PROPARGITE JMPR 1977 IDENTITY Chemical names 2-(4-tert-butylphenoxy)cyclohexyl prop-2-ynyl sulphite 2-(p-tert-butylphenoxy)cyclohexyl propargyl sulphite Synonyms Omite(R), DO 14, ENT 27226 Structural formulaOther information on identity and properties The technical grade material is a light to dark brown liquid of low volatility. It is miscible with most organic solvents. Solubility in water is about 0.5 mg/kg. The basic manufacturer states the composition of the technical product to be: 85% active ingredient 7% "high molecular weight sulphites" 5% "unreacted starting materials" 1% propylene oxide stabilizer (remainder unidentified) Propargite is commercially available in 68.1% and 755% emulsion concentrates, a 30% wettable powder, and a 4% dust. The manufacturer states that the technical product shows no degradation after 12 months when stabilized with propylene oxide. The odour of SO2 indicates breakdown. The product was introduced in the U.S.A. on an experimental basis in 1967 as a replacement for Aramite, another product of the same manufacturer, which was withdrawn from use on food crops in the U.S.A. The two compounds have similar chemical structures and properties. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, distribution, excretion and biotransformation Extensive degradation of propargite could be shown in in vitro as well as in vivo experiments. In vitro studies with liver homogenates showed that the major primary metabolites appear to be propargyl alcohol, the glycol ether and their conjugates, which are further degraded to secondary metabolites (Sullivan, 1968). In in vivo metabolism studies in rats that were orally treated with a single dose of 200 mg/kg propargite, propargyl alcohol and glycol ether were also found as primary metabolites in the excreta as well as in tissue samples. Following analysis of the excreta and tissues only about 5% of the administered dose was accounted for as unchanged propargite or the primary metabolites, indicating that the primary metabolites are further degraded (Sullivan, 1968). The oral administration of a single close of 271 mg/kg benzene ring labelled 140 propargite to rats was followed by fast excretion of the radiocarbon. Within 72 hours postdosage, 47% of the administered dose was eliminated via the urine. 32% via the faeces. The total carcass contained approximately 90% of the administered radioactivity. Identified metabolites excreted with the rat urine and faeces were tert-butylpyrocatechol and glycol ether (Ryer and Sullivan, 1969a) In cows treated with a single oral close of 4 mg/kg b.w. combined non-radioactive and 14C labelled propargite a similar excretion pattern was found. 54% of the administered dose was eliminated with the urine, 17% with the faeces. Approximately 0.3% was found in the milk. Identified metabolites were tert-butylpyrocatcohol, glycol ether and tertbutylphenol (Ryer and Sullivan, 1969b). In a feeding study, dairy cows were maintained on a diet containing 14C-labelled and unlabelled propargite at dosage levels of 3 and 20 ppm for 12 consecutive days. Peak urinary excretion observed at the seventh test day reached values of 4 and 23 mg/kg respectively for the 3 and 20 ppm dietary level; peak faecal excretion was approximately 1 and 4 mg/kg. Maximum milk residue values reached on the fourth test day were 0.02 and 0.06 mg/kg at the 3 and 20 ppm dose levels respectively. Residues in selected tissues ranged from 0.02 to about 1.3 mg/kg (Kennedy et al., 1970). Similar results were obtained after daily administration of a diet containing 50 and 100 ppm propargite to lactating cows for a period of 27 days (Smith and Roger, 1975). Pigs were maintained on a diet containing propargite at dosage levels of 20 and 100 ppm for 30 days. Residues in kidney and liver were below the detection limit of 0.1 mg/kg at both feeding levels and residues in muscle and fat ranged from below 0.1 to about 2 mg/kg (Ladd et al., 1974). Residues studies in hens that were treated with 3, 10 and 30 ppm 14C propargite in their diet for 30 days showed residue levels in eggs from 0.13, 0.49 and 0-145 µg/kg respectively at the 3, 10 and 30 ppm dose levels. Residues in muscle ranged from 2-12 µg/kg, liver 18-174 µg/kg kidney 2-25 µg/kg and fat 7-116 µg/kg depending on exposure level (Jenkins et al., 1972). After continuous exposure to a concentration of 0.025 mg/l 14C propargite in water for 35 days tissue residues in edible portions of fishes were about 2 mg/kg. After transfer to uncontaminated water 70% of the radioactivity present in the edible tissues was eliminated within 14 days (Sleight III, 1972), The in vivo metabolism studies in several animal species confirmed the rapid degradation of propargite already shown in in vitro experiments. The metabolic reactions are hydrolysis of the parent ester followed by other cleavage. The formed products are polar alcoholic and phenolic compounds which can rapidly be excreted or further metabolized and incorporated into natural tissue constituents by biochemical reactions which are well documented in the literature. See also the section "Fate of residues", "In animals". TOXICOLOGICAL STUDIES Special study on teratogenicity Female rats were orally dosed with 0, 50 and 100 mg/kg from day 6 through 15 of gestation. The treatment had no effect on maternal body weight, mortality or fertility. No reproductive adverse effects were found with respect to implantation and resorption sites. Embryonic and foetal development was not affected by the treatment (Haley et al., 1972). Special study on reproduction Rat See "Long term study". Special study on carcinogenicity Rat See "Long term study". Dog See "Short term study". Acute toxicity Species Sex Route LD50 References mg/kg Rat M, F oral approx. 2200 Carson, 1963 Rabbit M, F dermal approx. 