### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTIO N PREVENTION



### MEMORANDUM

Date: December 11, 2013

SUBJECT: Thiram. Update to the Aggregate Risk Assessment to Support th e Requested

PHI Reduction and Increased Tolerance Request on Strawberry

PC Code: 07980 I

Decision No

. : 4710 74

Petition No.: 2F81 06

Risk Assessment Type: Single Chemical, Aggregate

TXRNo.: NA

MRID No.: NA DP No.: D412465 Registration No.: NA Regulatory Action: Section 3

Case No.: NA

CAS No.: 137-26-8

40 CFR: §180

. 1 32



### FROM: Jessica Kidwell, Risk Assessor

# ~ .

# ~**~** Thurs to n G. Morton, Chemist

## ~~ q' .,/\/ Kelly O'Rourke, ORE

## ~**~ ~**  Sue Hummel, Chemist '- 

## J

Marquea King, PhD,**Toxicologi~~ ·**  

### Risk Assessment Branch IV, Health Effects**~ion** 

### (7509P)/

THROUGH: Elissa Reaves, Branch Chief

Risk Assessment Branch IV /Health Effects Division ( 509P)

TO: Shaunta Hill, RM21 Cynthia Giles-Parker, Branch Chief

F ungicide Branch, Registration Division (7505P)

1.0 Executive Summary

Taminco, Inc. submitted an amendment requesting a change in the preharvest interval (PHI)

from 3 days to 1 day for st rawberry on the label for Spotrete-F (EPA Reg. No. 45728

- 26), a Plowable (Soluble Concentrate or SC) formulation for thiram. Concurrently, the registrant

submitted a petition proposing an increase in the current tolerance of 7 ppm to 20 ppm for

residues ofthiram on strawberry. This risk assessment updates the dietary and res id ential postapplication dermal exposure assessments to support this petition. An updated worker



## exposure and risk assessment is not required to support the requested label amendment.

### Thiram/07980 1 Human H ealth Risk Assessment 04 1 2465

The toxicity database for thiram is considered adequate to support the current pet i tion. Endpoints, points of departure, a n d u n certain t y factors for this risk assessment rema i n unchanged

from our previous reviews. Th e residue chemistry database for thiram is comp l ete. P otential

areas of environmenta l justice concerns, to the ex t ent poss i ble, were considered in this human

health r i sk assessment.

H ED concludes that there are no r i sk issues that would preclude increasing the tolerance for the

residues ofthiram on strawber r y. The tolerance of20 ppm supports the amended strawber r y use pattern of a reduction to a 1 day PHI. No additional data are needed

.

H E D conducted an updated dietary risk assessment to support the requested label amendment

and to l erance increase

. No dietary risks of concern were identified. The acute and chronic dietary

risk estimates for food and drinking water are below HED's level of concern (i.e., <100% of the

acute and chronic population adjusted doses (PA D s)) for the general U.S. population and all population subgroups. Acute dietary exposure at the 99.9th exposure percentile for the general

U.S. population was 3.1% ofthe aPAD and 78% ofthe aPAD for females 13-49 years old, the population subgroup with the highest es t imated acute dietary exposure to thiram. Chron i c dietary

exposure for t h e general U.S. populat i on was 9.2% of the cPAD and 56% of the cPAD for

children 1-2 years old, the population subgroup with the highest estimated chronic dieta r y

exposure to th i ram. Thiram is classified as "Not L ike l y to be Carcinogenic to Humans" based on lack of evidence for carcinogenicity in mice or rats; therefore, a quantitative cancer risk

assessment is not required.

Thiram is not ava il able for sale or use by homeowner applicators; therefore, there are no residential handler exposure scenarios applicable to thiram. However, there is potential for

res i dential post-app li cation dermal exposure from treated golf course greens and tees

. Residential

exposures resulting from dermal contact w i th thiram

- t r eated turf were assessed for chi l d r en 6 to

< 1 1 years o l d, ch il dren 11 to <16 years old, and adults

. The dermal margins of exposure (MOEs)

for the populations assessed ranged from 850 to 1000 and a ll greatly exceeded t h e leve l of

concern of 100

. Inhalation post-application exposures for golf courses were not assessed since

inhalation exposures are thought to be negligible i n outdoo r post-application scenarios

.

HED also conducted updated aggregate risk assessments, and no aggregate risks of concern were identified. Acute and chronic aggregate risk assessments take into account exposure estimates

from dietary consumption ofthiram (food and dr i nk i ng water). As referenced above, both the

acute and chronic dietary risk estimates are not of concern to HED ( <1 00% aPAD and cPAD). In aggregating short/intermed i ate

- term risk, the Agency routinely combines background chronic dietary exposure (food+ water) with short- and intermediate-term residential exposure (derma l only). The combined exposure may then be used to calculate an MOE for aggregate risk. Using

the golfer scenario fo r adult males, adult females, and children >6 years old, combined with the

app li cable s u bpopu l ation with the greatest dietary exposure, the total short/intermediate

- term
food and resident i a l aggregate MOEs are 600, 600, and 370, respective l y. As these MOEs are greater than 100, the short- and intermediate

- term agg r egate risks do not exceed the HED's LOC.

An upda t ed worker exposure and risk assessment is not required to support the requested label

amendment. Since the subject amendment is lim i ted to a change in the PHI, approval of this use

Page 2 of21

### Thiram

/079801 Human Health Risk Assessment D412465

Page 3 of 21 does not impact the application rates, number of applications, or seasonal application rate; therefore, there is no impact on the occupational exposure from the proposed label amendment.

