Document ID: EPA-HQ-OPP-2012-0791-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-07-19T04:00Z

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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4)

Amended Petition Number 2E8083

	EPA has received a pesticide petition (PP# 2E8083) from Interregional Research Project Number 4 (IR-4), 500 College Road East, Suite 201 W., Princeton, NJ  08540, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a (d), to amend 40 CFR part 180.184 by establishing a tolerance for residues of linuron, (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) and its metabolites convertible to 3,4-dichloroaniline, calculated as linuron, in or on the raw agricultural commodities dillweed, fresh leaves at 1.5 ppm; dillweed, dried leaves at 7.1 ppm; dill, seed at 0.3 ppm; dill, oil at 4.8 ppm; cilantro, fresh leaves at 3.0 ppm; cilantro, dried leaves at 27 ppm; coriander, seed at 0.01 ppm; pea, dry, seed at 0.08 ppm; parsley, dry leaves at 8.3 ppm; parsley, leaves at 3.0 ppm; and horseradish at 0.05 ppm.  Additionally, IR-4 is requesting to amend 40 CFR part 180.184(c) by deleting the regional tolerance in or on parsley, leaves at 0.25 ppm.  EPA has determined that this petition contains data or information regarding the elements set forth in section 408(d)(2); however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant and animal metabolism.  The qualitative nature of the residue in plants is adequately understood. Metabolism studies with corn, soybeans, and potatoes indicate that linuron is absorbed from the soil and translocated. The metabolic pathway involves demethylation to 3- (3,4-dichlorophenyl)-1-methoxyurea which is further metabolized to 3,4-dichloroaniline; metabolism may also occur through demethoxylation of linuron. The terminal residues of concern are the parent and its metabolites which are convertible to 3,4-dichloroaniline.

2. Analytical method. Adequate enforcement methods are available for the determination of linuron in plant and animal commodities. A GC/MSD method involves hydrolysis of linuron and all metabolites by alkaline reflux to 3,4-dichloroaniline, followed by distillation of the 3,4-dichloroaniline into an acid solution.  Interferences present in the acidic distillate are removed by partition into hexane.  The acidic distillate is then made alkaline with concentrated base and 3,4-dichloroaniline is partitioned into hexane.  The extract is then analyzed for 3,4-dichloroaniline using gas chromatography with mass selective detection.  The LOQ is 0.01 ppm for all analytes.  

A second method involves extraction of linuron and metabolites using methanol and clean-up of the extract by using an ENVI-Carb SPE column, elution of linuron and its metabolites using methanol followed by methanol-toluene, and concentration of the eluate.  The eluate is dissolved in methanol, filtered, and analyzed for linuron and its metabolites using reversed phase high pressure liquid chromatography with MS/MS detection.  The LOQ is 0.01 ppm.  

3. Magnitude of residues. 

a. Plant residues.  

i. DILL: This petition proposes to establish tolerances for residue of linuron for the raw agricultural commodities dillweed, fresh leaves at 1.5 ppm, dillweed, dried leaves at 7.1 ppm, dill seed at 0.3 ppm and dill oil at 4.8 ppm.  Three field trials were conducted, one each in CA, FL and WA. The pesticide was applied under conditions simulating commercial application techniques. The dill leaves and stems samples were harvested simulating commercial practices. At the CA and WA trials dill seed samples were also collected. Additionally, at the WA trial only, dried dill and dill oil samples were generated to calculate concentration factors.  The samples were analyzed for 3,4-DCA (expressed as linuron) and the results indicate a maximum residue of 0.67 ppm in the fresh dill samples, 3.5 ppm in the dried dill samples, 0.12 ppm in the dill seed samples and 1.8 ppm in the dill oil sample. The concentration factor was calculated as 3.2 - 6.25 for dried dill and 3.2 for dill oil. Linuron residues in the dill seed samples were lower than the residues in the fresh dill implying no concentration in the seed. Storage stability recoveries also indicate that the residues were stable under the conditions in which the samples were held between harvest and analysis. 

