ORYZALIN PC Code: 104201 Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision ( or Registration Support) Document Date completed: 16 JUNE 2003 Prepared by: William Dykstra, Ph. D. Health Effects Division Office of Pesticide Programs U. S. Environmental Protection Agency Arlington, VA 22202 TXR# 0052045 form: FINAL June 21, 2000 EPA Reviewer: William Dykstra, Ph. D. , Date Reregistration Branch 4 ( 7509C) EPA Secondary Reviewer: Abdallah Khasawinah, Ph. D. , Date Reregistration Branch 4 ( 7509C)

TABLE OF CONTENTS 1.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.0 REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.0 DATA GAP( S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.0 HAZARD ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.1 Acute Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.2 Subchronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.3 Prenatal Developmental Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 4.4 Reproductive Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.5 Chronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.6 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4.7 Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.8 Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.9 Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.10 Special/ Other Studies ( optional section) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 5.0 TOXICITY ENDPOINT SELECTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.1 See Section 9.2 for Endpoint Selection Table. . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.2 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.3 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 6.0 FQPA CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 6.1 Special Sensitivity to Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 6.2 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 26 7.0 OTHER ISSUES ( optional section) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 8.0 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 9.0 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 9.1 Toxicity Profile Summary Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 9.1.1 Acute Toxicity Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 9.1.2 Subchronic, Chronic and Other Toxicity Tables . . . . . . . . . . . . . . . . . . . 31 9.2 Summary of Toxicological Dose and Endpoints . . . . . . . . . . . . . . . . . . . . . . . . 34 ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 3 1.0 HAZARD CHARACTERIZATION Oryzalin is of low acute toxicity by oral, dermal and inhalation routes of exposure ( Toxicity Category III or IV), but is an eye and skin irritant and a strong dermal sensitizer. Developmental studies in rats and rabbits demonstrate developmental effects in the presence of maternal toxicity. In rabbits, developmental effects include decreased live fetuses, increased resorptions and increased postimplantation loss in the presence of decreased body weight gain and food consumption in the does. In rats, decreased fetal weight and delayed ossification occurred in the presence of decreased body weight gain and food consumption in the dams. Pup toxicity was seen as decreased day 21 body weight in both the one generation and 3 generation rat reproduction studies.

The target organs of toxicity in rats and dogs are the thyroid, kidney and liver. There is no evidence of neurotoxicity. Parental toxicity consisted of increased kidney weight and kidney histopathology in the 1 generation study at all doses tested ( 19.4/ 22.3  178.8/ 205.5 mg/ kg/ day) and decreased body weight and food consumption ( 125/ 149 mg/ kg/ day) in the 3 generation study. In the 90 day rat feeding study, increased kidney weights and kidney histopathology ( 50  300 mg/ kg/ day) were the primary findings. The thyroid ( decreased T4) was the target organ in the 1 year dog gavage study. In the 2 year rat feeding study increased thyroid weights, thyroid histopathology and thyroid tumors, together with skin tumors and mammary gland tumors ( females), were identified. Thyroid tumors are common to the dinitroaniline class of herbicides, of which oryzalin is a member. Oryzalin was classified by the CARC as " likely to be a human carcinogen". A Q 1 * of 0.00779 ( mg/ kg/ day) 1 was established based on thyroid tumors. Only decreased weight gain was consistently seen in subchronic and chronic mouse studies. There was no tumorigenic potential in mice in an acceptable cancer study. Oryzalin is mutagenic in the sister chromatid exchange by intraperitoneally injection, but not oral intubation, and is also positive in the DNA repair test, but negative in the Ames assay, and UDS assay. The CARC required a mouse micro nucleus assay be performed.

A comparative thyroid assay in young rats and adults which measures hormone levels, organ weights, and histopathology is a critical data gap and is required. Additionally, a 28 day inhalation study and a mouse micro nucleus assay are required. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 4 2.0 REQUIREMENTS The requirements ( CFR 158.340) for food use for oryzalin are listed in Table 1. Use of the new guideline numbers does not imply that the new ( 1998) guideline protocols were used. Table 1.

Test Technical Required Satisfied 870.1100 Acute Oral Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 870.1200 Acute Dermal Toxicity . . . . . . . . . . . . . . . . . . . . . . 870.1300 Acute Inhalation Toxicity . . . . . . . . . . . . . . . . . . . . 870.2400 Primary Eye Irritation . . . . . . . . . . . . . . . . . . . . . . . 870.2500 Primary Dermal Irritation . . . . . . . . . . . . . . . . . . . . 870.2600 Dermal Sensitization . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchronic ( rodent) . . . . . . . . . . . . . . . . . . . . . 870.3150 Oral Subchronic ( nonrodent) . . . . . . . . . . . . . . . . . . 870.3200 21 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3250 90 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3465 90 Day Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes no no yes yes* yes

870.3700a Developmental Toxicity ( rodent) . . . . . . . . . . . . . . . 870.3700b Developmental Toxicity ( nonrodent) . . . . . . . . . . . . 870.3800 Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes 870.4100a Chronic Toxicity ( rodent) . . . . . . . . . . . . . . . . . . . . 870.4100b Chronic Toxicity ( nonrodent) . . . . . . . . . . . . . . . . . 870.4200a Oncogenicity ( rat) . . . . . . . . . . . . . . . . . . . . . . . . . . 870.4200b Oncogenicity ( mouse) . . . . . . . . . . . . . . . . . . . . . . . 870.4300 Chronic/ Oncogenicity . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes** yes yes** yes yes 870.5100 Mutagenicity C Gene Mutation  bacterial . . . . . . . . . 870.5300 Mutagenicity C Gene Mutation  mammalian . . . . . . 870.5xxx Mutagenicity C Structural Chromosomal Aberrations 870.5xxx Mutagenicity C Other Genotoxic Effects . . . . . . . . . . yes yes yes yes yes yes no yes 870.6100a Acute Delayed Neurotox. ( hen) . . . . . . . . . . . . . . . . 870.6100b 90 Day Neurotoxicity ( hen) . . . . . . . . . . . . . . . . . . . 870.6200a Acute Neurotox. Screening Battery ( rat) . . . . . . . . . 870.6200b 90 Day Neuro. Screening Battery ( rat) . . . . . . . . . . . 870.6300 Develop. Neuro . . . . . . . . . . . . . . . . . . . . . . . . . . . . no no

870.7485 General Metabolism . . . . . . . . . . . . . . . . . . . . . . . . 870.7600 Dermal Penetration . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes Special Studies for Ocular Effects Acute Oral ( rat) . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subchronic Oral ( rat) . . . . . . . . . . . . . . . . . . . . . . . . Six month Oral ( dog) . . . . . . . . . . . . . . . . . . . . . . .

* The one year chronic toxicity dog study satisfies the Guideline requirement for a subchronic dog study.

** The 2 year chronic toxicity/ oncogenicity rat study satisfies the Guideline requirements for Chronic Toxicity ( rodent) and Oncogenicity ( rat). ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 5 3.0 DATA GAP( S)

 a 28 day inhalation study ( § 870.3465)  a comparative thyroid assay in young rats and adults which measures hormone levels, organ weights, and histopathology ( no guideline reference)  a mouse micro nucleus assay ( § 870.5395)

4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of data base for acute toxicity: The data base for acute toxicity is considered complete. No additional studies are required at this time.

The acute oral, dermal, and inhalation toxicity studies are of low acute toxicity with all studies being in either Toxicity Category III or IV for the technical and 85% Surflan ® Dry Flowable. With the technical, the acute oral LD 50 and dermal LD 50 were greater than 10,000 mg/ kg and 2,000 mg/ kg ( 1 mortality/ 20), respectively. The clinical signs in the acute oral and dermal studies were ptosis, urine and feces colored yellow, and leg weakness, respectively. The acute oral LD 50 is greater than 500 mg/ kg for the formulation. Additionally with the formulation, there were no mortalities and toxic signs consisted of bright yellow urine, poor grooming and generalized leg weakness. At necropsy, yellow perineal staining was reported in all treated females. The acute dermal LD 50 was greater than 5,000 mg/ kg. There were no mortalities, toxic signs, or necropsy findings. The acute inhalation LC 50 for the technical and formulation are greater than 3.17 mg/ L and 3.48 mg/ L, respectively, with no mortalities, slight dyspnea and hypoactivity immediately postexposure and poor grooming. There were no compound related lesions at necropsy.

The acute toxicity data on Oryzalin technical and the Oryzalin 85% Surflan ® Dry Flowable is summarized below in Table 2.

Table 2. Acute Toxicity Data on ORYZALIN Technical Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity 00026592 LD 50 > 10 g/ kg IV 870.1200 Acute dermal toxicity 00106681 LD 50 > 2,000 mg/ kg III ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 6 870.1300 Acute inhalation toxicity 41034201 LC 50 > 3.17 mg/ L IV 870.2400 Acute eye irritation 00106681 corneal opacity clearing within 7 days III 870.2500 Acute dermal irritation 43910201 slight erythema IV 870.2600 Skin sensitization 44574102 strong sensitizer Table 2. Acute Toxicity Data on ORYZALIN 85% Surflan ® Dry Flowable Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity 00150104 LD 50 > 500 mg/ kg III 870.1200 Acute dermal toxicity 00150104 LD 50 > 5,000 mg/ kg IV 870.1300 Acute inhalation toxicity 00150104 LC 50 > 3.48 mg/ L IV 870.2400 Acute eye irritation 00150104 slight conjunctivitis, iritis, corneal opacity clearing within 7 days III 870.2500 Acute dermal irritation 00150104 slight erythema IV 870.2600 Skin sensitization 00150104 not a sensitizer 4.2 Subchronic Toxicity Adequacy of data base for subchronic toxicity: The data base for subchronic toxicity is not considered complete. A 28 day inhalation study and a comparative thyroid study in young and adult rats is required.