2.0 HED Recommendations

HED concludes that there are no risk issues that would preclude increasing the tolerance for the

residues of thiram on strawberry. The tolerance of 20 ppm supports the amended strawberry use pattern of a reduction to a 1 day PHI. No additional data are ne eded. Specific tolerance

recommendations are discussed in section 2.2.

2.1 Data Deficiencies

Toxicology: No new toxicity data are required to support this petition. A previously identified toxicity data gap with respect to immunotoxicity (OPPTS 870.7 800) has been resolved. An immunotoxicity study in mice has been submitted (MRID 48646401). The HASPOC determined

that a 28

- day inhalation toxicity study with neurotoxicity parameters in rats is required. Therefore, a 10X database uncertainty factor will b e retained for the inhalation route. An inhalation study is required for any future registration action that involves an updated inhalation assessment. However, the cholinesterase activity screening assay was waived by the HASPOC and is not required at thi s time

.

Chemistry: None

ORE: None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A colormetric a nalytical m ethod is available to enforce the proposed tolerances. The Pesticide Analytical Manual (PAM) Vol. II lists Method I, II, III, IV, and A for the determination of dithiocarbamate residues in/on plant commodities. These methods are based on the decomposition of dithiocarbamates with release of CS 2 

### . Using these methods, the CS 2 

### is swept through a trap to remove any H 2 

### S and into a reaction tube containing a solution of copper acetate and an amine. A colored copper dithiocarbamate complex is formed and its absorbance read as a measure of the original dithiocarbamate. T he stated limit of detection (LOD) for Method I is 0.5

- 4.0 ppm

.

Thiram may be detectable using PAM I multiresidue methods without Florisil cleanup, but is not detected when Florisil cleanup is used.

2.2. 2 Recommended Tolerances

A tolerance of 20 ppm supports the amended strawberry use pattern of a reduction to a 1 day

PHI. A summary of tolerance recommendations is presented in Table 2.2.3. The recommended

### Thiram

/079801 Human Health Risk Assessment D412465

Page 4 of 21 tolerance for strawberry was derived with the aid of the OECD tolerance cal culation procedure.

In 2009 HED issued guidance on tolerance expressions (S. Knizner, 2009)

. T he current thiram tolerance expression is not in accord with this guidance. The tolerance expression should read:

Tolerances for residues of the fungicide thir am (tetramethyl thiuram disulfide), including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified is to be determined by measuring only thiram.

The above recommendation is an interim solution until tolerances for dithiocarbamates are converted to being expressed as carbon disulfide. When this occurs, the tolerance expression

should read:

Tolerances are established for residues of fungicide thiram (tetramethyl thiuram disulfide), inclu ding its metabolites and degradates

, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only those thiram residues convertible to carbon disulfide , expressed as carbon

disulfid e , in or on the commodity.

Table 2.2.3. Tolerance Summary for Thiram

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Strawberry 20 20 When dithiocarbamate tolerances are changed to be expressed as carbon disulfide, the recommended tolerance

level becomes 1 3 ppm. (The conversion factor is 0.63x)



### 2.2. 3 Revisions to Petitioned

- For Tolerances

Tolerance proposals for raw agricultural commodities were not changed.

2.2. 4 International Harmonization

The Codex Alimentarius has established maximum residue limits (MRL), for “ t otal dithiocarbamates, determined and expressed as mg carbon disulfide per kg ” in strawberry of 5 mg/kg. As U. S . tolerances are currently established on the individual dithiocarbamates,

compa tibility is not possible with the proposed tolerances. However, HED has recommended that all tolerances for dithiocarbamates, including thiram be converted to be expressed as carbon disulfide. At that time, the tolerance expression will be compatible with CODEX, however the tolerance level will not be compatible, since there are differences in Good Agricultural Practices (GAP) and the current CODEX MRL would not cover actual residues seen in the U.S. field trials submitted to support the proposed label amen dment.

2.3 Label Recommendations

No label revisions are required.

### Thiram

/079801 Human Health Risk Assessment D412465

Page 5 of 21 3.0 Introduction

3.1 Chemical Identity

Thiram is a dimethyl dithiocarbamate fungicide used to prevent crop damage in the field and to protect harvested crops (apples, peaches, and strawberries) from deterioration in storage or transport. It is also used as a seed protectant (e.g., small

- seeded vegetables, large

- seeded vegetables, cereal grains, other seeds, coniferous seeds, cotton seed, ornamental seeds, and soybeans) and as a turf protectant from fungal diseases.

TABLE 3.1

. Test Compound Nomenclature.

Compound

Common name Thiram

IUPAC name tetramethylthiuram disulfide

CAS name tetramethylthioperoxydicarbonic diamide

CAS registry number 137

- 26

- 8

End

- use product s (EP s ) used in residue field study Banguard 42 PLUS (37.0% ai SC) or Banguard 60 (52.6% ai SC)



### 3.2 Physical / Chemical Characteristics

TABLE 3. 2. Physicochemical Properties of the Technical Grade of Thiram.

Parameter Value Reference

Melting range 142

- 150 oC Revised Thiram Product and Residue Chemistry Chapters

for the RED Document

, 12/16/03

. Density 0.32

- 0.35 g/mL

Water solubility at 20

- 25 oC 0.00165 g/100 mL

Solvent solubility at 20

- 25 oC petroleum ether (0.0005 g/100 mL), benzene (4.12 g/100 mL), acetone (6.97 g/100 mL), xylene (0.91 g/100 mL), and methanol (0.184 g/100 mL)

Vapor pressure 1.6

- 1.8 x 10
- 5 Torr at 25 °C

Dissociation constant, pK

a Not applicable

Octanol/water partition coefficient, P OW 39.5

- 54.1



### 3.3 Pesticide Use Pattern

A summary of the proposed end

- use product is presented in Table 3.3.

