CHLOROTHALONIL JMPR 1977 Explanation Chlorothalonil was reviewed by the 1974 Joint Meeting (FAO/WHO, 1975) and the following information was required by 1977. 1. Additional studies to resolve lower limit for kidney effects in the rat. 2. Determination of growth reduction in pups relative to dietary ingestion or secretion into maternal milk. 3. Data on residues of chlorothalonil and the 4-hydroxy metabolite in crops that may be fed to animals. 4. The results of feeding studies on dairy cattle, understood to be in progress, to determine the level and nature of residues in milk and tissues. In addition, the following information was considered to be desirable. 1. Observation in humans. 2. Residue data for food moving in commerce. 3. Further information on the effects of processing, including household cooking, on residues. The Codex Committee on Pesticide Residues at its 9th session (Alinorm 78/24, paras. 144, 145) also asked the Joint Meeting to present the residues levels and pre-harvest intervals in a more understandable manner so that countries would be in a better position to judge the data. Justification was requested for the suggested one day pre-harvest interval for such crops as sugar beets, carrots and potatoes. A considerable amount of information was submitted by the principal manufacturer concerning the specific requirements of the 1974 Joint Meeting, which is reviewed below. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Single cows were fed either 250 ppm technical chlorothalonil, 2 ppm pure 4-hydroxy metabolite of chlorothalonil, or normal diet for 44 days. A 15-day recovery period with all animals on normal diet preceded sacrifice of the test animals. Milk production was reduced in the cow receiving the 4-hydroxy-metabolite. Food consumption was comparable in all animals. Neither test animal showed any gross pathological lesions at sacrifice (IBT). No residues of chlorothalonil were detected in either meat or milk. The 4-hydroxy metabolite occurred in the milk of both test animals, being present as 23% of the administered dose of the 4-hydroxy-metabolite, and as 0.2% of the administered chlorothalonil dose (Ladd et al., 1971; Wolfe & Stallard, 1971). Further details are given in the section "Fate of Residues", "In animals". Degradation of chlorothalonil in cow bovine rumen fluid has been shown to result in 4-5% of the administered dose of chlorothalonil being converted to the 4-hydroxy metabolite in vitro (Duane, 1971). TOXICOLOGICAL STUDIES Special study on reproduction Five groups of 10 male and 20 female rats were fed 0, 10, 50, 100 or 200 ppm 4-hydroxy-2,5,6-trichloroisophthalonitrile in a three generation, one litter/generation reproduction study. Increased irritability in adults in the Fo, F1 and F2 generations and rough thin coats in weanlings of the F1, F2 and F3 generations were noted at 200 ppm. Soft stools occurred occasionally at 100 and 200 ppm. Body weight of offspring in all generations showed a decreased weight gain at 50, 100 and 200 ppm, the decrease being marginal (10-15%) at 50 ppm. In post-weaning animals, body weight gain was decreased in females of the Fo generation at 200 ppm. In other generations weight gain was similar to controls, but the initial losses during weaning were not recovered. Fertility index was reduced in the F2 parents at 100 and 200 ppm and in F1, parents at 200 ppm. Gestation index was comparable in all groups. The viability index was normal for all groups up to 24 hrs, decreased at 200 ppm in F2 