet is rapidly absorbed, translocated and excreted in mammals. Following a single oral administration of 14C (Carbonyl-labelled) phosmet to rats at doses ranging from 23 to 35 mg/kg body weight, phosmet was eliminated rapidly (within 48 hours) via the urine, greater than 75%) and feces (Ca 16%). Tissue residues accounted for a very small portion (less than 3%) of the Phosmet administered. The radiolabelled residue was fairly uniformly distributed among many tissues. The gonads and fat contained exceptionally low levels. Essentially no cleavage of the carbonyl carbon of the phthalimide, group occurred as no 14CO2 was observed. These data suggested the rapid absorption, distribution and elimination of phosmet in mammals (Ford et al., 1966) Phosmet was administered orally or by direct intra-amnionic injection to rats in the final stages of pregnancy. Phosmet was detected in fetuses following oral administration and in fetuses in the uterine horn opposite of the site of intra-amnionic injection. These studies readily demonstrated the rapid absorption as well as the placental passage of phosmet (Ackermann et al., 1976). Biotransformation Following oral administration of phosmet to pregnant rats and following injection directly into the fetus, metabolic (primarily hydrolytic) products were rapidly noted. These products, small amounts of the oxygen analog and the hydrolytic derivatives were observed and were further degraded. Phosmet was also rapidly metabolized in the fetus following direct injection into the fetus. Thus, fetal tissues have the capacity to rapidly metabolize phosmet which may pass the placental barrier during latter stages of pregnancy (Ackermann et al., 1976). In further characterization of the metabolites, the presence of phthalimide was noted which was further observed to breakdown to phthalic acid. All of these metabolites ware proposed for fetal tissue metabolism (Ackermann et al., 1978). Examination of urine and faces of rats treated with phosmet (oral administration, 27 mg/kg body weight) suggested that metabolic breakdown in vivo occurred primarily via hydrolytic pathways and is believed to resemble degradation products from many other organophosphorus pesticides. The major phosmet metabolite, identified in urine of both sexes, was phthalamic acid. Phthalic acid and a small number of unidentified minor metabolites. Oxidative conversion, in vitro, of phosmet to its oxygen analog was shown to occur in the presence of an active microsomal oxidation system (McBain et al., 1968). In cotton plants, following surface application to leaves, the major metabolites of phosmet were found again to be phthalic and/or phthalamic acid, benzoic acid and possibly some benzoic acid derivatives. It was suggested that oxidation in the plant to the active oxygen analog was bypassed in favor of hydrolysis as the oxygen was not found in plant extracts (Menn and McBain, 1964). Acute Toxicity Following acute intoxication with phosmet the typical parasympathomimetic signs of poisoning, generally seen with other anticholinesterase agents, were observed. The onset of signs of poisoning was rapid, generally within the first one-half hour after treatment and included: tremors, salivation, lacrimation, mastication, exophthalmia, bloody exudate from eyes, nose and mouth, dyspnea, diarrhea, convulsions and death. The sings of poisoning were transient, generally disappearing rapidly within 24 to 72 hours. On gross examination of animals acutely poisoned by gavage treatment, congested lungs and adrenals, discoloration of liver, spleen and kidney and distention and irritation of the GI tract were observed. Phosmet (3 mg technical) active ingredient or 0.1 ml of a 3EV emulsifiable concentrate formulation instilled into the conjunctival sac of rabbits was found to be irritating. The rabbits displayed erythema of the eyelid, vacularization of the sclera and nictitating membrane and lacrimation. The crystalline phosmet did not dissolve readily. The signs of irritation induced by the technical phosmet were transient, disappearing within 24 hours after treatment. The irritation induced by the formulation lasted longer than 7 days (Meyding, 1960; Meyding and Fogleman, 1962). Acute one hour inhalation exposure of male rats to an aqueous emulsion of phosmet at concentrations ranging from 50 to 800 ml/L air resulted in changes in behavior and signs of poisoning ranging from mild tremors and face washing to extreme tremors and distress. Mortality was not noted. Gross examination after a 14 day rest and recovery interval revealed lung, adrenal and pancreatic changes. The lungs were brightly colored (orange red) and the adrenals and pancreas were engorged or hemorrhagic (Hill, 1963). The results of acute toxicity studies are summarized in Table 1. TOXICOLOGICAL STUDIES Acute Toxicity LD50 Species Sex Route Solvent1 (mg/kg) 95% C.L. References Rat M Oral Me Cell 147 Fogleman, 1960 Oral CO 140 76-235 Ford & Fogleman, 1962 Oral Me Cell 220 180-268 Ford & Fogleman, 1962 Oral Me Cell 245 161-367 Meyding, 1963 Oral Me Cell 242 192-305 Meyding, 1963 Oral Me Cell 304 261-356 Meyding, 1963 Oral Me Cell 310 267-360 Ray, 1064 F Oral PEG 271 200-369 Johnston, 1963a oral PEG 369 271-501 Johnston, 1963a oral PEG 316 Johnston, 1963a oral PEG 224 176-286 Johnston, 1963a M IP Me Cell 100 Meyding, 1965a SC Me Cell 1200 