### Thiram

/079801 Human Health Risk Assessment D412465

Page 6 of 21 Table 3 .3

. Summary of Directions for Use of Thiram

Applic. Timing; Type; and Equip. Formulation

[EPA Reg. No.] Applic.

Rate,

lb ai/A Max. No.

Applic.

per Season Max.

Seasonal Applic.

Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Strawberry

Foliar Ground

Boom 4 lb/gal SC [ 45 7 28

- 26 ] 2.6 13.0 1 1 Use a 10 day interval between applications.



### 3. 4 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pd f

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on p atterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the National Health and

Nutrition S urvey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess diet ary exposure to smaller, specialized subgroups and exposure assessments are performed when

conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators a nd for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models t hat consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4 .0 H azard C haracterization and Dose

- Response Assessment

This assessment includes a summar y of the prior assessment (Memo, G. Kramer, D365442, 6/9/2009). The toxicity database for thiram is considered adequate to support the current petition which evaluates oral and dermal routes of exposure. HED also notes that an immunotoxicity study has been submitted and satisfies t he data requirement. The toxicity database is inadequate

, however, for the inhalation route of exposure. At this time, however, there is no residential inhalation exposure from thiram.

The Hazard and Science Policy Council (HASPOC) met on June 6, 2013 to discuss the need for

a 28

- day inhalation toxicity study with neurotoxicity measurements and a cholinesterase activity screening assay (TXR No. 0056685) . Based on a Weight of Evidence approach, the HASPOC

### Thiram

/079801 Human Health Risk Assessment D412465

Page 7 of 21 concluded that a 28

- day inhalation toxicity study with neurotoxicity parameters in rats is required. Therefore, a 10X database uncertainty factor is required for all inhalation exposure risk assessments. However, a cholinesterase activity screening assay is not required at this time

.

4.1 Summary of Tox icological Effects

Thiram has been shown to cause neurotoxicity following acute and subchronic exposures. In the acute and subchronic neurotoxicity studies submitted, neurotoxicity is characterized as lethargy, reduced and/or tail pinch response, changes in the functional

- observation battery (FOB) parameters, increased hyperactivity, changes in motor activity, and increased occurrences of rearing events. No treatment

- related changes were observed in brain weights or in the histopathology of the nervous sys tem. In a non

- guideline study published in the open literature, chronic feeding of thiram to rats caused neurotoxicity, with onset of ataxia in some animals 5

- 19 months after beginning of treatment. However, no evidence of neurotoxicity was seen following chronic exposures in mice or rats in guideline studies submitted to the Agency. In addition, no adverse effects on the developing fetal nervous system were seen in a DNT study. The chronic toxicity profile for thiram indicates that the liver, blood, and u rinary system are the target organs for this chemical in mice, rats, and dogs. There is no evidence for increased susceptibility following in utero exposures to rats or rabbits and following pre

- and post

- natal exposures to rats for two generations. There is low concern for the increased susceptibility seen in the developmental toxicity study since the dose response is well defined and this endpoint is used for assessing the acute dietary risk for the most sensitive population. Thiram is classified as “not likely to be carcinogenic to human s ” based on lack of evidence for carcinogenicity in mice or rats. There are no mutagenic/genotoxic concerns with thiram. The available toxicological database for thiram suggests that this chemical has a low to moderate acu te

- toxicity profile.

Thiram is readily absorbed (via the oral route), distributed, extensively metabolized and eliminated primarily in the expired air and urine of rats following single or repeated oral

administrations. Within 24 hours of administration of the compound, a high amount of radioactivity was eliminated as expired air ( 14 

### C O 2 

### , carbamyl sulfide, and carbon disulfide). T he parent compound was not detected in the urine. Fecal metabolites were not evaluated due to the low recovery of radioactivity in the feces. There is no apparent sex

- or dose

- related difference in

the distributi on, metabolism, or excretion of 14 

### C

- thiram. Bioaccumulation of 14 

### C

- thiram in tissues was low (1.54

- 4.24% of the administered dose). Therefore, an appreciable accumulation of thiram is not anticipated after repeated exposures.

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

For the current assessment which includes oral and dermal exposures, t he FQPA safety factor for

thiram is reduced to 1X

. The recommendation of 1X is based on the following considerations. The toxicological database for thiram is complete with acceptable neurotoxicity, developmental, and reproductive toxicity studies

. Thiram has been shown to cause neurotoxicity following acute and subchronic exposures. There was no evidence of increased susceptibility following in utero exposure to rats or rabbits or following pre

- and post natal exposures to rats. There is evidence of quantitative susceptibility in the DNT study. There is low co ncern for the enhanced susceptibility seen in the DNT study because clear NOAELs/LOAELs were establi shed for the offspring

### Thiram

/079801 Human Health Risk Assessment D412465

Page 8 of 21 effects, the dose

- response is well defined , and the dose/endpoint is used for acute dietary risk for the most sensitive population (females 13

- 49 years old. Consequently, there are no residual uncertainties for pre

- and post

- natal toxicity. There are no residual uncertainties in the thiram

exposure dat abase.

4.2.1 Completeness of the Toxicology Database

For this petition, t he toxicology database for assessing sensitivity and susceptibility is complete.
However, based on a Weight of Evidence approach, the HASPOC concluded that a 28

- day

inhalation toxi city study with neurotoxicity parameters in rats is required (TXR No. 0056685)

. Therefore, a 10X database uncertainty factor is required for all inhalation exposure risk assessments. A cholinesterase activity screening assay is not required at this time

.