ii. CILANTRO/CORIANDER: This petition proposes to establish tolerances for residues of linuron for the raw agricultural commodities fresh cilantro at 3 ppm, dried cilantro at 27 ppm and coriander, seed at 0.01 ppm.  Four field trials were conducted, one each in CA, OR, TN, and TX. The pesticide was applied under conditions simulating commercial application techniques.  The coriander leaves and stems samples were harvested simulating commercial practices. At the CA trial, 1 additional sample of coriander leaves and stems was collected from each plot and dried simulating commercial practices to calculate a concentration factor. At the TX trial, coriander seed samples were harvested 155 days after the 2nd application.  The samples were analyzed for 3,4-DCA (expressed as linuron) and the results indicate linuron residues ranged from 0.08 ppm to 1.14 ppm in the fresh coriander (leaves and stems) samples. In the dried coriander (leaves and stems) treated sample, the residue detected was 8.5 ppm implying a concentration factor of 9 (avg. residue in the fresh coriander samples from the CA trial was 0.94 ppm).  No detectable residues of linuron were found in the coriander seed samples. Storage stability recoveries also indicate that the residues were stable under the conditions in which the samples were held between harvest and analysis. 

iii. PEA (DRY):  A tolerance for residues of linuron is being proposed for the raw agricultural commodity pea (dry) at a level of 0.08 ppm.  Six field trials were conducted in the major dry pea producing regions of the US. The pesticide was applied under conditions simulating commercial application techniques. The pea (dry) seeds were harvested and sampled using techniques simulating local commercial practices. The samples were analyzed for 3,4-DCA (expressed as linuron) and the results indicate residues ranging between < 0.01 ppm and 0.052 ppm in the pea (dry) samples. Concurrent recoveries were all within the acceptable range of 70% to 120%. Storage stability recoveries also indicate that the residues were stable under the conditions in which the samples were held between harvest and analysis. 

iv. PARSLEY: This petition also proposes to replace the current regional tolerance for parsley leaves with a national tolerance for fresh parsley (leaves & stems) at 3.0 ppm and dried parsley (leaves & stems) at 8.3 ppm.  Two field trials were conducted, one each in CA and OR. The pesticide was applied under conditions simulating commercial application techniques. The parsley leaves and stems samples were harvested simulating commercial practices. Additionally, at the CA trial, one untreated and one treated dried parsley (leaves and stem) samples were generated to calculate a concentration factor. The samples were analyzed for 3,4-DCA (expressed as linuron) and the results indicate a maximum residue of 1.3 ppm in the fresh parsley samples and 2.8 ppm in the dried parsley sample. The concentration factor in the dried parsley sample was calculated as 2.75. Concurrent recoveries were mostly within the acceptable range of 70% to 120%. Storage stability recoveries also indicate that the residues were stable under the conditions in which the samples were held between harvest and analysis. 

v. HORSERADISH: This petition also proposes to establish a tolerance for horseradish at 0.050 ppm.  To support this petition, horseradish was treated with one application of linuron at a rate of approximately 1.5 lb ai/A.  One broadcast application to the soil surface, after transplanting but prior to crop emergence, was made.  Horseradish roots were collected 76 to 77 days following the application.  No quantifiable residues in any of the treated samples were found. No residues above the lowest level of method validation (0.050 ppm) were observed in the control samples, and method suitability testing indicates that these results are reliable.  

b. Animal residues: EPA determined, in earlier tolerances reassessments for linuron, that there is no reasonable expectation of secondary residues will occur in milk, and eggs, or meat, fat and meat byproducts of livestock.  Therefore, there remains a reasonable expectation that no residues of linuron will occur in meat, milk, poultry, or eggs from the current, and proposed, linuron tolerances.

B. Toxicological Profile

1. Acute toxicity.  In an acute oral toxicity study conducted in rats, the oral LD50 value for technical linuron was determined to be 2600 mg/kg (Toxicity Category III). The dermal LD50 in rats was established at >2000 mg/kg (Toxicity Category III).  A inhalation four hour LC50 exposure of rats to linuron resulted in a LC50 of >2.05 mg/L  (Toxicity Category IV).  Eye and skin irritation studies reported that linuron exposure resulted in limited eye irritation  (Toxicity Category III) and negligible skin irritation (Toxicity Category IV). No dermal sensitization occurred with linuron in guinea pigs.

2. Genotoxicity. Technical linuron did not produce gene mutation in an Ames assay, in which Salmonella typhimurium bacteria were tested without activation up to 5.0 ug/plate and with activation up to 100 ug/plate. In an in vitro assay using CHO cells, linuron did not produce gene mutations when tested up to 0.50 mM in a nonactivated system and up to 1.0 mM in an S9-activated system. Similarly, linuron did not induce bone marrow chromosome aberrations in vivo, and in other tests for genotoxicity, linuron did not induce unscheduled DNA synthesis in isolated rat hepatocytes.

