UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 October 12, 2001 MEMORANDUM Subject: EPA Id #. Asulam. Toxicology Chapter of the RED.

TXR No.: . PC Code No.: 106901; 106902 DP Barcode No.: Submission No.:

From: John J. Liccione ReRegistraion Branch III Health Effects Division 7509C To: Jose Morales Risk Assessor ReRegistration Branch III Health Effects Division 7509C Through: Catherine Eiden Branch Senior Scientist ReRegistration Branch III Health Effects Division 7509C OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES Attached is the Toxicology Chapter for the RED for asulam. An electronic copy is available in the LAN or in the IHAD system.

1 EPA Reviewer: John J. Liccione , Date ReRegistration Branch III ( 7509C) Secondary Reviewer: Catherine Eiden , Date ReRegistration Branch III ( 7509C)

2 TABLE OF CONTENTS 1.0 HAZARD CHARACTERIZATION ........................................... 4 2.0 REQUIREMENTS ........................................................ 5 3.0 DATA GAP( S) ........................................................... 7 4.0 HAZARD ASSESSMENT .................................................. 7 4.1 Acute Toxicity........................................................ 7 4.2 Subchronic Toxicity ................................................... 8 4.3 Prenatal Developmental Toxicity ........................................ 10 4.4 Reproductive Toxicity................................................. 11 4.5 Chronic Toxicity ..................................................... 12 4.6 Carcinogenicity ...................................................... 13 4.7 Mutagenicity ........................................................ 14 4.8 Neurotoxicity ....................................................... 15 4.9 Metabolism ......................................................... 15 4.10 Special/ Other Studies No special studies pertaining to asulam have been identified. ............ 16 5.0 TOXICITY ENDPOINT SELECTION........................................ 16 5.1 See Section 9.2 for Endpoint Selection Table. .............................. 16 5.2 Dermal Absorption ................................................... 16 5.3 Classification of Carcinogenic Potential................................... 16 6.0 FQPA CONSIDERATIONS ................................................ 17 6.1 Special Sensitivity to Infants and Children................................. 17 6.2 Recommendation for a Developmental Neurotoxicity Study ................... 17 7.0 OTHER ISSUES No other special issues have been identified. ............................... 17 8.0 REFERENCES .......................................................... 18 9.0 APPENDICES........................................................... 23 9.1 Toxicity Profile Summary Tables ........................................ 24 9.1.1 Acute Toxicity Table ......................................... 24 9.1.2 Subchronic, Chronic and Other Toxicity Tables .................... 24 3 Asulam ( December, 2001) RED Toxicology Chapter 1.0 HAZARD CHARACTERIZATION The acute toxicity of asulam is low. The acute oral LD50 for asulam in rats exceeded 5000 mg/ kg. The acute inhalation LC50 was greater than 5 mg/ L in rats. The acute dermal LD50 for asulam in rabbits exceeded 4000 mg/ kg. Application of technical asulam to rabbit eyes produced mild chemosis, irritation, and redness which cleared by day seven post treatment. Asulam was not an irritant in a primary skin irrigation study in rabbits. It did not cause dermal sensitization in guinea pigs.

Reproductive toxicity. The potential reproductive toxicity of asulam was examined in a two generation reproduction study in the rat. In this study, significantly fewer mean live births per litter were observed at 250 mg/ kg/ day and 1250 mg/ kg/ day in the first generation; the LOAEL for offspring toxicity is 250 mg/ kg/ day. A dose response relationship was evident. No effects on mean live births per litter were observed at 50 mg/ kg/ day, the NOAEL for offspring toxicity. The LOAEL for parental systemic toxicity is 1250 mg/ kg/ day and was based on decreased body weights ( F0 males, F1 females) and organ weight effects ( increased absolute and relative thyroid weights in F1 males and F2 males and females; increased absolute and relative liver weights in F1 females; and increased ovarian weights in F1 females at 31 days old but not at terminal necropsy). The NOAEL for parental systemic toxicity is 250 mg/ kg/ day. This study provided evidence for a quantitative increase susceptibility of the rat fetus.

Developmental toxicity. Asulam has been evaluated for potential developmental effects in the rat and the rabbit. In the developmental study in the rat, a slight to moderate increase in preimplantation loss was observed at the high dose level ( 1,500 mg/ kg/ day); the developmental NOAEL was 1,000 mg/ kg/ day. Decreased maternal body weight gain was noted at 1,500 mg/ kg/ day ( maternal LOAEL), but not at 1,000 mg/ kg/ day ( maternal NOAEL). There was no indication of treatment related effects on developmental parameters ( at dose levels up to 750 mg/ kg/ day) in a developmental toxicity study in the rabbit; the NOAEL for developmental toxicity is 750 mg/ kg/ day. Decreased maternal body weight gain was observed at 750 mg/ kg/ day ( the NOAEL is 300 mg/ kg/ day).

Systemic toxicity. Subchronic and chronic toxicity studies demonstrate that the thyroid gland is a target organ for asulam in the rat and dog. Thyroid findings, consisting of hyperplastic changes in thyroid follicular cells in male rats ( LOAEL = 180 mg/ kg/ day; NOAEL = 36 mg/ kg/ day), were reported in a two year combined chronic/ oncogenicity feeding study. Thyroid weights were not monitored in the study. Other toxicological effects included adrenal medullary hyperplastic alterations in male rats, and decreased body weight gains in male and female rats. The chronic RfD for asulam is derived from the NOAEL of 36 mg/ kg/ day, based on thyroid follicular hyperplasia at 180 and 953 mg/ kg/ day. An uncertainty factor of 100 was used to account for interspecies extrapolation and intraspecies variability.

In a six month dog study, increased thyroid weights ( elevated absolute weights in females at 300 mg/ kg/ day and elevated absolute and relative weights in males and females at 1500 mg/ kg/ day) were reported. Similar findings were noted in a three month gavage study in the dog.

In a 18 month carcinogenicity study with Carworth CF 1 outbred albino mice, decreased 4 Asulam ( December, 2001) RED Toxicology Chapter absolute and relative thyroid weights were observed in females administered 225 or 750 mg/ kg/ day in the diets. However, this study was classified as unacceptable. No pathological effects in the thyroid were reported in a repeat two year feeding study in the mouse; the strain was Charles River CD 1 mice. However, thyroid weights were not assessed in this study.

Carcinogenicity. A combined chronic toxicity/ oncogenicity study in the rat provided limited evidence for the carcinogenicity of asulam in this species. There was a statistically significant increase in thyroid gland C cell carcinomas in male rats fed diets containing 36 and 180 mg/ kg/ day asulam. There was also a statistically significant increase in adrenal medullary pheochromocytomas in males administered 953 mg/ kg/ day ( high dose tested). In a two year feeding study in the mouse, no evidence of carcinogenicity was found. Asulam has been classified as a Group C carcinogen ( possible human carcinogen) by the Agency. The Agency decided not to quantify the carcinogenic risk for asulam.