4.2.2 Evidence of Neurotoxicity

Although signs of neurotoxicity w ere observed in the database for thiram, there are no residual concerns since clear NOAELs were established and the PODs are protective of any neurotoxicity. In addition, no adverse effects on the developing fetal nervous system were seen in a DNT study.

4.2.3 Evidence of Sens i tivity/Susceptibility in the Developing or Young Animal

There was no evidence of increased susceptibility following in utero exposure to rats or rabbits or following pre

- and post natal exposures to rats. There is evidence of quantitative susceptibility in the DNT study. Offspring effects (increased locomotor activity in females on PND 17)

occurred at a lower dose than maternal effects (increased number of rearing events and elevated incidences of hyperactivity in females at weeks 8 and 13). There is low concern for the enhanced susceptibility seen in the DNT study because: 1) clear NOAELs/LOAELs were established for the offsprin g effects; 2) the dose

- response is well defined; 3) behavioral effect of concern w ere observed only in females on one evaluation time period; and 4) the NOAEL is used for acute dietary risk for the most sensitive population subgroup (females 13

- 49 years ol d )

. Consequently, there are no residual uncertainties for pre

- and post

- natal toxicity.

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the thiram database with regards to dietary exposure. A refined probabilis tic acute dietary

- exposure assessment was performed using maximum percent crop treated (%CT) provided by BEAD, tolerance, the highest residue found during field

- trials, distribution of field trial residues, Federal Drug Administration (FDA) monitoring data for apples, and empirical processing factors . A refined chronic dietary

- exposure assessment was performed using tolerances and average estimated % CT. Estimated drinking water

concentrations were used. An updated worker exposure and risk assessment is no t required to support the requested label amendment.

### Thiram

/079801 Human Health Risk Assessment D412465

Page 9 of 21 4.3 Toxicity Endpoint and Point of Departure Selections

A summary of the most updated toxicological endpoints and doses chosen for the relevant exposure scenarios for human risk assessment can be found in the 2009 risk assessment (Memo, G. Kramer, D365442, 6/9/2009). The endpoint summary table is included below.

Table 4.3.1 . Summary of Toxicological Doses and Endpoints for Thiram for Use in Dietary and Non

Occupational Human Health Risk Assessmen ts.

Exposure/

Scenario PoD Uncertainty/FQPA

SF s RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population) BMDL 10 =

64.94 mg/kg UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 0. 64 94

mg/kg/day

aPAD = 0. 64 94 mg/kg/day Acute Neurotoxicity Study

– Rat

MRID 42912401 LOAEL = 150 mg/kg/day based

on FOB effects (lethargy, lower temperature, reduced startle

response, no tail

- pinch response), reduced motor activity, and reduced brain weights.

Acute Dietary (Females 13

- 49 years old ) NOAEL =

1.4 mg/kg UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 0.014

mg/kg/day

aPAD =0.014 mg/kg/day Dev. Neurotoxicity Study

– Rat

MRID 46455201 LOAEL = 3.7 mg/kg/day based on increases in motor activity

seen in female offspring on PND

17.

Chronic Dietary (All populations)

NOAEL =

1.5 mg/kg UF A = 10x

UF H = 10x FQPA SF = 1x Chronic RfD = 0.015

mg/kg/day

cPAD =0.015 mg/kg/day Co

- critical: 1) Combined Chronic Toxicity/Carcinogenicity Study

– Rat and 2) Chronic Oral Toxicity

- Dog LOAEL = 7.3 mg/kg/day based on changes in hematology, clinical chemistry, incidences of bile duct hyperplasia, and

reduction in mean body

- weight gain from the chronic toxicity/carcinogenicity rat study

in conjunction with elevated

choles terol levels and increased liver weights reported in the Chronic Oral Toxicity Study in Dogs at a LOAEL = 7.23 mg/kg/day

Short

- and

Intermediate

Term

Incidental

Oral No incidental oral residential exposure.

### Thiram

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Page 10 of 21 Table 4.3.1 . Summary of Toxicological Doses and Endpoints for Thiram for Use in Dietary and Non

Occupational Human Health Risk Assessmen ts.

Exposure/

Scenario PoD Uncertainty/FQPA

SF s RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects

Short

- Term Dermal (1

- 30 days) NOAEL =

1.4 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x

( Dermal

- absorption

factor = 1%) Residential LOC for

MOE = 100

Occupational LOC for

MOE = 100 Dev. Neurotoxicity Study

– Rat

MRID 46455201

LOAEL = 3.7 mg/kg/day based on increases in motor activity

seen in female offspring on PND

17.

Intermediate

Term Dermal (1 to 6 months) NOAEL

=1.4 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x

( Dermal

- absorption

factor = 1%) Residential LOC for

MOE = 100

Occupational LOC for

MOE = 100 Dev. Neurotoxicity Study

– Rat

MRID 46455201 LOAEL = 3.7 mg/kg/day based on increases in motor activity seen in female offspring on PND

17.

Short

- and

Intermediate

Term

In halation Current assessment does not warrant an inhalation assessment.

Cancer (oral, dermal, inhalation) “Not Likely to be Carcinogenic to Humans”

Point of Departure (P o D) = A data point or an estimated point that is derived from o bserved dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse e ffect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members o f the human population (interspecies). FQPA SF = FQPA Safety Factor. PAD = population

adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Food Residue Profile

The proposed new use is a reduction in PHI to 1 day. As a result of the shorter PHI, quantifiable surface residues of thiram are likely to be found. Field trial results are summarized in Table 5.1.