3. Reproductive and developmental toxicity. In a developmental toxicity study conducted with technical linuron in Sprague-Dawley rats, dietary doses of 50, 125, or 625 ppm (5.0, 12.1, or 49.8 mg/kg/day, respectively) were administered on days 6-15 of gestation. The NOAELs for maternal systemic toxicity and developmental toxicity were 12.1 mg/kg/day. The LOAEL of 625 ppm (49.8 mg/kg/day) for maternal systemic toxic effects was based upon decreased body weight and food consumption values. The developmental toxicity LOAEL of 49.8 mg/kg/day was based on increased postimplantation loss and increases in the litter and fetal incidences of resorptions.  When linuron was administered by gavage to New Zealand White rabbits at doses of 5, 25, or 100 mg/kg/day on days 7 through 19 of gestation, a maternal systemic toxicity LOAEL was observed at 25 mg/kg/day. Based upon reduced maternal body weight, the NOAEL was 5 mg/kg/day. At the high-dose level (100 mg/kg/day), maternal body weight, food consumption, absolute liver weight, and liver-to-body weight ratios were decreased. The developmental toxicity NOAEL was 25 mg/kg/day, based upon increased abortions, decreased mean number of fetuses per litter, decreased fetal body weight, and increased incidence of fetuses with skeletal variations at100 mg/kg/day (the developmental toxicity LOAEL).

In a two-generation reproductive toxicity study in Sprague- Dawley rats, dietary levels of 12.5, 100, or 625 ppm linuron (males: 0.8, 6.8, or 40.3 mg/kg/day; females: 1.0, 8.3, or 54.1 mg/kg/day) were administered.  Since no evidence of adverse effects on fertility or reproductive performance was noted, the reproductive toxicity LOAEL was undetermined, and the reproductive toxicity NOAEL was estimated to be greater than 625 ppm (40.3 and 54.1 mg/kg/day for males and females, respectively). The parental systemic toxicity NOAEL was 12.5 ppm, and the systemic LOAEL was 100 ppm, based upon decrements in parental body weight gain. In addition, at the 625 ppm level, testicular and epididymal abnormalities (testicular atrophy and intratubular fibrosis; epididymal inflammatory response or oligospermia) and ocular abnormalities (mineralization of the cornea; lens degeneration) were observed at histopathological evaluation of the F1 adults. Further evaluation of reproductive organ weight and hormone data from the F1 adults of this 2-generation study combined with an in vitro analysis of the ability of linuron and its metabolites to compete for binding to the androgen receptor resulted in the conclusion that linuron is a weak androgen receptor antagonist. These results support the hypothesis that rats exposed to linuron could develop interstitial cell hyperplasia and subsequent adenomas (Leydig cell tumors) of the testicular tissue via a mechanism of sustained hypersecretion of luteinizing hormone induced by the antiandrogenic potential of linuron.

A three-generation reproductive toxicity study in Sprague-Dawley rats was conducted with linuron at dietary levels of 25, 125, or 625 ppm (approximately 2, 10.0, and 55.0 mg/kg/day for males and females). Parental systemic effects observed included reduced premating body weight in females of all three generations at 125 and 625 ppm, reduced body weights at weaning for 125 ppm dams, and alopecia in both sexes for the F0 and F1b adults at 625 ppm. Based upon the findings at the mid-dose level, the systemic LOAEL was determined to be 125 ppm (10.0 mg/kg/day), and the systemic NOAEL was 25 ppm (2.0 mg/kg/day). The reproductive toxicity NOAEL was 25 ppm (2.0 mg/kg/day) and the reproductive toxicity LOAEL was determined to be 125 ppm (6.25 mg/kg/day), based on the following findings. Fertility was reduced in generations at 625 ppm F2a through F3a. Pup survival was consistently decreased at 625 ppm, with most deaths occurring in the first 24 hours postpartum, and a trend for decreased viability from days 1-4. Weanling body weights were decreased for F1b and F2b male and female pups at 125 ppm and 625 ppm. Absolute liver and kidney weights of weanlings (both sexes) were decreased, and histopathology of the 625 ppm F2b weanlings identified an increased incidence of liver atrophy (decreased cytoplasmic clear spaces of hepatocytes). This study was flawed by the lack of histopathological data on the adult animals; however, the systemic study results are considered to be supportive of those obtained from the two-generation study with linuron.