Meyding, 1965a Mouse M Oral Me Cell 50.1 34.4-73.0 Meyding, 1965a M oral Polysorbate 80 25.2 22.9-27.7 Haley et al., 1975 F Oral Polysorbate 80 23.1 22.2-24.0 Haley et al., 1975 M IP Me Cell 40-50 Meyding, 1965a M SC Me Cell 300 Meyding, 1965a Rabbit M&F Dermal CO 3160 Meyding, 1960 (intact skin) LD50 Species Sex Route Solvent1 (mg/kg) 95% C.L. References Emulsifiable Concentrate Rat M Oral Socal #2 623 Ray, 1963a M Oral Water 501 344-730 Ray, 1963b Water 316 Meyding, 1965b Water 596 409-868 Meyding, 1965b Mice M Oral Water 96 79-116 Ray, 1963b Rabbit M&F Dermal None 1560 633-2220 Meyding & Fogleman, 1962 Wettable Powder Rat M Oral Water 223 143-378 Anonymous, 1963 Mice M Oral Water 108 74-157 Anonymous, 1963 Rat M Oral Water 275 245-308 Bullock & Kamienski, 1972 Rat F Oral Water 258 239-289 Bullock & Kamienski, 1972 Rabbit - Dermal Neat 4640 1Me Cell = Aqueous Methyl Cellulose CO = Corn Oil PEG = Polyethylene Glycol 300 Special studies Hen - Delayed Neurotoxicity Groups of white leghorn hens (10 hens per treatment group, 3 hens were used as a negative control) were fed dietary levels of phosmet at dose levels of 0, 100, 316 and 1000 ppm over a six week period. A positive control group was fed tri-o-cresyl phosphate (TOCP) at a dietary level of 1000 ppm over the same time interval. At the conclusion of the study surviving hens were sacrificed and histological examinations of the spinal cord, brain and sciatic nerve were performed following H&E staining of these tissues. A delayed neurotoxic response was not observed either clinically of histologically over the course of the study as a result of the presence of phosmet in the diet. The presence of TOCP in the diet resulted in ataxia and paralysis. Both clinical and histological examinations confirmed this event. Based upon this dietary study it was concluded that there was no delayed neurotoxic potential for phosmet (Johnston, 1963b). Potentiation Technical phosmet was tested alone and in combination with seventeen anticholinesterase insecticides (one carbamate and sixteen organophosphate esters) in an effort to evaluate its additive or potentiating effect. Groups of rats (5 females rats/group) were used to evaluate the potentiation. Mortality ratios were calculated from the toxicity of phosmet administered alone or in combination with another anticholinesterase agent at one-half or one-fourth of the respective LD50 value. Greater than additive mortality was observed with several other compounds when dose levels of one-half of the acute LD50 level were employed. However, when the dose level was reduced to one quarter of the LD50 potentiation was observed only with one organophosphate, fenchlorphos (Ronnel). The potentiation effect with fenchlorfos was, however, questionable because of possible interference from solvent effects (Johnston, 1963a). Mutagenesis Phosmet was tested for mutagenicity using a series of in vitro microbial assays. At levels up to 20 micrograms dissolved in DMSO, without metabolic activation, phosmet was inactive when tested against B. subtillis (H17 - Rec + and M45 - Reco-): E. coli B/r WP2hr+ and WP2hcr-, 2 tryptophan- requiring mutants and S. typhimurium (TA 1535, TA 1536, TA 1537 and TA 1538) (Shirasu, 1975, Shirasu et al, 1976). Teratology Rats Groups of CD rats (group size varied from 9 to 32 individuals/group) were either administered phosmet in the diet at concentrations yielding daily doses of 0, 10, 20, 27 and 29 mg/kg body weight or by gavage at doses of 0, 5, 10, 20, 25 and 30 mg/kg body weight from day 6-15 of gestation. Day 1 of gestation was the day semen was detected. The unusual dosage levels of the dietary treatment were a result of food rejection and correspond to actual intake of phosmet calculated from diet consumption data. On day 21 of gestation, the rats were sacrificed and fetuses examined for external and internal malformations. Maternal toxicity was evident in the two highest dietary levels. Food consumption was decreased and no weight gain was recorded at these two levels. There was no indication of fetal toxicity as measured by mortality, fetal weight or an overall incidence of malformation. Maternal mortality was evident at the two upper dose levels administered by gavages Against the incidence of fetal mortality and malformation was not significantly increased even in the presence of severely adverse maternal effects. There was no evidence of somatic or skeletal abnormalities in the pups attributable to the administration of phosmet (Staples et al., 1976). Groups of wistar rats (group size varied from 9 to 13 pregnant females/group) were administered phosmet orally by gavage at a single dose of 30 mg/kg (9 females) on day 9 of gestation; at a single dose of 30 mg/kg (8 females per dose) on day 13 of gestation; at doses of 0.06 or 1.5 mg/kg body weight (10 females/group) every other day throughout pregnancy. Day 1 of gestation was the day semen was detected. Suitable groups of controls varying from 10 to 13 animals per group were used to compare results (it was not indicated whether controls were administered solvent (not specified) or were not treated). Administration of phosmet on day 9 of pregnancy resulted in an insignificant increase in post implantation mortality of embryos and malformations described as hypognathia, edema and dislocation of extremities. Administration on