TABLE 5.1. Summary of Residue Data from Crop Field Trials with Thiram on Strawberries
Commodity Total Applic.

Rate (lb a.i./A) (kg a.i./ha) PHI

(days) Residue Levels (ppm)

n Min. Max. LAFT * HAFT* Median Mean Std.

Dev. Data from the use of Spotrete F (SC formulation) Five Applications at 2.62 lb ai/A, 1 day PHI Strawberry 13 1 10 <0.05 13 <0.05 11.4 4.25 4.89 2.99

* LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial.



### 5. 2 Water Residue Profile

The Environmental Fate and Effects Division has previously assessed residue s in drinking water

### Thiram

/079801 Human Health Risk Assessment D412465

Page 11 of 21 from the existing uses of thiram, including the currently registered use on strawberries. A new drinking water assessment is not required since, not only is the label amendment limited only to a PHI change, and the use rate, timing, number of applications, and seasonal application remain the same, but the use that drives the current drinking water assessment is turf; therefore

, this change in PHI has no impact on the drinking water assessment.

EFED provided estimated drinking water concentrations (EDWCs) in their memo entitled “Environmental Fate and Ecological Effects Assessment and Characterization Chapter for the Thiram Registration Eligibility Decision Document” (J. Carleton and F. Jenkins, 12/11/03 )

. Because mon itoring data are unavailable

, estimates of thiram concentrations were made only

with mathematical models. EDWC values were generated by the PRZM (Pesticide Root Zone Model)

- EXAMS (Exposure Analysis Modeling System) for the turf application scenario, since this crop yielded the highest EDWC values. Ground water sources were not included, as the EDWCs for this water source are minimal in comparison to those for surface water. Water

residues ( surface water EDWC of 0. 047 8 ppm for acute and 0.0025 ppm for chronic ) were incorporated in DEEM

- FCID TM 

### into the food categories “water, direct, all sources” and “water, indirect, all sources” for the dietary assessments.

Table 5. 2

. EDWCs for Use in the Human

- Health Risk Assess ment.

Crop Annual

App Rate (lbs ai/acre/yr) SCIGROW

concentration (ppb) PRZM/EXAMS*

Acute EEC (ppb) PRZM/EXAMS*

non

- cancer chronic EEC (ppb) PRZM/EXAMS*

cancer chronic EEC (ppb)

Turf farm 146.6 0.84 47.8 2.5 2.2

* Index Reservoir environment



### 5. 3 Dietary Risk Assessment

5. 3 .1 Description of Residue Data Used in Dietary Assessment

For strawberry, banana, and peach

, the highest residue from submitted field trials were used for the acute dietary exposure analysis. For apple, monitoring data from the Food a nd Drug Administration (FDA) pesticide monitoring study was used. In addition, washing factors and processing fa ctors from submitted studies were used. Tolerance level residues were used in the chronic dietary exposure analysis for all commodities.

5. 3 .2 Percent Crop Treated Used in Dietary Assessment

The following maximum percent crop treated estimates for t hi ram from the Screening Level Usage Analysis ( SLUA )

, dated January 12, 2012

, were used in the acute dietary risk assessment for the following crops that are currently registered for thiram: apples: 10%; peaches: 2.5%; and strawberry: 30%. The following aver age percent crop treated estimates were used in the chronic dietary risk assessments for the following crops that are currently registered for thiram: apples: 5%; peaches: 1.0%; and strawberry: 20%.

Table 5. 3 .2 presents percent crop treated (%CT) estimates that were used in the acute and chronic dietary exposure analysis.

### Thiram

/079801 Human Health Risk Assessment D412465

Page 12 of 21 Table 5. 3 .2. Summary of Percent Crop Treated Used in the Dietary Exposure Analyses

Commodity Average % CT Maximum %CT

Apple 5 10

Banana 100 100

Peach 1 2.5

Strawberry 20 30

Avocado 100 100



### 5. 3 .3 Acute Dietary Risk Assessment

A refined probabilistic acute dietary exposure assessment was performed using maximum percent crop treated (%CT) provided by BEAD, tolerance, the highest residue found during

field

- trials, distribution of field trial residues, Federal Drug Administration (FDA) monitoring data for apples, and empirical processing factors . Dietary risk estimates were determined considering exposures from food and drinking water using estimated drinking water concentrations (EDWCs) for surface water sources provided by the Environmental Fate and Effects Division (EFED).

The resulting acute dietary risk estimates for food and drinking water are below HED’s level of concern ( i.e. , <100% of the acute population adjusted dose; aPAD of 0.6494 mg/kg bw/day) for the general U.S. population and all population subgroups. Using DEEM

- FCID TM 

### , acute dietary

exposure at the 99.9 th 

### exposure percentile is estimated at 0.0 20104 m g/kg bw/day for the general U.S. population (3.1% of the aPAD) and 0.0 10887 mg/kg bw/day (78% of the aPAD) for

females 13

- 49 years old , the population subgroup with the highest estimated acute dietary exposure to thiram.