4. Subchronic toxicity. A 3-month subchronic study was conducted with linuron in rats at dietary levels of 80, 400, and 3000 ppm (4, 20, and 150 mg/kg/day).  Observations of decreased red blood cell count and increased white blood cell count were noted at 400 ppm. At the high-dose (3000 ppm) growth was retarded. Based upon hematological findings, 400 ppm (20 mg/kg/day) was established as the LOAEL; the NOAEL was 80 ppm (4 mg/kg/day). The requirement for a 90-day feeding study in dogs was satisfied by the completion of two acceptable chronic studies conducted with linuron in beagles.

USEPA previously concluded that the linuron database does not show any neurotoxicity in all the submitted and published studies at doses as high as 100 mg/kg.  Nevertheless, USEPA required the conduct of the acute and subchronic neurotoxicity studies to satisfy these data gaps.  In response, TKI agreed to conduct the acute neurotoxicity study and will submit this study by the required deadline set by the USEPA Data Call In; however TKI submitted a waiver for the subchronic neurotoxicity study based on the lack of neurotoxicity noted in previous repeat-dose toxicity studies. Due to the lack of neurotoxicity of linuron, a developmental neurotoxicity study is not warranted.  

A immunotoxicity study was conducted.  Dietary administration of linuron to male Crl:WI(Han) rats for 28 consecutive days resulted in no suppression of the humoral or innate components of the immune system at any dosage level tested. Therefore, the no-observed-effect-level (NOEL) for both the AFC assay (humoral immunity) and NK cell assay (innate immunity) was 1500/1000 ppm, the highest dietary concentration evaluated. At 1500/1000 ppm, a dosage level that exceeded the maximum tolerated dose (MTD), and 500 ppm, lower food consumption accompanied by lower body weights were observed.  Linuron is not immunotoxic and does not affect functional immunotoxicity even at the top dose which met or exceeded the Maximum Tolerated Dose.

5. Chronic toxicity.  In a 1-year dog study linuron was fed to groups of 4
beagles/sex/dose at dietary levels of 10, 25, 125, or 625 ppm (male: 0.29, 0.79, 4.17, or 18.6 mg/kg/day; females: 0.3, 0.77, 3.49, or 16.1 mg/kg/day, respectively). In a previous 2-year dog study, linuron was administered in the diet to beagle dogs at 25, 125, or 625 ppm (0.625, 3.13, or 15.63 mg/kg/day); increased incidences of abnormal pigment was observed in the blood of animals at all dose levels.  Decreased red blood cell count, hematocrit, and hemoglobin levels were also noted in males at 625 ppm. Since the abnormal pigment was postulated to be met- and sulfhemoglobin, assays for these substances were conducted in the 1-year study. The presence of one or both substances in the blood was confirmed for both sexes in the 125 and 625 ppm dose groups at all intervals tested (3, 6, 9, and 12 months). At 625 ppm, evidence of red blood cell destruction was noted as increased hemosiderin deposition in the Kupffer cells of the liver (male and female), slight decreases in erythrocyte count, hemoglobin, and hematocrit levels, and a small increase in the bone marrow erythropoiesis. Secondary hematological changes at 625 ppm included increased platelet count, leukocyte count, and serum cholesterol levels. In addition, absolute liver weight was increased in males at 625 ppm; relative liver weight was increased in males at 125 and 625 ppm. Based upon hematology changes, the LOAEL for systemic toxicity was 125 ppm (4.17 mg/kg/day for males; 3.49 mg/kg/day for females). The NOAEL was 25 ppm (0.79 mg/kg/day for males; 0.77 mg/kg/day for females). 

