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Physiochemical Properties Chemical Name: 2chloroN(2,6 diethylphenyl)N (methoxymethyl) acetamide Common Names: The common name alachlor is in general use Chemical Family: Acetanilide Colour: Colourless to white crystalline Physical State: Solid Toxicological Studies Acute Toxicity In studies using laboratory animals, alachlor generally has been shown to be of low acute toxicity. All studies have been classified as either Category III or IV, the two lowest classifications III or IV, the two lowest classifications ¾ Acute oral toxicity in rats LD50 = 930 mgkg ¾ Acute dermal toxicity in rats LD50 = 13.3 gkg ¾ Acute inhalation toxicity in rats LC50 > 1.04 mgL (4 hours)
12/8/2010 1 Alachlor C 2 H 5 N CH CHO 3 2 CO CH 2 Cl C 2 H 5 2 Alachlor is a herbicide used for weed control on corn, soybeans, sorghum, peanuts, and beans Physiochemical Properties Chemical Name: 2-chloro-N-(2,6 diethylphenyl)-N- (methoxymethyl) acetamide Common Names: The common name alachlor is in general use Chemical Family: Acetanilide Colour: Colourless to white crystalline Physical State: Solid Residue limits have been set for exposure to alachlor through both food and water by a series of laboratory exposure studies Alachlor Exposure Toxicological Studies Acute Toxicity In studies using laboratory animals, alachlor generally has been shown to be of low acute toxicity. All studies have been classified as either Category III or IV, the two lowest classifications Category III or IV, the two lowest classifications ¾ Acute oral toxicity in rats LD 50 = 930 mg/kg ¾ Acute dermal toxicity in rats LD 50 = 13.3 g/kg ¾ Acute inhalation toxicity in rats LC 50 > 1.04 mg/L (4 hours) 12/8/2010 2 Subchronic Toxicity In an oral toxicity study conducted in rats, they were administered doses of 0, 1.5, 15, or 146 mg/kg/day for a period of 90 days ¾ Systemic toxicity was noted in high dose animals as decreased body weights and body weight gains, decreased food consumption and efficiency, along with other symptoms of toxicity ¾ The NOEL was determined to be 15 mg/kg/day Another oral toxicity study was conducted in dogs that were administered alachlor in doses of 0, 5, 25, 50, or 75 mg/kg/day for 6 months ¾ There were signs of toxicity at all dose levels including the lowest dose level where an increase in liver weights was noted in males ¾ The NOEL could not be determined, however the LOEL was 5 mg/kg/day Chronic Toxicity In a one-year oral toxicity study conducted in dogs, alachlor was administered in doses of 0, 1.0, 3.0, or 10 mg/kg/day. ¾ Toxicity was noted at the 3 mg/kg/day dose as hemosiderosis in the kidney and in the spleen of male dogs ¾ At the high dose toxicity was reported as hemosiderosis and hemolytic anemia in the liver of males hemolytic anemia in the liver of males ¾ The NOEL was determined to be 1 mg/kg/day In a two-year oral toxicity study rats were administered doses of 0, 14, 42, or 126 mg/kg/day for approximately 117 weeks in males and 106 weeks in females. ¾ Toxicity was noted at 14 mg/kg/day and above as ocular lesions and as increased thyroid weights in both sexes, and as increased liver weight in the high dose group ¾ The NOEL was determined to be less than 14 mg/kg/day Chronic Toxicity In a second long-term study, rats were fed doses of 0, 0.5, 2.5, or 15 mg/kg/day of alachlor for 110 weeks. ¾ Toxicity was seen at the highest dose tested as molting of retinal pigmentation and as molting of retinal pigmentation and increased mortality in females, with abnormal disseminated foci of the liver in males ¾ The NOEL was determined to be 2.5 mg/kg/day Carcinogenicity In a carcinogenicity study conducted in mice, alachlor stablized with epichlorohydrin was adminstered at the start of the study for 11 months, and then with a lot stabilized with epoxidized soybean oil was administered in