### Thiram

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Page 13 of 21 Table 5. 3 .3 Results of Acute Dietary Exposure and Risk Analysis for Thiram (Food + Water )

Population Subgroup aPAD

(mg/kg/day) 95 th Percentile 99 th Percentile 99.9 th Percentile

Exposure (mg/kg/day) %

aPAD Exposure

(mg/kg/day) %

aPAD Exposure

(mg/kg/day) %

aPAD

General U.S. Population 0.6494 0.00 3419 <1 0.00 7029 1. 1 0.0 20104 3.1

All Infants (<1 year old) 0.6494 0.0 10016 1. 5 0.01 6352 2.5 0.0 40956 6.3

Children 1

- 2 years

old 0.6494 0.0 08983 1.4 0.0 24980 3.9 0.0 64254 9.9

Children 3

- 5 years

old 0.6494 0.00 5982 <1 0.0 14708 2.3 0.0 39745 6.1

Children 6

- 12 years old 0.6494 0.00 3733 <1 0.00 8783 1. 4 0.0 21715 3.3

Youth 13

- 19 years

old 0.6494 0.002 718 <1 0.00 4989 <1 0.0 11129 1.7

Adults 20

- 49 years old 0.6494 0.00 3017 <1 0.00 4806 <1 0.0 10891 1.7

Adults 50

- 99 years old 0.6494 0.00 2807 <1 0.00 5012 <1 0.0 11093 1.7

Females 13

- 49 years old 0.014 0.00 3074 22 0.00 5024 36 0.0 10887 78

The values for the highest risk population for each percentile are bolded.



### 5. 3 .4 Chronic Dietary Risk Assessment

A refined chronic dietary

- exposure assessment was performed using tolerance level residues and average estimated % CT. Dietary risk estimates were determined considering exposures from food and drinking water using EDWCs for surface water sources provided by EFED. The resulting chronic dietary risk estimates for food and water combined are below HED’s level of concern ( i.e. , <100% of the chronic population adjusted dose; cPAD of 0.015 mg/kg bw/day) for the general U.S. population and all population subgroups. Using DEE M

- FCID TM 

### , dietary exposure is estimated at 0.00 1384 mg/kg bw/day for the general U.S. population (9.2% of the cPAD) and 0.00 8369 mg/kg bw/day (56% of the cPAD) for children 1

- 2 years old, the population subgroup with the highest estimated chronic dietary ex posure to thiram. The estimated exposures/risks for combined food and water are summarized in Table 5. 3 .4. Additional refinements (i.e. monitoring data for commodities other than apple) could be done but

were not needed at this time.

### Thiram

/079801 Human Health Risk Assessment D412465

Page 14 of 21 Table 5. 3 .4

. Sum mary of Chronic Dietary Exposure and Risk for Thiram (Food + Water )

. Age Group cPAD (mg/kg/day) Exposure (mg/kg/day) % cPAD

General U.S. Population 0.015 0.00 1384 9.2

All Infants (<1 year old) 0.015 0.00 4443 30

Children 1

- 2 years old 0.015 0.00 8369 56

Children 3

- 5 years old 0.015 0.00 4947 33

Children 6

- 12 years old 0.015 0.00 2172 15

Youth 13

- 19 years old 0.015 0.00 0877 5.8

Adults 20

- 49 years old 0.015 0.000 716 4.8

Adults 50

- 99 years old 0.015 0.00 0947 6.3

Females 13

- 49 years old 0.015 0.00 0823 5.5 * The values for the highest exposed population is bolded.



### 5. 3.5 Cancer Dietary Risk Assessment

Thiram is classified as “ Not L ikely to be C arcinogenic to H umans” based on lack of evidence for carcinogenicity in mice or rats ; therefore

, a quan t itative cancer risk assessment is not required (D263948)

.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Thiram is not available for sale or use by homeowner applicators ; therefore, there are no residential handler exposure scenario s applicable to thiram . However, there is potential for

residential post

- application dermal exposure from treated golf course greens and tees.

Res idential exposures resulting from dermal contact with thiram

- treated turf were assessed for

children 6 to <1 1 years old , children 11 to <16 years old, and adults. When use is restricted to greens and tees, the duration of exposure is 1 hour to reflect the anticipated time a player would be spending in contact with those areas. The dermal margins of exposure (MO Es) for the populations assessed ranged from 850 to 1000 and all greatly exceeded the level of concern of

100 (Table 6.0)

. Inhalation post

- application exposures for golf courses were not assessed since

i nhalation exposures are thought to be negligible in outdoor post

- application scenarios.

### Thiram

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Page 15 of 21 Table 6.0

. Residential Post

- Application Dermal Exposure from Treated Golf Course Greens and Tees.

Formulation Lifestage TTR t 2
(ug/cm 2 ) Weight unit

conversion

factor (mg/ug) Transfer

Coefficient 3

(cm 2 /hr) Hours of

Exposure 4
(hr) Exposure 5

(mg/day) Absorbed

Dos e 6
(mg/kg/day) Dermal

MOE 7

Liquids 1 Adult 1.81 0.001 5,300 1 9.6 0.0014 1000

Liquids Children 11 to

<16 years 1.81 0.001 4,400 1 7.8 0.0014 1000

Liquids Children 6 to <11

years old 1.81 0.001 2,900 1 5.3 0.0016 850

1. Liquids is the representative formulation for flowable concentrate formulation.

2. TTRt = AR * F * (1

- F D ) t * CF2 * CF3 where, TTRt = turf transferable residue on day "t" (μg/cm 2 ); AR = application rate ( 16.3 lb ai/acre); F= fraction of ai retained on turf ( 0.01 ); F D = fraction of residue that dissipates daily ( 0.1 ); t= post

- application day on which exposure is being assessed (0); CF2= weight unit conversion factor (4.54 x 10 8 μg/lb); and CF3= area unit convers ion factor ( 2.47 x 10

- 8 acre/cm 2 ).