In a 2-year feeding/carcinogenicity study, linuron was administered to Crl:CD(SD)BR Sprague-Dawley rats at dietary levels of 50, 125, or 625 ppm (2.5, 6.25, or 31.25 mg/kg/day). Testicular interstitial cell adenoma incidences were increased in mid- and high-dose males (125 and 625 ppm, respectively). In addition, various indications of red blood cell destruction and turnover (increased mean corpuscular volume, decreased red blood cell count, and possible reticulocytosis) were observed in both sexes at 125 and 625 ppm. Hemoglobin content was not affected in males at any dose and was reduced at 6- and 12-months in > 125 ppm females. Therefore, based on reduced hemoglobin levels, the LOAEL for systemic toxicity for females was 125 ppm (6.25 mg/kg/day). The systemic NOAEL for females was 50 ppm (2.5 mg/kg/day), and the systemic NOAEL for males was 625 ppm (31.25 mg/kg/day).  In another two-year rat feeding study, in which groups of albino rats were treated with dietary linuron at levels of 25, 125, or 625 ppm (1.25, 6.25, or 31.25 mg/kg/day), the systemic NOAEL was determined to be 125 ppm. At the LOAEL of 625 ppm (31.25 mg/kg/day), growth retardation was observed. In addition, at that dietary level, hemosiderin content of the spleen was increased for both sexes, marrow fat was reduced for females, the ratio of myeloid-to-erythroid precursors was reduced for males, and the incidence of endometrial hypoplasia was increased for females. These findings were considered to be indicative of hemolysis. An 18-month feeding study was conducted in Crl:CD(SD)BR rats to study the effects of linuron (94.5%) on methemoglobin and  sulfhemoglobin blood concentrations. The dietary levels tested were 25, 125, or 625 ppm (1.25, 6.25, or 31.25 mg/kg/day). Based upon significant changes noted in blood pigments in mid- and high-dose female rats and in high-dose male rats, the LOAEL was determined to be 625 ppm (31.25 mg/kg/day) and 125 ppm (6.25 mg/kg/day) for male and female rats, respectively. The corresponding NOAELs for male and female rats were 125 and 25 ppm (6.25 and 1.25 mg/kg/day).  In a two-year feeding/oncogenicity study in CD-1 mice, linuron was administered in the diet at levels of 50, 150, or 1500 ppm (12, 35, or 455 mg/kg/day).  A statistically significant increase in the incidence of hepatocellular adenomas was observed at 1500 ppm for female mice. At 1500 ppm, body weight and body weight gain were decreased for both males and females throughout the study. Methemoglobin values were increased at all dietary levels for both sexes. Mean absolute and relative liver weights were increased for females at 1500 ppm. For both males and females at that level, histopathological evaluation identified increased incidences of hemosiderosis of the spleen and hepatocytomegaly, hepatocellular cytoplasmic alteration, hepatocellular vacuolization, hemorrhage, and necrosis of the liver. A NOAEL was not established; the systemic toxicity LOAEL, based on increased methemoglobin values, was < 50 ppm (12 mg/kg/day).

6. Carcincogenicity.  Based on USEPA review of the carcinogencity studies with linuron, linuron was categorized as a Group C carcinogen requiring no quantification of human cancer risk. 

7. Animal metabolism. The qualitative nature of the residue in ruminants and poultry is adequately understood. An acceptable metabolism study with goats indicates that linuron is rapidly metabolized by demethylation, demethoxylation, and hydroxylation and is primarily eliminated by excretion. The metabolism of linuron in poultry has been found to be consistent with the goat study. The terminal residues of concern are the parent and its metabolites which are convertible to 3,4-dichloroaniline.

8. Metabolite toxicology. The metabolism and tissue distribution of [phenyl- [14]C](U) 
linuron was studied in male and female Sprague-Dawley rats.  Radiolabeled linuron was administered as a single gavage dose to 2 rats/sex/dose at 24 mg/kg and 400 mg/kg and also as a single 400 mg/kg gavage dose following dietary pretreatment at 100 ppm (approximately 10 mg/kg) to 2 rats/sex/dose. To further elucidate the metabolic pathway of linuron, a second study was conducted in which a single oral dose of 400 mg/kg of [14]C-linuron was administered by gavage to five Sprague-Dawley rats  per sex. The results from these studies indicate that linuron was extensively metabolized by male and female rats at both the low- (24 mg/kg) and high-dose (400 mg/kg) levels when administered by gavage. The majority of the administered [14]C-linuron was eliminated in the urine and, to a lesser extent, in the feces, within 96-120 hours. In general, tissue and organ residues were very low (<1%) at both dose levels, and there was no indication of accumulation or retention of linuron or its metabolites. The major metabolites identified in the urine and feces were hydroxy-norlinuron and norlinuron. Approximately 4-5% and 6-8% of the urinary and fecal metabolites, respectively, remained unidentified. Exposure to linuron appears to induce mixed function oxidative enzymes.