day 13 of pregnancy did not affect mortality but did induce hydrocephaly in 33 of 55 embryos examined. Administration of phosmet (1.5 mg/kg bw every other day throughout pregnancy) resulted in a reduction in the number of live fetuses and the occurrence of hydrocephaly and subcutaneous hemmorhages. Embryo toxicity was a dose-dependent occurrence as it was not noted at the lowest concentration (0.06 mg/kg body weight) examined (Martson and Voronina, 1976). Monkey Groups of rhesus monkeys (Macaca mulatta, 7 pregnant females per group) were administered phosmet by gavage from days 22 through 32 of gestation at dose levels of 2, 4 and 8 mg/kg/ day. The females had previously borne normal young and served as their own controls in the study. A positive control was included utilizing various dose levels of thalidomide (5 or 10 mg/kg/day) administered on days 22 through 32 of gestation or (10 mg/kg/day) administered an days 25, 26 and 27. Malformations were observed in all fetuses delivered to females administered 10 mg thalidomide kg/day during days 25-27 of gestation. Administration of thalidomide from days 22-32 of gestation resulted in abortion of all parents with an exception being noted at the high dosage level (10 mg/kg/day) where 2 of 4 fetuses conceived were delivered. These fetuses were malformed. Over the entire course of this study all fetuses delivered to parents treated with thalidomide displayed various degrees of abnormality. In contrast, all fetuses delivered to females treated with phosmet showed no abnormalities. Two females at the low doses and one female at the high dose group aborted during the course of this study, All other females delivered live viable fetuses which were anatomically normal. There was no indication of a teratogenic event as a result of administration of phosmet during the sensitive period of organogenesis in the rhesus monkey (Courtney and Finkelstein, 1968). Rabbit Groups of pregnant rabbits (5 rabbits/group) were orally administered phosmet by gavage at levels of 0 or 35 mg/kg/day from day 7-12 of gestation. The day of mating was considered as day zero for calculation of gestation. There were no differences observed in the reproductive parameters (implantation, resorption, litter size, litter weight) and abnormalities were not observed over the course of the study. In contrast, a positive control using thalidomide administered orally at a dose of 150 mg/kg during the same period of gestation resulted in a significant number of malformed fetuses (Fabro et al., 1965). Reproduction Rabbit Groups of rabbits (10-12 males and 10-13 females/group) were administered phosmet either in the diet or by dermal application for three weeks prior to mating and thereafter for 18 consecutive days of gestation. Rabbits subjected to dietary administration were fed dosage levels of 0, 10, 30 and 60 mg/kg/day, 7 days per week. Rabbits subjected to dermal application received a dose of 0, 10, 30 and 60 mg/kg/day 5 days per week for the same treatment interval. At the conclusion of the study, day 29 of gestation, pups were delivered by Caesarian section. Gross and microscopic examination of tissues and organs of parental animals and gross and skeletal examinations of pups were performed. Cholinesterase activity of females, performed during the course of the study, was depressed confirming that exposure to phosmet had occurred. Depression of cholinesterase was evident at all dose levels in animals administered phosmet by both the dermal and dietary route. There was no mortality observed in the study attributable to phosmet. A slight reduction in growth was observed at the highest dose level in animals of both the oral and dermal treatments. Gross and microscopic examination of tissues and organs of the parents showed no effects of the administration of phosmet. Reproductive parameters were not affected by phosmet and teratogenic events were not observed over the course of this study. Dietary and dermal administration of phosmet at dose levels of 60 mg/kg/body weight per day prior to and during mating and over the entire period of gestation, did not affect reproductive parameters in rabbits and induced no teratogenic event in offspring (Kidwell et al., 1966). Rat Groups of rats (20 males and 20 females/group) were fed dietary concentrations of phosmet and utilized in a standard three-generation, two-litter generation, reproduction study. Two groups of rats were used in the first generation and three groups were used for the second and third generations. The first generation, consisting of two complete litters, were fed dietary concentrations of 0 and 40 ppm. Immediately after weaning the test material was withdrawn for 3-4 weeks. The second and third generations were fed dietary concentrations of 0, 40 and 80 ppm, the latter group being derived from offspring of parents previously fed 40 ppm in the diet. The first litters of each generation were sacrificed at weaning and the second litter was used as the parental group of the following generation. At weaning of the accord litter the parental animals were discarded. A 2-9 day withdrawal period from the phosmet diet occurred immediately after weaning. At the conclusion of the F3b offspring, representatives of the second litter were grossly examined at necropsy and histological examination of selected tissues and organs