3200 Weir, 1967 Rat Groups of 5 male and 5 female rats were treated for 90 days with amounts of propargite in their diet to provide daily intakes of 10, 20, 40, 100 and 200 mg/kg b.w. corresponding to dietary levels in adult animals of 200, 400, 800, 2000 and 4000 ppm respectively. The control group existed of 15 male and 15 female rats. Treatment with 2000 and 4000 ppm caused a dose-related growth retardation and reduction of food intake. Haematological examinations and clinical chemistry tests revealed no abnormalities. At 2000 and 4000 ppm the relative liver weights were increased, the relative kidney weights were increased only in the 4000 ppm groups. Gross and microscopic examinations of tissues disclosed no treatment-related pathological alterations (Carson, 1964). Dog Groups of 3 male and 3 female dogs were maintained on a diet containing propargite at dose levels of 0 and 2000 to 2500 ppm (increase of dosage after 3 weeks) for 90 days. The treatment did not affect appearance, behaviour, results of haematological. and clinical chemistry tests and urinalyses. In most treated dogs reduced food consumption and body weight loss and an increase of relative liver and kidney weights were observed, No compound-related alterations were found macroscopically. Histopathological examinations revealed an increased amount of pigment in the liver reticuloendothelial cells and increased haemosiderosis of the spleen (Holsing, 1968). Groups of 8 dogs were fed a diet containing propargite at 100, 300 and 900 ppm for 24 months. The control group consisted of 12 animals. The treatment had no effect on growth rate, results of clinical laboratory studies, urinalyses and organ weights. Gross and microscopic examination did not reveal abnormal pathological findings. No tumours were found (Osert 1966). Long term Study Rat Groups, each comprising 25 male and 25 female rats were fed dietary levels of propargite to provide daily intakes of 5, 15 and 45 mg/kg b.w. corresponding to adult levels of 100, 300 and 900 ppm for a period of 24 months. The control group consisted of 37 animals of each sex. After 26 test weeks without noticeable evidence of a treatment-related effect, a supplementary study was started with a control-and a test group comprising 25 male and 25 female rats receiving 100 mg/kg b.w. corresponding to 2000 ppm for 78 weeks. Rats that died during the study and those sacrificed after 104 and 78 weeks were examined grossly and microscopically. The treatment had no effect on appearance, behaviour, growth rate and mortality at the dietary levels up to and including 900 ppm. At the 2000 ppm level at the end of the study there was a reduction of food consumption and also a reduction of the body weight gain of about 30%; mortality of the male rats increased to 32% compared to 7% of the corresponding control. Haematological examinations and clinical laboratory studies did not reveal abnormal findings. Absolute and relative liver and kidney weights of the animals treated with dietary levels of 100, 300 and 900 ppm which died or were sacrificed after 104 weeks showed inconsistent variations without any dose-relationship. At 2000 ppm an increase of the relative liver and kidney weights of about 30%. were observed. Gross autopsy findings in 1 male (of 25) and 7 females (of 23) in the 2000 ppm group were enlarged and/or dark red lymph nodes which in some cases were involved in abdominal masses. In the corresponding control group 2 male rats of 29 animals showed this alteration. No dose-dependent increase of the frequency of this lymph node alteration was found at the 100, 300 and 900 ppm levels. A variety of benign and malignant tumours was observed in the control and treated groups. No dose-relationship of the frequency of tumours was found. Four sarcomas were found in rats sacrificed after 78 weeks ingestion of 2000 ppm, whereas in the corresponding control group no sarcomas were seen (Oser, 1966). Additionally a 3-generation reproductive was included in the 2-year feeding experiment with 20 pairs of male and female rats from the control and 100 ppm test groups. Dosage was raised to 300 ppm in the F2 pups at the time of weaning. The treatment revealed no abnormal findings (Oser, 1966). COMMENTS Propargite is readily absorbed from the gastrointestinal tract and is excreted rapidly as metabolites which are formed mainly by hydrolysis of the sulphite ester. After feeding a diet containing 20 ppm of propargite the residues in milk or in tissues were of the order of 0.1 mg/kg. The compound is not teratogenic in the rat. In a 3-generation reproductive study no adverse effects were revealed at concentrations up to 300 ppm. This concentration is therefore regarded as a no-effect level. In a 2-year feeding study with up to 900 ppm in dogs which included extensive laboratory and histological investigations, no adverse effects were noted. A 2-year feeding study in rats up to 2000 ppm showed appreciable but not dose-related variations in the relative liver and kidney weights in all treated groups. However, no major adverse effects were seen. Owing to a poor survival rate and the termination of the study with the high dose animals after 78 weeks, the finding that the tumour incidence was not elevated is of limited value. This study was not considered to fulfil the criteria for an acceptable lone-term study. Therefore a safety factor of 200 was used. Propargite is structurally related to Aramite, a compound which is suspected of being a carcinogen. Although there are no indications that propargite acts similarly, the need for satisfactory carcinogenicity studies was expressed. TOXICOLOGICAL EVALUATION Level causing no toxicological effect Rat: 300 mg/kg in the diet, equivalent to 15 mg/kg bw Dog: 900 mg/kg in the diet, equivalent to 22 mg/kg bw ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR HUMANS 0-0.08 mg/kg bw RESIDUES IN FOOD AND THEIR EVALUATION USE PATTERN Propargite is an acaracide said to be effective on a variety of mites on food crops and ornamentals. Table 1 shows the use patterns registered in the U.S.A. Information has been received that the product is also used in Italy, Australia, New Zealand, South Africa, Argentina, Mexico, and France. The government of the Netherlands has informed the Meeting that the compound was used until 1976, at which time its use was discontinued. A country statement was received from New Zealand regarding uses and tolerances. The uses permitted in these countries generally parallel those shown in Table 1. Significant exceptions are included in the footnotes. RESIDUES RESULTING FROM SUPERVISED