9. Endocrine disruption.  EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system.  EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife.  For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations.  As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). 

Linuron was included on the EPA initial list of compounds required to be tested in the EDSP.  Six of the eleven required EDSP Tier 1 assays were waived by the EPA.  Five studies (two in vitro and three in vivo) were required to be conducted.  Based on the results from the two in vitro assays, Linuron was classified as "not-interactive" at the estrogen receptor in the Estrogen Receptor in vitro Assay (OPPTS 890.1250), and linuron was categorized as equivocal for aromatase inhibition in the aromatase in vitro assay (OPPTS 890.1200). In the uterotrophic assay (OPPTS 890.1600), linuron dosed to rats at 30, 60, or 120 mg/kg bw/day resulted in no significant increases in uterus weights as compared to the vehicle control group.  Therefore, the results of this study indicate that there was no positive response for estrogenic activity as a result of administration of linuron at dose levels as high as 120 mg/kg bw/day.  In the short term reproduction study with fathead minnow, no adverse effects (e.g., mortality, abnormal behavior or notable changes in secondary sex characteristics) were observed at the two lowest dose levels (0.099 and 0.92 mg/L).  At the top dose 9.1 mg/kg, significant toxicity was noted, including changes in coloration, lethargy, and up to 25% mortality; other effects were also noted, including increased spermatogonia, changes in gonadal staging, decreased yolk synthesis, and increased oocyte atresia of predominantly pre-vitellogenic follicles. However, general and excessive toxicity at this top dose cannot be excluded as a significant factor in the reductions of the core endocrine endpoints.  Linuron was also tested in the EDSP female pubertal study (OCSPP 890.1450); in this study, rats were dosed with 0, 50, or 100 mg linuron/kg/day from PND 22 through PND 42or 43.  Effects of linuron in this study were limited to lower body weights and body weight gains at the high dosage level of 100 mg/kg/day and lower total T4 levels at dosage levels of 50 and 100 mg/kg/day.  The significance of the lower T4 is not clear, since there was no statistically significant change in mean serum TSH levels, no change in thyroid gland weights, and no test substance-related microscopic findings in the thyroid gland.  However, based on the lack of effects on any of the female pubertal specific endpoints, linuron was not considered to be a pubertal developmental toxicant.

C. Aggregate Exposure

1. Dietary exposure -- Residue of concern. Tolerances for residues of linuron in/on plant and animal commodities are expressed in terms of linuron (3-(3,4-dichlorophenyl)-1- methoxy-1-methyl-urea) [40 CFR §180.184(a) and (b)].  The EPA has concluded that the residues of concern are linuron and its metabolites convertible to 3,4-dichloroaniline, expressed as linuron; residues of 3,4-dichloroaniline need not be regulated separately.  Adequate enforcement methods are available for the determination of linuron residues of concern in/on plant and animal tissues. The current enforcement methods determine linuron and all metabolites hydrolyzable to 3,4-dichloroaniline.

2. Food. The EPA established the relevant toxicity endpoint for linuron at an acute reference dose of 0.12 mg/kg/day (females 13-49 only). The acute dietary exposure is 5.41% of the acute population adjusted dose for the highest estimated population subgroup (females 13-49 years old). Since the estimated risk is not greater than 100% of the aPAD, acute risk does not exceed HED's level of concern.

Chronic dietary exposure, resulting from the registered and proposed uses of linuron on proposed new crops is well within the acceptable limits for all sectors of the population, as predicted by the Chronic Module of the Dietary Exposure Evaluation Model (DEEM-FCID(TM) software Version 2.16).  The percentage or proportion of a crop that is treated can have a significant effect on the exposure profile.  In this case, it was assumed for all crops that 100% were treated with linuron.  

Chronic dietary (food) risk estimates associated with the use of linuron does not exceed the Agency's level of concern (> 100% cPAD) for any population subgroup including the most highly exposed population subgroup, non-nursing infants. The chronic dietary risk for non-nursing infants is 4.03% of the chronic PAD, and 0.88% for the general U.S. population.  The chronic reference dose is 0.0077 mg/kg/day.  Because the predicted exposures, expressed as percentages of the cRfD, are well below 100%, there is reasonable certainty that no chronic effects would result from dietary exposure to linuron. 