was made. There were no differences in any of the test and control groups with respect to mortality, survival, general condition, growth and reproductive performance. Malformations were not observed over the course of the study. Gross and microscopic examinations of tissues and organs at the conclusion of the study showed some slight degenerative hepatic changes in both groups fed phosmet in the diet. These changes were believed to be minor and included slight hepatic cell vaculation and reduced glycogen content. Based upon comparison of data from corresponding phosmet-treated and control litters in the three generation reproduction study, the administration of phosmet at 80 ppm in the diet for two generations and 40 ppm in the diet over a single generation (all generations producing two litters) resulted in no effect or any reproductive parameter (Hollingeworth et al., 1965). Short Term Studies Rabbit Groups of rabbits (2 males and 2 females per group) were administered phosmet (an emulsifiable concentrate or wettable powder formulation) dermally five days/week for three weeks. Phosmet was administered to both normal and abraded skin at daily doses of 0, 0.08, 0.16, 0.8 and 1.6 mg/kg/body weight (this dosage of the emulsifiable concentrate corresponds to a concentration of 0, 30, 60, 300 and 600 mg/kg/body weight) and 0, 0.1, 0.5 and 1.0 gms/kg body weight (this dosage of the 50% wettable powder formulation corresponds to a concentration of 0, 50, 250 and 500 mg/kg body weight). Mortality was evident with the emulsifiable concentrate as all animals dosed at 600 mg/kg died and three out of four animals treated with 300 mg/kg also died within the first week. Animals dosed at the two intermediate dose levels lost weight. No effects were seen at the lowest dose level. Repeated application of the emulsifiable concentrate produced thickening of the skin in the treated area followed by a dry, scaly condition. Cholinesterase depression was observed at all dosage levels and did not appear to be affected by skin abrasion. Cholinesterase depression was noted at 60 mg/kg body weight with the emulsifiable concentrate. Cholinesterase was not depressed at 50 mg/kg body weight when the wettable powder formulation was used. These data suggested differences in dermal absorption or penetration patterns with the two formulated materials. Brain cholinesterase evaluated at the conclusion of the study showed significant depression only at 300 mg/kg with the emulsifiable concentrate and at 50 mg/kg with the wettable powder formulation. Gross and microscopic examination of tissues and organs with the exception of dermal thickening, showed no changes attributable to phosmet administration (Hill and Moulten, 1963). Rabbit Groups of rabbits (10 males and 10 females/group, 5 of each sex were used as the controls) were dermally administered phosmet (emulsifiable concentrate formulation, 3-E) at dose levels of 0, 30 and 60 mg/kg/day, 5 days a week for 3 consecutive weeks. Phosmet was again administered to either intact or abraded skin. Mortality was observed in the high dose group with all animals dying within one week having been treated with from 2-4 applications. In the surviving animals no overt signs of poisoning were observed at the low dosage level. Food consumption and body weight was reduced. Dermal irritation was evident with no differences noted in the intact and abraded skin with respect to evaluating the degree of irritation. Hematology and urinalysis determinations at the end of the study were normal. Cholinesterase depression was observed particularly with red blood cell and again no differences were observed in animals with intact or abraded skin. Gross and microscopic examination of selected tissues and organs showed no somatic response to the dermal treatment (Meyding, et al., 1965). In a repeat experiment, groups of male and female rabbits were administered phosmet dermally to intact or abraded skin at dose levels varying from 0 to 300 mg/kg/day, 5 days a week for 3 weeks. Again, mortality was observed at the high dose level and overall results of this experiment confirmed that reported previously. One additional group was used to evaluate the inert ingredients of the emulsifiable concentrate formulation. Irritation of the intact and abraded dermal surface was noted with this formulation suggesting that skin irritation vas a property of the formulation rather than of the active ingredient (Meyding and Horton, 1965). Cattle Groups of steers (15 hereford steers/group) were fed phosmet (ProlateR, as a 50% wettable powder) in the diet at concentrations of 0 and 1 mg/kg for 8 weeks end thereafter at levels of 0 and 2 mg/kg for an additional 8-week period. There were no adverse effects on behavior, growth and hematological parameters. Whole blood cholinesterase depression was observed at the 2 mg/kg group after 6 weeks of dietary administration. Regeneration of cholinesterase was slow over a 4-week control diet treatment after the 16 week trial (Meyding, 1965c). Rat Two groups of rats (10 males and 10 females per group) were fed varying dietary levels of phosmet over a sixteen week range-finding study. A third group of rats consisting of 10 males and 10 females were designated as controls and fed diets containing no phosmet for the same sixteen week interval. A high level group was fed 800 