Interregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 1 of 11 ----------------------------------------------------------------------- **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)**  **Am ended**  **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 d illweed, fresh leaves at 1.5 ppm; d illweed, dried leaves at 7.1 ppm; d ill , seed at 0.3 ppm; d ill , oil at 4.8 ppm; c ilantro, fresh leaves at 3 .0 ppm; c ilantro, 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) b y 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 an imal metabolism. The qualitative nature of the residue in plants is adequatel y understood. Metabolism studies with corn, so ybeans, and potatoes indicate that linuron is absorbed from the soil and translocated . The metabolic pathway involves demethylation to 3
- (3,4
- dichlorophen yl )
- 1
- methoxy urea 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
- dic hloroanili ne. 2. Analy tical method. Adequate enforcement methods are available for the determination of linuron in plant and animal commodities. A GC/MSD method involves hydrol ys is of linuron and all metabolites by alkaline reflux to 3,4
- dichloroaniline, followed by distillation of the 3,4
- dichloro aniline 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 i s then anal yz ed for 3,4
- dichloroaniline using gas chromatography with mass selective detection . The LOQ is 0.01 ppm for all anal yt es .Interregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 2 of 11 A second method involves extraction of linuron and metabolites using methano l 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 anal yz ed for linuron an d its metabolites using reversed phase high pressure liquid chromatograph y with MS/MS detection . The LOQ is 0.01 ppm
. 3. Magnitude of residues.
a . Plant residues. i. DI LL : T his petition proposes to establish tolerances for residue of linuron for the raw agricultural commodities di ll weed, fresh leaves at 1.5 ppm, dill weed, dried leaves at 7.1 ppm, dill seed at 0.3 ppm and dill oil at 4.8 ppm. T hree field trials were conducted, one each in CA, FL and WA. The pesticide was applied under conditions s imulating 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 sample s were generated to calculate concentration factors. The samples were anal yz ed 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 see d 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. L inuron 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 anal ys is. ii. C ILANTRO /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 ca lculate a concentration factor. At the TX trial, coriander seed samples were harvested 155 day s after the 2nd application. The samples were anal yz ed 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 p pm). 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 anal ys is. iii. PEA (DRY): A t olerance for residues of linuron is being proposed for the raw agricultural commodity pea (dry) at a level of 0.0 8 ppm. Six field trials were conductedInterregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 3 of 11 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 anal yz ed 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 anal ys is. iv. PARSL EY: 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 anal yz ed 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 mostl y within the acceptable range of 70% to 120%. Storage stability

recoveries also indicate that the re sidues were stable under the conditions in which the samples were held between harvest and anal ys is. v. HORSERADI SH: 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 day s 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 . Anima l 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 b yproducts of livestock. Therefore, there remains a reasonable exp ectation 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 LD 50 value for t echnical linuron was determined to be 2600 mg/kg (Toxicity Category III). The dermal LD 50 in rats was established at >2000 mg/kg (Toxicity Category III). A inhalation four hour L C50 exposure of rats to linuron resulted in a L C 50 of >2.05 mg/L (Toxicity C ategory I V). Ey e and skin irritation studies reported that linuron exposure resulted in limited ey e irritation (Toxicity Category I II) and negligible skin irritation (Toxicity Category I V). No dermal sensitization occurred with linuron in guinea pigs.Interregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 4 of 11 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 μg/plate and with activation up to 100 μg/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 s ystem and up to 1.0 mM in an S9
- activated sy stem. Similarly , linuron did not induce bone marrow chromosome aberrations in vivo , and in other tests f or genotoxicity , linuron did not induce unscheduled DNA sy nthesis in isolated rat hepatocy tes. 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 , respectivel y) were administered on day s 6
- 15 of gestation. The NOAELs for maternal s ystemic toxicity and developmental toxicity were 12.1 mg/kg/day . The LOAEL of 625 ppm (49.8 mg/kg/day) for maternal s ys temic toxi c effects was based upon decreased body weight and food consumption values. The developmental toxicity L OAEL 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 a dministered by gavage to New Zealand White rabbits at doses of 5, 25, or 100 mg/kg/day on day s 7 through 19 of gestation, a maternal s ys temic toxicity L OAEL was observed at 25 mg/kg/day . Based upon reduced maternal bod y 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 o f fetuses per litter, decreased fetal bod y weight, and increased incidence of fetuses with skeletal variations at100 mg/kg/day (the developmental toxicity L OAEL). In a two
- generation reproductive toxicity study in Sprague
- Dawley

rats, dietary

levels of 1 2.5, 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 L OAEL was undeter mined, and the reproductive toxicity NOAELwas estimated to be greater than 625 ppm (40.3 and 54.1 mg/kg/day for males and females, respectivel y). The parental sy stemic toxicity