Neurotoxicity. No neurotoxicity studies were available for asulam. There was no evidence of neurotoxicity ( clinical signs, cholinesterase inhibition, or pathology) in subchronic and chronic toxicity studies in the rat, dog, or mouse.

Immunotoxicity. None of the available data on asulam suggest an immunotoxic potential for this chemical.

The mutagenicity/ genetic toxicity data base is considered complete and there is no concern for adverse mutagenicity effects.

Inhalation toxicity. Data regarding the potential inhalation toxicity of asulam are limited to a one month inhalation and an acute inhalation study in the rat. No effects of apparent toxicological significance were noted in rats exposed ( nose only) to asulam at concentrations up to 15.3 mg/ L for 4 hours per day, 5 days per week, for 1 month. However, there was no examination of thyroid weights or thyroid pathology.

Metabolism. Metabolism studies in the rat demonstrate that asulam was rapidly eliminated, primarily in the urine, following administration of a single oral or intravenous dose, or after repeated intravenous doses for 14 days. No unusual localization of asulam occurred in tissues. Unchanged parent compound was identified as the major excretory product, with acetylasulam and acetylsulphanilamide as minor metabolites.

The dermal absorption of asulam has not been determined.

2.0 REQUIREMENTS The data requirements ( CFR 158.340) for the several uses for Asulam are in Table 1. Use of the new guideline numbers does not imply that the new ( 1998) guideline protocols were used. Most studies were conducted well before the 1998 guidelines and follow earlier guidelines. Note: The data gaps and additional data required are more simply presented in the following section ( 3.0 below).

5 Asulam ( December, 2001) RED Toxicology Chapter 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 ( c) ( a) Yes ( b) N/ A No 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   Gene Mutation  bacterial .......... 870.5300 Mutagenicity   Gene Mutation  mammalian ....... 870.5xxx Mutagenicity   Structural Chromosomal Aberrations 870.5xxx Mutagenicity   Other Genotoxic Effects ........... Yes Yes Yes Yes Yes Yes Yes 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 ( d) ( d) No

N/ A N/ A N/ A 870.7485 General Metabolism .......................... 870.7600 Dermal Penetration ........................... Yes No Yes N/ A Special Studies for Ocular Effects Acute Oral ( rat) .............................. Subchronic Oral ( rat) .......................... Six month Oral ( dog) ......................... No No No N/ A N/ A N/ A ( a) Interim data from the chronic toxicity satisfy this requirement. ( b) A 21 day dermal toxicity study in the rat was available, however, the study did not include an examination of the thyroid gland, the target organ for asulam. The HIARC ( 11/ 13/ 01) determined that a 21 day dermal toxicity study, with examination of thyroid weight and pathology, is required. ( c) A one month inhalation toxicity study was available; however, this study did not examine the thyroid gland, the target organ. The HIARC ( 11/ 13/ 01) determined that a 28 day inhalation toxicity study, with examination of thyroid weight and pathology, is required. HIARC did not identify a need for a 90 day inhalation study.

6 Asulam ( December, 2001) RED Toxicology Chapter ( d) The HIARC determined that the acute, subchronic, and developmental neurotoxicity studies were not required. HIARC recommended the requirement for a comparative thyroid rat assay in adults and offspring. It was further recommended that the adult study should include interim measures ( e. g., 7, 14, and 28 days). The HIARC also recommended that thyroid parameters selected for the comparative study should be based on Agency guidance ( under current development) for thyroid toxicity testing.

3.0 DATA GAP( S)

On November 13, 2001, the HIARC identified the following data gaps:

  Comparative thyroid rat assay in adult and offspring. It was further recommended that the adult study should include interim measures ( e. g., 7, 14, and 28 days). HIARC also recommended that thyroid parameters selected for the comparative study should be based on Agency guidelines ( under current development) for thyroid toxicity testing.

  21 day Dermal Study in Rats with examination of thyroid weight and pathology.

  28 day Inhalation Study in Rats with examination of thyroid weight and pathology.

4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of data base for acute toxicity: The data base for acute toxicity is considered complete. The acute toxicity data on asulam is summarized below in Table 2.

Table 2. Acute Toxicity of asulam.

Study Type MRID No.: Result 81 1. Acute Oral Toxicity  rat. Rhone Poulenc Ag Co., Study No.: 51 260, November 7, 1988 409605 01 LD50 > 5000 mg/ kg. Toxicity Category IV Classification: Guideline 81 2. Acute Dermal Toxicity  rabbit. Rhone Poulenc Ag Co., Study No.: 51 260, November 8, 1988 409605 01 LD50 > 4000 mg/ kg. Toxicity Category III Classification: Guideline 7 Asulam ( December, 2001) RED Toxicology Chapter 81 3. Acute Inhalation Toxicity  rat. Rhone Poulenc Ag Co., Study No.: 51 583, November 7, 1988 409605 02 413616 01 LC50 > 5 mg/ L Toxicity Category IV Classification: Minmum 81 4. Primary Ocular Irritation  rabbit. Rhone Poulenc Ag Co., Study No.: R. Tox. 57, June 1981 00098534 Some chemosis, redness, and irritation were noted, but eyes were clear by day 7. Toxicity Category III Classification: Minimum 81 5. Primary Dermal Irritation  rabbit. Rhone Poulenc Ag Co., Study No.: RES 2853, March 1977 00098535 No dermal irritation was observed. Toxicity Category III Classification: Minimum 81 6. Dermal Sensitization  guinea pig. Rhone Poulenc Ag Co., Study No.: RES 2853, March 1977 00098535 No evidence of sensitization in the Guinea Pig. Classification: Minimum.

Subchronic Toxicity Adequacy of data base for subchronic toxicity: No subchronic oral toxicity studies in the rodent per se were identified in the data base for asulam. However, the chronic oral studies in the rodent provided frequent monitoring of clinical signs and interim measurements of body weights, food consumption, hematology, clinical chemistry and urinalysis, and the results provided insight into potential subchronic effects.

In a subchronic oral ( 90 day) study, dogs displayed increased thyroid weights. Although the study was classified as   unacceptable guideline , it was supported by the findings of the 6 month oral dog study. The results of the two studies were similar ( i. e., the LOAEL and NOAEL ( based on increased thyroid weights) for the 6 month dog study were 300 mg/ kg/ day and 60 mg/ kg/ day, respectively, while the LOAEL and NOAEL ( also based on increased thyroid weights) for the 3 month dog study were 500 mg/ kg/ day and 50 mg/ kg/ day, respectively).

A one month inhalation toxicity study and 21 day dermal toxicity study were available; however, neither study included assessment of thyroid weights and pathology. The data base for subchronic toxicity is considered complete for oral and dermal studies. A 28 day subchronic inhalation study is required, one that includes examination of thyroid weights and thyroid pathology.