3. Drinking water. Chronic drinking water exposure analyses were calculated for linuron using EPA screening concentration models for ground water SCI-GROW and surface water FIRST.  Results indicate that a reasonable certainty exists that linuron residues in drinking water will not contribute significantly to the aggregate human risk.

The predicted chronic concentration for linuron maximum surface water value was 38 ppb and mean was 18 ppb.  When the surface water concentration was included in the chronic dietary risk assessment, the chronic dietary risk for non-nursing infants is 27.4% of the chronic PAD and 7.38% for the general U.S. population.   Because the predicted exposures, expressed as percentages of the cRfD, are well below 100%, there is reasonable certainty that no chronic effects would result from exposure to linuron.

D. Cumulative Effects

EPA has not made a common mechanism of toxicity finding as to linuron.

Although linuron, diuron, and propanil all contain 3,4-DCA in their structures, HED has previously concluded that the three active ingredients do not share a common mechanism of toxicity.  The analytical method for quantifying residues of concern form applications of linuron converts all residues to 3,4-DCA as a technical convenience.  However, 3,4-DCA is not a significant residue in diuron and animal plant metabolism or hydrolysis studies.

For purpose of this tolerance action, therefore, linuron does not have a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. 
a. Acute risk. Based on the completeness and reliability of the acute toxicology database EPA has established an acute RfD of 0.12 mg/kg/day only for the population subgroup females 13 to 49 years of age. The acute dietary exposure from food and water to linuron will occupy 6.49% of the acute population adjusted dose (aPAD) for this subgroup.  This risk assessment is based on upper-end (99.9[th] percentile) exposure estimates and assumed 100% crop treated.  

b. Chronic risk.  Based on the completeness and reliability of the toxicology database and using the conservative assumptions presented earlier, EPA has established a chronic RfD of 0.0077 mg/kg/day. It has been concluded that the aggregate exposure for existing crops plus the tolerances being proposed would utilize less than 8% of the cRfD for the US population. Generally, exposures below 100% of the RfD are of no concern because it represents the level at or below which daily aggregate dietary exposure over a lifetime will not pose appreciable risk to human health. Thus, there is reasonable certainty that no harm will result from aggregate exposures to linuron residues.   

2. Infants and children. In assessing the potential for additional sensitivity of infants and children to residues of linuron.
USEPA considered the currently available literature information and the acceptable guideline developmental toxicity studies in rats and rabbits and multigeneration reproduction toxicity studies in rats. A 2-generation reproduction study in rats also examined histopatholgy of the reproductive organs of F0 and F1 generation males and females. A 3-generation reproduction study is also available.  In addition, several mechanistic studies were conducted by the registrant to explore biochemical and histopathological effects of linuron on young and adult male rats. A cross mating study was also conducted with linuron. These special mechanistic studies evaluated a variety of endpoints including reproductive organ weights and histopathology, and hormone levels (leutenizing hormone, testosterone, and estradiol). The results indicate there is no increase in susceptibility of the developing fetuses and developing young rats exposed to linuron during pre- and post-natal periods. Additionally, the anti-androgenic effects of linuron on the rats occurred at doses much higher than the effects on the hematological system in the dogs. Therefore, selecting the toxicity endpoint and the point of departure (0.77 mg/kg/day) from the chronic dog study would be protective of the effects seen in the reproduction study as a result of the antiandrogenic effects of linuron (36 mg/kg/day). Based on this analysis HED has determined that it would be safe for infants and children to reduce the FQPA safety factor to lx.

FFDCA section 408 provides that EPA may apply an additional uncertainty factor for infants and children in the case of threshold effects to account for pre- and post-natal toxicity and the completeness of the database. Based on current toxicological data requirements, the database for linuron relative to pre- and post-natal effects for children is complete.  Conservative assumptions utilized to estimate aggregate dietary exposures of infants and children to linuron demonstrated that 27.4% of the cRfD would be utilized for the highest exposed group, non-nursing infants.  Therefore, it may be concluded that there is reasonable certainty that no harm will result to infants and children from aggregate exposures to linuron.  

F. International Tolerances

There are no Codex or Mexican MRLs for linuron on the proposed crops.