UNITED STATES ENVIRONMENTAL 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 

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Other Attendees: Angela Howard, Christopher Schlosser, Christina Swartz, Elizabeth Holman, 

Jessica Kidwell, Jolene Trujillo, Kelly Lowe, Matthew Lloyd, Myron Ottley, Nancy Dodd 

(phone), Scott Miller, Whang Phang 

I. PURPOSE OF MEETING:

Risk Assessment Branch IV (RAB IV) is currently addressing a waiver request submitted by the 

registrant for outstanding toxicology studies for asulam (D404872), including acute 

neurotoxicity, and subchronic neurotoxicity 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 support the registered uses of 

asulam: a developmental thyroid toxicity study, acute and subchronic neurotoxicity studies 

(870.6200), a subchronic dermal toxicity study (GLN 870.3200), and a subchronic inhalation 

study (GLN 870.3465). 

II. SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENT:

Asulam (methyl sulfanilyl carbamate) is a selective, postemergent systemic, sulfanilyl carbamate 

herbicide whose chemical structure and biological properties differ considerably from those of 

N-methyl carbamate insecticides. It is structurally 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 potential 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; junipers; 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 and 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 POD of 36 mg/kg/day was used 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 adverse effect level (LOAEL) of 180 mg/kg/day in the 

combined chronic toxicity/carcinogenicity study in the rat. Dermal and inhalation endpoints for 

worker exposure and potential residential handler exposure were identified in the TRED 

assessment (although there are currently no registered 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. Therefore, and oral POD of 50 mg/kg/day was used 

to assess risk from dermal and inhalation exposure scenarios. The end point of concern was the 
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decrease in mean live births per litter at 250 mg/kg/day in a two-generation reproduction study in 

rats. 

Asulam is of low acute toxicity by oral, dermal and inhalation routes of exposure. It is not an 

eye or skin irritant 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. A two-year combined 

chronic/oncogenicity feeding study in rats showed hyperplastic changes in thyroid follicular 

cells. Subchronic studies in dogs showed increased absolute and relative thyroid weights in both 

sexes. Other toxicological effects included adrenal medullary hyperplastic alterations in male 

rats, and decreased body weight gains 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 developmental 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 the rat showed treatment related decrease in 

mean live births per litter in the first generation providing evidence for a quantitative increased 

susceptibility of the rat fetus relative to adults. Parental systemic toxicity included decreased 

body weights and organ weight effects (increased absolute and relative thyroid 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 quantitative cancer risk assessment was not required. 

The chronic dietary risks from the registered uses of asulam are below the Agency’s level of 

concern (LOC; < 100% chronic population adjusted dose (cPAD)) for all population subgroups. 

The chronic dietary risk estimate for children 1-6 years (the highest exposed population 

subgroup) is 1% of the cPAD. 

The resulting estimated dermal handler MOEs ranged 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 application for ornamentals, sod and sugarcane, 

respectively. 

III. STUDY WAIVER REQUESTS

1. Neurotoxicity Studies: 

Acute and subchronic neurotoxicity studies are required in the 2007 revised 40 CFR Part 158 

Toxicology Data Requirements because they provide important scientific information on 

potential nervous system effects from pesticide exposure. These studies can provide data on a 

wide range of functional tests for evaluating neurotoxicity including sensory effects, 

neuromuscular effects, learning and memory and histopathology of the nervous system. The 

HASPOC used a WOE when considering the need for acute and subchronic neurotoxicity studies 

to support the registered uses of asulam. 

 Evidence for neurotoxicity in the asulam database of toxicology studies: There are 

no clear signs of neurotoxicity following subchronic or chronic dosing in multiple 
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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 structurally similar to chlorpropham and phenmedipham. The risk 

assessment team conducted a data search using 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 neurotoxicity studies. The acute and subchronic 

neurotoxicity and immunotoxicity studies were 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; therefore, an acute dietary exposure assessment was 

not conducted for the general population or females 13-49. The acute oral toxicity study 

resulted in an LD50 greater than 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 the available toxicology studies for asulam, 2) chemicals similar to 

asulam were not shown to be neurotoxic, 3) the 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 histopathological lesions following subchronic and 

chronic exposures in mice, rats and dogs. There is concern for the potential toxicity to the 

thyroid glands in the young because of the thyroid toxicity seen in adult animals and the 

influence of the thyroid glands on development of organ systems. 

Therefore, the HASPOC concludes that a developmental thyroid assay is required for 

asulam based on the presence of thyroid toxicity in adult animals and the concern for 

potential toxicity to the young. 
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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 applications. 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 toxicological effects up to the limit dose (1,000 mg/kg/day) 

following repeated dermal exposures in a rabbit 21-day dermal toxicity study with 

asulam. Asulam is of low acute toxicity by oral, dermal, and inhalation routes of 

exposure. It is not an eye or skin irritant 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 rabbit developmental toxicity study. 

Developmental effects were seen in the rat study but only at maternally toxic 

doses. A two-generation reproduction study in the rat showed treatment related 

decrease in mean live births per litter in the first generation providing evidence 

for a quantitative increased susceptibility of the rat fetus relative to adults. 

Parental systemic toxicity included decreased body weights and organ weight 

effects (increased absolute and relative 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 developmental study in the rabbit, and the NOAEL of 

1000 mg/kg/day from the 21-day dermal toxicity study in the rabbit. RAB VI has 

updated the dermal and inhalation margins of exposure (MOEs) based on the 

current oral PODs. The resulting 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 ornamentals, sod and sugarcane, respectively. 

The HASPOC used a weight of evidence (WOE) approach to evaluate the Registrant’s data 

waiver request for the subchronic dermal toxicity 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 the concern for potential thyroid toxicity following 

dermal exposure since thyroid toxicity was not evaluated in the available dermal toxicity study. 

The registrant is given the following options: 1) conduct the 21 day dermal toxicity study to 

ascertain target organ toxicity following repeated dermal exposure, or 2) perform an in vivo

dermal penetration study (GLN.870.7600) for refinement of the dermal absorption factor that is 

currently being used for dermal risk assessment. If the registrant elects to conduct the dermal 
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toxicity study, then this study should include evaluation of thyroid hormones thyroid weight and 

thyroid histopathology. 

4. Subchronic Inhalation Toxicity Study 

Based on the WOE approach and the above exposure and hazard considerations, the HASPOC 

recommends that subchronic inhalation toxicity study is not required. This approach considered 

all of the available hazard and exposure information for asulam including: (1) the low/volume 

minor use characteristics; (2) that all occupational inhalation MOEs > 3,000; and (3) thyroid 

metrics from an inhalation toxicity study would not contribute to a more 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 dermal toxicity study is not conducted, then a rat 

dermal absorption study should be conducted to confirm 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 and a comparative thyroid assay, the current 10X 

safety factor will apply to all routes of exposure for new use risk assessments.