UNITED STATES ENVIRO NM ENTAL PROTECTION AGENCY

MEMORANDUM

DATE: May 16, 2013

TXR # 0056558 WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION

SUBJECT: Asulam: Summary of Hazard and Science Policy Council (HASPOC) Meeting
of January 17, 2013: Recommendations on data requirements for acute and
subchronic neurotoxicity studies and re

- evaluation of previously waived studies.

PC Code: 106901/106902
Decision No.: N/A
Petition No .: N/A
Risk Assessment Type: N/ A

TXR No.: 0056558

MRID No.: N/A DP Barcode: N/A Registration No.: N/A Regulatory Action: N/ A
Case No.: N/A
CAS No.: N/A
40 CFR: N/A

FROM: Kristin Rury, MPH

# '<-~ Executive Secretary,

## HAS**~** Health Effects Division (7509P)

THROUGH: Jess Rowland, MS. Co-Chair
Anna Lowit, Ph.D, Co

- Chair

HASPOC
Health Effects Division (7509P)

TO: Ayaad Assaad, D.V.M., Ph.D., Toxicologist Kelly O'Rourke, ORE assessor Elissa Reaves, Ph.D., Branch Chief
RABIV
Health Effects Division (7509P)

MEETING ATTENDEES:

HASPOC Members: Anna Lowit, Elissa Reaves, Jess Rowland

, John Kough

, Jonathan Chen,
Julie Van Alstine, Kristin Rury

, Michael Metzger, Ray Kent

Presenters: Ayaad Assaad and Kelly O'Rourke

Page I of6Page 2 of 6 Other Attendees: Angela Howard, Christopher Sc hlosser, Christina Swar tz, Elizabeth Holman, Jessica Kidwell, Jolene Tr ujillo, Kelly Lowe, Matthew Lloyd, Myron Ottley, Nancy Dodd (phone), Scott Miller, Whang Phang

I. PURPOSE OF MEETING:

Risk Assessment Branch IV (RAB IV) is curren tly addressing a waiver request submitted by the registrant for outstanding toxicology studies for asul am (D404872), including acute neurotoxicity, and subchronic neur otoxicity studies, as cited in the HED Registration Review scoping document (D387013). The HED Hazard and Science Policy Council (HASPOC) met on January 17, 2013 to discuss the need for the following studies to s upport the registered uses of asulam: a developmental thyroid toxicity st udy, acute and subchronic neurotoxicity studies (870.6200), a subchronic dermal toxicity study (GLN 870.3200), and a su bchronic inhalation study (GLN 870.3465).

II. SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENT :

Asulam (methyl sulfanilyl carbamate) is a select ive, postemergent systemic, sulfanilyl carbamate herbicide whose chemical structure and biological properties differ considerably from those of N-methyl carbamate insecticides. It is structur ally related to chlorpropham and phenmedipham. Asulam acts by inhibiting cell division in plants. There are no registered residential uses of asulam; therefore, there are no pot ential residential handler exposures from asulam applications. Asulam is registered for use on sugarcane; spinach grown for seed (Washington and Oregon only); Christmas trees; sod farm turf; junipe rs; yews; along fencerows and hedgerows; in lumberyards, storage areas, and industrial plant sites; and in warehouse lots.

Asulam is applied with aircraft, ground sprayers , granular spreader, and handheld equipment. Exposure for occupational handlers is expected to be of short- and intermediate-term duration. Registered asulam labels require gloves when handling asulam.

The most recent risk assessment for asulam was conducted in February, 2002 (J. Morales, D276505, 02/28/2002) in support of the Tolerance Reassessment Eligibility Decision (TRED) which was also issued in February, 2002.

In the 2002 assessment (D276505, 02/28/2002), toxicity endpoints or points of departure (PODs) were selected for oral (dietary and drinking water), dermal a nd inhalation exposure to asulam. No acute dietary toxicity endpoint was identified because no adverse effect attributable to a single dose of asulam was observed. An oral P OD of 36 mg/kg/day was us ed for chronic dietary risk assessment based on hyperplastic changes in the adrenal medulla and in the thyroid follicular
cells of males seen at the lowest observed adve rse effect level (LOAEL) of 180 mg/kg/day in the combined chronic toxicity/carcinog enicity study in the rat. Derm al and inhalation endpoints for worker exposure and potential residential handler exposure we re identified in the TRED assessment (although there are currently no register ed residential uses). Although dermal and inhalation toxicity studies were available, these studies did not include an examination of the thyroid gland, the target organ for asulam. Ther efore, and oral POD of 50 mg/kg/day was used to assess risk from dermal and inhalation expos ure scenarios. The end point of concern was thePage 3 of 6 decrease in mean live births pe r litter at 250 mg/kg/day in a two-generation reproduction study in

rats.