Systemic toxicity in rats was manifested as increased kidney weight and increased incidence of hyaline droplets. In subchronic mouse studies, decreased body weight gain was the predominant finding.

870.3100 90 Day Oral Toxicity  Rat ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 7 In a 90 day oral toxicity study ( MRID 44574103) Oryzalin ( 97.3% a. i., lot # TSN100719) was administered to 10 Fischer 344 rats/ sex/ dose in the diet at targeted dose levels of 0, 5, 50 or 300 mg/ kg/ day ( actual doses were 0, 4.56, 45.88 or 276.34 mg/ kg bw/ day for males and 0, 4.65, 46.79 or 283.09 mg/ kg/ day for females).

All animals survived to study termination. The only treatment related effect was discoloration of the fur, dark urine and perineal soiling in males and females at 300 mg/ kg/ day due to the orangeyellowish color of the test material. Body weight was significantly decreased ( 3 8%) throughout the study in females at 300 mg/ kg/ day; overall body weight gain was also decreased ( 17%). Food consumption in females at 300 mg/ kg/ day was decreased ( 7 13%) throughout the study. Corneal lesions ( cloudiness and mineralization) observed in both treated and control groups were not considered treatment related. Hematology parameters ( RBC, HGB and HCT) were decreased in males and females at 300 mg/ kg/ day. Males at 300 mg/ kg/ day had increased RBC polychromasia. Although there were multiple significant clinical chemistry changes, the only one considered treatment related was an increased total bilirubin in males at 300 mg/ kg/ day. Higher urine pH and increased number of triple phosphate crystals were observed in all treated animals. These findings could be related to the excretion of oryzalin in the urine. However, both sexes at 300 mg/ kg/ day also had lower urine specific gravity and increased numbers of animals with glucosuria and bilirubinuria; males at 300 mg/ kg/ day had a greater degree of proteinuria. Some of these effects at 300 mg/ kg/ day could be treatment related as there were kidney alterations on necropsy.

At necropsy, absolute and/ or relative kidney and liver weights were significantly increased in males and females at 50 and 300 mg/ kg/ day. Increased absolute and/ or relative spleen weights were observed in males and females at 300 mg/ kg/ day. The increases in relative weight of the heart in both sexes at 300 mg/ kg/ day and in males at 50 mg/ kg/ day and relative weight of the brain in females at 300 mg/ kg/ day were attributable to lower body weights. The relative weight of the thyroid was significantly increased in males at 300 mg/ kg/ day; the absolute and relative weights were increased in females at 300 mg/ kg/ day. These thyroid effects were not considered treatment related as there were no histopathological changes in the organ. Male and female rats at 50 or 300 mg/ kg/ day had an increased incidence of hyaline droplet formation in the cytoplasm of the proximal tubular epithelial cells in the outer portion of the cortex; the severity was increased in males at these doses. All female rats at 300 mg/ kg/ day had very slight amount of brown pigment in the cytoplasm of the proximal tubules of the outer cortex. Males and females at 300 mg/ kg/ day had a very slight degree of erythroid hyperplasia of the spleen. One female at 50 mg/ kg/ day also had this change. A very slight increase in hematogenous pigment within macrophages of the spleen was present in 3 of 10 females at 50 mg/ kg/ day and 10 of 10 females at 300 mg/ kg/ day. A very slight increase in hematopoiesis of the bone marrow was present in 5 of 10 males and 9 of 10 females at 300 mg/ kg/ day. Hepatocellular hypertrophy was observed in the centrilobular region of the liver in 3 of 10 males at 300 mg/ kg/ day.

The LOAEL is 50 mg/ kg/ day, based on increased kidney weights and increased incidence of hyaline droplet formation in renal tubular epithelial cells. The NOAEL is 5 mg/ kg/ day.

This 90 day oral toxicity study in the rat is acceptable ( guideline) and satisfies the guideline ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 8 requirement for a 90 day oral toxicity study ( OPPTS 870.3100; OECD 408) in the rat.

870.3100 90 Day Oral Toxicity  Mouse In a 90 day oral toxicity study ( MRID 00026773) Oryzalin ( Compound 67019) ( 99.8% a. i., Lot# 9UA45) was administered to15 B 6 C 3 F 1 mice/ sex/ dose in the diet at dose levels of 0, 450, 900, 1800, 3650 or 8000 ppm ( equivalent to approximately 0, 64, 129, 257, 521, 1143 mg/ kg bw/ day based on 1 ppm in food equals 0.15 mg/ kg/ day). Assays of fresh mash, fresh pellets and aged ( 3 ½ months) pellets showed that the concentrations were less than theoretical values ( 77 97% for fresh mash, 71 88% for fresh pellets and 78 88% for aged pellets).

There were no treatment related deaths during the study. Terminal body weight was comparable to controls in treated males but was significantly decreased ( 12%) in females at 8000 ppm. There were no treatment related hematology changes. A significant decrease in BUN and slight increase in alkaline phosphatase in males at 8000 ppm was not considered treatment related. At necropsy, there was a significant increase in absolute spleen weights in females at 8000 ppm. Significant increases in the relative weights of the liver, kidney and heart of male mice at 8000 ppm and increases in the relative weights of the liver, kidney and spleen in females at multiple doses were not considered toxicologically significant as they were slight. On histopathology, there was an increased incidence of chronic cystitis in females at 900 ppm and above and of pyelonephritis in females at 1800 ppm and above; however, there was no dose response. The cystitis was characterized by the accumulation of inflammatory cells within all layers of the urinary bladder. The pyelonephritis was characterized by the accumulation of lymphoid inflammatory cells within the interstitial tissues of the renal pelvis and was proposed to be due to an ascending infection secondary to the chronic cystitis. The pathogenesis of the cystitis is unknown. It was observed in 1/ 15 female mice treated at 10000 ppm for three months ( MRID 00026774) and in both sexes treated for one year at 3650 ppm ( MRID 00038681) but was not observed in mice treated for two years at doses up to 8000 ppm ( MRID 00244746). All studies were conducted in the same strain and at the same laboratory. If the cystitis resulted from bladder irritation due to chemical precipitation, it is expected that both sexes would be affected and that there would be a dose response. In a recent study ( MRID 44574104), there was no sex related difference in the metabolism of oryzalin which could explain finding of cystitis in only one species. In the present study, since there was no dose response in the incidence of cystitis and it occurred in only one sex, it is not considered toxicologically significant. The LOAEL in males is > 8000 ppm [ 1143 mg/ kg/ day ( 892 mg/ kg/ day corrected based on 78% of theoretical value)]. The NOAEL is

8000 ppm. The LOAEL in females is 8000 ppm [ approximately 1143 mg/ kg/ day ( 892 mg/ kg/ day corrected based on 78% of theoretical value) based on decreased terminal body weight. The NOAEL is 3650 ppm [ 521 mg/ kg/ day ( 406 mg/ kg/ day corrected based on 78% of theoretical value)] .

This 90 day oral toxicity study in the mouse is acceptable ( guideline) and satisfies the guideline requirement for a 90 day oral toxicity study ( OPPTS 870.3100; OECD 408) in mice. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 9 870.3100 90 Day Oral Toxicity  Mouse In a 90 day oral toxicity study ( MRID 00026774) Oryzalin ( Compound 67019) ( 99.8% a. i., Lot# X 28607) was administered to 20 B 6 C 3 F 1 mice/ sex in the diet at a dose level of10000 ppm ( equivalent to approximately 1429 mg/ kg bw/ day based on 1 ppm in food equals 0.15 mg/ kg/ day). Ten B 6 C 3 F 1 mice/ sex served as untreated controls. The study was designed to evaluate the chronic cystitis observed in an earlier study ( MRID 00026773) at doses

900 ppm. Parameters measured included: survival and clinical observations, weekly body weights, clinical chemistry, urinalysis ( 50% of animals at 2 days, 1, 2 and 3 weeks and 3 months) and histopathology on urinary bladder and kidneys. The concentration of oryzalin in fresh mash was 98% of theoretical value but was only 72% in pelleted feed. The discrepancy was thought to be due to difficulties in oryzalin recovery from the pellets during the analysis, which was noted in other studies.

There were no deaths during the study. During the first week, males failed to gain weight and females lost weight; however, both sexes gained weight thereafter so that terminal weights in treated animals were only slightly decreased. There was a significant increase in SGPT and glucose in treated male and female mice. The toxicological significance of these changes is unknown since only limited toxicology parameters were evaluated. A decrease in creatinine in both sexes of treated mice was not considered toxicologically significant. There were no treatment related changes on urinalysis. One treated female had an elevation in BUN and chronic cystitis, which was characterized by accumulation of inflammatory cells within all layers of the bladder. This lesion is similar to that observed in multiple females at

900 ppm in another 90 day study ( MRID 00026773). However, since only one animal was affected at a dose 10x that which produced cystitis in the previous study, the finding is not considered treatment related. The LOAEL is 10000 ppm ( approximately 1429 mg/ kg/ day) based on failure to gain weight during the initial weeks of dosing. The NOAEL is < 10000 ppm.

This 90 day oral toxicity study in the mouse is acceptable ( non guideline) and does not satisfy the guideline requirement for a 90 day oral toxicity study ( OPPTS 870.3100; OECD 408) in mice. It was intended as a special study to pursue the cause of chronic cystitis observed in oryzalintreated mice in a previous study.