the diet of mice for 18 months The doses administered were 0, 26, 78, or 260 mg/kg/day ¾ Thyroid follicular atrophy was noted in the mid and high dose males and the high dose females ¾ Males and females had a significant increased trend in bronchioaveolar adenomas 12/8/2010 3 Carcinogenicity In a two-year carcinogenicity study conducted in rats, a dose of 126 mg/kg/day was administered in the diet for two years. ¾ It was observed that females were more sensitive than males ¾ Nasal, thyroid, and gastric tumors were observed ¾ The nasal tumors were noted after 2 years in a group that was exposed to alachlor for only the first 5 to 6 months ¾ The NOEL was determined to be 0 5 mg/kg/day ¾ The NOEL was determined to be 0 . 5 mg/kg/day A second carcinogenicity study was conducted on mice receiving 0, 16.64, 65.42, or 262.4 mg/kg/day for males and 0, 23.73, 90.34, 399.22 mg/kg/day for females of alachlor over an 18 month period ¾ The mice showed evidence of bronchoalveolar adenomas and/or carcinomas in the lung ¾ The NOEL was determined to be 16.64 mg/kg/day for males and 90.34 mg/kg/day for females Developmental Toxicity In a developmental toxicity study, rats were administered 0, 50,150, 400 mg/kg/day of alachlor by gavage on gestation days 6 through 19, inclusive ¾ Toxicity was noted at the high dose as a slight increase in the mean number of early and late resorptions with related increased implantation loss and a slight reduction in the mean number of viable fetuses ¾ The NOEL was determined to be 150 mg/kg/day In a rabbit developmental toxicity study, they received doses of 0, 50, 100, or 150 mg/kg/day of alachlor by gavage on days 7 through 19, inclusive ¾ There were no signs of developmental toxicity noted in this study at any dose level used ¾ The NOEL was determined to be equal to or greater than 150 mg/kg/day Reproductive Toxicity In a three-generation reproduction study, rats received either 0, 3, 10, or 30 mg/kg/day of alachlor in the diet ¾ The high dose females of each parental generation and the third generation females had lower ovary weights ¾ No microsco p ic chan g es were re p orted in the pg p ovaries and no effect was noted on reproductive parameters ¾ The parental/offspring NOEL was determined to be 10 mg/kg/day Summary of Alachlor Study Results NOELAlachlor Study mg/kg/day 15(rats)Subchronic Toxicity 5.0*(dogs) 1.0(dogs)Chronic Toxicity/ < 14(rats)Carcinogenicity * This is based on a LOEL, because no NOEL value was determined from the study 2.5(rats) 16.64males(mice)Carcinogenicity 90.34females 0.5(rats) 150(rats)Developmental Toxicity > 150(rabbits) 10(rats)Reproductive 12/8/2010 4 Reference Dose for Alachlor The NOEL in the chronic rat study of 0.5 mg/kg/day was considered to be the appropriate endpoint for establishing the non-cancer RfD for alachlor An uncertainty factor of 100 was applied to account for both the interspecies extrapolation and intraspecies variability variability ¾ RfD = 0.5 mg/kg/day = 0.005 mg/kg/day 100 On this basis the RfD was calculated to be 0.005 mg/kg/day However LED 10 for Alachlor Th EPA d i li i f Since alachlor is classified as a “likely” human carcinogen additional safety factors must be invoked Th e EPA agree d upon us i ng a non- li near marg i n o f exposure (MOE) approach for the purpose of risk assessment of alachlor Since there were rare tumors seen with alachlor exposure in animal studies, for the purposes of risk assessment, the MOE for the nasal tumors should be determined with 0.5 mg/kg/day as the “ point of departure” or LED 10 as no tumor response was seen at this dose level Margin of Exposure for Alachlor MOE = LED 10 Human exposure of interest Therefore for alachor Therefore , for alachor MOE = 0.5 mg/kg/day Human exposure of interest With a margin of exposure (MOE) < 100 being considered an unacceptable risk Margin of Exposure for