3. The transfer coefficients used for the “golfer” dermal scenarios were derived using the best available data. In this case, data collected during a golf course maintenance study (Klonne and Bruce, 2005) was considered to provide the best representation of the exposures that might be experienced by golfers. The recommended point estimates for use in post

- application adult, children 11<16 years old, and children 6<11 years old dermal exposure assessment are 5,300; 4,400; a nd 2,900 cm 2 /hr, respectively

4. For a chemical that has a label restriction for greens and tees, a 1 hour exposure calculation is assumed.

5. E xposure (mg/day) = TTRt * CF1 * TC * ET where, TTRt = turf transferable residue on day "t" (μg/cm 2 ); CF1 = weight un it conversion factor (0.001 mg/μg); TC = transfer coefficient (cm 2 /hr); and ET = exposure time ( 1hr/day).

6. Absorbed Dose (mg/kg

- day), where, E= exposure (mg/day); AF= absorption factor ( 0.01 );

and BW = body weight ( 69, 57, and 32 kg for adults, children 11 to <16 yrs and children 6 to <11 yrs, respectively ).

7. MOE = POD ( 1.4 mg/kg/day) / Absorbed Dose (mg/kg/day)

. The level of concern (LOC) is 100.



### 7 .0 Aggregate Exposure/Risk Characterization

7 .1 Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from d ietary consumption of thiram (food and drinking water). The acute dietary risk estimates are not of concern to HED (<100% aPAD) at the 9 9 .9 th 

### exposure percentile for the general U.S. po pulation and all other population subgroups. T he refore, the acute aggregate risk associated with the proposed uses o f thiram is not of concern to HED for the general U.S. population or any population subgroups.

7 .2 Short

- and Intermediate

- Term Aggregate Risk

In aggregating short

- and intermediate

- term risk, the Agency routinely combines background chronic dietary exposure (food + water) with short / intermediate

- term residential exposure (dermal only)

. The combined exposure may then be used to calculate a n MOE for aggregate risk. Using the golfer scenario for adult males, adult females, and children >6 years old , combined

with the applicable subpopulation with the greatest dietary exposure

, the total

### Thiram

/079801 Human Health Risk Assessment D412465

Page 16 of 21 short / i ntermediate

- term foo d and residential aggregate MOEs are 600, 600, and 370

, respectively . As th ese MOE s are greater than 100, the short

- and intermediate

- term aggregate
risk s do not exceed the HED’s LOC. For children <6 years old, there is no residential exposure, therefore, a short/intermedia te term aggregate risk assessment is not required for this population.

Table 7 .2 summarizes the short/intermediate

- term aggregate exposures to thiram

.

Table 7.2 Short

- Term and/or Intermediate Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5



### Adult 6 

### Male 1.4 100 0.01 4 0.00 0947 0.00 14 0.002347 600



### Adult 6 

### Female 1.4 100 0.01 4 0.00 0947 0.00 14 0.002347 600

Children 6 >6 years old 1.4 100 0.014 0.002172 0.0016 0.003772 370

1 The Level of Concern (LOC) is based on the 10X for interspecies extrapolation, 10X for intraspecies variations, and 1X FQPA SF, totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. In this case, only dermal exposure is applicable. S ource of resid ential exposure values used in aggregate assessment (Table 6.0 ).

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure

5

6 Relevant population subgroup with highest exposures (Tables 5.2.4 and 6.0).



### 7.3 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account exposure estimates from d ietary consumption of thiram (food and drinking water). The chro nic dietary risk estimates are not of concern to HED (<100% aPAD) at the 9 9.9 th 

### exposure percentile for the general U.S. population and all other population subgroups. T he refore, the chronic aggregate risk associated with the proposed uses o f thiram is no t of concern to HED for the general U.S. population or any population subgroups.

8.0 Occupational Exposure/Risk Characterization

An updated work er exposure and risk assessment is not required to support the requested label amendment. Since the subject amendment is limited to a change in the PHI, approval of this use does not impact the application rates, number of applications, or seasonal applicat ion rate; therefore, there is no impact on the occupational exposure from the proposed label amendment.

9.0 References

Carleton, J. and Jenkins,F. 12/11/03

. “Environmental Fate and Ecological Effects Assessment and Characterization Chapter for the Thira m Registration Eligibility Decision Document”

### Thiram

/079801 Human Health Risk Assessment D412465

Page 17 of 21 Hummel, S. 6/ 6 /2013. D407356, D407357, D407358, D302803

. Thiram on Strawberry, PP#2F8106. Summary of Analytical Methods and Residue Data

.

Kramer, G. and Greear, W. 06/09/2009. D365442. Thiram in/on Imported Bananas. Revised

Human Health Risk Assessment.

Knizner, S. 05/27/2009. “ Interim Guidance on Tolerance Expressions,” EPA Memorandum

.

Mendez, E. 5/30/2000. D263948. HED DOC No. 014193. Thiram

- Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision Document.

Morton, T. 06/26/2013. D405397. Thiram: Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment to Support a Petition for an Increased Tolerance on Strawberry.

.

Rury, K. 6/30/2013 . TXR No. 0056685

. Thiram: Summary of Hazard and Science Policy Council (HASPOC) Meeting of June 6, 2013: Recommendations on the Need for a 28

- day Inhalation Study and Cholinesterase Assessment Screening Assay.

### Thiram

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Page 18 of 21 A ppendix A

. Toxicity Profiles

Table A.2.1. Acute Toxicity Profile

– Thiram

.

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral (rat) 00163854 LD 50 = 2.6 g/kg III

870.1200 Acute dermal 00259250 LD 50 ≥2.0 g/kg III

870.1300 Acute inhalation (rat) 00165855 LC 50 ≥0.1 mg/L II

870.2400 Primary eye irritation (rabbit) 00259250 Moderate eye

irritant II

870.2500 Primary dermal irritation (rabbit) 00259250 Very slight dermal

irritant IV

870.2600 Dermal sensitization 00153068 Moderate skin

sensitizer N/A

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 40773601 (1988)

Unacceptable/guideline 0, 50, 500

, or 1000 ppm (0, 2.5, 25

, or 50 mg/kg bw/day ) NOAEL = could not be determined due to lack of information on stability.