870.3100 One Year Oral Toxicity  Mouse In a one year oral toxicity study ( MRID 00038681) Oryzalin ( Compound 67019) ( 99.8% a. i., Lot# X 28607) was administered to15 B 6 C 3 F 1 mice/ sex/ dose in the diet at dose levels of 0, 500, 1350 or 3650 ppm ( equivalent to approximately 0, 71, 193 or 521 mg/ kg bw/ day based on 1 ppm in food equals 0.15 mg/ kg/ day). The concentration of oryzalin in fresh mash was fresh approached the theoretical value; however, the concentrations in the fresh and aged pellets was much lower. The discrepancy was thought to be due to difficulties in oryzalin recovery from the pellets during the analysis, which was noted in other studies. The mean content of N nitrosodipropylamine, a B 2 ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 1 According to IRIS, male rats administered N nitrosodi N propylamine in the drinking water at doses of 1.8 mg/ kg/ day, 5 days/ week for 30 weeks developed liver carcinomas, esophageal papillomas and carcinomas and nasal adenocarcinomas. Rats of both sexes treated in a similar manner with 0.9 mg/ kg/ day developed esophageal carcinomas and forestomach tumors. No studies in mice are included in the IRIS report.

10 probable human carcinogen, in the diet was 0.24 ± 0.011 ppm. 1 There were no treatment related effects on survival, clinical signs of toxicity or body weights. There was a significant decrease in hemoglobin and RBC values in males and females, respectively, at 3650 ppm. The decreases were slight and within the normal range for this laboratory; therefore, the effects are not considered toxicologically significant. A number of significant differences in clinical chemistry, including decrease in BUN in males at 1350 ppm, decrease in creatinine in males at 1350 and 3650 ppm, increase in bilirubin in males at 3650 ppm and increase in alkaline phosphatase in all treated females, were not considered toxicologically significant because they were within normal limits. In male mice, significant increases in relative kidney ( 1350 and 3650 ppm), heart ( 3650 ppm) and testes ( 1350 and 3650 ppm) weights were not considered toxicologically significant because they were slight. On histopathology, chronic cystitis was observed in 1/ 15 males and 3/ 15 females at 3650 ppm vs 0/ 15 in controls. Pyelonephritis was observed in 2/ 15 males and 2/ 15 females at 3650 ppm and 1/ 15 males at 1350 ppm vs 1/ 15 male and 0/ 15 female controls. The cystitis was characterized by the accumulation of inflammatory cells within all layers of the urinary bladder. The pyelonephritis was characterized by the accumulation of lymphoid inflammatory cells within the interstitial tissues of the renal pelvis. A second urinary tract lesion observed in males was obstruction and extreme urinary bladder distension. It occurred in both treated and control animals and was associated with injury to the penis during fighting. The pathogenesis of the cystitis is unknown. It was observed in 1/ 15 female mice treated at 10000 ppm for three months ( MRID 00026774) and in females at 900 ppm and above, with no dose response, in another subchronic study ( MRID 00026773. It was not observed in mice treated for two years at doses up to 8000 ppm ( MRID 00244746). All studies were conducted in the same strain and at the same laboratory. If the cystitis resulted from bladder irritation due to chemical precipitation, it is expected that both sexes would be affected and that there would be a dose response. In a recent study ( MRID 44574104), there was no sex related difference in the metabolism of oryzalin which could explain finding of cystitis in only one species. Based on the inconsistent findings in other studies, the chronic cystitis is not considered toxicologically significant. The LOAEL is > 3650 ppm ( approximately 521 mg/ kg/ day). The NOAEL is

3650 ppm ( approximately 193 mg/ kg/ day).

This chronic study in the mouse is acceptable ( guideline) and satisfies the guideline requirement for a chronic oral study [ OPPTS 870.4100, OECD 452] in mice.

870.3200 21/ 28 Day Dermal Toxicity B Rat ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 11 In a 21 day dermal toxicity study ( MRID No. 00150106 ), oryzalin ( 98.4 % a. i., L 1385A) was applied to the shaved skin of 5 New Zealand White rabbits/ sex/ dose at dose levels of 0 or 1,000 mg/ kg bw/ day, 6 hours/ day for 7 days/ week during a 21 day period.

No changes in mortality, mean body weight or mean body weight gains, and food consumption were observed in the test group as compared to controls. Total bilirubin levels were decreased by 29% in males and 31% in females due to oryzalin treatment. Thyroid and parathyroid weights were increased by 27% ( absolute weight) and 26% ( relative weight) in oryzalin treated male rabbits. Increase in thyroid and parathyroid weights in oryzalin treated females was not significant. Gross pathological and histopathological parameters remain unchanged due to oryzalin treatment. The LOAEL is 1000 mg/ kg bw/ day, based on bilirubin changes in males and females and weight of thyroid and parathyroids in males. A NOAEL is not established.

This 21 day dermal toxicity study in the rabbits is acceptable ( non guideline) and does satisfy the guideline requirement for a 21 day dermal toxicity study ( OPPTS 870.3200 ; OECD 410).

4.3 Prenatal Developmental Toxicity Adequacy of data base for Prenatal Developmental Toxicity: The data base for prenatal developmental toxicity is considered complete. No additional studies are required at this time.

Developmental studies in rats and rabbits demonstrate developmental effects in the presence of maternal toxicity. In rabbits, developmental effects include decreased live fetuses, increased resorptions and increased postimplantation loss in the presence of decreased body weight gain and food consumption in the does. In rats, decreased fetal weight and delayed ossification occurred in the presence of decreased body weight gain and food consumption in the dams.

870.3700a Prenatal Developmental Toxicity Study  Rat In a developmental toxicity study ( MRID 41163801) Oryzalin ( 96.2% a. i., lot # L1385A) was administered to 25 female Crl: CD( SD) rats/ dose by gavage at dose levels of 0, 50, 225 or 1000 mg/ kg bw/ day from days 6 through 15 of gestation.

There were no deaths during the study. The only clinical sign of toxicity was increased alopecia at1000 mg/ kg/ day. Yellow orange urine observed in all treated animals was due to urinary elimination of the test material. Mean body weight gain was significantly decreased by 11% and 22% in the 225 and 1000 groups, respectively, over the course of the study. The overall effect was mostly due to the decreases during the initial days of treatment ( days 6 9) when the 225 ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 12 mg/ kg/ day group had a 36% decrease and the 1000 mg/ kg/ day group had a negative weight gain. Corrected body weight gain was non significantly decreased ( 7%) at 225 mg/ kg/ day and significantly ( 26%) at1000 mg/ kg/ day. Mean food consumption was significantly decreased in the 225 ( 6 11%) and 1000 mg/ kg/ day ( 5 49%) groups during days 6 9 and 10 13. The maternal LOAEL is 225 mg/ kg bw/ day, based on decreased body weight gain and food consumption. The maternal NOAEL is 50 mg/ kg bw/ day.

Pre implantation loss was non significantly increased in the 225 and 1000 mg/ kg/ day groups. Mean fetal body weights were significantly decreased in the 225 mg/ kg/ day males ( 8%) and females ( 11%) and 1000 mg/ kg/ day males ( 19%) and females ( 23%) groups. There was incomplete ossification of multiple bones, including the forepaw metacarpals, vertebral column, pelvic girdle and skull in the 225 and 1000 mg/ kg/ day groups. The developmental LOAEL is 225 mg/ kg bw/ day, based on decreased fetal body weights and increased incidence of incomplete ossification of multiple bones. The developmental NOAEL is 50 mg/ kg bw/ day.

The developmental toxicity study in the rat is classified acceptable ( guideline) and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in the rat.

870.3700b Prenatal Developmental Toxicity Study  Rabbit In a developmental toxicity study ( MRIDs 00026785, 00052557 and 00073552) Compound 67019 ( oryzalin; 97.4% a. i., lot # X28491) was administered to 15 Dutch Belted rabbits/ dose by gavage ( 5 ml/ kg body weight) at dose levels of 0, 25, 55 or 125 mg/ kg bw/ day from days 6 through 18 inclusively of gestation.

One animal at 125 mg/ kg/ day dose died on gestation day ( GD) 26; necropsy showed that the cause of death was an acute upper respiratory infection. One animal at 55 mg/ kg/ day was sacrificed due to a gavage error on GD 10; another animal in this group aborted on GD 28. There was a non significant decreased body weight gain during the treatment period for the 55 and 125 mg/ kg/ day groups ( loss of 0.1 and 0.18 kg, respectively, vs gain of 0.02 kg in the control). Overall body weight gain was decreased in the 55 and 125 mg/ kg/ day groups which was statistically significant only in the 125 mg/ kg/ day group. Food consumption was decreased in the 55 and 125 mg/ kg/ day groups throughout the study but more adversely during the treatment period. There was a decrease in the number of corpora lutea ( not considered due to dosing), and live fetuses, and an increase in resorptions and postimplantation loss in the 55 and 125 mg/ kg/ day groups, although none of the changes were statistically significant and some were not doseresponsive Therefore, the toxicological significance of these findings is questionable.

The maternal LOAEL is 55 mg/ kg bw/ day, based on decreased body weight gain and food consumption. The maternal NOAEL is 25 mg/ kg bw/ day.

The developmental LOAEL is 55 mg/ kg bw/ day, based on decrease in the number of live ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 13 fetuses, and an increase in resorptions and postimplantation loss. The developmental NOAEL is 25 mg/ kg bw/ day.

Although the number of animals in the study ( 15) was less than the current requirement of 20 rabbits, the study does meet the guideline requirement of 12 pregnant rabbits. This developmental toxicity study in the rabbit is classified acceptable ( guideline) and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in rabbits.