ppm for three weeks, 1600 ppm for weeks 4-9, 2000 ppm during the tenth week, 3000 ppm during the eleventh week and 6000 ppm from the 12-16 weeks. The low level group was fed 450 ppm for the first three weeks, 900 ppm for weeks 4-9 and 1120 ppm the tenth week and thereafter until the conclusion of the study. Mortality was observed in the high dietary level group where two females died at the sixteenth week. Abnormalities in behavior were observed after the third week where all treated animals appeared to develop a degree of hyperexcitability. By the fourth week, tremors were noted which continued throughout the remainder of the study. Persistent low grade diarrhea occurred in all test animals after the 5th or 6th week. Growth was slightly depressed at fifteen weeks in the low group and was more significantly depressed in the high dose group. Growth depression was associated with decreased food intake after the eight week. Hematological values were normal in all groups. Cholinesterase depression was observed in red blood cell and brain in both groups while plasma cholinesterase was only partially depressed. Gross and microscopic pathological changes were observed. Mean organ weights were increased in the high level. This occurred in liver, kidney, spleen and adrenal gland. In addition, testes weight was increased in both treatment groups. There were some additional gross events noted in the low level group. Histologically, hepatic degenerative changes were noted particularly in the high level. To a lesser degree these changes were observed in the low level animals. Adrenal hypertrophy use also reported. In this range finding study it was observed that high levels of phosmet in the diet resulted in significant toxicological effects (Johnston, 1963c). Rat Groups of rats (30 males and 30 females per group) were fed phosmet in the diet at concentrations of 0, 20, 100 and 500 ppm for periods varying from 19-24 weeks. The animals were fed a constant dietary preparation over the course of this study. There was no mortality attributable to the presence of phosmet in the diet. Growth, as evidenced by weight gain, was reduced in males at 500 ppm. Females were not affected. General appearance and behavior of all animals over the course of the study was unaffected by the presence of phosmet. Hematological evaluations made periodically over the course of the study were within normal limits. Cholinesterase activity was depressed at the dietary levels of 100 ppm and above. Red blood cell cholinesterase was significantly more depressed than was plasma. Brain cholinesterase, examined in a selected group of animals at thirteen weeks, was found to be depressed in a manner similar to that observed with cholinesterase from red blood cells. Gross and microscopic examination of tissues and organs, performed on a small group of animals sacrificed at fourteen weeks, showed no outstanding abnormalities attributable to the presence of phosmet in the diet. Based upon cholinesterase depression observed at 100 ppm, 20 ppm phosmet in the diet was considered to be a no-effect level (Johnston, 1962). Dog Groups of beagle dogs (4 males and 4 females per group) were fed dietary concentrations of phosmet at dosage levels of 0, 10, 75 and 563 ppm. Growth and behavior over the course of the study were unaffected by the presence of phosmet in the diet. Hematological and blood chemistry determinations were made periodically during the course of the 20 week study. With the exception of blood cholinesterase activity, all values were normal. Plasma and red blood cholinesterase (and brain cholinesterase at the conclusion of the study) were significantly inhibited by 563 ppm phosmet in the diet. At 75 ppm in the diet the red blood cell was slightly depressed in females. Plasma cholinesterase activity was not depressed at this dose level. Gross examination of tissues and organs performed at the fourteen week interval showed a slightly increased kidney and adrenal organ weight at the high dose level. Microscopic examination of sections of tissues and organs suggested no cellular changes attributable to the presence of phosmet in the diet (Johnston, 1962). Dog - Two Year Study Groups of purebred beagles (3 males and 3 females/group) were fed dietary concentrations of phosmet for two years. Phosmet was mixed with a dry diet at concentrations yielding 0, 20, 40 and 400 ppm. With the exception of one dog, which was sacrificed in extremis at one year of age, there was no mortality observed over the course of the study. Growth, as evidenced by body weight changes, was unaffected. Hematological values, clinical chemistry values, urinalysis values and physical and physiological measurements taken at periodic intervals and at the conclusion of the study showed no effects due to the presence of phosmet in the diet. Transient physiological evidence of the presence of an anticholinesterase agent in the diet was sporadically reported as lacrimation and diarrhea noted in the treated groups. Red blood cell, plasma and brain cholinesterase activity (brain cholinesterase activity was recorded only at the conclusion of the study) showed a distinct effect of phosmet at 400 ppm in the diet. Depression of red blood cell and brain cholinesterase activity was observed. Cholinesterase activity at 40 ppm in the diet was normal, Neurological and