US Federal Register

IR-4. Pesticide Petition. PP 6E7150. Proposal to establish a tolerance for residues of the insecticide etoxazole in or on food commodities:

Practical analytical methods for detecting and measuring levels of etoxazole have been developed and validated in/on all appropriate agricultural commodities and respective processing fractions. The LOQ of etoxazole in the methods is 0.02 ppm which will allow monitoring of food with residues at the levels proposed for the tolerances.

VALENT. Pesticide Tolerance. FINAL RULE.

A summary of the toxicological endpoints for etoxazole used for human risk assessment is discussed in Unit III.B. of the final rule published in the Federal Register of September 26, 2003 (see below)
• Prenatal and postnatal sensitivity. There is qualitative evidence of increased susceptibility following exposure to etoxazole in the rat reproduction study. Therefore, EPA performed a Degree of Concern Analysis to determine the LOC for the effects observed when considered in the context of all available toxicity data, and to identify any residual uncertainties after establishing toxicity endpoints and traditional UFs to be used in the risk assessment of this chemical. If residual uncertainties are identified, EPA examines whether these residual uncertainties can be addressed by a special FQPA safety factor and, if so, the size of the factor needed. In performing the Degree of Concern Analysis, EPA noted that the effects in the pups in the rat reproduction study are well-characterized with a clear NOAEL. In addition, the pup effects occur at the same dose as maternal toxicity. Furthermore, the doses selected for various risk assessment scenarios are lower than the doses that caused off spring toxicity. There are no residual uncertainties for prenatal/postnatal toxicity in this study. Therefore, although there is evidence of increased qualitative susceptibility in the rat reproduction study, the concern is low. For the reasons stated above, EPA has concluded that there is low concern for prenatal and/or postnatal toxicity resulting from exposure to etoxazole.
• EPA determined that the 10X SF (safety factor) to protect infants and children should be removed.
• Acute exposure... EPA evaluated the suitability of the developmental toxicity study in rabbits in which the developmental NOAEL of 200 milligram/kilogram/day (mg/kg/day) is based upon increased incidences of 27 presacral vertebrae and 27 presacral vertebrae with 13th ribs (skeletal variations) in the fetuses at the LOAEL of 1,000 mg/kg/day (limit dose). Although these developmental effects may be attributed to a single dose, EPA concluded that these effects are minor in magnitude and were observed only at the limit dose (1,000 mg/kg/day). Therefore, quantitation of the acute risk was not performed.

VALENT. Pesticide Petition to Establish a Tolerance in or on Food:

• The results of a grape processing study indicate that etoxazole residues concentrate in both grape juice and raisins. The concentration factor for raisins was determined in this study to be 3.5X. The theoretical concentration factor for raisins is, however, 4.7x.

• Almond, hull is the only commodity under consideration that is a significant feed item for beef and dairy cattle.

• Rabbit developmental study. A statistically significant increased incidence of 27 presacral vertebrae with 13th ribs was observed in fetuses at 1,000 mg/kg/day compared with controls. This finding was within historical control range for fetal incidence but above the historical control range for litter incidence. No dose response was evident and the variation is considered to be equivocally treatment related. The NOAEL for developmental toxicity was 200 mg/kg/day based on statistically significant increased incidence of 27 presacral vertebrae with 13th ribs in fetuses at 1,000 mg/kg/day.

• Subchronic toxicity. Subchronic toxicity studies conducted with etoxazole technical in the rat (oral and dermal), mouse and dog indicate a low level of toxicity. Effects observed at high dose levels consisted primarily of anemia and histological changes in the adrenal gland, liver and kidneys.

• Rat chronic feeding/oncogenicity study. Sprague Dawley rats for 2-years at dietary concentrations of 4, 16, and 64 mg/kg/day. A trend toward decreased body weight gain for males at 64 mg/kg/day in the latter half of the study was observed. Hemotology and clinical chemistry changes, increased liver weights and hepatic enlargement at 16 mg/kg/day or above were observed. Testicular masses, centrilobular hepatocellular swelling and testicular interstitial (Leydig) cell tumors occurred at or above 16 mg/kg/day. The interstitial (Leydig) cell tumors were believed to be incidental. The NOAEL was 4 mg/kg/day for males and 16 mg/kg/day for females. Because an MTD level was not achieved in this study, a second study was conducted in which etoxazole technical was fed to male and female Sprague Dawley rats for 2-years at dietary concentrations of 50, 5,000, and 10,000 ppm. In this study, decreased mortality, body weight and food consumption/ efficiency (females) at 10,000 ppm was observed. Hematological, clinical, and histopathological changes of the incisors, and increased liver weights occurred in both sexes at 5,000 and 10,000 ppm. Centrilobular hepatocellular hypertrophy was observed in both sexes at 10,000 ppm. The interstitial (Leydig) cell tumors observed in the first study, were not observed in the repeat study. The NOAEL in the repeat study was 50 ppm (1.8 mg/kg/day).