870.3700b Prenatal Developmental Toxicity Study  Rabbit In a developmental toxicity study ( MRID 00098461) Compound 67019 ( oryzalin; 97.0% a. i., lot number 9SY47) was administered to two replicates of 15 Dutch Belted rabbits/ dose by gavage ( 5 ml/ kg body weight) at dose levels of 0, 10, 25, 55 or 125 mg/ kg bw/ day from days 6 through 18 inclusively of gestation.

The pregnancy rates of both replicate studies were very low, and the HIARC concluded that when the replicate studies are combined, the combined data are less than marginally acceptable.

No animals died during the study. In the first replicate, one animal each in the 25 mg/ kg/ day group and 125 mg/ kg/ day groups aborted on gestation day ( GD) 26 and 15, respectively. There was no treatment related effect on body weight gain. There was a slight decrease in food consumption in the 55 mg/ kg/ day ( 85% of control) and 125 mg/ kg/ day ( 84%) groups during the treatment period of the second replicate. There was no evidence of a treatment related effect on the combined Cesarean section parameters for both replicates; however, the fertility rates were low in all groups. The maternal LOAEL is 55 mg/ kg bw/ day, based on decreased food consumption. The maternal NOAEL is 25 mg/ kg bw/ day.

There was no evidence of developmental toxicity. The developmental LOAEL was not established. The developmental NOAEL is 125 mg/ kg bw/ day.

The pregnancy rates of both replicate studies were very low, and the HIARC concluded that when the replicate studies are combined, the combined data are less than marginally acceptable and, therefore, the developmental toxicity study in the rabbit is classified unacceptable/ not upgradable and does not satisfy the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in rabbits.

4.4 Reproductive Toxicity Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered complete. No additional studies are required at this time. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 14 Pup toxicity was seen as decreased day 21 body weight in both the one generation and 3 generation rat reproduction studies.

870.3800 Reproduction and Fertility Effects  Rat In a three generation reproduction study ( MRIDs 00038564 and 00042908) Compound 67019 [ Oryzalin ( 99% a. i., lot # X 28607)] was administered to 25 Fischer 344 rats/ sex/ dose in the diet at concentrations of 0, 0.025, 0.075 and 0.225% or 0, 250, 750 and 2250 ppm ( equivalent to approximately 0, 13, 40 and 125 mg/ kg/ day for males; 0, 16, 48 and 149 mg/ kg/ day for females). Four adults died during the study but none of the deaths was considered treatment related. The only clinical signs were dry, yellow urogenital staining and yellow discoloration of fur in treated animals. There was no treatment related effect on body weight, body weight gain or food consumption in the F 0 generation. Body weight was non significantly decreased in the F 1 and F 2 males ( 8 10%) and females ( 8 15%) in the 0.225% group at the end of the treatment period. This effect was due in part to decreased weanling weights of offspring. Body weight gain was decreased slightly but significantly in the F 1 generation males ( 5%) and females ( 12%) at 0.225%. Food consumption was decreased slightly and non significantly in the F 1 and F 2 males ( 6 13%) and females ( 8 18%) in the 0.225% group.

There was no treatment related effect on reproduction parameters.

The parental systemic LOAEL was 0.225% ( approximately 125 mg/ kg/ day in males and 149 mg/ kg/ day in females) based on decreased body weight, body weight gain and food consumption. The parental systemic NOAEL 0.075% ( approximately 40 mg/ kg/ day in males and 48 mg/ kg/ day in females).

The reproductive LOAEL was not established. The reproductive NOAEL was 0.225% concentration ( approximately 125 mg/ kg/ day in males and 149 mg/ kg/ day in females).

Mean weight in the F 1 and F 2 pups was comparable to controls on Day 1 but was decreased in the high dose on Day 21 ( 4 12%, p  0.05 in F 2 generation). The offspring LOAEL was 0.225% ( approximately 125 mg/ kg/ day in males and 149 mg/ kg/ day in females) based on decreased body weight on Day 21. The offspring NOAEL was 0.075% ( approximately 40 mg/ kg/ day in males and 48 mg/ kg/ day in females).

This study is acceptable ( guideline) and satisfies the guideline requirement for a multigeneration reproductive study ( OPPTS 870.3800); OECD 416 in the rat.

870.3800 Reproduction and Fertility Effects  Rat In a one generation reproduction study ( MRID 42401501) EL 119 [ Oryzalin ( 97.6% a. i. for Study R21990; 96.5% a. i. for Study R10991, lot # 88 1282)] was administered to 40 Fischer 344 rats/ sex/ dose in the diet at concentrations of 0, 0.025, 0.075 and 0.225% ( equivalent to 0, 0, 19.4, 58.7 and 178.8 mg/ kg/ day for males; 0, 22.3, 68.2 and 205.5 mg/ kg/ day for females). This study ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 15 was conducted to supplement a three generation reproduction study ( MRIDs 00038564 and 00042908) and provide histopathology on the reproductive organs of parental animals. Histopathology was also conducted on the kidney and liver which are considered the target organs for oryzalin.

There were no deaths during the study. The only clinical signs were dry, yellow urogenital staining and yellow discoloration of fur in animals in the 0.075% and 0.225% groups. Body weight was slightly but significantly decreased during the premating period in the high dose F 0 males ( 4%) and females ( 6 8%) and during the growth period in the high dose F 1 males ( 6 7%) and females ( 10 12%). Body weight in F 1 mid dose females was slightly but significantly decreased ( 3 4%) during the growth period. Body weight gain was also slightly but significantly decreased during the premating period in the high dose F 0 males ( 4%) and females ( 9 11%) and during the growth period in the high dose F 1 females ( 16%). Mean food consumption during premating was significantly decreased in the high dose F 0 males ( 2 14%) and females ( 4 14%) and during the growth period in the high dose F 1 females ( 5 8%). Mean body weight was slightly but significantly decreased in the high dose females during gestation ( 5 7%) and lactation ( 6 10%). Mean body weight gain was decreased ( 12% of control) in the high dose females during gestation and significantly decreased in the latter part of gestation in the mid ( 13 56%) and high dose ( 38 76%) groups.

There was no evidence of a treatment related effect on reproduction parameters. On necropsy of the F 0 generation, there was a dose related significant increase in the absolute and relative weights of the kidneys in all treated males. There was a significant increase in absolute kidney weight in the mid dose females and a significant increase in the relative kidney weights in the mid and high dose females. There was a dose related increase in the absolute and relative liver weights in all treated males and in the mid and high dose females. In the F 1 generation, absolute and relative kidney and liver weights were significantly increased in males of all treatment groups. Relative kidney weights were significantly increased in all treated females. Absolute and relative liver weights were significantly increased in the mid and high dose females. On microscopic examination, there was a dose related increase in incidence and severity of bilateral cortical tubular hyaline droplets in the kidneys of all treated males and females in both generations. Females in the mid and high dose groups of both generations also had an increased incidence of cortical tubular necrosis. There was no evidence of treatment related microscopic hepatic changes in the treated animals. The parental systemic LOAEL was < 0.025% ( 19.4 mg/ kg bw/ day in males and 22.3 mg/ kg bw/ day in females), based on increased kidney weights ( males) and increased incidence of bilateral cortical tubular hyaline droplets in the kidneys. The parental systemic NOAEL was not established.

The reproductive LOAEL was not established. The reproductive NOAEL was 0.225% concentration ( 178.8 mg/ kg/ day in males and 205.5 mg/ kg/ day in females).

Mean weight in the F 1 pups was comparable to controls on Day 1 but was decreased in the high dose males ( 13%) and females ( 13%) on Day 21. The offspring LOAEL was 0.225% ( 178.8 mg/ kg/ day in males and 205.5 mg/ kg/ day in females) based on decreased body weight on ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 16 Day 21. The offspring NOAEL was 0.075% concentration ( 58.7 mg/ kg/ day for males and 68.2 mg/ kg/ day for females).

This study is acceptable ( non guideline) and does not satisfy the guideline requirement for a multi generation reproductive study ( OPPTS 870.3800); OECD 416 in the rat. The study was conducted to supplement a three generation reproduction study ( MRIDs 00038564, 00042908) and provide more histopathological data on reproductive and target organs.

4.5 Chronic Toxicity Adequacy of data base for chronic toxicity: The data base for chronic toxicity is considered complete. No additional studies are required at this time.

870.4100a ( 870.4300) Chronic Toxicity B Rat In a combined chronic / carcinogenicity study ( MRIDs 00026779, 00044332 and 00070569), Oryzalin [ 96.5% ( Lot X23607) or 96% ( Lot 9SY47)] was administered to a total of 120 Fischer rats/ sex/ dose in the diet at dose levels of 0, 300, 900 or 2700 ppm ( equivalent to 0, 12.16, 36.86 and 112.46 mg/ kg bw/ day in males; 0, 13.82, 42.89 and 135.86 mg/ kg bw/ day in females) for two years. Two replicate studies were conducted; the results are combined as the studies were conducted at the same time using the same protocol. The study report states that an assay for nitroso di n propylamine content in the diet indicated very low levels were present; however, the Appendix referred to for the analysis is not included.

Survival was significantly decreased in the 2700 ppm males and females at Month 24 of the study. Mean body weight gain was statistically significantly decreased in the 2700 ppm males ( 8 17%) during the last year of the study, throughout the study in the 2700 ppm females ( 14 37%) and occasionally in the 900 ppm females ( 4 13%). Food consumption was comparable between treated and control groups. Feed efficiency was decreased in the 2700 ppm females. RBC parameters ( Hgb, Hct and RBC) were significantly decreased in the 2700 ppm males and females and in the 900 ppm females.