TRIALS A submission to the Joint Meeting contained data from supervised trails on twenty-six crops (Uniroyal, 1977). Most of the trials were conducted in the U.S.A. A country statement was received from New Zealand with data on peaches. Analyses in all U.S. trials, the procedure described under "Methods of residue analysis" (PAM II, 1973). Analyses of untreated controls (crop blanks) were reported in each experiment, along with the recovery of propargite from fortified controls. Controls were generally reported as 0 and recoveries were adequate. A brief discussion of the residue finding for each crop follows. Data are summarized in tabular form when feasible. The use patterns employed in Mexico and France on apples, peaches, plums and citrus differed significantly from the other countries. In the absence of residue data reflecting good agricultural practice in those countries, it was not possible to predict residue levels. The recommended DIRLs for apples, peaches, plums and citrus therefore are based on the national use patterns which can be related to supervised residue trails. Alfalfa There are no national tolerances or registrations for propargite use on alfalfa. However, the submission to the Meeting contained some residue data on alfalfa hay, fresh forage and trash. Single and multiple applications were made at 1.4 to 4.7 kg a.i./ha. Residues on fresh forage ranged 0.0 to 328 mg/kg at 28 and 0 day intervals from treatment, respectively. Residues on hay and trash ranged from 2.6 to 100 mg/kg with intervals from treatment of 22 to 52 days. With a 28 day pre-harvest interval, MRLs of 50 and 75 mg/kg on fresh alfalfa and alfalfa hay, respectively, would be adequate. TABLE 1. Registered use patterns for propargite (USA) Application No. of Pre-harvest Crop Formulation rate, a.i. treatments Interval (days) Notes Almond 30% WP 0.03-0.05%(4) 2 28(5) low volume 68.1% EC 2.5-3.4 kg/ha 1 post-harvest aerial application only Apples 30% WP 0.04-0.05(1)(6) 3 7(2)(7)(12) Apricots 30% WP 0.05%(4) 2 14(5) low volume 68.1% EC 1.7-2.5 kg/ha 2 post-harvest aerial application only Cranberries 68.1% EC 1.6 kg/ha 1 14 Beans 75% EC 2.8 hg/ha(4) 2 7(fresh)(5) 28 (dry) Corn 75% EC 1.9 kg/ha 1 30 (field) Cotton 75% EC 0.85-1.9 kg/ha 3 before bolls open Figs 30% WP 0.03-0.05%(3)(4)(11) 2 14 Grapes 30% WP 1.7-3.0 kg/ha 2 21 4% Dust 0.2 kg/ha 2 14 Grapefruit, 75% EC 0.025-0.05(4)(8) 2 7 (5) oranges Lemons 30% WP 0.05% (8) 2 7 Hops 68.1% EC 1.7 kg/ha(4) 2 14 (5) 30% WP 1.7 kg/ha 2 14 Mint 68.1% EC 1.7-2.5 kg/ha 2 14 Nectarines 30% WP 0.05% (4) 2 14 (5) Peaches 30% WP 0.04-0.05%(4)(8) 2 14(5)(10)(13) Peanuts 30% WP 1.0-1.7 kg/ha 2 14 Pears 30% WP 0.04-0.05%(8) Plums 30% WP 0.04-0.05(4)(8) 2 14(5)(10) Potatoes 75% EC 1.4-2.4 kg/ha 2 14 68.1% EC 1.7-2.5 kg/ha 2 14 TABLE 1. (Continued) Application No. of Pre-harvest Crop Formulation rate, a.i. treatments Interval (days) Notes Sorghum 75% EC 1.5-1.9 kg/ha 1 30 silage 60 grain Strawberries 30% WP 1.7-3.4 kg/ha(9) 3 3 4% Dust 1.8 kg/ha 3 3 Walnuts 68.1% EC 0.03-0.05% (4) 2 14 (5) (1) France 0.12, Italy 0.06% (2) France 21, Italy 15, New Zealand 14 (3) France 0.6-0.9 kg/ha (4) Italy 0.06% (5) Italy 21 (6) Mexico 0.08-0.12% (7) Mexico 28 (8) Mexico 0.12% (9) East U.S.A. 0.84 kg/ha (10) Argentina 21 (11) Argentina 0.05% (12) South Africa 14 (13) South Africa 21 Almonds Field trials were conducted in California: 63 samples of nut meats were anlayzed. Residues on the nut meats from two applications of 0.03 and 0.06% sprays were < 0.1 mg/kg at post-treatment intervals of 21 to 28 days. Residues on almond hulls from treatment with 0.05% spray (30% WP) followed by 3.4 kg a.i./ha (68.1% EC) ranged from 5.2 to 31 mg/kg with pre-harvest intervals of 28-35 days. Under good agricultural practice, residues are not likely to exceed 55 mg/kg. Apples Field trials were conducted in nine U.S.A. states, South Africa and Australia, some 452 samples being analysed. The residue data are summarized in Table 2. All controls were reported zero. Residues from applications of up to 0.06% spray after 7 days were less than 3 mg/kg. Residue data indicate that residues remain associated with the apple pomace and are not destroyed in drying. Residues in the juice were barely detectable (ca. 0.02 mg/kg) while residues in the wet and dried pomace were 16-21 mg/kg and 56-80 mg/kg, respectively. Thus, residues concentrate by factors of 15-22 in the manufacture of dried pomace from treated apples (Uniroyal, 1972), An MRL of 80 mg/kg in dried apple pomace is therefore appropriate. TABLE 2. Range of residues in apples, mg/kg. Application rate, Interval (days, last treatment to harvest) % 0-1 6-7 14 21 28 0.03 0.1-3.1 0.6-1.8 0.2-1.0 0.2-0.7 0.2-0.9 0.06 0.3-6.3 0.5-1.6 0.3-2.4 0.5-1.1 0.2-0.6 Apricots, peaches and plums Field trials were conducted in California, Connecticut, Georgia, North and South Carolina, Maryland, Michigan, Pennsylvania, Washington, New York and New Zealand. Some 385 test samples of fresh fruit and 65 controls were anlaysed from one and two applications at four dosage rates, including the maximum and twice the maximum label rates (Table 1). The residue data are summarized in Table 3. Only one residue on peaches was greater than 7 mg/kg at 14 days after treatment at the maximum rate. Residues will not exceed 7 mg/kg from sprays up to 0.06%, provided that treatments are not made within 14 days of harvest. A study was conducted on plums (fresh prunes) using a standard commercial drying process to determine residues on dried prunes. The average residue value for the dried fruit was ca. 20% of the average value for the fresh fruit. Thus no additional MRL is needed for the dried fruit. TABLE 3. Range of residues on apricots, peaches and plums, mg/kg Application rate. Interval (days, last treatment to harvest) % 0-1 6-7 13-14 21-23 0.03 0.4-12 0.2-7.0 0.4-10.0 0.3-5.0 0.05 0.7-6.7 2.6-14.0 0.6-5.6 0.0-1.7 0.06 1.3-17.0 1.3-8.7 0.2-5.5 0.3-9.3 0.10 1.6-27.0 0.3-8.4 0.8-11.0 0.8-3.5 Beans Field trials were conducted in the states of Washington, California and Idaho on snap beans, succulent lima beans and dry beans. 