ophthamological examinations performed at the conclusion of the study were normal. Based upon cholinesterase depression at 400 ppm in the diet, a no-effect level of 40 ppm was observed in the study (Lobdell and Johnston, 1966). Long Term Studies Rat Groups of Charles River rats (25 males and 25 females/group) were fed dietary levels of phosmet for two years at dosage levels of 0, 20, 40 and 400 ppm (the animals were originally fed dietary levels of 0, 10, 20 and 200 ppm for three weeks after which time the dietary levels was increased to compensate for differences in food intake). There was no mortality nor behavioral differences in these animals that were attributable to the presence of phosmet in the diet. Growth was depressed at the dietary level of 400 ppm and was more readily apparent in males. Food consumption was normal in all groups. Hematological parameters, examined at various intervals over the course of the study, were unaffected by phosmet in the diet. Plasma and red blood cell cholinesterase activity evaluated at various time intervals and brain cholinesterase, evaluated at the conclusion of the study, were depressed at the highest dose levels at dietary levels of 40 ppm and below there were no effects on cholinesterase activity. In addition, cholinesterase activity measured initially at 14 weeks, was constant over the course of the study in each of the dietary groups. Gross and microscopic examination of tissues and organs at the conclusion of the study showed no consistent dose-related effects. Histopathological changes noted were common in normal aging rats although a degree of liver cell vaculation, observed 400 ppm, may have been attributable to the presence of phosmet in the diet. There were no differences with respect to neoplasms in the study although a larger proportion of rats sacrificed at the conclusion of the study having been fed 40 ppm phosmet and above showed the presence of pituitary neoplasms. As the frequency of this event was significantly small, no conclusion could be reached. In addition, thyroid adenomas were observed at the 400 ppm group in greater frequency than were noted in other dose groups. Again, the number of animals sacrificed at the conclusion of the study was too small to fully evaluate this parameter. Based upon cholinesterase depression at 400 ppm, a proposed no-effect level would be 40 ppm equivalent to 2 mg/kg/bw/day (Lobdell and Johnston, 1966). Observations in Man No specific studies available. Limited observations of occupationally exposed workers show no adverse effects although depressed peripheral cholinesterase activity suggested that exposure had occurred in some instances. COMMENTS The lipophilic nature of the phosmet molecule allows rapid gastrointestinal absorption and dermal penetration but is not of such a nature to suggest bioaccumulation in adipose tissue. Phosmet in rapidly translocated in the body, metabolized and excreted. The metabolic products in mammals and plants appear to be similar and are well defined. The acute toxicity of phosmet has been evaluated and data have been presented to demonstrate its anticholinesterase activity and parasympathomimetic properties. It is moderately toxic on an acute basis. Short term studies, in vitro bioassays for potential mutagenic hazard and delayed neurotoxicity have been negative. Teratology bioassays using a variety of species and protocols have, with one exception, been negative. A teratological response in rat for phosmet using a protocol not generally followed by other investigators, has shown effects at exceptionally low levels. A no-effect level of 0.06 mg/kg noted in this teratology bioassay was of significant concern to the Meeting. These teratology results served as a basis for applying an unusually large safety margin to the allocated temporary ADI. In another study in rat using high dose levels and a longer treatment interval, data showed no teratological response. Negative results obtained in the rat study and in a primate teratology bioassay did not fully reduce the concern raised above with respect to the teratogenic potential of phosmet. Short term and long term bioassay programmes in dogs and rats have shown no significant effects on a variety of physiological biochemical and pathological parameters. As expected, a sensitive indicator of effect, cholinesterase depression was observed at high dietary levels in all tests. Growth depression and cholinesterase activity depression in two species served as the basis for estimating the no-effect level. TOXICOLOGICAL EVALUATION Level causing no significant toxicological effect in animals Rat: 40 ppm in the diet equivalent to 2.0 mg/kg bw Dog: 75 ppm in the diet equivalent to 1.9 mg/kg bw Estimate of temporary acceptable daily intake for man 0 - 0.005 mg/kg body weight RESIDUES IN FOOD AND THEIR EVALUATION RESIDUES RESULTING FROM SUPERVISED TRIALS Potatoes Supervised trials of spray applications of phosmet to potatoes at six sites in the USA and five sites in Canada in 1970 yielded only one result (at 0.04 mg/kg) above the detection limit of 0.02 mg/kg for either the parent compound or its oxygen analogue (Stauffer, 1970). Sweet potatoes Supervised trials of dust and dip treatments of stored sweet potatoes yielded residues of phosmet which ranged up to 203 mg/kg. Most results on unwashed tubers were in the