Alachlor using the Non-Linear Model Observed Range Extrapolation Range s e Confidence Limit on Dose 50% Central Estimate Dose of Alachlor MOE Respon s 0.5 Human Exposure of Interest for Alachlor ED 10 10% 0% 12/8/2010 5 Alachlor Residues in Food The estimated maximum alachlor exposure from food to the average person in the U.S. was calculated as 0.000011 mg/kg bw/day RfD = 0.005 mg/kg/day and the TMDI = 0.000011 mg/kg bw/day RfD > TMDI, therefore the use is safe. Alachlor Residue in Water The estimated maximum alachlor exposure from water to the average person in the U.S. was calculated as 0.0000571 mg/kg bw/day RfD = 0.005 mg/kg/day and the TMDI = 0.0000571 mg/kg bw/day RfD > TMDI, therefore the use is safe. Total Alachlor Residue Exposure An aggregate exposure to alachlor can be calculated : Total residue exposure = sum of residue from food and water = TMDI food + TMDI water food water = 0.000011 + 0.0000571 = 0.0000681 mg/kg/day RfD = 0.005 mg/kg/day RfD > ∑ TMDI Therefore, the use of alachlor is safe when considering chronic exposure to the general population Carcinogenic Food Residue Risk for Alachlor (Using the MOE Approach) The estimated maximum alachlor exposure from food once again is 0.000011 mg/kg bw/day TMDI = 0.000011 mg/kg bw/day Now, instead of comparing the TMDI to the RfD, a margin of exposure must be calculated for the food residue exposure 12/8/2010 6 Carcinogenic Food Residue Risk for Alachlor (Using the MOE Approach) For nasal tumors the LED 10 or the “point of departure” was determined to be 0.5 mg/kg/day Since the MOE = LED 10 / human exposure of interest Since the MOE LED 10 / human exposure of interest = LED 10 / TMDI food = 0.5 / 0.000011 ≈ 45000 Since the MOE is greater than 100, the use of alachlor is safe meaning there is an acceptably low risk of cancer from alachlor residue in food Carcinogenic Drinking Water Residue Risk for Alachlor (Using the MOE Approach) The estimated maximum alachlor exposure from drinking water once again is 0.0000571 mg/kg bw/day TMDI = 0.0000571 mg/kg bw/day Just as for the food residue, instead of comparing the TMDI to the RfD, a margin of exposure is calculated for drinking water residue exposure Carcinogenic Drinking Water Residue Risk for Alachlor (Using the MOE Approach) The LED 10 or the “point of departure” once again is 0.5 mg/kg/day And the MOE = LED 10 / human exposure of interest = LED 10 /TMDI t LED 10 / TMDI wa t er = 0.5 / 0.0000571 ≈ 8800 Since the MOE is greater than 100, the use of alachlor is safe meaning there is an acceptably low risk of cancer from alachlor residue in drinking water Total Carcinogenic Residue Risk for Alachlor (Using the MOE Approach) An aggregate exposure to alachlor can be calculated : Total residue exposure = sum of residue from food and water = TMDI food + TMDI water = 0.000011 + 0.0000571 = 0.0000681 mg/kg/day Now, an aggregate carcinogenic risk can be calculated by determining the MOE 12/8/2010 7 Total Carcinogenic Residue Risk for Alachlor (Using the MOE Approach) MOE = LED 10 / total human exposure = LED 10 / TMDI food + TMDI water = 0.5 / (0.000011 + 0.0000571) ≈ 7300 Since the MOE is greater than 100, the use of alachlor is safe meaning there is an acceptably low risk of cancer from chronic exposure to alachlor residue in the diet . (MOE) approach for the purpose of risk assessment of alachlor Since there were rare tumors seen with alachlor exposure in animal studies, for the purposes of risk assessment, the MOE for the. significant increased trend in bronchioaveolar adenomas 12/ 8/2010 3 Carcinogenicity In a two-year carcinogenicity study conducted in rats, a dose of 126 mg/kg/day was administered in the diet for. of alachlor is safe meaning there is an acceptably low risk of cancer from alachlor residue in food Carcinogenic Drinking Water Residue Risk for Alachlor (Using the MOE Approach) The estimated