and F3 and at 50 ppm in the F3 offspring over the 0-4 day period, decreased at 200 ppm in the F2 and F3 and at 50 & 100 ppm in the F3 offspring over the 0-7 day period. After culling to 10/litter at 7 days, viability index over the 7-14 day period was reduced at 200 ppm in all generation, and at 100 ppm in the F3 generation. Total pup mortality was increased in all generations at 200 ppm, at 100 ppm in the F2 and F3 litters, and at 50 ppm in the F3 litters. A marginal increase also occurred at 10 ppm in the F3 litters.Litter size was reduced at 200 ppm in all generations, and at 100 ppm in the F3 litters. Incidence of stillbirths was comparable in all groups. Examination of pups from F1, F2 & F3 generations either grossly or by alizarin staining did not reveal terata (Hastings, 1975). Histopathological examination of F3 weanlings (5 male and 5 female/group) did not reveal any abnormalities (Ferrell, 1975). Pups, culled at 7 days of age, were subject to analysis of stomach content. No solid matter was found in the stomach. Levels of 4-hydroxy-2,5,6-trichloroisophthalonitrile increased with increasing-dose level (Ferrel, 1975). Short-term studies Rat Seven groups of 15 male and 15 female Young adult Wistar rats were fed 1, 2, 4, 15, 30, 60 or 120 ppm chlorothalonil in the diet for 17 weeks. A concurrent control group of 30 male and 30 female rats were fed normal laboratory chow. All rats were stated to present a healthy appearance throughout the study. Body weight, food consumption and survival were comparable in all groups. At termination of the study, all rats were sacrificed. Kidney, liver and thyroid from each animal were removed and grossly examined. Most kidneys had fat-like nodules on them and a number of livers were mottled and discoloured (Hastings & Jessop, 1975). Kidney histopathology did not reveal compound or dose-related changes (Busey, 1975). COMMENTS The data previously required from additional studies to resolve the lowest dose limits for kidney effects in the rat and the determination of growth reduction in pups relative to dietary intake or secretion into maternal milk were submitted for consideration by the Meeting. The absence of sufficient detail in the reports on kidney pathology and discrepancies in body weight data in the rat reproduction studies made evaluation of these data impracticable. However, since data have been submitted in response to the previous request, the Committee extended the current temporary ADI for humans for an additional 2 years. TOXICOLOGICAL EVALUATION Levels causing no toxicological effect Rat: 60 mg/kg in the diet, equivalent to 3.0 mg/kg bw Dog: 120 mg/kg in the diet, equivalent to 3.0 mg/kg bw ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR HUMANS 0-0.03 mg/kg bw RESIDUES IN FOOD AND THEIR EVALUATION USE PATTERN As indicated by the 1974 Joint Meeting, chlorothalonil is a wide spectrum fungicide effective against many fungus diseases of fruits, vegetables, turf and ornamental crops. A very important use at present is in tropical areas such as Central and South America and Southeast Asia for protecting bananas from Sigatoka disease (Cercospora musae), fruit spot and pitting disease, among others. The compound is usually formulated as a 75% wettable powder and a 720 g/l suspension concentrate. Additional specific data on use patterns were submitted by the Netherlands. (Table 1). RESIDUES RESULTING FROM SUPERVISED TRIALS The 1974 Joint Meeting made a comprehensive tabulation of the available data on residues