range 50 to 100 mg/kg; washing the tubers reduced the residue to between 2 and 10 mg/kg. The bulk of the residue remains in the peel, levels in the edible pulp being generally below 1 mg/kg (Stauffer, 1972). Apples and pears Additional data on residues in apples grown in Czechoslovakia (Batora, 1978) have confirmed those reported by the 1976 Meeting, observed levels ranging from 0.80 mg/kg just after treatment to 0.10 mg/kg 18 days later. Similar residues (0.85 to 0.11 mg/kg were observed on pears. Apricots and nectarines Data on residues of phosmet on apricots and nectarines (Stauffer, 1968) showed that levels were similar to those reported in 1976 for residues on peaches; they were below 5 mg/kg 7 days after treatment and below 1 mg/kg after 21 days. Grapes Grapes treated with phosmet showed residues up to 15 mg/kg most results lying in the range 1 to 8 mg/kg and showing limited diminution with time up to 28 days after treatment (Stauffer, 1969). Kiwifruit Kiwifruit (Actinidia chinensis) is a major horticultural product exported from New Zealand. Because of the hairy nature of its skin, pesticide spray residues are retained to an appreciable extent. Data reported by the 1976 Meeting showed that residues of phosmet ranged up to 25 mg/kg, though most results were below 10 mg/kg. Further recent information has shown that most of this residue (ca 90%) is associated with the inedible skin, levels in the fruit pulp being in the range 0.3 to 2.5 mg/kg with a mean of 1 mg/kg (Love et al., 1978). These data have been supported by monitoring studies, results from 57 samples examined in 1975, 1977 and 1978 ranged up to 23 mg/kg with a mean value of 4 mg/kg (New Zealand, 1978). Citrus fruit Residues of phosmet on grapefruits, lemons and oranges, ranged from 0.6 to 4 mg/kg at a pre-harvest interval of 7 or 8 days, most being between 1 and 3 mg/kg. Studies on oranges and grapefruits showed that nearly all of the residues in the peel, very little appearing in the flesh or the juice. The proportion of the total residue occurring as the oxygen analogue varied widely, from 1 to over 50% (Stauffer, 1974). Maize (field corn) On maize ears (i.e. kernels plus cob with husks removed) phosmet residues were generally below 0.05 mg/kg but ranged up to 0.2 mg/kg; residues in the stalks were appreciably higher, reaching 12 mg/kg (Stauffer, 1974). Nuts Data were available on phosmet residues in almonds, filberts, pecans and walnuts (Stauffer, 1974). Residues in the nut meat were all below 0.08 mg/kg most being in the range 0.01 to 0.05 mg/kg. Residues in almond hulls ranged up to 5.6 mg/kg. Blueberries and cranberries Phosmet residues on blueberries and cranberries showed a similar pattern, ranging from 1 to 7 mg/kg at a 3-day pre-harvest interval (Stauffer, 1974). Peas On peas plus pods, phosmet residues ranged from 0.07 to 0.34 mg/kg at a 7-day pre-harvest interval. Residues in dry peas were not greater than 0.02 mg/kg (Stauffer, 1974). NATIONAL MAXIMUM RESIDUE LIMITS National MRLs reported to the Meeting are given in Table 2. TABLE 2. National MRLs reported to the Meeting Country Commodity MRL, mg/kg Australia Fat of meat of cattle, pome fruit, stone fruit 1 Milk and milk products (fat basis) 0.2 Canada Apples, grapes, peaches, pears 10 Cherries 7 Plums 5 Netherlands Apples, pears 1 Potatoes 0.02 New Zealand Fruit 10 Switzerland Peas 0.1 Pome fruit 1 Potatoes 0.05 USA Alfalfa 40 Almond hulls, apples, blueberries. cherries, corn forage and fodder (including sweet corn, field corn and popcorn), cranberries, grapes, peaches, pears, pea forage and hay, sweet potatoes (from post harvest application). 10 Apricots, citrus fruits, nectarines, plums. 5 Fresh corn including sweet corn (kernels plus cobs with husk removed), corn grain (including popcorn), peas 0.5 Meat, fat and meat by-products of cattle, goats, hogs, horses and sheep 0.2 Potatoes 0.1 Nuts 0.1 (negligible residues) APPRAISAL Some additional data have become available concerning residues of phosmet in several crops. As the Meeting allocated a temporary ADI, the previously recorded guideline levels were converted to temporary maximum residue limits and some additional and amended limits were also recommended. RECOMMENDATIONS The previously recorded guideline levels are replaced by the following temporary maximum residue limits, which now refer to the sum of phosmet and its oxygen analogue. Commodity Temporary MRL, mg/kg Pre-harvest intervals on which limits are based, days Sweet potatoes (washed before analysis) 10 - Kiwifruit 10 10 Blueberries 10 3 Grapes 5 21 Forage crops (dry) 5 14 Citrus fruit 5 7 Cranberries 5 7 Apples 1 21 Apricots 1 21 Nectarines 1 21 Peaches 1 21 Pears 1 21 Fat of meat of cattle 1 - Maize (kernels & cobs, husks removed) 0.2 14 Commodity Temporary MRL, mg/kg Pre-harvest intervals on which limits are based, days Milk products (fat basis) 0.2 - Tree nuts (shelled) 0.1 - Peas (fresh or dried) 0.1 7 Potatoes 0.05 20 Milk (whole) 0.01 - FURTHER WORK OR INFORMATION Required (on or before June 30, 1979) 1. Additional teratogenic studies in rodents. REFERENCES Ackermann, H., Faust, H., Kagan, Y.S. and Voronina, V.H. (1978) Metabolic and toxic behaviors of phthalimide derivatives in albino rat. II Placental Passage of chloromethyl phthalimide oxymethylphthalamide and phthalimide their fetal metabolism. Arch Toxicol. 