870.3100 90 Day Oral Toxicity  Rat Refer to the chronic toxicity studies below.

870.3150 90 Day Oral Toxicity  Dog Executive Summary. In a subchronic toxicity study ( MRID# 00056414), asulam ( purity not stated)

8 4.2 Asulam ( December, 2001) RED Toxicology Chapter was administered to beagle dogs ( 3 dogs/ sex/ group) by gavage at dose levels of 0, 5, 50, or 500 mg/ kg/ day for three months. All but one dog were apparently infected with ascarids. An increase in white blood cell counts, most likely reflecting infection, was observed in all control and treated females, and in the low and high dose males, toward the end of the study. In addition, diarrhea was present in all dogs during the last 3 weeks of the study. The diarrhea may have been associated with ascarid infection. At the end of the treatment period, mean body weights of treated males were lower than those of controls, while mean body weights of treated females were higher than controls. Interpretation of the body weight differences is complicated by the differences in initial body weights of the control dogs ( i. e., control male body weight was more than 10% greater, while control female body weight was 5 15% lower, than those of treated animals). Overall mean body weight gains ( day 0  91) in treated dogs were for the most part higher than those of control dogs. Absolute and relative thyroid weights were elevated in both high dose males and females. There were no apparent treatment related effects on survival or pathology findings.

The LOAEL is 500 mg/ kg/ day based on increased absolute and relative ( to body weight) thyroid weights in male and female dogs. The NOAEL is 50 mg/ kg/ day.

Classification: This subchronic study in the dog is Unacceptable Guideline, and does not satisfy the guideline requirement for a subchronic nonrodent study ( 82 1) in this species. No information on purity of the test material, no food consumption data, the lack of individual pathology sheets, no information on the care and feeding of the dogs, the failure to randomize animals to groups on the basis of body weights so that initial body weights were comparable between groups, and no rationale provided for dose selection. Although the sample size was less than guideline requirements ( i. e., 3 rather than 4 dogs), the thyroid weight effects observed in this study are supported by a six month dog study ( MRID No. 00098536); the LOAEL in the six month dog study was 300 mg/ kg/ day, while the NOAEL was 60 mg/ kg/ day.

870.3200 21/ 28 Day Dermal Toxicity   Rat Executive Summary. In a repeat dose dermal toxicity study ( MRID # 41076901), asulam ( 88% a. i.) was applied to the clipped skin of 10 New Zealand rabbits/ sex/ dose at dose levels of 0 ( carboxymethylcellulose vehicle control) or 1,000 mg/ kg/ day ( limit dose), once daily for 7 days/ week during a 21 day period.

No apparent treatment related systemic effects were observed when body weight, food consumption, clinical pathology, organ weights, ophthalmology, urinalysis, and histopathology were examined. The NOAEL is greater than or equal to 1,000 mg/ kg/ day.

Local skin irritation, which was slight and transient, was observed in a small number of treated females.

Classification: This 21 day dermal toxicity study is classified as Acceptable Guideline.

870.3465 90 Day Inhalation   Rat 9 Asulam ( December, 2001) RED Toxicology Chapter There are no 90 day inhalation toxicity studies available on asulam. However, a one month inhalation toxicity study ( MRID # 00098537) in the rat was available. In the one month inhalation study, asulam ( purity not stated) was administered to 15 CD rats/ sex/ group by nose only exposure at concentrations of 0, 1.6, 3.9, or 15.3 mg/ L for 4 hours per day, 5 days per week, for 4 weeks. Control rats were exposed to clean air only. The estimated mass median diameter of the particles was 4.5 Fm. No effects due to exposure were observed, as judged by survival, clinical signs, body weights, food consumption, ophthalmoscopic examinations, hematology, clinical chemistry, urinalysis, and pathology. Although several significant organ weight changes ( i. e., increased absolute and relative lung, heart and adrenal weights; decreased absolute and relative spleen weights; increased relative pituitary weights) were observed in high dose males immediately following exposure, these changes were not seen in the high dose males sacrificed 5 7 days after final dosing ( suggesting reversibility of the effects). In addition, there were no corresponding histological lesions in these organs. Females sacrificed 5 7 days after final dosing displayed increased absolute and relative liver and heart weights. However, the liver and heart weight alterations were not accompanied by histological findings. The organ weight changes in the males and females are of equivocal toxicological significance. The NOAEL is 15.3 mg/ L. This study is limited because of the lack of thyroid weight measurements and pathological examination of the thyroid.

Prenatal Developmental Toxicity Adequacy of data base for prenatal developmental toxicity: The data base for prenatal developmental toxicity is considered complete.

870.3700a Prenatal Developmental Toxicity Study  Rat Executive Summary. In a developmental toxicity study ( MRID # 00098538), asulam ( 98.0 99.9 % a. i.) was administered to 23 27 pregnant Charles River ( CD) rats/ dose by oral gavage at dose levels of 0, 500, 1,000, or 1,500 mg/ kg/ day from days 5 through 17 of gestation.

Mean maternal body weight gain ( days 5 18) was 9% lower in the high dose group than in controls. There were no treatment related effects on other maternal parameters including mortality, clinical signs, and food consumption. A slight to moderate increase ( not statistically significant) in preimplantation loss was observed in the mid and high dose groups ( compared to controls). The slight increase in postimplantation loss at the high dose ( 1500 mg/ kg/ day) was not statistically significantly different from control values, and was not of any apparent biological significance. The maternal LOAEL is 1,500 mg/ kg/ day based on body weight gain decrement. The maternal NOAEL is 1,000 mg/ kg/ day.

The developmental LOAEL is 1,500 mg/ kg/ day based on slight to moderate increase in preimplantation loss. The developmental NOAEL is 1,000 mg/ kg/ day.

Classification: This prenatal developmental toxicity study in the rat is Acceptable Guideline.

870.3700b Prenatal Developmental Toxicity Study  Rabbit 10 4.3 Asulam ( December, 2001) RED Toxicology Chapter Executive Summary. In a developmental toxicity study ( MRID # 00098539), asulam ( 98.0 99.9 % a. i.) was administered to 15 23 pregnant New Zealand rabbits/ dose by oral gavage at dose levels of 0, 60, 300, or 750 mg/ kg/ day from days 5 through 20 of gestation. Rabbits were sacrificed on gestation day 29. Originally, the high dose selected was 1,500 mg/ kg/ day. However, severe maternal toxicity ( greater than 20% weight loss, mortality, and signs of starvation) occurred after administration of the 1,500 mg/ kg/ day dose level. All animals in this group died or were sacrificed for humane reasons. A new group was added to the study using a lower dose of 750 mg/ kg/ day.