52 analyses were reported. Single and multiple applications were made at the maximum and at twice the maximum label rate (Table 1), by aerial and ground application. The residues are summarized in Table 4 for fresh and dry beans, 7 and 28 days after the last treatment, respectively. No residue data were submitted for bean vines; however there is a restriction against the feeding or foraging of treated bean vines. The only other feed item, cannery waste, would consist of cull beans with some bean vines and pods present as a result of mechanical harvesting. Residue levels would not be likely to exceed 20 mg/kg on cannery waste. TABLE 4. Range of residues in beans, mg/kg Application rate, kg a.i./ha 2.8 5.6 Fresh (7 days after last treatment) <0.2-15 <0.2-12 Dry (29 days after last treatment <0.1-0.1 <0.1-0.24 Maize Residue data for maize were made available from five U.S.A. sites, two in California and one each in Colorado, Texas and Nebraska. Following applications at the maximum and twice the maximum label rates (Table 1), silage stage maize sampled 28-35 days after application contained maximum residues of 2.4 and 18 mg/kg, respectively; maize stover, sampled after 47-105 days, contained maximum residues of 4 and 11 mg/kg, respectively. Interpolation of the 2X data shows that MRLs on maize forage and fodder of 10 mg/kg are appropriate. No detectable residues (< 0.1 mg/kg) were found on either the grain or ears of maize sampled 60-105 days after the above applications. No data on grain reflecting a 30 day pre-harvest interval were submitted. However, since propargite does not translocate to any extent, residues on grain are not expected to exceed 0.1 mg/kg. Cotton Five field studies from locations in California, Arkansas and Mississippi were reported. The studies reflect treatment at the maximum and twice the maximum label rate (Table 1). Analyses were performed on 96 samples of cottonseed and processed products, hulls, oil, meal and soapstock. All values on cottonseed were reported as < 0.1 mg/kg. All samples of meal and soapstock contained < 0.05 mg/kg as did all but on refined oil sample which contained a level of 0.1 mg/kg after treatment at an excessive rate. Almost all of the hull samples had low but detectable residues, 0.03-0.06 mg/kg. Thus, an MRL of 0.1 mg/kg is appropriate for cottonseed. There is a restriction in the U.S.A. against feeding treated foliage or cotton trash to livestock. Cranberries Seven studies were reported from Massachusetts, with a total of 36 analyses. The studies reflect applications at 1.68 kg a.i./ha (4 by ground and 3 by air) with one study at 3.36 kg a.i./ha. Several of the studies show decline rates (at 7, 14 and 21 days). The residue declines rapidly between 0 and 7 days and then shows little further decline from 7 to 21 days. At the recommended rate (Table 1), residues are not likely to exceed 10 mg/kg. Residues are summarized in Table 5. TABLE 5. Range of residues in cranberries, mg/kg Application rate, Interval (days, last treatment to harvest) kg a.i./ha 0 7 14 21 1.68 2.2-11 <0.1-1.9 <0.1-7.1 0.1-1.0 3.36 3.3-14.9 Figs The residue data for figs consists of four studies made in California, including two decline studies. Various applications were made including the maximum and twice the maximum label rate (Table 15). Residues on fresh figs are summarized in Table 6. While the data are limited, it is not likely that residues will exceed 3 mg/kg at 14 days after treatment. TABLE 6. Residues on figs, mg/kg Application rate, Interval (days, last treatment to harvest) kg a.i./ha 0-1 7 13-14 21 28 1.27 3.3 1.9 0.8 0.45 2.02 1.6-2.8 1.0-1.4 0.2-1.4 0.3-0.6 4.04 2.5-5.3 2.2-3.2 0.7-4.2 Grapefruit, oranges and lemons Field trials were conducted in Texas, Florida and California. Some 281 harvest samples were analyzed. One and two applications were made at the recommended and twice the recommended rates (Table 1). The results are summarized in Table 6. For applications up to 0.06% spray with a 7 day interval, 5 mg/kg would not be exceeded. Washed oranges bearing residues of 1.9 mg/kg were processed to dried pulp by a procedure simulating the commercial process. The residue in the dried pulp was 15.5 mg/kg. The residue in the dried pulp is about eight times that on the whole fruit, so 40 mg/kg is an appropriate MRL. TABLE 6. Range of residues in grapefruit, oranges and lemons, mg/kg Application rate, Interval (days, last treatment to harvest) % 0 7 14 28 0.03 0.3-0.5 0.2-0.8 0.2-0.3 0.9-1.0 0.05 1.7-3.6 0.2-4.8 1.1-2.1 0.6-3.1 0.06 1.0-1.4 0.9-2.5 0.0-0.9 0.6-1.2 0.10 1.0-5.1 0.8-7.2 1.2-3.2 1.2-2.9 Grapes Residue trials were conducted in Washington and California, with analyses of 254 samples of grapes. A wide range of experimental conditions in the various field tests and the resulting variation in residues preclude a tabular summary of the data. No residues exceeded 10 mg/kg from the maximum recommended rate with a 21 day interval after treatment. A residue concentration factor of 2.5 was observed in the commercial production of raisins from fresh grapes. Thus a 25 mg/kg MRL for raisins would be appropriate. The data showed a concentration of residues on dried grape pomace to 4 times that found on fresh grapes, therefore, 40 mg/kg would be appropriate for grape pomace. Hops Eight field trials were conducted in the State of Washington. Residues on green hops resulting from three applications at the maximum and twice the maximum label rate (Table 1) are summarized in Table 7. Residues on green hops from good agricultural practices are not likely to exceed 15 mg/kg. Residues on dried hops ranged from 11 to 30 mg/kg 14 days after treatment. A 30 mg/kg MRL would be appropriate for dried hops since residues from two applications will probably be somewhat lower than those noted above. TABLE 7. Range of residues on green hops, mg/kg Application rate, Interval (days last treatment to harvest) kg a.i./ha 0 6-7 13-14 20 1.7 24-50 5-17 6-15 2-6 3.4 36-92 24-66 11-43 6-24 Mint Field studies were conducted in Washington, Oregon and Idaho. A total of 89 analyses were made on fresh hay, spent hay and mint oil, including controls. In four studies, two applications were made at rates of 2.5 and 5 kg a.i./ha resulting in maximum residues of 19 and 50 mg/kg respectively, 15-17 days after treatment. Three residue