The absolute weight of the following organs was increased in one or both replicates in the 2700 ppm animals: liver ( males), thyroid ( males), heart ( males) and adrenal ( females). The absolute weight of the liver was also increased in the 900 ppm males. The relative ( to body weight) weight of the following organs was increased in one or both replicates in the following organs: liver ( both sexes), thyroid ( males), kidneys ( both sexes), spleen ( females), adrenal ( females) and testes ( males). The absolute weights of the liver and kidneys were also increased in the 900 ppm males and females. Only microscopic alterations were observed in the thyroid and spleen; therefore, the toxicological significance of the increases in the other organs is questionable. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 17 In one replicate, there was a non significant increase in the incidence of extramedullary hematopoiesis of the spleen in the 2700 ppm females. In the other replicate, there was an nonsignificant increase in the incidence of skin lesions ( abscess, edema, keratin cyst and suppurative dermatitis) in the 2700 ppm males and females and an increase in the incidence of purulent endometritis in the 2700 ppm females. In both replicates, there was a dose related increase in cystic follicles and focal follicular hyperplasia of the thyroid which was most pronounced in the 900 and 2700 ppm group males and females.

The LOAEL in males is 2700 ppm ( 112.46 mg/ kg/ day), based on decreased survival, decreased body weight gain, decreased hematology parameters, increased thyroid weight, increased incidence of skin lesions and microscopic findings in the thyroid. The NOAEL is 900 ppm ( 36.86 mg/ kg/ day).

The LOAEL in females is 900 ppm ( 42.89 mg/ kg/ day), based on decreased body weight gain, decreased hematology parameters and increased microscopic findings in the thyroid. The NOAEL is 300 ppm ( 13.82 mg/ kg/ day).

This chronic/ carcinogenicity study in the rat is acceptable( guideline) and satisfies the guideline requirement for a chronic/ carcinogenicity study OPPTS 870.4300); OECD 453] in rats. Although some clinical pathology parameters were not measured, ophthalmology examinations were not conducted and clinical observations were not reported, these deficiencies did not affect the study results.

870.4100b Chronic Toxicity  Dog In a chronic toxicity study ( MRID 40024801), compound 67019 [ Oryzalin ( 98.9% a. i., Lot # L 1385A)] was administered to four young adult beagle dogs/ sex/ dose in capsules at dose levels of 0, 1.5, 5, 15, or 50 mg/ kg bw/ day for one year. The 15 mg/ kg/ day dose was changed twice during the study due to the lack of overt toxicity. The dogs in this group received daily doses of 15, 250 or 500 mg/ kg/ day for weeks 0 14, 15 32 and 33 to termination, respectively.

All animals survived the study, except for one male treated at 50 mg/ kg/ day that was sacrificed moribund in week 52 due to severe chronic dermatitis. There were no clinical signs of toxicity and no treatment related effects on body weight, body weight gain, food consumption, ophthalmic examinations, electrocardiograms and urinalysis. There were some statistically significant changes in hematology parameters ( decreases in RBC, HCT, HGB; increases in platelets and MCHC); however, there was no dose response and the effects were transient. Therefore, the changes were not considered toxicologically significant. There were statistically significant increases in cholesterol, alkaline phosphatase, and total bilirubin, and decreases in ALT, AST and phosphorus in males and females at 15/ 250/ 500 mg/ kg/ day at some of the testing intervals; however, there was no evidence that the magnitude of the effects responded to increasing doses. T 4 concentrations were measured on weeks 47, 50 and 51. The values were significantly decreased at ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 18 week 47 in the 500 mg/ kg/ day males and at weeks 47, 50 and 51 in the 500 mg/ kg/ day females. There were also significant decreases in the 1.5 mg/ kg/ day females at weeks 50 and 51. A TSH stimulation test was conducted on week 51. The T 4 values were significantly decreased in the 1.5 and 500 mg/ kg/ day females; however, the animals in these groups responded in a normal manner to the stimulation ( two to four fold increase in T 4). At necropsy, there was a statistically significant increase in the absolute weight of the liver in females at 500 mg/ kg/ day and a decrease in the absolute weight of the adrenals in the 50 and 500 mg/ kg/ day males. The relative ( to body weight) weights of the liver, brain and kidney were increased in the 500 mg/ kg/ day males; the absolute weight of the liver was increased in the 500 mg/ kg/ day females. The toxicological significance of the organ weight effects is questionable as there were no accompanying microscopic changes. One male and female each in the 500 mg/ kg/ day group were observed to have enlarge thyroids on gross examination; however, the organs were normal on microscopic examination. Two males in this group had " follicular prominence"; the toxicological significance of these findings is questionable since the thyroid weights were not increased. The LOAEL is 15/ 250/ 500 mg/ kg/ day based on a slight decrease in thyroid function ( decreased T4 concentrations, primarily) in both sexes. The NOAEL is 50 mg/ kg/ day.

This chronic study in the dog is acceptable ( guideline) and satisfies the guideline requirement for a chronic oral study [ OPPTS 870.4100, OECD 452] in the dog.

4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The data base for carcinogenicity is considered complete. No additional studies are required at this time.

Thyroid, skin and mammary gland ( females) tumors were produced in Fischer 344 rats, whereas B6C3F1 mice were negative for carcinogenicity.

870.4200a Carcinogenicity Study  rat In a combined chronic/ carcinogenicity study ( MRIDs 00026779, 00044332 and 00070569), Oryzalin [ 96.5% ( Lot X23607) or 96% ( Lot 9SY47)] was administered to a total of 120 Fischer rats/ sex/ dose in the diet at dose levels of 0, 300, 900 or 2700 ppm ( equivalent to 0, 12.16, 36.86 and 112.46 mg/ kg bw/ day in males; 0, 13.82, 42.89 and 135.86 mg/ kg bw/ day in females) for two years. Two replicate studies were conducted; the results are combined as the studies were conducted at the same time using the same protocol. The study report states that an assay for nitroso di n propylamine content in the diet indicated very low levels were present; however, the Appendix referred to for the analysis is not included.

Survival was significantly decreased in the 2700 ppm males and females at Month 24 of the study. Mean body weight gain was statistically significantly decreased in the 2700 ppm males ( 8 17%) during the last year of the study, throughout the study in the 2700 ppm females ( 14 37%) and occasionally in the 900 ppm females ( 4 13%). Food consumption was comparable between ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 19 treated and control groups. Feed efficiency was decreased in the 2700 ppm females. RBC parameters ( Hgb, Hct and RBC) were significantly decreased in the 2700 ppm males and females and in the 900 ppm females.

The absolute weight of the following organs was increased in one or both replicates in the 2700 ppm animals: liver ( males), thyroid ( males), heart ( males) and adrenal ( females). The absolute weight of the liver was also increased in the 900 ppm males. The relative ( to body weight) weight of the following organs was increased in one or both replicates in the following organs: liver ( both sexes), thyroid ( males), kidneys ( both sexes), spleen ( females), adrenal ( females) and testes ( males). The absolute weights of the liver and kidneys were also increased in the 900 ppm males and females. Only microscopic alterations were observed in the thyroid and spleen; therefore, the toxicological significance of the increases in the other organs is questionable.

In one replicate, there was a non significant increase in the incidence of extramedullary hematopoiesis of the spleen in the 2700 ppm females. In the other replicate, there was an nonsignificant increase in the incidence of skin lesions ( abscess, edema, keratin cyst and suppurative dermatitis) in the 2700 ppm males and females and an increase in the incidence of purulent endometritis in the 2700 ppm females. In both replicates, there was a dose related increase in cystic follicles and focal follicular hyperplasia of the thyroid which was most pronounced in the 900 and 2700 ppm group males and females.

The LOAEL in males is 2700 ppm ( 112.46 mg/ kg/ day), based on decreased survival, decreased body weight gain, decreased hematology parameters, increased thyroid weight, increased incidence of skin lesions and microscopic findings in the thyroid. The NOAEL is 900 ppm ( 36.86 mg/ kg/ day).

The LOAEL in females is 900 ppm ( 42.89 mg/ kg/ day), based on decreased body weight gain, decreased hematology parameters and increased microscopic findings in the thyroid. The NOAEL is 300 ppm ( 13.82 mg/ kg/ day).

Carcinogenic findings occurred in both sexes. Follicular cell thyroid tumors and skin tumors occurred in both sexes, whereas fibroadenomas of the mammary gland occurred in females.

This chronic/ carcinogenicity study in the rat is acceptable( guideline) and satisfies the guideline requirement for a chronic/ carcinogenicity study OPPTS 870.4300); OECD 453] in rats. Although some clinical pathology parameters were not measured, ophthalmology examinations were not conducted and clinical observations were not reported, these deficiencies did not affect the study results.

870.4200b Carcinogenicity ( feeding)  Mouse ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 20 In two separate replicates ( MRIDs 00244746, 00244747 and 00244748), Oryzalin ( 96.5% a. i.; Lot X 28607) was administered to 40 B6C3F 1 mice/ sex/ dose/ replicate in the diet at dose levels of 500, 1350 or 3650 ppm ( equivalent to approximately 71, 193 or 521 mg/ kg bw/ day based on 1 ppm equals 0.150 mg/ kg/ day) for two years. Sixty ( 60) B6C3F 1 mice/ sex/ replicate served as untreated controls. Since the studies were conducted using the same protocol, results were combined.

The 12 month mortality was decreased in treated males and increased in treated females but survival was comparable at the end of the study. There was no evidence of a treatment related increase in clinical observations. Minor decreases in body weight gain were observed in treated males during the study. At three months, weight gain was non significantly decreased 13% in one replicate and at 24 months was significantly decreased 18% in the other replicate. Body weight gain was significantly decreased 17 35% in females at 3650 ppm from 12 months until termination. Food consumption was not measured due to spillage; therefore, the actual mg/ kg/ day doses of oryzalin intake could not be calculated.