NOAEL was 12.5 ppm, and the sy stemic LOAEL was 100 ppm, based upon decrements in parental body weight gain. In addition, at the 625 ppm level, testicular and epidid ym al abnormalities (testicular atrophy and intratubular fibrosis; epididy mal 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 anal ys is 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 hy

pothesis that rats exposed to linuron could develop interstitial cell hy perplas ia and subsequent adenomas (Leydig cell tumors) of the testicular tissue via a mechanism of sustained hy persecretion of luteinizing hormone induced by the antiandrogenic potential of linuron. A three
- generation reproductive toxicity study in Sprague
- Dawle y rats was conducted with linuron at dietary

levels of 25, 125, or 625 ppm (approximately 2, 10.0, and 55.0Interregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 5 of 11 mg/kg/day

for males and females). Parental s ys temic effects observed included reduced premating bod y weight in females of all three generations at 1 25 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 sy stemic LOAEL was determined to be 125 ppm (10.0 mg/kg/day), and the s ys t emic 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 L OAEL was determined to be 125 ppm (6.25 mg/kg/day), based on the following findings. Fertility was reduced in generations at 62 5 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 day s 1
- 4. Weanling bod y 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 cy toplasmic clear spaces of hepatocytes). This study was flawed b y the lack of histopathological data on the adult animals; however, the sy stemic study

results are considered to be supportive of those obtained from the two
generation stud y with linuron. 4. Subchronic toxicity
. A 3
- month subchron ic 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 NOAELwas 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 s ubchronic neuro to xicity 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 subchron ic 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

a dministration of linuron to male Crl:WI(Han) rats for 28 consecutive day s resulted in no suppression of the humoral or innate components of the immune sy stem at an y 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
- ye ar dog stud y 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 , respectivel y). In a previousInterregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 6 of 11 2
- ye ar dog stud y, 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. Si nce the abnormal pigment was postulated to be met
- and sulfhemoglobin, assay s 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 al l 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 ery throcy te count, hemoglobin, and hemato crit levels, and a small increase in the bone marrow ery thropoiesis. 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 6 25 ppm; relative liver weight was increased in males at 125 and 625 ppm. Based upon hematology

changes, the LOAEL for s ys temic 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
- ye ar 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 wer e increased in mid
- and high
- dose males (125 and 625 ppm, respectivel y). In addition, various indications of red blood cell destruction and turnover (increased mean corpuscular volume, decreased red blood cell count, and possible reticulocy tosis) were obse rved in both sexes at 125 and 625 ppm. Hemoglobin content was not affected in males at an y dose and was reduced at 6
- and 12
- months in > 125 ppm females. Therefore, based on reduced hemoglobin levels, the L OAEL for sy stemic toxicity for females was 125 ppm (6.25 mg/kg/day). The sy stemic NOAEL for females was 50 ppm (2.5 mg/kg/day), and the s ys temic NOAEL for males was 625 ppm (31.25 mg/kg/day). In another two
- ye ar 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 s ys temic NOAELwas 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 my eloid
- to - erythroid precursors was reduced for males, and the incidence of endometrial hy poplasia was increased for females. These findings were considered to be indicative of hem ol ys is. An 18
- month feeding stud y 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). Bas ed 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, respectivel y. The correspondin g NOAEL s for male and female rats were 125 and 25 ppm (6.25 and 1.25 mg/kg/day). In a two
- ye ar 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 levelsInterregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 7 of 11 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 hepat ocytomegal y, hepatocellular cy

toplasmic alteration, hepatocellular vacuolization, hemorrhage, and necrosis of the liver. A NOAEL was not established; the sy stemic toxicity L OAEL, based on increased methemoglobin values, was < 50 ppm (12 mg/kg/day). 6. Car cincogenicity . Based on USEPA review of the carcinogencit y 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 adequatel y understood. An acceptable metabolism study with goats indicates that linuron is rapidly metabolized by demethylation, demethoxylation, and h ydrox yl ation and is primarily eliminated by

excretion. The metabolism of linuron in poultry has been found to be consistent with the goat stud y. 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) l inuron 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 (app roximately