Asulam is of low acute toxicity by oral, dermal a nd inhalation routes of exposure. It is not an eye or skin irritant or a dermal sensitizer. S ubchronic and chronic toxicity studies in the rat and dog demonstrate that the thyroid gland is a targ et organ for asulam. A two-year combined chronic/oncogenicity feeding study in rats showed hyperplastic changes in thyroid follicular cells. Subchronic studies in dogs showed increase d absolute and relative thyroid weights in both sexes. Other toxicological effects included adre nal medullary hyperplastic alterations in male rats, and decreased body weight ga ins in male and female rats.

Developmental toxicity studies in the rat and the rabbit are available for asulam. There was no
indication of treatment-related effects on develo pmental parameters in the rabbit developmental toxicity study. Developmental effects were seen in the rat study but only at maternally toxic doses. A two-generation reproduction study in th e rat showed treatment related decrease in mean live births per litter in the first generation providing evid ence for a quantitative increased susceptibility of the rat fetus relative to adults. Parental systemic toxi city included decreased body weights and organ weight e ffects (increased absolute an d relative thyr oid and liver weights). Asulam is classified as Group C, possible human carcinogen, based on thyroid and adrenal tumors in the rat study. HED determined that a low dose linear extrapolation risk model was not appropriate and that a quantitativ e cancer risk assessment was not required.

The chronic dietary risks from th e registered uses of asulam ar e below the Agency’s level of concern (LOC; < 100% chronic population adjust ed dose (cPAD)) for all population subgroups. The chronic dietary risk estimate for childre n 1-6 years (the highest exposed population subgroup) is 1% of the cPAD.

The resulting estimated dermal handler MOEs ra nged from 14 to 2,000 with baseline attire and 77 to 5,400 with gloves (required on asulam labels ). The inhalation MOEs range from 3,000 to 120,000 with baseline attire (i.e., no respirator). For post application exposure, dermal MOEs reached 1,000 at 4, 6 and 19 days after appli cation for ornamentals, sod and sugarcane, respectively.

III. STUDY WAIVER REQUESTS

1. Neurotoxicity Studies:

Acute and subchronic neurotoxic ity studies are required in the 2007 revised 40 CFR Part 158 Toxicology Data Requirements because they pr ovide important scientific information on potential nervous system effects from pesticide exposure. These studies can provide data on a wide range of functional test s for evaluating neurotoxicity including sensory effects, neuromuscular effects, learni ng and memory and histopathology of the nervous system. The HASPOC used a WOE when considering the need fo r acute and subchronic neurotoxicity studies to support the registered uses of asulam.

 Evidence for neurotoxicity in the asul am database of toxicology studies: There are no clear signs of neurotoxicity following subchronic or chronic dosing in multiplePage 4 of 6 species in the asulam database. In the March 31, 1998 HIARC meeting, the HIARC
concluded that: " The data and information provided by the Registrant demonstrate that Asulam, being a carbamate herbicide rather than a carbamate insecticide, has
chemical structure and biological properties considerably different from those of the
insecticides. Several studies were cited to illustrate the lack of cholinesterase inhibition and the absence of clinical signs suggestive of neurotoxicity. Based on these factors, the Agency waived the requirements for acute, subchronic, and developmental neurotoxicity studies” (L. Taylor 0009071, 01/29/1992 ).

 Evidence for neurotoxicity in the database of toxicology studies for other sulfanilyl carbamate pesticides: Asulam is a member of the sulfanilyl carbamate class of
herbicides which are structur ally similar to chlorpropham and phenmedipham. The risk
assessment team conducted a data search us ing the Integrated Structure, Toxicology, Endpoints and Properties (ISTEP) database to explore evidence of neurotoxicity for structurally related chemicals to asulam. Two chemicals similar to asulam, chlorpropham and phenmedipham, do not have neurotoxic ity studies. The acute and subchronic neurotoxicity and immunotoxicity studies we re required for chlorpropham as part of Registration Review (A. Dunbar, D378551, 11/ 02/2010); the Registration Review has not begun for phenmedipham.

 Risk assessment considerations: There was no toxic effect attributable to a single dose identified in the database for asulam; theref ore, an acute dietary exposure assessment was not conducted for the general population or fema les 13-49. The acute oral toxicity study resulted in an LD50 greater th an 5,000 mg/kg. The thyroid is the target organ for asulaminduced toxicity; therefore, neurotoxicity is not a concern for risk assessment.

The HASPOC concludes, based on a weight of evidence (WOE) approach, that acute and sub-chronic neurotoxicity studies are not required at this time. This decision is based 1) on the lack of neurotoxicity in th e available toxicology studies for asulam, 2) chemicals similar to asulam were not shown to be neurotoxic, 3) th e thyroid gland, not the nervous system is the target organ of concern.