Minor alterations in clinical pathology parameters were not consistent between replicates and were judged not to be biologically significant. On necropsy, the absolute weight of the uterus was decreased in the 1350 and 3650 ppm groups; the relative weight of the uterus was decreased in this group in one replicate only. On histopathology, there was a decreased incidence of cystic endometrial hyperplasia in females at 3650 ppm. The toxicological significance of these uterine findings is questionable. No other non neoplastic findings were considered treatment related.

The LOAEL is conservatively established at 3650 ppm ( 521 mg/ kg/ day), based on decreased body weight gain. The NOAEL is 1350 ppm ( 193 mg/ kg/ day).

The carcinogenic potential was negative.

This carcinogenicity study in the mice is acceptable ( guideline) and satisfies guideline requirement for a carcinogenicity study [ OPPTS 870.4200; OECD 451] in mice.

4.7 Mutagenicity Adequacy of data base for Mutagenicity: The data base for Mutagenicity is considered incomplete based on 1991 mutagenicity guidelines. A mouse micro nucleus study is required.

Oryzalin was not mutagenic in bacteria. However, there is evidence of damage to DNA as indicated by the evidence in bacteria and weak SCE induction in the bone marrow of Chinese hamsters via intraperitoneal but not oral routes of exposure. In contrast, UDS was not seen in treated primary rat hepatocytes. Although the data suggest DNA damage, it appears that this effect on DNA is not manifested as gene mutations. No conclusion can be reached regarding ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 21 chromosme aberrations, since no acceptable study is available. To resolve this issue, a mouse micronucleus assay is required.

Gene Mutation Guideline # 870.5100, Ames Assay MRID 00130427 Acceptable Oryzalin was negative for mutagenic activity against several strains of histidine auxotrophs of Salmonella typhimurium and tryptophan auxotrophs of Escherichia coli ( WP2uvrA) both in the presence and absence of S 9 over the concentrations tested ( 25 300 ug/ plate)

Cytogenetics Guideline # 870.5915, Sister Chromatid Exchange MRID 00087801 Acceptable Oryzalin was tested in Chinese hamster bone marrow cells to evaluate sister chromatid exchange with intraperitoneal or oral doses of 200, 300, 400, or 500 mg/ kg of oryzalin. Cytotoxicity was produced at 400 and 500 mg/ kg oryzalin. Oryzalin produced SCE in the bone marrow when administered intraperitoneally, but not orally.

Other Genotoxicity Guideline # 870.5550, Unscheduled DNA Synthesis MRID 00086801 Acceptable Oryzalin was negative in an unscheduled DNA synthesis test in rat hepatocytes up to cytotoxic levels (> 500 nmoles/ mL)

Guideline # 870.5500, DNA Repair Test MRID 44574101 Acceptable Oryzalin was positive in a DNA repair test at 125 and 250 ug/ disc without S 9 and 42.5 and 85 ug/ disc with S 9 in the recombination proficient H17 ( rec+) and recombination deficient M45 ( rec) strains of Bacillus subtilis.

4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: Since there was no evidence of neurotoxicity in any study, these studies are not required at this time.

4.9 Metabolism Adequacy of data base for metabolism: The data base for metabolism is considered to be complete. No additional studies are required at this time. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 22 870.7485 Metabolism  Rat In a metabolism study ( MRID 44574104), C14 Oryzalin ( 98.4% a. i., lot # B930 94, ring labeled), was administered to eight groups of 3 Fischer 344 rats/ sex/ dose by gavage at dose levels of 5 or 50 mg/ kg. Two groups at each dose level were sacrificed at 1 hr, 24 hr or 7 days post dosing. An additional two groups in which the animals had bile duct cannulations were sacrificed at 24 hr post dosing.

Oryzalin absorption was rapid with peak blood radioactivity levels reached by 0.5 1 and 2 3 hr post dosing with the 5 mg/ kg and 50 mg/ kg doses, respectively. Overall absorption was greater than 71% for both dose levels.

Blood radioactivity decreased post dosing in a bi exponential fashion for both dose levels. At 5 mg/ kg, there was a rapid   elimination phase ( t ½ = 4 5 hr and  8 hr for 5 mg/ kg and 50 mg/ kg, respectively) and a slower   elimination phase ( t ½ = 51 63 hr and 61 66 hr for 5 mg/ kg and 50 mg/ kg, respectively). The blood concentration time course curve ( AUC) across dose levels demonstrated an increase in AUC that was not proportional to the increase in administered dose. The 10 fold increase in dose was followed by a 3 fold increase in AUC, suggesting that the blood clearance of 14C oryzalin may be a saturable process.

In total, < 9% of the 5 mg/ kg dose was recovered in tissues 24 hr post dosing. At 7 days postdosing the only tissues with > 0.1% of dose were the carcass ( 0.5 0.6%), blood ( 0.17 0.3%), skin ( 0.17 0.29%) and liver ( 0.11 0.13%). At 50 mg/ kg, by 24 hr post dosing, no tissue contained more than 3% of the dose. The GI/ ingesta contained  2 3%, while the blood, carcass, skin and liver contained  0.4 1.7%. By 7 days post dosing, only the carcass and skin had > 0.5% of the dose. A limited number of tissues were examined from the bile duct cannulated animals at 24 hr post dosing. At 5 mg/ kg, the GI/ ingesta contained 4% of the dose, followed by carcass, skin and blood with 2 5% of the dose. At 50 mg/ kg, the GI/ ingesta contained about 10% of the dose, followed by carcass and skin with approximately 3% of the dose.

Neither volatile organics nor 14CO 2 in expired air contained sufficient radioactivity to quantify. Urine was the primary route of elimination. At 5 mg/ kg, urine comprised approximately 42% of the dose at 24 hr post dosing and 48 52% at 7 days post dosing. Approximately 30% of the 5 mg/ kg dose was recovered in the feces at 24 hr and approximately 35 39% at 7 days post dosing. Males and females at 5 mg/ kg eliminated greater than 80% of the dose by 24 hr and greater than 88% by 7 days post dosing. At 50 mg/ kg, radioactivity recovered in the urine was 49 53% by 24 hr and 42 51% by 7 days post dosing. At this dose, feces accounted for approximately 35% of the dose at 24 hr and 40 43% by 7 days. Males and females eliminated greater than 85% of the 50 mg/ kg by 24 hr. There were no sex differences at either dose.

The HPLC analysis of urine, bile, feces, and selected tissues demonstrated extensive overall metabolism of oryzalin. The metabolic profiles were comparable between the sexes and between ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 23 the low and high dose groups. No parent was detected in the urine or feces at either dose; however, small amounts were detected in some of the tissues ( liver, kidney and spleen). Twentyseven metabolites were detected by HPLC in male and female pooled urine. Three of the metabolites in male urine each accounted for > 5% of the dose ( U 4, U 10 and U 19) and one additional metabolite accounted for > 5% of the dose ( U 23) in females. Other peaks accounted for < 5% of the dose. A chemical structure was proposed for these four metabolites. Twenty metabolites were detected in the feces of males and females. A single metabolite which accounted for greater than 5% of the 50 mg/ kg dose in males and females co eluted with metabolite U 10 in the urine. In male excreta, two additional peaks ( U 8 and U 12) accounted for greater than 5% of the dose when fecal data ( F 13 and F 16) were combined with urine data at 5 mg/ kg. A structure was proposed for U 8 but the data for U 12 were inconclusive. Based on these results, a scheme for the metabolism of oryzalin was proposed.

4.10 Special/ Other Studies None 5.0 TOXICITY ENDPOINT SELECTION 5.1 See Section 9.2 for Endpoint Selection Table.

5.2 Dermal Absorption  Monkey In a dermal absorption study ( MRID No. 43207001), two Rhesus monkeys/ sex were administered 14C labeled oryzalin ( 2  Ci/ kg BW, 97.8 98.5% a. i., Lot # 553 T84 067) equivalent approximately to 2.0 mg/ kg bw, intravenously as well as dermally to approximately 6 cm2 of body surface area and monitored up to 168 hrs. Absolute alcohol was used as a vehicle with 0.2 ml for intravenous dosing and 0.05 ml for topical application. For intravenous administration, mean radioactivity of 43% was collected in the urine at 7 days post dose, with 26% present in first 24 hrs. In the feces, mean radioactivity of 41% was measured at 7 days post dose with 30% occurring within the first 24 hours. For topical application, the mean radioactivities determined at 168 hours post dose were 1% for urine and 0.6% for feces. Approximately, 73% of the topically applied dose was recovered in the dressing and washes 24 hrs after application. Comparison of the dermal and intravenous results indicate the percent absorbed dermal dose as 1.6%, 1.9% and 2.3% based on the blood concentration ( AUC) or total ( urine and feces) excretion or urinary excretion, respectively. For human risk assessment, 2.3% may be used as the dermal absorption value.

Although rats are recommended species for the dermal penetration study, the study using monkeys is acceptable and satisfies the guideline requirement ( guideline § 85 3, OPPTS Number 870.7600) since the test species are close to humans. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 1 See memo  Deriving Q 1 * s Using the Unified Interspecies Scaling Factor, P. A. Fenner Crisp, Director, HED, 7/ 1/ 94.

24 Dermal Absorption Factor: 2.3%

5.3 Classification of Carcinogenic Potential In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment ( July 1999), the CARC classified oryzalin into the category " Likely to be Carcinogenic to Humans". The Committee further recommended using a linear low dose extrapolation approach for the quantification of human cancer risk based on female rat combined follicular cell thyroid tumors.