Mean maternal body weight gain was markedly reduced ( 35% but not statistically significant) in the 750 mg/ kg/ day group than in controls during the dosing period ( days 5  21). In addition, mean maternal body weight gains were markedly reduced during days 5 9, 5 13, and 5 17. During the postdosing period, mean body weights of rabbits treated with 750 mg/ kg/ day were comparable to those of controls, and rabbits displayed some improvement in body weight gain. Rabbits given 750 mg/ kg/ day exhibited a non statistically significant decrease in food consumption at several intervals during dosing ( days 5 9, 9 13, 13 17). There were no apparent treatment related effects on mortality or clinical signs. The maternal LOAEL is 750 mg/ kg/ day based on decreased body weight during the dosing period. The maternal NOAEL is 300 mg/ kg/ day.

There were no apparent treatment related effects on developmental parameters at dose levels up to 750 mg/ kg/ day. The developmental NOAEL is 750 mg/ kg/ day.

Classification: This prenatal developmental toxicity study in the rabbit is Acceptable Guideline.

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.

870.3800 Reproduction and Fertility Effects  Rat Executive Summary. In a two generation reproduction toxicity study ( MRID 00098540), groups of 12 male and 24 female Charles River CD rats were administered asulam ( 98.0 100.6 % a. i.) in the diet at concentrations of 0 ( control), 1,000, 5,000, or 25,000 ppm ( equivalent to approximately 50, 250, and 1250 mg/ kg/ day, respectively). F0 animals were mated after being on diet for 100 days. Following weaning, F1 animals ( 16 males and 32 females) continued treatment for a further 120 days prior to mating.

Systemic effects observed at the high dose ( 25,000 ppm) included decreased body weights in F0 males and F1 females, increased absolute and/ or relative thyroid weights in F1 males and F2 males and females, increased absolute and relative liver weights in F1 females, and increased ovarian weights in F1 females ( at age 31 but not at terminal necropsy). The LOAEL for 11 4.4 Asulam ( December, 2001) RED Toxicology Chapter systemic toxicity is 25,000 ppm ( 1250 mg/ kg/ day) based on decreased body weights ( F0 males, F1 females) and organ weight effects ( increased absolute and relative thyroid weights F1 males and F2 males and females, increased absolute and relative liver weights in F1 females, and increased ovarian weights in F1 females at 31 days old but not at terminal necropsy). The NOAEL is 5,000 ppm ( 250 mg/ kg/ day).

Significantly fewer mean live births per litter were observed at 5,000 and 25,000 ppm in the first generation. Also, a dose response relationship was evident. Fertility index was slightly lower in F1 parents at 5,000 and 25,000 ppm; however, the decreases were not statistically significant when compared to controls and did not display a dose response. The LOAEL for reproductive/ offspring toxicity is 5,000 ppm ( 250 mg/ kg/ day) based on decreased mean live births per litter. The NOAEL is 1,000 ppm ( 50 mg/ kg/ day).

Classification: This two generation reproduction study in the rat is Acceptable Guideline 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   Rat Refer to the Combined Chronic Feeding/ Carcinogenicity study below.

870.4100b Chronic Toxicity  Dog Executive Summary. In a six month toxicity study ( MRID # 40977601), asulam ( 98.0 100.6% a. i.) was administered to 6 beagle dogs/ sex/ dose by oral gavage at dose levels of 0, 60, 300, or 1,500 mg/ kg/ day. Doses were selected on the basis of the results of preliminary acute, subacute, and subchronic studies. There was no apparent relationship between test material administration and mortality. Treatment related findings included reductions in body weight gains and food consumption in the high dose males and females; increased frequency of emesis and diarrhea in the high dose males and females; increased absolute thyroid weights in the mid and high dose females and in the high dose males; increased relative ( to body weight) thyroid weights in the high dose males and females; decreased absolute testes and lung weights in the high dose males; decreased relative testes weights in the high dose males; and increased relative kidney weights in the high dose males. No histopathological effects of toxicological significance were observed. There were no apparent effects on prothrombin time, kaolin partial thromboplastin time or platelet counts in males. Platelet counts were slightly decreased in treated females; however, the decreases were not dose related at most intervals and control values appeared to be slightly elevated. Platelet count in the high dose females was significantly lower at the 26 week interval only. Plasma and brain cholinesterase activities were not affected by treatment in either sex.

The LOAEL is 300 mg/ kg/ day, based on significant ( p < 0.05) increases in absolute thyroid weights in females. Absolute and relative thyroid weights were elevated at the high dose ( 1500 mg/ kg/ day) in both males and females. The increased absolute thyroid weights in the mid and high dose females appeared dose related. Although histological effects in the 12 4.5 Asulam ( December, 2001) RED Toxicology Chapter thyroid were not observed in the dog study, the duration of the study was 6 months, which is less than recommended by guidelines ( i. e., 12 months). The NOAEL is 60 mg/ kg/ day.

Classification: This chronic oral study in the dog is Acceptable Nonguideline.

4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The carcinogenicity data base for asulam is considered complete. There is one acceptable combined chronic toxicity/ oncogenicity dietary study in the rat, and one acceptable oncogenicity dietary study in the mouse.

870.4200a Carcinogenicity Study  rat Executive Summary. In a two year combined chronic feeding/ carcinogenicity study ( MRID# 00098543), CD rats ( 50/ sex/ dose) were administered asulam ( 97.5 99.9%) at dose levels of 0, 1,000 ( low dose), 5,000 ( mid dose) or 25,000 ppm ( high dose). These dietary levels were equivalent to 0, 36, 180 and 953 mg/ kg/ day in males and 0, 47, 243 and 1,280 mg/ kg/ day in females, respectively. An additional group ( 15/ sex/ dose) was administered asulam for 78 weeks. Bodyweight change in the high dose animals for various intervals was more than 10% lower than controls. Mean bodyweight change was significantly lower than controls in high dose females from week 0 52 and in the mid and high dose females from weeks 6 52. Mean bodyweight change was significantly lower in the high dose males ( p< 0.01) from weeks 6 52. Hyperplastic changes were observed in the adrenal medulla and in thyroid follicular cells of males at the mid and high dose levels.

There was a statistically significant increase in thyroid gland C cell carcinomas in both the low and mid dose males. There was also a statistically significant increase in adrenal medullary pheochromocytomas at the high dose in males. With the exception of a non dose related enlargement of the pituitary gland in female rats ( 3/ 15 controls; 7/ 15 low dose; 8/ 15 mid dose; 7/ 15 high dose), no unusual toxicological findings occurred in the animals sacrificed at 78 weeks.

The LOAEL is 5,000 ppm ( 180 mg/ kg/ day) based on hyperplastic changes in the adrenal medulla and in thyroid follicular cells of males. The NOAEL is 1,000 ppm ( 36 mg/ kg/ day).