2

. Developmental Thyroid Assay:

The thyroid gland is the target organ for asulam-induced toxicity. Toxicity to the thyroid glands manifests as increased thyroid weights and hi stopathological lesions following subchronic and chronic exposures in mice, rats and dogs. There is concern for the pote ntial toxicity to the thyroid glands in the young because of the thyr oid toxicity seen in adult animals and the influence of the thyroid glands on development of organ systems.

Therefore, the HASPOC concludes that a de velopmental thyroid assay is required for asulam based on the presence of thyroid toxi city in adult animals and the concern for potential toxicity to the young.Page 5 of 6 3. Subchronic Dermal Toxicity Study

a. Use Pattern & Exposure Scenarios:

There are no registered residential uses of asulam; therefore, there are no potential residential exposures from asulam applica tions. Auslam is registered for use on sugarcane; spinach grown for seed (Washington and Oregon only); Christmas trees; sod farm turf; junipers; yews ; along fencerows and hedgerows; in lumberyards, storage areas, and industrial plant sites; and in warehouse lots.

b. Toxicological Considerations:

There were no toxicologi cal effects up to the lim it dose (1,000 mg/kg/day) following repeated dermal exposures in a ra bbit 21-day dermal t oxicity study with asulam. Asulam is of low acute toxicity by oral, dermal, and inhalation routes of exposure. It is not an eye or skin irrita nt or a dermal sensitizer. Subchronic and chronic toxicity studies in the rat and dog demonstrate that the thyroid gland is a target organ for asulam. There was no indication of treatment-related effects on developmental parameters in the ra bbit developmental toxicity study. Developmental effects were seen in th e rat study but only at maternally toxic doses. A two-generation reproduction study in the rat showed treatment related
decrease in mean live birt hs per litter in the firs t generation providing evidence for a quantitative increased susceptibility of the rat fetus relative to adults. Parental systemic toxicity included d ecreased body weights and organ weight effects (increased absolute and relati ve thyroid and liver weights).

c. Margins of Exposure:

Dermal absorption was conservatively estimated to be 30%, based on the NOAEL of 300 mg/kg/day from the developmenta l study in the rabbit, and the NOAEL of 1000 mg/kg/day from the 21-day dermal toxic ity study in the rabbit. RAB VI has updated the dermal and inhalation margin s of exposure (MOEs) based on the
current oral PODs. The re sulting estimated dermal handler MOEs ranged from 14 to 2,000 with baseline attire and 77 to 5,400 with gloves (required on asulam labels). For post application exposure, dermal MOEs reached 1,000 at 4, 6 and 19 days after application for ornamental s, sod and sugarcane, respectively.

The HASPOC used a weight of evidence (WOE) a pproach to evaluate the Registrant’s data waiver request for the subchronic dermal t oxicity study. Based on the above exposure and hazard considerations, HASPOC recommends that a 21-day rat dermal toxicity study is required for asulam based on dermal MOEs ranging from 77 – 5,400 with the personal protective equipment required by the labels (gloves) and th e concern for potential thyroid toxicity following dermal exposure since thyroid toxicity was not ev aluated in the available dermal toxicity study. The registrant is given the following options: 1) conduct the 21 day derm al toxicity study to ascertain target organ toxici ty following repeated dermal exposure, or 2) perform an in vivo dermal penetration study (GLN.870. 7600) for refinement of the derm al absorption factor that is currently being used for dermal risk assessment. If the registra nt elects to conduct the dermalPage 6 of 6 toxicity study, then this study should include evaluation of thyr oid hormones thyroid weight and thyroid histopathology.

4. Subchronic Inhalation Toxicity Study

Based on the WOE approach and the above expo sure and hazard considerations, the HASPOC recommends that subchronic inhalation toxicity st udy is not required. This approach considered all of the available hazard and exposure inform ation for asulam including: (1) the low/volume minor use characteristics; (2) that all occ upational inhalation MOEs > 3,000; and (3) thyroid metrics from an inhalation toxicity study would not contribute to a mo re refined risk assessment.

IV. HASPOC RECOMMENDATIONS

Therefore, based on a WOE approach, a subchronic dermal toxicity study, and a developmental thyroid assay are required for asulam. If a derm al toxicity study is not conducted, then a rat dermal absorption study should be conducted to c onfirm the estimated dermal absorption factor (30%) that is currently used in the dermal risk assessment. Acute and subchronic neurotoxicity
studies and a subchronic inhalation toxicity study are not required for asulam at this time. In absence of a subchronic dermal toxicity study an d a comparative thyroid assay, the current 10X safety factor will apply to all routes of exposure for new use risk assessments.