5.3.1 Quantification of Carcinogenic Potential The unit risk, Q 1 * ( mg/ kg/ day) 1, of Oryzalin based upon female rat thyroid follicular cell combined adenoma and carcinoma tumor rates is 7.79 x 10 3 in human equivalents ( converted from animals to humans by use of the 3/ 4' s scaling factor  Tox_ Risk program, Version 3.5, K. Crump, 1994) 1. The dose levels used from the 105 week dietary study were 0, 300, 900, and 2700 ppm of Oryzalin. The corresponding tumor rates for the female rat combined thyroid follicular cell tumors were 1/ 55, 1/ 58, 3/ 54, and 9/ 50, respectively.

6.0 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children The HIARC concluded that there is not a concern for pre and/ or postnatal toxicity resulting from exposure to oryzalin.

There was no indication of pre/ or postnatal quantitative increased susceptibility in the developmental studies in rats and rabbits or the one generation and three generation reproduction studies in rats. However, there was an indication of qualitative prenatal increased susceptibility in the rabbit developmental study. At the LOAEL of 55 mg/ kg/ day, does had decreased body weight and food consumption, while there were decreased live fetuses, increased resorptions and increased post implantation loss in the offspring.

Since there is qualitative evidence of increased susceptibility of the young following exposure to oryzalin in the rabbit developmental study, HIARC performed a Degree of Concern Analysis to: ( 1) to determine the level of concern for the effects observed when considered in the context of all available toxicity data; and ( 2) identify any residual uncertainties after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment of this chemical. If ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 25 residual uncertainties are identified, HIARC examines whether these residual uncertainties can be addressed by a special FQPA safety factor and, if so, the size of the factor needed. The results of the HIARC Degree of Concern analysis for oryzalin follow. There was low concern for the qualitative susceptibility seen in the developmental rabbit study, since the dose response was well characterized; there was a clear NOAEL/ LOAEL for maternal and developmental toxicities: There are no residual uncertainties for pre and/ or post natal toxicities since the doses selected for overall risk assessments will address the concerns seen in the prenatal developmental toxicity study.

The special FQPA safety factor was reduced to 1x because, there are low concerns and no residual uncertainties for pre and/ or post natal toxicity.

Note: This FQPA assessment assumes that the exposure databases ( dietary food, drinking water, and residential) are complete and that the risk assessment for each potential exposure scenario includes all metabolites and/ or degradates of concern and does not underestimate the potential risk for infants and children.

6.2 Recommendation for a Developmental Neurotoxicity Study Based on the weight of evidence presented, the HIARC concluded that a developmental neurotoxicity study is not required for oryzalin.

A. Evidence that suggest requiring a Developmental Neurotoxicity study: There is no evidence for requiring a DNT B. Evidence that do not support a need for a Developmental Neurotoxicity study: There is no evidence of neurotoxicity in any study.

There is no evidence of neuropathology in any study.

7.0 OTHER ISSUES The HIARC did require a comparative thyroid assay in young and adult rats which included hormonal measurements for thyroid function, since T4 levels were affected in the one year dog study and thyroid weight and histopathology, as well as thyroid tumors were produced in the 2 year rat feeding study. The absence of the comparative thyroid study, however, did not result in a database uncertainty factor of 10x ( UFDB of 10x) being applied to the acute ( females 13 50) and chronic RfD and all residential scenarios due to new HIARC guidance provided by OPP management. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 26 8.0 REFERENCES in MRID order MRID No.

00026773 Kitchen, D. N. ( 1979). The Toxicological Evaluation of Oryzalin ( Compound 67019) Given to Mice in the Diet for Three Months. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study M 9276, June 1979. Unpublished.

00026774 Kitchen, D. N. ( 1979). The Toxicological Evaluation of Oryzalin ( Compound 67019) Given to Mice in the Diet for Three Months. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study M 9058, June 1979. Unpublished.

00026779, 00044332, 00070569 Carter, J. L. ( 1980). Combined Chronic/ Oncogenicity Study of Oryzalin Administered in Feed to F 344 Rats for 24 Months. Replicate Studies No. R 167 and R 177 Performed by Eli Lilly and Company Research Laboratories, Greenfield, IN; Sponsor: Elanco Products Co., Indianapolis, IN. dated March, 1980. Unpublished.

00038681 Kitchen, D. N. ( 1979). The Toxicological Evaluation of Oryzalin ( Compound 67019) Given to Mice in the Diet for One Year. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study M 9137, June 1979. Unpublished.

00086801 Jordan, W. H. ( 1981). The Effect of Oryzalin ( Compound 67019) on the Induction of DNA Repair Synthesis in Primary Cultures of Adult Rat Hepatocytes, Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study 810217 337 UDS, June 1981. Unpublished.

00087801 Jordan, W. H. ( 1981). The Effect of Oryzalin ( Compound 67019) on the in vivo Induction of Sister Chromatid Exchange in Bone Marrow of Chinese Hamsters, Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Studies 810601SCE, 810707SCE, 810720SCE, December, 1981. Unpublished. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 27 00106681 Dermal Toxicity and Eye Irritation Studies; Study B D 6 68 and Study B E 5 68; Lilly Research Laboratories; December 29, 1972 00130427 Jordan, W. H. ( 1983). The Effect of Oryzalin ( Compound 67019) on the Induction of Reverse Mutations in Salmonella typhimurium Using the Ames Test, Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study 830214AMS1188, June 1983. Unpublished.

00150104 Acute Oral Toxicity Study; Lilly Research Laboratories; Study No. R O 215 84; November 13, 1984; Acute Dermal Toxicity and Irritation Study; Lilly Research Laboratories; Study No. B D 173 84; Primary Eye Irritation Study; Lilly Research Laboratories; Study No. B E 187 84; November 5, 1984.; Acute Inhalation Toxicity Study; Lilly Research Laboratories; Study No. R H 71 84; November 6, 1984.; Dermal Sensitization Study; Lilly Research Laboratories; Study No. G 01584; January, 1985.

00244746, 00244747, 00244748 Carter, J. L. ( 1981). Oncogenicity Study of Oryzalin Administered in Feed to B6C3F1 Mice for 24 Months. Eli Lilly Studies No. ML 9087 and M 9097; Performed by Eli Lilly and Company Research Laboratories, Greenfield, IN. Sponsor: Elanco Products Co., Indianapolis, IN. dated March, 1981; Unpublished 40024801 Jordan, W. H. ( 1986). A One Year Chronic Oral Toxicity Study of Oryzalin in Beagle Dogs. Hazleton Laboratories America, Inc. Study Number 6180 102. dated November 12, 1986. Sponsor: Elanco Products Co., Indianapolis, IN. Unpublished.

41034201 Acute Inhalation Toxicity Study; Report R H 001 88; Toxicology Division, Lilly Research Laboratories; June 15, 1989.

43910201 Gilbert, K. S. ( 1996). Oryzalin. Primary Dermal Irritation Study in New Zealand White Rabbits; DowElanco Laboratory; Lab Project Study ID: DR 0320 8068 001B; January 25, 1996. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 28 44574101 Aiuchi, M. ( 1996). DNA Repair Test ( Rec assay) with Oryzalin in Bacterial System, Nippon Experimental Medical Research Institute Co., Ltd., ( JAPAN), Laboratory Project No. H 96014, November 18, 1996. Unpublished.

44574102 Glaza, S. M. ( 1996). Dermal Sensitization Study of Oryzalin in Guinea Pigs Maximization Test. Corning Hazleton, Inc., Madison, WI. Laboratory ID No. CAW 6736 100. September 13, 1996.

44574103 Stabbing, K. E., Copse, PF., Yan, B. L. ( 1996). Oryzalin: 13 Week Dietary Toxicity Study in F344 Rats. Dow Laboratory Study ID DR 0320 8068 004. Dow Chemical Company, Midland, MI. dated June 20, 1996. Unpublished.

44574104 Mendrala, A. L., Markham, D. A., Hansen, S. C. ( 1997). Oryzalin: Metabolism of C14 Oryzalin in Fischer 344 Rats. Dow Laboratory Project Study ID DR 0320 8068 005. Dow Chemical Company, Midland, MI. dated January 17, 1997. Unpublished. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 29 9.0APPENDICES Tables for Use in Risk Assessment ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 30 9.1 Toxicity Profile Summary Tables 9.1.1 Acute Toxicity Table  See Section 4.1 9.1.2 Subchronic, Chronic and Other Toxicity Tables Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100 90 Day oral toxicity rodents 44574103 ( 1996) Acceptable/ guideline 0, 5, 50, 300 mg/ kg/ d M: 0, 4.56, 45.88, 276.34 mg/ kg/ d F: 0, 4.65, 46.79, 283.09 mg/ kg/ d NOAEL = 5 mg/ kg/ day [ M/ F] LOAEL = 50 mg/ kg/ day based on increased kidney weights and increased incidence of hyaline droplet formation in renal tubular epithelial cells.

870.3200 21/ 28 Day dermal toxicity 00150106 ( 1985) Acceptable/ Nonguideline 0, 1000 mg/ kg/ d NOAEL < 1,000 mg/ kg/ day LOAEL = 1,000 mg/ kg/ day based on decreased bilirubin levels in both sexes and increased thyroid weight in males.

870.3700a Prenatal developmental in rodents 41163801, 41640201 ( 1989) Acceptable/ Guideline 0, 50, 225, 1,000 mg/ kg/ d Maternal NOAEL = 50 mg/ kg/ day LOAEL = 225 mg/ kg/ day based on decreased body weight gain and food consumption. Developmental NOAEL = 50 mg/ kg/ day LOAEL = 225 mg/ kg/ day based on increase in preimplantation loss, decreased fetal weight, and incomplete ossification.