decline studies were also submitted. Samples were taken 0, 1, 2 and 4 weeks after a single aerial application at 1 and 2 times the maximum label rate (Table 1). From a decline curve based on these data, residues resulting from the recommended use are ca. 50 mg/kg on fresh mint hay. Five samples of fresh mint hay bearing residues of 8.7-50 mg/kg were fractionated by steam distillation and the resulting mint oil and spent hay contained residues of 1.6-7.9 mg/kg and 12-97 mg/kg respectively. Residues in mint oil are not likely to exceed those on fresh mint hay and there is a restriction against feeding spent mint hay to livestock. Nectarines Seven trials were conducted at locations in California and Pennsylvania. One or two applications were made at one and two times the maximum label rate (Table 1). The residue data are summarized in Table 8. Residues were no higher than 3-4 mg/kg at the prescribed pre-harvest interval. However, extrapolation of data from peaches, apricots, and plums would indicate that a 7 mg/kg MRL would be appropriate. TABLE 8. Range of residues in nectarines, mg/kg Application rate, Interval (days, last treatment to harvest) % 0 6-7 13-15 20-21 0.05 0.66-7.3 0.24-3.1 0.44-3.4 0.39-1.3 0.10 1-3-10.5 0.34-5.1 0.91-3.4 0.41-1.5 Peanuts Residue studies were conducted in Georgia, Florida, North Carolina, Oklahoma, Mississippi and Arkansas. Two applications were made in all but four decline studies on peanut vines, where only one application was made. Dosages ranged from 0.6 times to twice the maximum recommended rate (Table 1). Six of the studies reflect a 14 day preharvest interval, but in the other ten studies intervals were from 19 to 66 days. Peanut kernels All residue values were reported as < 0.1 mg/kg. Since no detectable residues were found in peanuts, no MRLs are needed for peanut by-products, meal, oil and soapstock. Peanut hulls Residues were < 0.1 mg/kg in five of seven studies. Residues of 0.14 mg/kg, 0.3 mg/kg and 1.2 mg/kg were found after applications at twice, 6 times and 1.2 times the recommended rates respectively, in the other two studies. Peanut vines and hay Residues were less than 10 mg/kg 14 days after application at the maximum rate. The data indicate that residues decline rapidly from a maximum of 38 mg/kg at 0 days to 3.6 mg/kg at 14 days. Pears Four field studies were conducted in California, Pennsylvania, Michigan and Washington, one and two applications were made with 0.03 and 0.06% sprays. The residue data are summarized in Table 9. All residues were less than 3 mg/kg, 14 days after treatment. TABLE 9. Range of residues in pears, mg/kg Application rate, Interval (days, last treatment to harvest) % 0 7 14 21 0.03 0.6-1.6 0.3-1.2 0-2.7 0.1-2.4 0.06 2.2-4.1 0.9-2.6 0.3-2.2 0.1-1.7 Potatoes Seven residue studies were made available, four from Washington and one each from Idaho, Vermont and Illinois. After two applications at rates of 1.5 to 4.5 kg a.i./ha, all residues were less than the limit of detection of the method (0.1 mg/kg) 14 days after treatment. Sorghum Field studies were conducted in Texas, Nebraska and Iowa on grain sorghum. Applications were made at the maximum and twice the maximum recommended rates (Table 1). Samples of grain and forage or fodder were harvested at 28, 30, 44 and 50 days after application. Residues in forage ranged from < 0.1 to 4.1 mg/kg. Residues in forage and fodder are not likely to exceed 10 mg/kg 30 days after treatment. Residue levels in grain ranged from < 0.1 to 2.4 mg/kg 60 days or more after treatment. Thus an MRL of 5 mg/kg with a 60 day interval after treatment is appropriate for sorghum grain. Strawberries Field trials were conducted in California, Louisiana and Florida. Strawberries treated with two formulations in California, reflecting three applications at the maximum recommended rate (Table 1) had residues ranging from 0.19 to 4.0 mg/kg for 3 days after treatment. Residues from applications of 0.84 and 1.7 kg/ha in Louisiana and Florida are summarized in Table 10. Under good agricultural practice, residues are not likely to exceed 7 mg/kg. TABLE 10. Range of residues in stramberries, mg/kg Application rate Interval (days, last treatment to harvest) kg a.i./ha 0 3 7 1.7 0.9-2.0 0.3-3.8 0.2-0.7 3.4 1.4-4.1 0.7-9.2 0.4-1.1 Sugar beets There are no national tolerances or registrations for propargite on sugar beets; however, this use is pending in the U.S.A. The submission to the Meeting therefore contained some residue data on sugar beet tops, roots and by-products. Sugar beet root samples from Idaho, Washington and California reflecting two treatments at 2.8 and 5.6 kg a.i./ha and a 21 day interval from treatment# showed residues ranging from 0.05 to 0.23 ind/kg and 0.13 to 0.28 mg/kg respectively. In a residue decline study, on sugar beet tops, a single application at 2.8 kg a.i./ha yielded residues of 40-114 mg/kg at 0 days. 20-80 mg/kg at 14-17 days and 2.4-34 mg/kg at 27-28 days. Adiitional data for tops representing two ground treatments at 2.8 and 5.6 kg a.i./ha show residues ranging from 11-24 mg/kg and 19-59 mg/kg respectively (21 day interval). In order to obtain data on processing fractions, sugar beet roots bearing 0.1 mg/kg residues were processed to wet and dry pulp, molasses and sugar. Propargite residues in wet pulp, molasses and sugar were less than or equal to 0.1 mg/kg. The data for dry pulp show a maximum residue concentration factor of 5, with residues from 0.1-0.5 mg/kg. Tea There are no national tolerances or registrations for propargite in tea, however, a tolerance for this use is pending in the U.S.A. The submission to the Meeting contained some residue data on dried tea leaves, both green and black. The data are summarized in Table 11. TABLE 11. Range of residues in tea, mg/kg Application rate, Interval (days, last treatment to harvest) kg a.i./ha 0 7 14 28 0.31 <0.1-0.3 <0.1-0.2 0.75 48-178 1.1-4.2 <0.1-0.2 <0.1 Walnuts Six field trials were conducted at locations in California. Both 30% WP and 75% EC formulations were applied at the maximum recommended rate (Table 1). No residues were detected in any of the walnut meat samples 45 to 48 days after treatment. Although the interval is greater than that