Under the conditions of this study, there was evidence of an increase in tumor incidence in males when compared to controls. Therefore, asulam is a potential oncogen in this study. Dosing is considered adequate to assess the oncogenic potential of asulam.

Classification: This combined chronic toxicity/ carcinogenicity study in the rat is Acceptable Guideline.

870.4200b Carcinogenicity ( feeding)  Mouse 13 Asulam ( December, 2001) RED Toxicology Chapter Executive Summary. In a two year carcinogenicity study with Charles River CD 1 mice ( MRID# 42338201), asulam ( 88% a. i.) was administered in the diet at 0, 500, 5,000 or 50,000 ppm. Concentrations were corrected for 88% a. i. These dietary levels were equivalent to 0, 74, 730 and 8,040 mg/ kg/ day in males and 0, 95, 938 and 10,353 mg/ kg/ day in females, respectively. Mean body weights of the high dose males were generally less than 6% lower than control values during the first 24 weeks of treatment, while body weights of females were less than 6% lower than control values throughout the study. The high dose males displayed a reduction ( greater than 10%) in mean body weight gain when compared to the control group at various intervals. Increased mortality was observed in the high dose females; however, the number of high dose females was adequate to assess the carcinogenic potential of asulam. There was no treatment related effect on food consumption. Hematologic findings in the high dose males and females consisted of increased leukocyte counts, decreased erythrocyte counts, and decreased hematocrit levels. Organ weight changes included decreased brain weight in the high dose females, and increased spleen weight in the high dose males. There was an increased incidence of brown granular pigment deposits in the livers of males of all treatment groups and high dose females. Increased incidences of brown granular pigment deposits were also noted in the spleens of the high dose rats of both sexes. The brown granular pigment deposit was not identified, and is therefore of uncertain toxicological significance. There was no increase in the incidence of any tumors.

The LOAEL is 50,000 ppm, based on increased spleen weight and decreased body weight gain in males, and decreased brain weight and survival in females. The NOAEL was 5,000 ppm.

Under the conditions of this study, there was no evidence of carcinogenicity of asulam. Dosing is considered adequate to assess the carcinogenic potential of asulam based on decreased body weight gain, spleen and brain weight changes, and decreased survival.

Classification: This carcinogenicity study in the mouse is Acceptable Guideline 4.7 Mutagenicity Adequacy of data base for Mutagenicity: With the exception of the dominant lethal mutation assay in mice, all other mutagenicity assays were found to be acceptable. These studies satistfy the pre 1991 guideline requirements for mutagenicity studies; no further testing is required at this time. The data indicate that there is no mutagenicity/ genetic toxicity concern. The following table summarizes the mutagenicity/ genetic toxicity data base.

Study Results Bacterial mutagenicity ( Ames test)  Salmonella typhimurium. Litton Bionetics, Inc., Study No.: E 9177, 1983. MRID No.: 40415302 Not mutagenic with and without metabolic activation at doses up to 2000 Fg/ plate. Classification: Acceptable Guideline 14 Asulam ( December, 2001) RED Toxicology Chapter Study Results Dominant lethal  Mouse  Hess & Clark ( Div. of Rhodia), Study No.: SEH 75, 1975 MRID No.: 00082250 No evidence of induction of dominant lethal effect at dietary concentrations of 1500 or 5000 ppm. Classification: Unacceptable because purity information on the test material was not provided.

In vitro cell transformation assay in C3H/ 10T1/ 2 cells. Mason Research Institute. Study No.: 596 249 8, October 1979. MRID No.: 00098542 No evidence of induction of morphological transformation at dose levels of 256, 512, 1024, or 2048 Fg/ mL for 18 hours exposure. Cytotoxicity was apparent at 2048 Fg/ mL. Classification: Acceptable ( Nonguideline).

In vitro cytogenetics in human lymphocytes. Litton Bionetics, Inc. Study No.: 20990, March 1984. MRID No.: 40415301 Cabinet d Etudes et de Recherches en Tox. Study No.: 658, May 10, 1982. MRID No.: 00144051 No evidence of induction of a clastogenic response at doses of 125 2500 Fg/ mL ( absence of metabolic activation) or 250 2500 Fg/ mL. Classification: Acceptable.

4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: There are no series 81 8, 82 7 or 83 6 acute, subchronic or developmental neurotoxicity studies available. The HIARC ( November 13, 2001) determined that these neurotoxicity studies are not required.

870.6100 Delayed Neurotoxicity Study  Hen Asulam is not an organophosphate insecticide and this type of study is not required.

870.6200 Acute Neurotoxicity Screening Battery As per the November 13, 2001 HIARC recommendations, this study is not required.

870.6200 Subchronic Neurotoxicity Screening Battery As per the November 13, 2001 HIARC recommendations, this study is not required.

870.6300 Developmental Neurotoxicity Study As per the November 13, 2001 HIARC recommendations, this study is not required.

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. The urinary route is the predominant route of elimination in the rat.

870.7485 Metabolism  Rat 15 Asulam ( December, 2001) RED Toxicology Chapter Executive Summary: Metabolism studies were conducted in male and female Sprague Dawley rats ( MRID 41345601). The tests used a single oral or i. v. dose, or repeated oral doses for 14 days. The pharmacokinetics of asulam were similar after all dose regimens in both sexes. Peak blood levels were attained at 0.5 hours. No unusual localization of asulam occurred in tissues and all tissue levels were low at 72 hours. Asulam was rapidly eliminated, mostly within 24 hours. Most of the administered dose ( 76.5% to 101.5%) was eliminated in the urine, and 1.4% to 25.3% of the dose in feces. The major excretory product was unchanged parent compound ( 70% to 80%), with acetylasulam ( 3% to 8%) and acetylsulphanilamide (< 3%) being the two major metabolites.

Overall Conclusion. The metabolism of asulam in rats is considered to be demonstrated and no additional data are required at this time.

Classification.

4.10 Special/ Other Studies No special studies pertaining to asulam have been identified.

5.0 TOXICITY ENDPOINT SELECTION 5.1 See Section 9.2 for Endpoint Selection Table.

5.2 Dermal Absorption Dermal Absorption Factor: 100%. There are no dermal absorption studies with asulam. HIARC ( 11/ 13/ 01) concluded that a comparison of the developmental oral rabbit study to the dermal rabbit study is not appropriate. The dermal rabbit study did not include examination of the thyroid, the target organ.

870.7600 Dermal Absorption  Rat No dermal absorption studies with asulam are available.

5.3 Classification of Carcinogenic Potential 5.3.1 On November 12, 1987 the HED Carcinogenicity Peer Review Committee classified asulam as Group C, a possible human carcinogen, based on thyroid and adrenal tumors in the rat sutdy ( MRID 00098543). They also recommended that the mouse study be repeated and agreed to reconsider the cancer classification upon receipt and evaluation of the new mouse study. On September 22, 1994 the HED RfD peer Review committee met to review the new mouse study ( MRID 42338201). The committee concluded that the findings of the new mouse study have no impact on the current classification of the chemical as a   Group C,  possible human carcinogen, They determined that a low dose linear extrapolation risk model was not appropriate for asulam.