40/255-261. Anonymous, Imidan 50W. Unpublished report from Toxicology Section, (1963) Stauffer Chemical Co. submitted by Stauffer Chemical Co. to the WHO. Batora, V. Information on phosmet residues resulting from supervised (1978) trials. Unpublished report. Bullock, C.H. and Kamienski, F.X. Toxicological Laboratory Report (1972) T-4027. Unpublished report from Stauffer Chemical Company, Western Research Centre. submitted by Stauffer Chemical Co. to the WHO. Courtney, K.D. and M. Finkelstein Teratological Investigation of (1968) Captan, Imidan and Thalidomide in Macaca mulatta. Unpublished report from Bionetics Research Laboratories, Inc. submitted by Stauffer Chemical Co. to the WHO. FAO/WHO 1976 evaluations of some pesticide residues in food, FAO/AGP: (1977) 1976/M/14. Fabro, S., R.L. Smith and R.T. Williams Embryotoxic activity of (1965) some pesticides and drugs related to phthalimide, Food and Cosmetic Toxicology 3:587. Fogleman, R.W. Acute Oral Administration-Rats. Unpublished report (1960) from Hazelton Laboratories, Inc. submitted by the Stauffer Chemical Co. to the WHO. Ford, I.M., and R.W. Fogleman Acute Oral Administration-Rats, (1962) Unpublished report from Hazelton Nuclear Science Corp. submitted by Stauffer Chemical Co. to the WHO. Fod, I.M., J.J. Menn and G.D. Meyding Metabolism of (1966) N-(mercaptomethyl)-Phthalimide- Carbonyl-C14-S-(O,O-dimethylphosphorodithioate) (Imidan-C14): Balance Study in the Rat. J. Agr. Fd. Chem. 14(1):83-86. Haley, T.J., J.H. Famer, J.R. Harmon and K.L. Dooley Estimation (1975) of the LD1 and Extrapolation of the LD0.1 for Five Organothiophosphate Pesticides. Eur. J. Toxicol. 4:229-35. Hill, R. Aerosol LD50-Rats. Unpublished report from Diablo (1963) Laboratories submitted by Stauffer Chemical Co. to the WHO. Hill, R. and J.E. Moulton 21-Day Subacute Dermal Toxicity (1963) Evaluation. Unpublished report from Diablo Laboratories submitted by Stauffer Chemical Co. to the WHO. Hollingworth, R.L., C.D. Johnston and G. Woodward. Imidan-Three (1965) Generation Reproduction Study In Rats. Unpublished report from Woodard Research Corp. submitted by Stauffer Chemical Co. to the WHO. Johnston, C.D. Imidan-An Evaluation of Safety of Imidan in the (1962) Rat and the Dog. Unpublished report from Woodard Research Corp. submitted by Stauffer Chemical Co. to the WHO. Johnston, C.D. Imidan-Potentiation Studies in the Rat with Other (1963a) Organophosphate Insecticides. Unpublished report from Woodard Research Corp. submitted by Stauffer Chemical Co. to the WHO. Love, J.L., Keating, D.L. and Ferguson, A.M. Residues of phosmet (1978) on kiwifruit (in press). Meyding, G.D. Imidan 3E-Acute Oral LD50 -Rats. Unpublished report (1965) from Toxicology Section, Stauffer Chemical Co. submitted by Stauffer Chemical Co. to the WHO. Meyding, G.D. Toxicity of Prolate an a Feed Additive for Control (1965c) of Cattle Grubs. Unpublished report from U.S. Department of Agriculture, Kerrville, Texas and Toxicology Section, Stauffer Chemical Co. submitted by Stauffer Chemical Co. to the WHO. Meyding, G.D. and R.J. Horton Imidan-21 Day Subacute Dermal Toxicity (1965) in Rabbits. Unpublished report from the Toxicology Section, Stauffer Chemical Co. submitted by Stauffer Chemical Co. to the WHO. Meyding, G.D. T.E. Elward and R.J. Horton 21-Day Subacute Dermal (1965) Toxicity-Rabbits. Unpublished report front the Toxicology Section, Stauffer Chemical Co. submitted by the Stauffer Chemical Co. to the WHO. New Zealand Residues of phosmet in kiwifruit. Unpublished report by (1978) Ministry of Agriculture and Fisheries, Wellington, New Zealand. Ray, D.G. Acute Oral LD50-Male SD Rats. Unpublished report (1963a) from Toxicology Section, Stauffer Chemical Co. submitted by the Stauffer Chemical Co. to the WHO. Ray, D.G. Acute Oral LD50 -Rats and Mice. Unpublished report (1963b) from Toxicology Section, Stauffer Chemical Co. submitted by the Stauffer Chemical Co. to the WHO. Ray, D.G. Acute Oral LD50 -Rats. Unpublished report from (1964) Toxicology Section, Stauffer Chemical Co. submitted by the Stauffer Chemical Co. to the WHO. Shirasu, Y. Significance of Mutagenicity Testing on Pesticides. (1975) Env. Qual. and Safety 4: 226-231. Shirasu, Y., M. Moriya, K. Kato, A. Furuhashi and T. Kada (1976) Mutagenicity Screening of Pesticides in the Microbial Systems. Mutation Res. 40:19-30. Staples, R.E., R.G. Kellam and J.K. Haseman Development Toxicity (1976) in the Rat After Ingestion or Gavage of Organophosphate Pesticides (Dipterax, Imidan) During Pregnancy. Env. Health Perspectives 13:133-140. Stauffer Imidan residues in tree fruits and grapes. Unpublished data (1969) from Stauffer Chemical Co. Stauffer Imidan residues in potatoes. Unpublished data from Stauffer (1970) Chemical Co. Stauffer Imidan residues in sweet potatoes. Unpublished data from (1972) Stauffer Chemical Co. Stauffer Imidan residues in blueberries, citrus, corn, cranberries, (1974) nuts and peas. Unpublished data from Stauffer Chemical Co.
See Also: Toxicological Abbreviations Phosmet (ICSC) Phosmet (JMPR Evaluations 2003 Part II Toxicological) Phosmet (Pesticide residues in food: 1976 evaluations) Phosmet (Pesticide residues in food: 1979 evaluations) Phosmet (Pesticide residues in food: 1981 evaluations) Phosmet (Pesticide residues in food: 1984 evaluations) Phosmet (Pesticide residues in food: 1994 evaluations Part II Toxicology)