recommended (14 days), since propargite is non-systemic, any residues found on nut meats would be expected to arise as a result of contamination in de-hulling and de-shelling processes. Under good agricultural practice, an MRL of 0.1 mg/kg (at or about limit of determination) would be appropriate. There is a restriction against grazing or feeding livestock on cover crops growm in treated orchards, therefore no feed items are involved in this use. Meat, milk, poultry and eggs Propargite is used on a number of crops which yield by-products used commercially for animal feeds. Primary sources would be dried citrus pulp, sorghum grain, forage and fodder and maize forage and fodder. Some additional contribution could occur from dried pomace, almond hulls and dried grape pomace. Per this reason, some animal feeding studies were submitted. These are also referred to in the section "Biochemical aspects", where references are given. In one study, cattle were fed at levels of 3 and 20 ppm in the total dry diet for 12 days. Maximum residues in milk (whole milk basis) were 0.059-0.067 mg/kg. The latter is equivalent to 1.7 mg/kg on the fat basis. Maximum residues in tissues were as follows: liver, 1.3 mg/kg, kidney, 0.27 mg/kg, fat, 0.21 mg/kg and muscle, 0.18 mg/kg. In a second study, cows received 0, 50 and 100 ppm in the diet for 27 days. Analysis of milk showed all samples at both feeding levels to be < 0.08 mg/kg. Residues ranged up to 1.6 mg/kg on a fat basis. Residues in muscle, kidney and liver from both feeding levels were 40.03 mg/kg (limit of determination). Residues in fat ranged from 0.32 to 0.42 mg/kg at the 10 and 100 ppm feeding levels, respectively. Poultry were fed 3, 10 or 30 ppm in the diet for 30 days (3 chickens in each group). Eggs were sampled daily and the animals were sacrificed 24. hours after treatment. Maximum levels In eggs were 0.013 mg/kg at the 3 PPM level, 0.043 mg/kg at the 10 ppm feeding level, and 0.106 mi/kg at the 30 ppm level. Liver tissue had the highest residue levels ranging from 0.047 to 0.089 mg/kg at the 10 diet level and from 0.17 to 0.18 mg/kg at the 30 diet level. Hogs were fed 20 and 100 ppm in the total diet. Two hogs at each level and one control were maintained for 30 days. No residues (< 0.1 mg/kg) were found in liver or kidney. No residues were found in muscle at the 20 ppm level but up to 0.23 mg/kg at the 100 ppm intake. In fat, residues up to 0.18 and 0.2 mg/kg were found at the 20 and 100 ppm intakes, respectively. The studies show that residues may transfer to meat, milk, poultry and eggs. A mixed ration for cattle could consist of 15% dried apple pomace, 15% dried citrus pulp and 70% sorghum grain, forage and fodder or maize forage and fodder. This diet could theoretically contain propargite residues of ca. 25 mg/kg. A maximum possible intake of 10 mg/kg could result from the hogging down of peanut fields and other swine feed items such as maize grain and cooked potatoes. Poultry feed items, sorghum grain, grape pomace, maize grain and cooked potatoes, could contribute ca. 8 mg/kg propargite to the diet. Residues are unlikely to exceed 2 mg/kg in milk fat and 0.1 mg/kg in the meat, meat by-product, and fat of cattle, goats, hogs, horses, poultry and sheep. FATE OF RESIDUES In animals The available data on metabolism by animals are more conclusive than those on metabolism by animals are move conclusive than those on metabolism by plants. See also "Biochemical aspects." Propargite -14C feeding tests have been conducted on a number of animals including the rat, cow, pig and chicken. Additional information on degradation was available from in vitro experiments with buffered liver homogenates. A general metabolism scheme has been proposed for animals, part of which has been verified experimentally, and part of which is based on analogy with biochemical reactions reported in the literature. Identification of some metabolites was by TLC comparison with prepared standards. In other cases less positive identification was made by partition co-effecients (p values) and solvent extraction scheme. In cow liver the bulk of the 14C activity was identified only as polar metabolites. The experiments apparently were carried out over a number of years, the studies in some animals being repeated with refinements in analytical techniques. None of the work on propargite submitted to the Meeting has been published. Certain general conclusions appear justified. (a) Propargite is metabolized in animals to polar compounds which are excreted, principally in the urine. (b) There is not a pronounced tendency to storage or accumulation in the body, but the compound is not completely metabolized because the parent compound was the principal residue in the milk of cows, was tentatively identified as a portion of the 14C activity in animal fat, and was found in excreta. (c) The parent compound is detected in the liver only for short periods after ingestion. d) The primary hydrolysis products, the glycol ether and propargyl alcohol, are further degraded. (e) Some polar metabolites are in conjugated forms. A list of the metabolits and the sites in which they were reported is given in Table 12. The sequence of the metabolic scheme is not definitely known. TABLE 12. Propargite metabolites Compound Found in Parent Cow: butter fat, body fat (1) Rat: liver (1) liver homogenate (1) Glycol ether Cow: urine, faeces, milk (2) Rat: faeces, liver (1) liver homogenate (1) Propargyl alcohol liver homogenate (1) Butylphenol Cow: urine (2) Rat: liver (1) liver homogenate (1) Butylcatechol Cow: urine (2) Rat: urine, faeces (2) Cyclohexandiol urine (2) "Polar metabolites" Rat: liver (2) Cow: liver (2) (1) Identified by GLC or TLC (2) Tentatively characterized by solvent fractionation scheme, p values, literature analogies. In plants Propargite is generally considered to be "non-systemic" by mode of miticidal action. According to information made available to the Meeting aged residues are primarily surface residues of the parent compound (Uniroyall 1977). Residue decline was attributed to volatilization of the parent compound and hydrolysis to propargyl alcohol and the "glycol ether", 2-(p-tert-butylphenoxycyclohexanol). The