5.3.2 Classification of Carcinogenic Potential 16 Asulam ( December, 2001) RED Toxicology Chapter The Agency has classified asulam as Group C, possible human carcinogen.

5.3.3 Quantification of Carcinogenic Potential Not applicable.

6.0 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children The HIARC concluded that there is no quantitative/ qualitative evidence of increased susceptibility of rat or rabbit fetuses following in utero exposure to asulam in the developmental toxicity studies in these species. However, there was evidence of quantitative susceptibility in a two generation reproduction study in the rat. In this study, the decreased mean live births per litter ( offspring NOAEL = 50 mg/ kg/ day) was observed at lower dose levels than that associated with parental/ systemic toxicity ( NOAEL = 250 mg/ kg/ day).

6.2 Recommendation for a Developmental Neurotoxicity Study The HIARC concluded that a developmental neurotoxicity study was not needed. However, HIARC recommended the requirement for a comparative thyroid rat assay in adults and offspring. It was further recommended that the adult study should include interim measures ( e. g., 7, 14, and 28 days). HIARC also recommended that thyroid parameters selected for the comparative study should be based on Agency guidelines ( under current development) for thyroid toxicity testing.

7.0 OTHER ISSUES No other special issues have been identified.

17 Asulam ( December, 2001) RED Toxicology Chapter 8.0 REFERENCES in MRID order 00056414 Farr, M. J.; Heath, S. A. B.; Rivett, K. F.; et al. ( 1968) Herbicides: Asulam: Chronic Oral Toxicity in the Dog: PRG/ 180. ( Unpublished study received Jun 11, 1972 under 2G1200; prepared by May & Baker, Ltd., submitted by Rhodia, Inc., New Brunswick, N. J.; CDL: 091017 Q).

00081183 Hastings, S. E.; Winbigler, J. C.; Page, J. G.; et al. ( 1978) Eighteen Month Carcinogenicity Study of Asulam Technical in Mice: Report No. SEH 77: 1. ( Unpublished study received Apr 12, 1979 under 359 662; submitted by Rhone Poulenc Chemical Co., Monmouth Junction, N. J.; CDL: 238026 A; 238027; 238028).

00082250 Hastings, S. E.; Huffman, K. W. ( 1975) Dominant Lethal Study of Asulam in Mice: Report No. SEH 75: 94. ( Unpublished study re ceived Dec 17, 1975 under 6F1717; submitted by Rhodia, Inc., New Brunswick, N. J.; CDL: 098085 E).

00083453 Hastings, S. E.; Huffman, K. W. ( 1975) Dominant Lethal Study of Asulam in Mice: Report No. SEH 75: 94. ( Unpublished study re ceived on unknown date under 6F1716; submitted by Rhodia, Inc., New Brunswick, N. J.; CDL: 097998 J).

00098533 Brentnall, D. W. ( 1977) Asulam: Acute Inhalation Toxicity of the Dry Powder in Rats: RES. No. 2938. ( Unpublished study received Apr 16, 1982 under 359 662; prepared by May & Baker, Ltd., Eng land, submitted by Rhone Poulenc Chemical Co., Monmouth Junc tion, N. J.; CDL: 070776 C)

00098534 Ward, R. J. ( 1981) Asulam ( Technical Grade): Primary Eye Irrita tion Study in the Rabbit: Report Ref. R. Tox. 57. ( Unpublished study received Apr 16, 1982 under 359 662; prepared by May & Baker, Ltd., England, submitted by Rhone Poulenc Chemical Co., Monmouth Junction, N. J.; CDL: 070776 D)

00098535 Dale, E. A.; Grimmett, J. E. ( 1977) Asulam: Tests for Primary Skin Irritation in Rabbits and Skin Sensitization in Guinea Pigs: RES/ 2853. ( Unpublished study received Apr 16, 1982 under 359 662; prepared by May & Baker, Ltd., England, submitted by Rhone Poulenc Chemical Co., Monmouth Junction, N. J.; CDL: 070776 E)

00098536 Dale, E. A.; Ingham, B.; Woolf, N.; et al. ( 1979) Asulam: Six Month Oral Toxicity Study in Beagles: Report Ref. RES 3699. ( Unpub lished study received Apr 16, 1982 under 359 662; prepared by May & Baker, Ltd., England, submitted by Rhone Poulenc Chemical 18 Asulam ( December, 2001) RED Toxicology Chapter Co., Monmouth Junction, N. J.; CDL: 070776 F)

00098537 Brentnall, D. W.; Farr, M. J.; Woolf, N. ( 1977) Asulam: 1 Month Inhalation Toxicity of the Dry Powder in Rats: RES/ 3014. ( Un published study received Apr 16, 1982 under 359 662; prepared by May & Baker, Ltd., England, submitted by Rhone Poulenc Chemical Co., Monmouth Junction, N. J.; CDL: 070776 G)

00098538 Copping, G. P. ( 1981) Asulam: Teratogenicity Study by the Oral Route in the Rat: Report Ref. R. Tox. 11. ( Unpublished study received Apr 16, 1982 under 359 662; prepared by May & Baker, Ltd., England, submitted by Rhone Poulenc Chemical Co., Mon mouth Junction, N. J.; CDL: 070776 H)

00098539 Copping, G. P. ( 1981) Asulam: Teratogenicity Study by the Oral Route in the Rabbit: Report Ref. R. Tox. 37. ( Unpublished study received Apr 16, 1982 under 359 662; prepared by May & Baker, Ltd., England, submitted by Rhone Poulenc Chemical Co., Mon mouth Junction, N. J.; CDL: 070776 I)

00098540 Brentnall, D. W.; Woolf, N. ( 1981) Asulam: Two Generation Repro duction Study in the Rat: Report Ref. R. Tox. 34. ( Unpublished study received Apr 16, 1982 under 359 662; prepared by May & Baker, Ltd., England, submitted by Rhone Poulenc Chemical Co., Monmouth Junction, N. J.; CDL: 070776 J)

00098541 McGregor, D. B.; Crichton, C. ( 1977) Mutagenicity Testing of Asulam, M & B 9057: Report No. 807. ( Unpublished study received Apr 16, 1982 under 359 662; prepared by Inveresk Research International, Scotland, submitted by Rhone Poulenc Chemical Co., Monmouth Junction, N. J.; CDL: 070776 K).