resulting from supervised trials with chlorothalonil. Although the 9th session of the Codex Committee on Pesticide Residues expressed its concern that the data presented could not be readily understood, the absence of the original data sets does not allow the reviewer to make any changes in the tabulation to make it clearer. It also appears that the reservations expressed at the CCPR were due to a misunderstanding since they concerned pre-harvest intervals used in supervised trials, whereas the recommendations mention pre-harvest intervals which were used as the basis of the proposed maximum residue limits. Additional residue data were provided by the principal manufacturer for peaches and bananas. In both cases two types of extraction were used, namely simple surface rinsing and the more exhaustive total maceration. In the case of peaches the differences between the two procedures were not significant (Table 2), so surface rinsing was used to gather residue data from several locations in the United States (Table 3). Occurence of the metabolite 2,5,6-trichloro-4-hydroxy-1,3-benzenedicarbonitrile (DAC-3701) was low (Table 4). In bananas, there also appears to be no significant difference between the residue levels obtained by surface stripping and maceration (Table 5). Analysis shows that the fungicide remains mainly in the peel and very little is translocated to the edible portion, as shown in Table 6. Formation of DAC-3701 is also minimal. Residue data from the Netherlands on gherkins, leeks, potatoes and wheat are shown in Table 7. FATE OF RESIDUES General comments The only identified metabolite in the degradation of chlorothalonil is the 4-hydroxy compound, DAC-3701, mentioned previously. In animals To determine whether or not dairy cattle fed with a diet containing chlorothalonil and DAC-3701 will produce milk containing residues, a study was done in which one cow was fed with 250 mg/kg of 97% chlorothalonil and another with 2 ppm pure DAC-3701 for 44 days followed by a 15-day recovery period (Ladd at al., 1971; Wolfe and Stallard, 1971; referred to in the section "Biochemical aspects). Milk samples were collected during the test and recovery TABLE 1. Use pattern of chlorothalonil in the Netherlands Crop or situation Kind of pest Extent of use/ Application Formulation Treatment Pre-harvest In use controlled economic importance kg. a.i./ha interval since (days) potato Phytophthora small scale 1.5-2.2 w.P. 75T repeated ----- 1966 treatments mushroom Verticillium small scale 3 g/m2 w.p. 75% first treatment 5 days 1977 sp. after covering; repeat two weeks later after first harvest onion Botrytis small scale 2 kp/ha W.P. from 1 4 weeks 1976 squamosa 50% maneb June., repeat 25% every 7-10 days chlorothalonil potato Phytorphthora moderate 0.75-1 idem repeated ----- 1976 kg/ha treatments Wheat powdery mildew moderate 1.2kg/ha w.p. 1 treatment, 6 weeks 1976 ripening diseases 40% sulfur repeated 20% maneb once, if 20% necessary just chlorothalonil before blossoming other uses: floriculture and against blue staining of wood W.P. = wettable powder TABLE 2. Chlorothalonil residues on peaches by surface and maceration extraction Application Preharvest Location Type of Formulation Rate Number interval, days Residues, mg/kg Mean extraction Louisiana Surface 720 g/l 1.0 pt. 10 7 2.51 3.55 10.08 5.65 suspension concentrate Macerate " 1.0 pt. 10 7 1.86 2.04 2.28 2.06 Surface " 1.0 pt. 10 7 1.76 2.32 1.88 1.99 Macerate " 1.0 pt. 10 7 1.14 0.92 1.60 1.22 Surface " 1.5 pt. 10 