two hydrolysis products have not been detected in samples by chemical analysis at a detection level of 0.1 mg/kg. In experiments on bean plants to investigate possible photolytic degradation, the same two compounds could not be detected. It has been suggested that if the glycol ether and propargyl alcohol are intermediates in the degradation scheme, their presence is fleeting because of their volatility. Other evidence cited in the manufacturer's submission on the behavior of propargite in plants was: (a) comparison of surface and pulp analysis of apples showed no absorption (of parent); (b) mites confined to upper leaf surfaces were not affected by sprays on the lower surfaces (c) there was no effect on mites of an adjacent leaf when on leaf of a bean plant was treated; (d) volatility losses of the parent compound under field conditions have been correlated with model laboratory experiments (loss from aluminum foil). The above experiments partially support the idea that propargite is not translocated in plants and that the residue of concern is propargite per se. However, much of the evidence is indirect, and it would be desirable to have conventional metabolism studies on some representative crops, using 35S and/or 14C, to confirm the fate of propargite in plants. In soil Only a summary was made available (Uniroyall 1977). The half-life in a variety of soils was said to range from 2 to 18 weeks. Leaching is negligible. Laboratory and field studies have shown that propargite is hydrolysed in soil. The major soil degradation product found was the glycol ether. Summary, metabolism The available metabolism studies do not firmly identify the residue components in plants or animals. However, there is sufficient information to indicate a probable metabolic scheme. It is fairly certain that the primary metabolites are the hydrolysis products tert-butylphenoxycyclohexanol and propargyl alcohol. It is probable that further breakdown to butylphenol and cyclohexanediol occurs. If correlations are to be made between metabolic schemes and toxic potential for propargite and aramite, it should be noted that both compounds hydrolyze at the sulfite ester, aramite yielding 2-chloroethanol and propargite yielding propargyl alcohol. Whether any further confirmatory studies are needed would depend on the toxic potential of the postulated fragments. EVIDENCE OF RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION Propargite is detected in the multi-residue screening procedure employed by the Canadian Department of Health and Welfare, The compound is eluted from Florisil in fraction 3 as described in the method (15% acetone in hexane). Only 4 positive findings of propargite were reported in the Canadian surveillance programs (as of 1977). The highest residue was found in a nectarine sample at 0.57 mg/kg (Health Protection Branch, 1977), The U.S. Food and Drug Administration multi-residue method has not been validated for propargite. The specific GLC/FPD analytical method has not been applied in the U.S. surveillance programme. Therefore propargite has not been reported in foods in channels of commerce in the U.S.A. No reports from other governments have been received on occurrence in commerce. There were no data available on reduction of residues through washing, cooking or processing. The principal exposure through ingestion would be from fruits eaten raw and unpeeled. METHODS OF RESIDUE ANALYSIS The early residue data on propargite (mid 1960s) were obtained by gas chromatography with flame ionization or microcouclometric (SO2) detection. Some difficulties were experienced by government laboratories in validation studies on the method at that time were because the clean-up and extraction procedures were unsatisfactory. Through a series of modifications, a basic procedure using gas chromatography with flame photometric detection (FPB) has evolved which is satisfactory for a wide variety of fruits, vegetables, and animal tissues (Devine and Sisken, 1972). In the basic method, residues are extracted with 1:1 hexane and isopropanol, followed by an aqueous NaCl wash and Florisil column chromatography. For oily or waxy samples an optional step is included in which the residues are partitioned into nitromethane. Other modifications are prescribed for certain crops. The method has been validated in U.S. government laboratories on milk, apples and animal tissues (PAM III, 1973). Depending on the substrate, the limit of determination is about 0.05 to 0.2 mg/kg. A similar GC-FPD method for propargite residue in citrus has been reported by Westlake et al, (1971). Propargite is not known to be recovered through the U.S. Food and Drug Administration multiresidue procedure. Information received from NATIONAL TOLERANCES REPORTED TO THE MEETING Tolerance, mg/kg Commodity USA Canada New Zealand Australia Almonds 0.1 Almonds, hulls 55 Apples 3 3 3 3 Apples, pomace, dried 80 Apricots 7 3 Bananas 3 Beans, dry 0.2 Beans, succulent 20 Citrus, dried pulp 40 Corn, fodder 10 Corn, forage 10 Corn, grain 0.1 Cottonseed 0.1 3 Cranberries 10 Eggs 0.1 Figs 3 Grapefruit 5 5 Grapes 10 7 Grapes, pomace 40 Hops 15 3 Hops, dried 30 30 Lemons 5 5 Milk 0.08 NATIONAL TOLERANCES REPORTED TO THE MEETING (Continued) Tolerance, mg/kg Commodity USA Canada New Zealand Australia Milk, fat 2 Mint 50 Nectarines 4 3 Oranges 5 5 Passion fruit 3 Peaches 7 7 3 Peanuts 0.1 Peanuts, forage 10 Peanuts, hay 10 Peanuts, hulls 10 3 Pears 3 3 3 Plums (prunes) 7 3 3 Potatoes 0.1 Raisins 25 Sorghum, fodder 10 Sorghum, forage 10 Sorghum, grain 10 Strawberries 7 7 3 Walnuts 0.1 Meat, meat by-products and fat of cattle, goats, hogs, horses, poultry and sheep 0.1 Canadian authorities is that it is recovered through their multiresidue procedure. It is eluted from Florisil in fraction 3 of the Canadian procedure (15% acetone/hexane). APPRAISAL Propargite is an acaricide which has been used on a wide variety of food crops and ornamentals since its introduction in 1967. Available information indicates that the product is used in Australia, New Zealand, Argentina, Mexico, France, South Africa, Italy and the U.S.A. The primary manufacturer has submitted a report on supervised trials on 26 crops, all of