870.3700b Prenatal developmental in nonrodents 00026785, 00052557, 00073552 ( 1979) Acceptable/ Guideline 0, 25, 55, 125 mg/ kg/ d Maternal NOAEL = 25 mg/ kg/ day LOAEL = 55 mg/ kg/ day based on decreased body weight gain and food consumption. Developmental NOAEL = 25 mg/ kg/ day LOAEL = 55 mg/ kg/ day based on decrease in live fetuses, increase in resorptions, and increase in postimplantation loss.

870.3700b Prenatal developmental in nonrodents 00098461 ( 1982) Unacceptable/ Not upgradable 0, 10, 25, 55 125 mg/ kg/ d Pregnancy rates were less than marginally acceptable Maternal NOAEL = 25 mg/ kg/ day LOAEL = 55 mg/ kg/ day based on decreased food consumption. Developmental NOAEL = 125 mg/ kg/ day LOAEL > 125 mg/ kg/ day [ HDT]. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 31 870.3800 Reproduction and fertility effects  one generation 42401501 ( 1992) Acceptable/ Nonguideline 0, 250, 750, 2,250 ppm M: 0, 19.4, 58.7, 178.8 mg/ kg/ d F: 0, 22.3, 68.2, 205.5 mg/ kg/ d Parental/ Systemic NOAEL < 19.4/ 22.3 mg/ kg/ day LOAEL > 19.4/ 22.3 mg/ kg/ day based on increased kidney weight in males and increased incidence of bilateral cortical tubular hyaline droplets in the kidney in both sexes. Reproductive NOAEL = 178.8/ 205.5 mg/ kg/ day LOAEL > 178.8/ 205.5 mg/ kg/ day [ HDT]. Offspring NOAEL = 58.7/ 68.2 mg/ kg/ day LOAEL = 178.8/ 205.5 mg/ kg/ day based on decreased pup body weight on Day 21.

870.3800 Reproduction and fertility effects  three generation 00038564, 00042908 ( 1980) Acceptable/ Guideline 0, 250, 750, 2,250 ppm M: 0, 13, 40, 125 mg/ kg/ d F: 0, 16, 48, 149 mg/ kg/ d Parental/ Systemic NOAEL = 40/ 48 mg/ kg/ day LOAEL = 125/ 149 mg/ kg/ day based on decreased body weight, body weight gain, food consumption. Reproductive NOAEL = 125/ 149 mg/ kg/ day LOAEL > 125/ 149 mg/ kg/ day [ HDT] . Offspring NOAEL = 40/ 48 mg/ kg/ day LOAEL = 125/ 149 mg/ kg/ day based on decreassed pup body weight on Day 21.

870.4100b Chronic toxicity dogs 40024801 ( 1986) Acceptable/ Guideline 0, 1.5, 5, 15/ 250/ 500, 50 mg/ kg/ d NOAEL = 50 mg/ kg/ day LOAEL = 15/ 250/ 500 mg/ kg/ day based on slight decrease in thyroid function in both sexes ( decreased T 4 levels).

870.4200 Chronic Toxicity/ Carcino genicity rats 00026779, 00044332, 00070569 ( 1980) Acceptable/ Guideline 0, 300, 900, 2700 ppm M: 0, 12.16, 36.86, 112.46 mg/ kg/ d F: 0, 13.82, 42.89, 135.86 mg/ kg/ d NOAEL = 13.82 mg/ kg/ day ( F) and 36.86 mg/ kg/ day ( M) LOAEL = 42.89 mg/ kg/ day ( F) and 112.46 mg/ kg/ day ( M) mg/ kg/ day based on decreased body weight gain, decreased hematology parameters, and increased microscopic findings in the thyroid in females and decreased survival, decreased weight gain, decreased hematology parameters, increased thyroid weight, increased incidence of skin lesions, and microscopic findings in the thyroid in males. Follicular cell thyroid tumors in both sexes, skin tumors in both sexes, and mammary gland tumors in females ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 32 870.4300 Carcinogenicity mice 00244746, 00244747, 00244748 ( 1981) Acceptable/ Guideline 0, 500, 1350, 3650 ppm 0, 71, 193, 521 mg/ kg/ d NOAEL = 193 mg/ kg/ day LOAEL = 521 mg/ kg/ day based on decreased body weight gain. ( no) evidence of carcinogenicity Gene Mutation 870.5100, Ames Assay 00130427 ( 1983) Acceptable/ Guideline 25 300 ug/ plate Oryzalin was negative against several strains of Salmonella typhimurium and Escherichia coli ( WP2uvrA) both in the presence and absence of metabolic activation.

Cytogenetics 870.5915, Sister Chromatid Exchange 00087801 ( 1981) Acceptable/ Guideline 200, 300, 400, or 500 mg/ kg Oryzalin was tested in Chinese hamster bone marrow cells to evaluate sister chromatid exchange intraperitoneal or oral doses. Cytotoxicity was produced at 400 and 500 mg/ kg oryzalin. Oryzalin produced SCE in the bone marrow when administered intraperitoneally, but not orally.

Other Effects 870.5550, Unscheduled DNA Synthesis 00086801 ( 1981) Acceptable/ Guideline > 500 nmoles/ mL Oryzalin was negative in an unscheduled DNA synthesis in rat hepatocytes up to cytotoxic levels (> 500 nmoles/ mL).

Other Effects 870.5500, DNA Repair Test 44574101 Acceptable/ Guideline 42.5, 85, 125, or 250 ug/ disc Oryzalin was positive in a DNA repair test at 125 and 250 ug/ disc without S 9 and 42.5 and 85 ug/ disc with S 9 in the recombinant proficient H17 ( rec+) and recombination deficient M45 ( rec) strains of Bacillus subtilis.

870.7485 Metabolism and pharmacokinetic s 44574104 ( 1997) Acceptable/ Guideline 5, 50 mg/ kg C14 Oryzalin Rapid absorption, comparable metabolism between sexes, small amounts in liver, kidney, spleen 870.7600 Dermal penetration in Monkey 43207001 ( 1986) Acceptable/ Nonguideline 0, 2.0 mg/ kg C14 Oryzalin 2.3% dermal penetration Special studies none none ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 33 9.2 Summary of Toxicological Dose and Endpoints for Oryzalin for Use in Human Risk Assessment1 Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment to be completed later for risk assessment Study and Toxicological Effects Acute Dietary females 13 50 years of age NOAEL = 25 mg/ kg/ day UF = 100 Acute RfD = 0.25 mg/ kg/ day FQPA SF = 1x aPAD = acute RfD FQPA SF = 0.25 mg/ kg/ day Rabbit Developmental Study LOAEL = 55 mg/ kg/ day based on decreased live fetuses, increased resorptions, and increased postimplantation loss.

Chronic Dietary all populations NOAEL= 13.82 mg/ kg/ day UF = 100 Chronic RfD = 0.14 mg/ kg/ day FQPA SF = 1x cPAD = chr RfD FQPA SF = 0.14 mg/ kg/ day 2 Year Rat Feeding Study LOAEL = 42.89 mg/ kg/ day based on decreased body weight gain, decreased hematology parameters, and increased microscopic findings in the thyroid.

Short Term Incidental Oral ( 1 30 days)

( Residential) oral study NOAEL= 25 mg/ kg/ day LOC for MOE = 100 ( Residential, includes the FQPA SF) Rabbit Developmental Study LOAEL = 55 mg/ kg/ day based on based on decreased body weight gain and food consumption in does.

Intermediate Term Oral ( 30 days  6 months)

( Residential) oral study NOAEL= 13.82 mg/ kg/ day LOC for MOE = 100 ( Residential, includes the FQPA SF) 2 Year Rat Feeding Study LOAEL = 42.89 mg/ kg/ day based on decreased body weight gain, decreased hematology parameters, and increased microscopic findings in the thyroid.. ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment to be completed later for risk assessment Study and Toxicological Effects 34 Short Term Dermal ( 1 30 days), Intermediate Term Dermal ( 1 6 months) and Long Term Dermal (> 6 months)

( Occupational/ Residential) dermal study LOAEL= 1000 mg/ kg/ day LOC for MOE = 300 ( Occupational)

LOC for MOE = 300 ( Residential, includes the FQPA SF) 21 Day Dermal Toxicity Study LOAEL = 1000 mg/ kg/ day based on increased thyroid weights in males, and increased bilirubin in both sexes.

Short Term Inhalation ( 1 30 days)

( Occupational/ Residential) inhalation ( or oral) study NOAEL= 25 mg/ kg/ day ( inhalation absorption rate = 100%) LOC for MOE = 100 ( Occupational)

LOC for MOE = 100 ( Residential, includes the FQPA SF) Rabbit Developmental Study LOAEL = 55 mg/ kg/ day based on decreased body weight gain and food consumption in does.

Intermediate Term Inhalation ( 1  6 months) and Long Term Inhalation (> 6 months)

( Occupational/ Residential) inhalation ( or oral) study NOAEL= 13.82 mg/ kg/ day ( inhalation absorption rate = 100%) LOC for MOE = 100 ( Occupational)

LOC for MOE = 100 ( Residential, includes the FQPA SF) 2 Year Rat Feeding Study LOAEL = 42.89 mg/ kg/ day based on decreased body weight gain, decreased hematology parameters, and increased microscopic findings in the thyroid..

Cancer ( oral, dermal, inhalation) " Likely" to be carcinogenic to humans low dose extrapolation based on thyroid follicular cell tumors; Q1* = 0.00779 ( mg/ kg/ day) 1 increases in thyroid follicular cell tumors in both sexes, skin tumors in both sexes and fibroadenomas in females ORYZALIN/ JUNE/ 2003 TRED Toxicology Chapter 35 1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, LOC = level of concern, MOE = margin of exposure