7 8.66 5.04 1.16 4.95 Macerate " 1.5 pt. 10 7 2.56 2.64 2.52 2.57 Arkansas Surface " 1.5 pt. 5 15 0.51 0.90 1.02 0.81 Macerate " 1.5 pt. 5 15 0.47 0.52 0.14 0.38 Surface " 1.5 pt. 9 7 4.50 2.66 0.75 2.64 Macerate " 1.5 pt. 9 7 0.24 0.60 1.73 0.86 Surface " 1.5 pt. 9 0 1.56 2.32 3.55 2.48 Macerate " 1.5 pt. 9 0 1.22 1.09 1.08 1.13 Georgia Surface " 1.5 pt. 4 14 0.71 1.13 1.50 1.11 Macerate " 1.5 pt. 4 14 0.80 0.91 0.84 0.85 Surface " 1.5 pt. 4 4 1.92 1.16 2.05 1.71 Macerate " 1.5 pt. 4 4 1.60 1.44 1.52 1.52 Surface " 1.5 pt. 4 1 2.86 2.37 1.80 2.59 Macerate " 1.5 pt. 4 1 1.83 1.80 1.80 1.81 TABLE 3. Residues of chlorothalonil on peaches 1/ Application Residue, mg/kg Rate per 100 % a.i. Number Preharvest Samples Range Mean gals.2/ interval analyzed 0 0 - 0 42 ND - 0.20 0.03 0.75 0.015 4 8 3 6.0 - 8.0 6.7 1.0 0.02 4 0 4 6.15 - 15.8 11.49 4-10 7-8 18 0.92 - 10.08 3.42 4 12 33 1.04 - 3.08 1.78 1.25 0.025 7 0 3 7.4 - 19.2 15.0 7 7 3 12.9 - 17.5 14.8 7 14 3 6.4 - 9.8 7.6 1.50 0.03 8-10 0 11 1.08 - 16.2 6.77 4 1-4 12 1.16 - 2.86 1.91 4-11 6-8 27 0.24 - 22.2 5.29 4-6 12-15 27 0.14 - 6.4 2.14 1.75 0.035 6-7 0 12 14.1 - 45.0 29.6 6 4 18 4.4 - 29.5 14.8 6-7 7 12 15.5 - 25.8 21.3 6-7 14 12 4.9 - 16.6 10.1 6 25 9 1.3 - 6.6 4.1 2.0 0.04 4 8 3 26.6 - 28.4 27.8 3.0 0.05 8 0 3 41.3 - 50.5 44.8 4 8 3 32.4 - 54.0 45.1 1/ Refers to both surface and macerated extraction data. 2/ Both using the 75%. w.p. and 720 g/l s.c. formulations. TABLE 4. Formation of DAC-3701 on peaches treated with chlorothalonil. Application 1/ Residues, mg/kg % a.i. Number Preharvest Number Range Mean interval analyzed - 0 21 0.00 - 0.09 0.01 0.015 3 0 3 0.12 - 0.31 0.18 3 10 3 0.13 - 0.21 0.18 0.02 3 0 3 0.14 - 0.31 0.30 2-10 4 11 0.01 - 0.37 0.13 10 7 6 0.01 - 0.02 0.02 3-4 10-12 8 0.01 - 0.42 0.14 0.025 3-9 0 6 0.00 - 0.48 0.17 4 1-4 6 0.00 0.00 9-10 7 6 0.00 - 0.01 0.00 3-4 10-12 11 0.01 - 0.22 0.06 1/ Applied either as the W-75 or 6F TABLE 5. Mean residues of chlorothalonil in whole bananas using two extraction procedures. Surface Striping Maceration Treatment Chlorothalonil Chlorothalonil DAC-3701 (g a.i./1H2O) 0.75 0.03 0.02 ND 1.5 0.52 0.30 ND 3.0 1.49 1.32 ND Control - 0.04 ND TABLE 6. Distribution of chlorothalonil residues in bananas. Treatment Chlorothalonil DAC-3701 Chlorothalonil DAC-3701 (g a.i./1H2O) 0.75 0.02 ND 0.09 ND 2.0 0.02 ND 0.22 ND 4.0 0.03 ND 3.80 0.01 Control 0.05 ND -- 0.01 TABLE 7. Residues of chlorothalonil in various crops (supervised trials, Netherlands). Application Residues (mg/kg) at intervals (days) after application Crop Year No. Rate Formulation 0/ 3 7 14 41 41 41 kg a.i./ha Potato 1971 6/7 2.2 75% WP <0.02 (washed, unpeeled potatoes) Leek 1971 11 1.5 75% WP 13 7.7 (11-16) (4.8-9.9) Gherkin 1973 1 2.2 75% WP unwashed unwashed (glasshouse) 4.1 0.83 (2.9-5.4) (0.64-1.13) washed washed 1.2 0.30 (0.9-1.7) (0.24-0.37) Wheat 1974 2 1.2 75% WP whole kg/ha in ear combination 0.52 with 2.4 kg (0.36-0.94) sulphur and 1.2 mg maneb 1974 2 " 75% WP 0.46 (0.27-0.93) Whole bran grain 1976 1 " 75% WP 0.37-0.78 0.04-0.06 1.5-3.4 TABLE 8. DAC-3701 residues in milk of cows fed chlorothalonil or DAC-3701. DAC-3701, mg/kg, in milk of Test Period Control Chlorothalnil-fed DAC-3701 fed Cow Cow (250 PPM in diet) (2.0 ppm in diet) Pre-test 0.05 0.05 0.05 2 0.05 0.10 0.19 4 0.04 0.27 0.19 8 0.04 1.30 0.75 16 0.04 0.62 0.66 18 0.09 0.84 0.94 20 0.01 0.96 1.54 22 0.01 0.92 0.96 26 0.10 1.19 1.27 30 0.13 0.94 1.12 32 0.02 0.97 0.90 34 0.01 0.83 1.26 38 0.01 1.00 0.95 44 0.01 0.59 1.16 Recovery Period 