which were conducted in the U.S.A. Limited residue data were received from New Zealand on peaches). U.S.A., Canada, New Zealand and Australia have set national tolerances (MRLs) for propargite. Propargite is non-syrtemic by mode of action against mites, and data indicate that residues which do occur are surface residues. Residues on the harvested commodities are primarily propargite per se. No significant metabolites or alteration products have been reported on harvested crops. However, much of the evidence regarding the fate of propargite on plants is indirect. It would be desirable to have 35S or 14C radiotracer studies to confirm the degradation pathways in plants. Radioactively labelled propargite (14C) has been used in some animal experiments, including studies on the rat, cow and chicken. Techniques used to fractionate and identify the activity were not as definitive as would be desired, but it is fairly certain that propargite is hydrolysed in the body to tert-butylphenoxyoyclohexanol and propargyl alcohol. It is probable that there is further degradation to butylphenol and cyclohexanediol and excretion as conjugates in the urine. However, some residues of unchanged parent compound do occur in milk, body fat and briefly in liver. If any correlations are to be made between the metabolism of propargite and the related compound aramite, it may be significant to compare the toxic potential of the hydrolysis product propargyl alcohol with that of the corresponding hydrolysis product of eremite, ß-chloroethanol. An analytical method suitable for regulatory purposes is available. It is a gas chromatographic method (published) with flame photometric detection that has been validated in government laboratories. Propargite is also measured by the multi-residue method employed in the Canadian surveillance programme. It has not been studies in the U.S. Food and Drug Administration's multi-residue method. RECOMMENDATIONS Temporary maximum residue limits for propargite on the following commodities are recommended. Commodity Limit mg/kg Pre-harvest intervals on which recommendations are based (days) Apple pomace 80 Alfalfa hay 75 28 Almond hulls 55 28 Alfalfa, fresh 50 28 Mint hay 50 14 Dried citrus pulp 40 Grape pomace 40 Dried hops 30 Raisins 25 Beans (in pod) 20 7 Corn fodder and forage 10 30 Cranberries 10 14 Grapes 10 14-21 Peanut hay and forage 10 14 Sorghum fodder and forage 10 30 (if silaged) Apricots, peaches, plums, nectarines 7 14 Strawberries 7 3 Citrus 5 7 Sorghum grain 5 60 Apples, pears 3 Pigs 3 14 Milk (fat) 2 Beans, dry 0.2 28 Almonds 0.1* 28 Cottonseed 0.1* before bolls open Eggs 0.1 Fat of poultry 0.1 Fat of meat 0.1 Maize (kernels) 0.1* 30 Milk, whole 0.1 Peanuts (kernels) 0.1* 14 Potatoes 0.1* 14 Walnuts 0.1* 14 * At or about the limit of determination FURTHER WORK OR INFORMATION REQUIRED (Before July 1981) 1. A carcinogenic study DESIRABLE 1. Mutagenicity studies 2. Observations in humans 3. Data from supervised trials in countries other than the USA 4. Information on the occurrence of residues on commodities in commerce 5. Confirmation of the postulated degradation pathway in plants using radio-labelled propargite. REFERENCES Carson S. (1963) Acute Oral LD50 in Rats. Unpublished report from Food and Drug Research Lab., submitted by Uniroyal Chemcial, Inc. Carson S. (1963) Subacute Feeding Studies with D-014 in Rats. Unpublished report from Food and Drug Research Lab., submitted by Uniroyal Chemical, Inc. Haley, G., Kennedy, G.L. and Keplinger, M.L. (1972) Teratogenic Study with Omite in Albino Rats. Unpublished report from Bio-Test Laboratories, submitted by Uniroyal Chemical. Health Protection Branch (1977) Personal communication, Canada Bu. Chem. Safety, Health Protection Branch to FAO Panel of Experts, 1977. Holsing, G.C. (1968) 13-Week Dietary Feeding - Dogs. Unpublished report from Hazleton Laboratories, Inc., submitted by Uniroyal Chemical. Jenkins, D.H., Kennedy, G. and Keplinger, M.L. (1972) Study with Omite in White Leghorn Chickens. Unpublished report from Industrial Bio-Test Laboratories, submitted by Uniroyal Chemical. Kennedy, G., Jenkins, D.H. and Keplinger, M.L. (1970) Metabolism of 14C-Omite in the Cow. Unpublished report from Industrial Bio-Test Laboratories, submitted by Uniroyal Chemical. Ladd, R., Jenkins, D.H. and Keplinger, M.L. (1974) Tissue Residue Study with Omite in Crossbred Swine. Unpublished report from Bio-Test Laboratories, submitted by Uniroyal Chemical. Oser, B.L. (1966) Chronic (2-Year) Feeding Studies with D-014 in Rate and Dogs. Unpublished report from Food and Drug Research Lab.9 submitted by Uniroyal Chemical. PAM II Pesticide Analytical Manual, Vol. II, revised (1973); U.S. Department of Health, Education and Welfare, Food and Drug Administration. Ryer, F.H. and Sullivany J.B. (1969) Rachiotracer Drug Metabolism Study with Omite 14C. Unpublished report from Hazleton Laboratories, Inc., submitted by Uniroyal Chemical. Ryer, F.H. and Sullivany J.B. (1969b) The Fate of Omite 14C in the Cow. Unpublished report from Hazleton Laboratoriesy Inc., submitted by Uniroyal Chemical. Sleight III, B.H. and Maceky K.J. (1972) 14C Omite Fish Accumulation. Unpublished report from Bionomics, Inc., submitted by Uniroyal Chemical. Smith, K.S. and Roger, J.C. (1975) Omite Milk and Tissue Residue Study in Dairy Cows: Unpublished report from Cannon Laboratories, submitted by Uniroyal Chemical. Sullivan, J.B. (1968) An Investigation of the In-Vitro and In-Vivo Metabolism of Omite. Unpublished report from Hazleton Laboratories Inc., submitted by Uniroyal Chemical. Uniroyal Unpublished information (1977), Uniroyal Inc., to U.S. Environmental Protection Agency. Weir, RJ. (1967) Acute Dermal Application to Rabbits. Unpublished report from Hazleton Laboratories Inc., submitted by Uniroyal Chemical. Westlake, W.E., Gunther, P.A. and Jeppson, L.R. J. Agr. Fd. Chem., 19:894.
See Also: Toxicological Abbreviations Propargite (Pesticide residues in food: 1978 evaluations) Propargite (Pesticide residues in food: 1979 evaluations) Propargite (Pesticide residues in food: 1980 evaluations) Propargite (Pesticide residues in food: 1982 evaluations) Propargite (JMPR Evaluations 1999 Part II Toxicological)