00098543 Hunter, B.; Barnard, A. V.; Street, A. E.; et al. ( 1981) Asulam: Tox icity and Tumorigenicity in Prolonged Dietary Administration to Rats: HRC Report No. M & B 95/ 80554. Final rept. ( Unpublished study received Apr 16, 1982 under 359 662; prepared by Hunting don Research Centre, England, submitted by Rhone Poulenc Chem ical Co., Monmouth Junction, N. J.; CDL: 070777 A).

00108811 Rhone Poulenc Chemical Company ( 1981?) Animal: Metabolism Studies with Asulam|. ( Unpublished study received Apr 16, 1982 under 359 662; CDL: 070778 C).

40415301 Galloway, S.; Myhr, B. ( 1984) Asulum: Mutagenicity Evaluation of Asulum Technical ( Dried) in an in vitro Cytogenetic Assay Meas uring Chromosome Aberration Frequencies in Human Lymphocytes: LBI Proj. No. 20990. Unpublished study prepared by Litton Bio netics, Inc. 24 p.

19 Asulam ( December, 2001) RED Toxicology Chapter 40415302 Hoorn, A. ( 1983) Asulum: Mutagenicity Evaluation of Asulam Techni cal in the Ames Salmonella/ Microsome Plate Test Preincubation Method: Genetics Assay No. E 9177. Unpublished study prepared by Litton Bionetics, Inc. 22 p.

40960501 Myers, R.; Christopher, S. ( 1988) Asulam Sodium Salt: Acute Peroral ( Rat) and Percutaneous ( Rabbit) Toxicity Studies: Laboratory Project ID 51 620. Unpublished study prepared by Union Carbide Bushy Run Research Center. 16 p.

40960502 Nachreiner, D.; Klonne, D. ( 1988) Asulam ( Sodium Salt): Acute Dust Aerosol Inhalation Toxicity Test in Rats: Laboratory Project ID 51 583. Unpublished study prepared by Union Carbide Bushy Run Research Center. 28 p.

40977601 Dale, E.; Ingham, B.; Woolf, N.; et al ( 1980) Asulum: Six Month Oral Toxicity Study in Beagles: Supplemental Raw Data: Proj. ID RES/ 3699. Unpublished study prepared by Rhone Poulenc Ag Co. 207 p.

41361601 Nachreiner, D.; Klonne, D. ( 1988) Asulam ( Sodium Salt): Acute Dust Aerosol Inhalation Toxicity Test in Rats: Lab Project Number: 51 583. Unpublished study prepared by Bushy Run Research Cent er. 28 p.

42110001 Cummins, H. ( 1987) FR 1398/ 1: Acute Oral Toxicity Study in the Rat: Lab Project Number: 87/ MBL071/ 011. Unpublished study prepared by Life Science Research Ltd. 20 p.

42110002 Blair, M. ( 1989) Eight Week Range Finding Dietary Toxicity Study in Mice: Lab Project Number: 347 033. Unpublished study prepared by International Research and Development Corp. 182 p.

42338201 Blair, M. ( 1992) Two Year Dietary Oncogenicity Study in Mice: Asulam Sodium Salt: Lab Project Number: 347 036. Unpublished study prepared by International Research and Development Corp. 2959 p.

43185701 Godward, P. ( 1980) Asulam Content of Fortified Rat Diets Used in a Reproduction Study: Lab Project Number: AR/ 1715. Unpublished study prepared by May & Baker Ltd. 28 p.

20 Asulam ( December, 2001) RED Toxicology Chapter 43185702 Copping, G. ( 1981) Mating Records and Randomization Procedures for the Asulam: Teratogenicity Study by the Oral Route in the Rat ( MRID 00098538): Supplement: Lab Project Number: R/ TOX/ 11: 39361. Unpublished study prepared by May & Baker Ltd. 8 p.

44052001 Brentnall, D.; Woolf, N. ( 1981) Asulam: Two Generation Reproduction Study in the Rat: Replacement of MRID 98540: Lab Project Number: R. TOX. 34. Unpublished study prepared by May & Baker, Ltd. and Middlesex Hospital Medical School. 206 p.

21 Asulam ( December, 2001) RED Toxicology Chapter 22 Asulam ( December, 2001) RED Toxicology Chapter 9.0APPENDICES Tables for Use in Risk Assessment 23 Asulam ( December, 2001) RED Toxicology Chapter 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 in rodents See combined chronic feeding and carcinogenicity study. See combined chronic feeding and carcinogenicity study.

870.3150 90 Day oral toxicity in nonrodents 00056414 ( 1968)/ Unacceptable/ Guideline/ 0, 5, 50 or 500 mg/ kg/ day. LOAEL = 500 mg/ kg/ day, based on increased absolute and relative thyroid weights in male and female dogs.

NOAEL = 50 g/ kg/ day 870.3200 21 Day dermal toxicity in rabbits 41076901 ( 1989) Acceptable/ Guideline/ 0 or 1000 mg/ kg/ day. NOAEL = 1000 g/ kg/ day 870.3250 90 Day dermal toxicity No study. No study.

870.3465 90 Day inhalation toxicity No study. No study 870.3700a Prenatal developmental in rodents 00098538/( 1981)/ Accept  able/ guideline/ 0, 500, 1,000, or 1,500 mg/ kg/ day Maternal l LOAEL = 1,500 mg/ kg/ day based on body weight gain decrement. aternal Maternal NOAEL = 1,000 mg/ kg/ day.

Developmental LOAEL = 1,500 mg/ kg/ day based on slight to moderate increase in preimplantation loss. Developmental NOAEL = 1,000 mg/ kg/ day.

870.3700b Prenatal developmental in rabbits 00098539/ 1981/ Acceptable/ Guideline/ 0, 60, 300, or 750 mg/ kg/ day Maternal LOAEL = 750 mg/ kg/ day based on decreased body weight during the dosing period.

Maternal NOAEL = 300 mg/ kg/ day.

Developmental NOAEL = 750 mg/ kg/ day. m m The m 24 Asulam ( December, 2001) RED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3800 Reproduction and fertility effects 00098540/ 1981/ Acceptable/ 0, 50, 250 or 1250 mg/ kg/ day. Parental/ Systemic LOAEL = 1250 g/ kg/ day ( HDT) based on decreased body weights ( F0 males, F1 females) and organ weight effects ( increased absolute and relative thyroid weights in F1 males and F2 males and females, increased absolute and relative liver weights in F1 females, and increased ovarian weights in F1 females at 31 days old but not at terminal necropsy).

Parental/ Systemic NOAEL = 250 mg/ kg/ day.

Reproductive/ Offspring LOAEL = 250 mg/ kg/ day based on decreased mean live births per litter.

Reproductive/ Offspring NOAEL = 50 mg/ kg/ day.

870.4100a Chronic toxicity rodents See combined chronic feeding and carcinogenicity study. See combined chronic feeding and carcinogenicity study.