1 0.01 0.60 1.30 3 0.01 0.42 1.10 6 0.04 0.37 0.90 10 0.06 0.23 0.56 15 0.04 0.19 0.32 period. The animals were then milked and samples of liver, kidney, muscle and fat were analyzed. No chlorothalonil was detected in the milk of the cow fed with chlorothalonil but DAC-3701 was detected in the milk of both cows (Table 8). Only 0.2% of the ingested chlorothalonil was eliminated in the milk as DAC-3701. Residues of the metabolite became constant after about 18 days of treatment but declined rapidly during the recovery period. In the tissues, no residues of either compound could be detected in the muscle or fat but 0.7 and 1.2 mg/kg of DAC-3701 were detected in the kidneys of the chlorothalonil- and DAC-3701- fed cows, respectively. Traces (0.1 mg/kg) of DAC-3701 were found in the liver of the cow fed with DAC-3701. In silage The effect of ensiling treated foliage is important in view of its probable effect on the residue levels in milk or meat of animals consuming the silage as feed. This is particularly important with chlorothalonil since residues are expected to remain in the treated plant material prior to ensiling. On the other hand, chlorothalonil is biodegradable and this could minimize residue levels. This latter observation was borne out by ensiling studies which showed that with corn silage, 90% degradation was observed after 18 days (from 30 mg/kg to 3 mg/kg) and the half-life was approximately 4 days. No formation of DAC-3701 was observed. In a second experiment in which the bound materials in the silage were converted to an extractable form, DAC-3701 constituted only 2% of the chlorothalonil in the silage on the first day of ensiling. During processing The 1974 Joint Meeting reported the effect of washing with water on chlorothalonil residues. For the present Meeting, the principal manufacturer submitted the results of studies of the effect on residues of processing tomatoes and peaches. For tomatoes, it was shown that 94% of the chlorothalonil residues were removed by washing fresh tomatoes and that no detectable chlorothalonil or DAC-3701 was found in the products canned tomato pulp, tomato paste or tomato juice. The dry cannery waste (tomato pomace), which is sometimes used for feed, contained less than 1 mg/kg of total residues at roughly a 6:1 chlorothalonil:DAC-3701 ratio. Washing peaches with water followed by a caustic wash removed 97% of the field residues remaining on the peaches. The caustic wash will increase chlorothalonil removal because chlorothalonil is unstable at pH 10 and above. No chlorothalonil or DAC-3701 could be detected in canned peach puree. RESIDUES IN FOOD MOVING IN COMMERCE No data were made available but the principal manufacturer mentioned that this could be supplied by the United States Food and Drug Administration, presumably through the Chairman of the U.S. Delegation to the Codex Committee on Pesticide Residues. APPRAISAL The compound was re-evaluated in the light of information requested by the 1974 Joint Meeting and the decision of the 1977 Codex Committee on Pesticide Residues to change the temporary maximum residue limit in oranges to encompass all citrus fruits. The 1974 Meeting recommended a maximum residue limit of 30 mg/kg in peaches, but the principal manufacturer suggested that this could be reduced to 25 mg/kg. Supporting data, mainly from the United States, justifies such a reduction. In bananas, the fungicide remains mainly in the peel. When dairy cows were fed diets containing very high levels of