• Animal metabolism... Plasma levels were significantly lower in females. Concentrations of radioactivity were significantly higher in the tissues of male rats compared to females. ... By 168 hours, the concentration in most tissues was below the concentration in the corresponding plasma, with only the liver and fat having significant
levels of radioactivity.

VALENT. Pesticide tolerance. FINAL RULE.

-- 90-Day oral toxicity rodents (rat). NOAEL = 61.8/69.0 milligrams/kilogram/ day (mg/kg/day) Male/Female (M/F) LOAEL = 183.7/204.8 mg/kg/day (M/F), based upon increases in hepatic enzyme levels, increased liver weights and centrilobular hepatocellular swelling in both sexes and liver enlargement in females only
-- 90-Day oral toxicity rodents (mouse). NOAEL = 213.6/250.5 mg/kg/day (M/F) LOAEL = 878.4/994.5 mg/kg/day (M/F), based upon periportal hepatocellular necrosis, increased alkaline phosphatase levels, accompanied by increased relative liver weight, liver enlargement, and centrilobular hepatocellular swelling
-- 90-Day oral toxicity nonrodents (dog). NOAEL = 5.33/5.42 mg/ kg/day (M/F) LOAEL = 53.7/55.9 mg/ kg/day (M/F), based upon clinical signs (vomiting foamy fluid and mucous stool), clinical chemistry, increased liver weights, and centrilobular swelling in the liver and acinar cell atrophy in the prostate.
-- Prenatal developmental toxicity in nonrodents (rabbit). Maternal NOAEL = 200 mg/kg/day LOAEL = 1,000 mg/kg/day based upon liver enlargement and decreased body weight gains and food consumption. Developmental NOAEL = 200 mg/kg/day LOAEL = 1,000 mg/kg/ day based upon increased incidences of 27 presacral vertebrae and 27 presacral vertebrae with 13th ribs in the fetuses.
-- Reproduction and fertility effects (rat). Parental/Systemic NOAEL = 20 mg/kg/ day LOAEL = 100 mg/kg/ day (M/F), based upon increased liver weights in the P and F₁ males and increased adrenal weights in the P females Offspring/Systemic NOAEL = 20 mg/kg/ day LOAEL = 100 mg/kg/ day (M/F), based upon pup mortality Reproductive NOAEL = 100 mg/kg/day LOAEL = not determined.
-- Combined chronic toxicity/ carcinogenicity rodents (rat). NOAEL = 64 mg/kg/day (M/F). LOAEL = not determined Equivocal evidence of carcinogenicity.
-- 2-Year feed/ carcinogenic (rat) . NOAEL = 1.83/2.07 mg/kg/day (M/F) LOAEL = 187/216 (M/ F), based upon effects on the incisors including abnormal amelogenesis. No evidence of carcinogenicity
-- Chronic toxicity nonrodents (dog). NOAEL = 4.62/4.79 mg/kg/day (M/F). LOAEL = 23.5/23.8 mg/ kg/day (M/F), based upon increased alkaline phosphatase activity, increased liver weights, liver enlargement (females), and incidences of centrilobular hepatocellular swelling in the liver.
-- 78-Week carcinogenic mouse. NOAEL = 242/243 (M/ F). LOAEL = 484/482 (M/ F), based on a slight increase in the incidence of a fatty change in the centrilobular hepatocytes in males.
-- Gene mutation - in vitro forward gene mutation assay in mouse lymphoma cells. When tested up to cytotoxic levels, mutagenic in the presence of S9 activation and equivocal for mutagenicity in the absence of S9 activation.
-- Cancer. EPA has determined that etoxazole is not likely to be a human carcinogen and EPA therefore, does not expect it to pose a cancer risk. As a result, a quantitative cancer dietary exposure analysis was not performed.