870.4100b Chronic toxicity dogs 00098536/ 1979/ Acceptable/ Nonguideline / 0, 60, 300, or 1,500 mg/ kg/ day. LOAEL = g/ kg/ day, based on significant ( p < 0.05) increases in absolute thyroid weights in females. roid weights were elevated at the high dose ( 1500 mg/ kg/ day) in both males and females. roid weights in the mid and high dose females appeared dose related.

NOAEL = 60 mg/ kg/ day.

870.4200 Combined Chronic Feeding and Carcinogenicity rats 00098543/ 1981/ Acceptab le Guideline/ 0, 36, 180 and 953 mg/ kg/ day in males and 0, 47, 243 and 1,280 mg/ kg/ day in females. LOAEL = 180 mg/ kg/ day, based on hyperplastic changes in the adrenal medulla and in thyroid follicular cells of males.

NOAEL = 36 mg/ kg/ day. Under the conditions of this study, there was evidence of an increase in tumor incidence in males when compared to controls. Therefore, asulam is a potential oncogen in this study.

870.4300 Carcinogenicity mice 42338201/ 1982/ Acceptable/ Guideline/ 0, 74, 730 and 8,040 mg/ kg/ day in males and 0, 95, 938 and 10,353 mg/ kg/ day in females LOAEL = 8,040 mg/ kg/ day in males, and 10,353 mg/ kg/ day in females, based on increased spleen weight and decreased body weight gain in males, and decreased brain weight and survival in females.

NOAEL = 730 mg/ kg/ day in males and 938 mg/ kg/ day in females.

Under the conditions of this study, there was no evidence of carcinogenicity of asulam. m 300 m Absolute and relative thy The increased absolute thy 25 Asulam ( December, 2001) RED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.4300 Carcinogenicity mice 00081183/ 1978/ Unacceptable/ Guideline/ 0, 225, and 750 mg/ kg/ day. LOAEL = 225 mg/ kg/ day, based on enlargement of the spleen in females, decreased absolute and relative thyroid weights in females, intestinal calcification in males and females, and a dose related increase in the incidence of mild skin/ subcutis hyperkeratosis in males.

NOAEL was not achieved.

Under the conditions of this study, there was no definitive evidence of carcinogenicity of asulam.

One Month Inhalation study in the rat 00098537/ 1977/ Accept able Nonguideline/ nose only exposure at concentrations of 0, 1.6, 3.9, or 15.3 mg/ L for 4 hours per day, 5 days per week, for 4 weeks. NOAEL = 15.3 mg/ L ( HDT).

Oral Range Finding in mice 42110002/ 1989/ Accept able Nonguideline/ 0, 512, 1,673, 5,103, and 9,022 mg/ kg/ day for males, and 0, 675, 2,263, 6,835, and 10,828 mg/ kg/ day for females LOAEL = 9,022 mg/ kg/ day based on decreased body weight and body weight gain in males.

NOAEL is 5,103 mg/ kg/ day.

Gene Mutation 870. A table presenting the mutagenicity data base is already included under section 4.7.

870.6200a Acute neurotoxicity screening battery No study. No study 870.6200b Subchronic neurotoxicity screening battery No study. No study.

870.6300 Developmental neurotoxicity Not required.

26 Asulam ( December, 2001) RED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.7485 Metabolism and pharmaco kinetics 41345601 ( 1989) Metabolism studies in the rat demonstrate that asulam was rapidly eliminated, primarily in the urine, following administration of a single oral or intravenous dose, or after repeated intravenous doses for 14 days. No unusual localization of asulam occurred in tissues. Unchanged parent compound was identified as the major excretory product, with acetylasulam and acetylsulphanilamide as minor metabolites.

870.7600 Dermal absorpt ion No Study. No Study.

27 9.2 Summary of Toxicological Dose and Endpoints for Asulam for Use in Human Risk Assessment1 Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary No appropriate study for a single dose risk assessment.

Chronic Dietary all populations NOAEL= 36 mg/ kg/ day UF = 100 Chronic RfD = 0.36 mg/ kg/ day FQPA SF = cPAD = chr RfD FQPA SF = mg/ kg/ day Combined Chronic Toxicity/ Oncogenicity study ( MRID No.: 00098543). LOAEL = 180 mg/ kg/ day based on hyperplastic changes in the adrenal medulla and in the thyroid follicular cells of males.

Short Term Oral ( 1 30 days)

( Residential) A toxicity endpoint was not selected because there are no residential uses.

Intermediate Term Oral ( 30 days to six months)

( Residential) A toxicity endpoint was not selected because there are no residential uses.

Short Term Dermal ( 1 30 days)

( Occupational) Oral study NOAEL= 50 mg/ kg/ day LOC for MOE = 100 ( Occupational) Two Generation Reproduction Study ( MRID No.: 00098540). LOAEL = 250 mg/ kg/ day based on significant decreases in mean live births per litter.

Intermediate Term Dermal ( 30 days to six months)

( Occupational) Oral study NOAEL= 50 mg/ kg/ day LOC for MOE = 100 ( Occupational) Two Generation Reproduction Study ( MRID No.: 00098540). LOAEL = 250 mg/ kg/ day based on significant decreases in mean live births per litter.

Long Term Dermal ( several months  lifetime)

( Occupational) NOAEL= 36 mg/ kg/ day LOC for MOE = 100 ( Occupational) Combined Chronic Toxicity/ Oncogenicity study ( MRID No.: 00098543). LOAEL = 180 mg/ kg/ day based on hyperplastic changes in the adrenal medulla and in the thyroid follicular cells of males. Asulam ( December, 2001) RED Toxicology Chapter 28 Asulam ( December, 2001) RED Toxicology Chapter Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Short Term Inhalation ( 1 30 days)

( Occupational) Oral study NOAEL= 50 mg/ kg/ day ( inhalation absorption rate = 100%) LOC for MOE = 100 ( Occupational) Two Generation Reproduction Study ( MRID No.: 00098540). LOAEL = 250 mg/ kg/ day based on significant decreases in mean live births per litter.

Intermediate Term Inhalation ( 30 days to six months)

( Occupational) Oral study NOAEL= 50 mg/ kg/ day LOC for MOE = 100 ( Occupational) Two Generation Reproduction Study ( MRID No.: 00098540). LOAEL = 250 mg/ kg/ day based on significant decreases in mean live births per litter.

Long Term Inhalation ( several months  lifetime)

( Occupational) NOAEL= 36 mg/ kg/ day LOC for MOE = 100 ( Occupational) Combined Chronic Toxicity/ Oncogenicity study ( MRID No.: 00098543). LOAEL = 180 mg/ kg/ day based on hyperplastic changes in the adrenal medulla and in the thyroid follicular cells of males.

Cancer Classified as a Group C carcinogen ( possible human carcinogen). No quantification of carcinogenic risk. Not Applicable Not Applicable 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 29