chlorothalonil or 2,5,6-trichloro-4-hydroxy-1,3-benzocarbonitrile (DAC-3701), approximately 0.2% of the chlorothalonil and 23% of the DAC-3701 were eliminated in the milk as DAC-3701. Of the tissues examined, only the kidneys contained residues above the limit of determination. After being ensiled for 18 days, maize forage was found to contain 10% of the initial residues. Washing removed up to 94% of the chlorothalonil residues in tomatoes and up to 97% in peaches and residues could not be detected (< 0.01 mg/kg) in tomato and peach processing products. RECOMMENDATIONS The temporary maximum residue limits recommended in 1974 are maintained as temporary limits with the exception of that for peaches which is lowered and for "oranges" which is changed to "citrus fruit". An additional temporary limit is recommended for bananas. Commodity Limit, mg/kg Peaches 25 Citrus fruit 5 Banana (whole) 4 Banana (pulp) 0.1 FURTHER WORK OR INFORMATION Required (before July 1979) 1. Additional studies to resolve the lower dose limits for kidney effects in rats. 2. Studies to define the growth reduction after administration of chlorothalonil or its metabolite 4-hydroxy-2,5,6-trichloroisothalonile in pups relative to ingestion or secretion into milk. Desirable 1. Observations in humans. 2. Information on the extent of metabolism to 4-hydroxy-2,5,6-trichloroisothalonile in mammals. 3. Information on the effects of cooking on residues. REFERENCES Busey, W.M. (1975) Project 24-201. Unpublished Report by Experimental Pathology Laboratories Inc. submitted to WHO by Diamond Shamrock Corp. Duane, W.C. (1971) Reinvestigation of the degradation of Chlorothalonil by Bovine Rumen Fluid. Unpublished Report submitted to WHO by Diamond Shamrock Corp. Ferrell, J.F. (1975) Pathology Report on F3 Rats. Unpublished Report by Experimental Pathology Laboratories Inc. submitted to WHO by Diamond Shamrock Corp. Hastings, T.F. (1975) Three generation Reproduction Study in Albino Rats DAC-3701. Unpublished Report by Bio/Tox Research Laboratories Inc., submitted to WHO by Diamond Shamrock Corp. Hastings, T.J. and Jessop, D.C. (1975) 4-Month Dietary Toxicity Study - Rats. Chlorothalonil. Final Report. Unpublished Report by Bio/Tox Research Laboratories Inc. submitted to WHO by Diamond Shamrock Corp. Ladd, K., Jenkins, D.H. and Kepplinger, M.L. (1971) Meat and Milk Residue Study with Technical Daconil 2787 - 97% and pure DAC-3701 in Dairy Cattle. Unpublished Report by Indistrial Biotest Laboratories, submitted to WHO by Diamond Shamrock Corp. Wolfe, A.L. and Stallard, D.E. (1971) Supplementary Milk and Meat Study. Unpublished Report submitted to WHO by Diamond Shamrock Corp. FAO/WHO (1975) 1974 evaluations of some pesticide residues in food. AGP:1974/M/11; WHO Pesticide Residues Series, No. 4.
See Also: Toxicological Abbreviations Chlorothalonil (EHC 183, 1996) Chlorothalonil (HSG 98, 1995) Chlorothalonil (ICSC) Chlorothalonil (WHO Pesticide Residues Series 4) Chlorothalonil (Pesticide residues in food: 1981 evaluations) Chlorothalonil (Pesticide residues in food: 1983 evaluations) Chlorothalonil (Pesticide residues in food: 1985 evaluations Part II Toxicology) Chlorothalonil (Pesticide residues in food: 1987 evaluations Part II Toxicology) Chlorothalonil (Pesticide residues in food: 1990 evaluations Toxicology) Chlorothalonil (Pesticide residues in food: 1992 evaluations Part II Toxicology) Chlorothalonil (IARC Summary & Evaluation, Volume 30, 1983) Chlorothalonil (IARC Summary & Evaluation, Volume 73, 1999)