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 b y gavage to five Sprague
- Dawley rats per sex. The result s 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 majorit y of the administered 14 C
- linuron was eliminated in the urin e 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 ident ified in the urine and feces were h ydrox y - norlinuron and norlinuron. Approximately 4
- 5% and 6
- 8% of the urinary and fecal metabolites, respectivel y, remained unidentified. Exposure to linuron appears to induce mixed function oxidative enzy mes. 9
. Endocrine disruption. EPA is required under the FFDCA, as amended by F QPA, 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 n aturally o ccurring estrogen, or other such endocrine effects as the Administrator may

d esignate.” F ollowing recommendations of its Endocrine Disruptor and Testing Advisory

C ommittee (EDSTAC), EPA determined that there was a scientifi c basis for including, as part of the program, the androgen and thy roid hormone sy stems, in addition to the estrogen hormone sy stem. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. F or pesti cide chemicals, EPA will use FI FRA and, to the extent that effects in wildlife may h elp determine whether a substance may h ave an effect in humans, FFDCA authority t o require the wildlife evaluations. A s the science develops and resources allow, screeningInterregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 8 of 11 of additional hormone sy stems may b e 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 assay s 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 assay s, L inuron was classified as “not
- interactive” at the estrogen receptor in the Estrogen Receptor in v itro Assay (OPPTS 8 90.1250), and linuron was categorized as equivocal for aromatase inhibition i n the aromatase in vitro assay (OPPTS 890.1200)
. Inthe 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 l inuron 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 c hanges 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 c hanges in coloration, lethargy , and up to 25% mortality ; other effects were a lso noted, including increased spermatogonia, changes in gonadal staging, decreased yo lk s ynthesis, and increased oocyte atresia of predominantly pre - vitellogenic follicles. However, general and excessive toxicity at this top dose cannot be excluded as a s ignificant 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 T 4 levels at dosage levels of 50 and 100 mg/kg/day . The significance of the lower T 4 is not clear, since there was no statistically

significant change in mean serum TSH levels, no change in th yr oid gland weights, and no test substance
- related microscopic findings in the th yroid gland. However, based on the lack of effects on an y 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
- dich lorophenyl)
- 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 re gulated 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 l inuron 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 estimatedInterregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 9 of 11 population subgroup (females 13
- 49 y ears old)
. S ince the estimate d 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
- FCIDTM 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. C hronic 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 c hronic 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 anal ys es 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 wi ll not contribute significantl y to the aggregate human risk. The predicted chronic concentration for linuron maxi mum surface water value was 38 ppb and mean was 18 ppb . When the surface water concentration was included in the chronic dietary

risk assessm ent, 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 effect s would result from exposure to linuron. D. Cumulative Effects EPA has not made a common mechanism of toxicity finding as to linur on. 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 anal yt ical 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 res idue in diuron and animal plant metabolism or hydrol ys is studies. For purpose of this tolerance action, therefore, linuron does not have a common mechanism of toxicity

with other substances.Interregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 10 of 11 E. Safet y Determination 1. U.S. population. a. Acute risk. B ased on the completeness and reliability of the acute toxicology database EPA has established an acute RfD of 0.12 mg/kg/day onl y for the population subgroup females 13 to 49 y ears of age. The acute dietary exposure from food and water to linuron will occu py 6.49 % of the acute population adjusted dose (aPAD) for this subgroup. This risk a ssessment 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 dail y aggregate dietary exposure over a lifetime will not pose appreciable risk to human health. Thus , there is reasonable certaint y 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 currentl y avai lable literature information and the acceptable guideline developmental toxicity studies in rats and rabbits and multigeneration reproduction toxicity

studies in rats. A 2
- generation reproduction s tudy in rats also examin ed histopatholgy of the reproductive organ s of F 0 and F 1 ge neration males and females. A 3
- generation reproduction study is also available. In addition, several mechanistic studies were conducted b y the registrant to explore biochemical and histopathological effects of linuron on y oung 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 y oung rats exposed to linuron during pre
- and post
- natal periods. Additionally , the anti
- androg enic effects of linuron on the rats occurred at doses much higher than the effects on the hematological sy stem 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 protectiv e of the effects seen in the reproduction study

as a result of the antiandrogenic effects of linuron (36 mg/kg/day). Based on this analy sis HED has determined that it would be safe for infants and children to reduce the FQPA safety factor to lx. FFDCA sec tion 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 toInterregional Research Project No. 4 (IR
- 4); Tessenderlo Kerley, Inc. LINURON

Page 11 of 11 estimate aggregate dietary exposures of infants and children to linuron demonstrated that 27.4 % of the cRfD would be utiliz ed for the highest exposed group, non - nursing infants . There fore, 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 C odex or M exican MRL s for linuron on the proposed crops.