LOAEL = 25 mg/kg/day, based on decreases in body

- weight gain , hematology and clinical chemistry parameters.

870.3150 90

- Day oral

toxicity (dog) 461503608 (1990)

Acceptable/guideline 0, 75, 250

, or 500 ppm (0, 1.94

- 2.58, 6.17

- 7.85

, or 10.55

- 14.69 mg/kg bw/day) NOAEL = 1.9 mg/kg/day.

LOAEL = 6.3 mg/kg/day, based on adverse changes in clinical chemistry, and decreases in mean body weight and food consumption.

870.3200 21

- Day dermal

toxicity (rabbit) 42642501 (1992)

Acceptable/guideline 0, 250, 500, or 1000 mg/kg bw/day NOAEL = 300 mg/kg/day. LOAEL = 1000 mg/kg/day, based on decreases

in body

- weight gain and food consumption as well as alterations in clinical chemistry.

870.3700a Prenatal

developmental (rat) 00151610 (1978)

Unacceptable/guideline 0, 12.5, 25, 50

, or 100 mg/kg bw Maternal NOAEL = 12.5 mg/kg. LOAEL = 25 mg/kg, based on reduced body

weight gain s and food consumption. Developmental NOAEL could not be

determined.

LOAEL = 12.5 mg/kg, based on reduced

ossification.

870.3700a Prenatal

developmental (rat) 40534101; 41498301

(1988) Acceptable/guideline 0, 7.5, 15

, or 30 mg/kg bw Maternal NOAEL could not be determined.

LOAEL = 7. 5 mg/kg, based on decreases in body

- weight gain , alopecia, scars, damaged digits, red

- stained paws and excessive

salivation. Developmental NOAEL = 7.5 mg/kg.

LOAEL = 15 mg/kg based on retarded growth and rudimentary 13 th rib, and reduced

ossification.

### Thiram

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Page 19 of 21 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700b Prenatal

developmental (rabbit) 40444702(1987)

Acceptable 0, 1, 3, 5, 7.5, 10, 20, 40

, or 80 mg/kg bw (range

- finding) Maternal NOAEL = 3 mg/kg bw/day. LOAEL = 5 mg/kg/day, based on decreased

maternal body

- weight gain s. Developmental NOAEL was not determined.

LOAEL was not determined.

870.3700b Prenatal

developmental (rabbit) 40577301 (1988)

Acceptable 0, 1, 2.5

, or 5mg/kg bw (range

- finding) Maternal NOAEL = 5 mg/kg bw/day.

LOAEL was not determined. Developmental NOAEL = 5 mg/kg.

LOAEL was not determined.

870.3700b Prenatal

developmental (rabbit) 42223601 (1992)

Acceptable 0, 1, 5

, or 10 mg/kg bw Maternal NOAEL = 10 mg/kg bw/day

LOAEL was not determined Developmental NOAEL = 10 mg/kg

LOAEL was not determined.

870.3800 2

- Gen.

reproduction and fertility effects (rat) 42095901 (1991)

Acceptable/guideline 0, 30, 60

, or 180 ppm (F0: 0/0, 1.2/1.9, 2.4/3.9,

or 8.5/11.8 mg/ kg bw/day [M/F]) (F1: 0/0, 1.5/2.0, 3.24.3

, or 9.2/13.4 mg/kg bw/day [M/F] Parental/Systemic NOAEL = 30 ppm (1.9 mg/kg/day [M/F]). LOAEL = 60 ppm (2.6/3.1.7 mg/kg/day [M/F])

based on decreases in body

- weight gain and food consumption.

Reproductive NOAEL was not determined. LOAEL >180 ppm (8.9 mg/kg/day).

Offspring NOAEL = 180 ppm (11.8 mg/kg/day). LOAEL = 60 ppm (3.9 mg/kg/day), based on decreased mean body weight.

870.3800 2

- Gen.

reproduction and fertility effects

(rat) 45441203 (1997)

Acceptable/guideline 0, 20, 60

, or 180 ppm (0, 1.4, 4.2

, or 12.2 mg/kg bw/day) Parental/Systemic NOAEL = 2 0 ppm (1.4 mg/kg/day). LOAEL = 60 ppm (4.7 mg/kg/day) based on

reduced body

- weight gain s during gestation

.

Reproductive NOAEL ≥ 180 ppm (12.2 mg/kg/day).

LOAEL was not determined.

Offspring NOAEL = 20 ppm (1.4 mg/kg/day). LOAEL = 60 ppm (4.2 mg/kg/day), based on decreases in pup body weight and body

- weight gain

.
870.4100 Chronic toxicity (1

year; dog) 41967901 (1991)

Acceptable/guideline 0, 30, 90

, or 250 ppm M; 0, 0.84, 2.61

, or 7.35 mg/kg bw/day F: 0, 0.90, 2.54

, or 7.23 mg/kg bw/day NOAEL (M) = 30 ppm (0.84 mg/kg/day). NOAEL (F) = 90 ppm (2.54 mg/kg/day). LOAEL (M) = 90 ppm (2.61 mg/kg/day, based

on increased mean cholesterol levels. LOAEL (F) = 250 ppm (7.23 mg/kg/day),

based on increased mean cholesterol levels and

increased liver

- to

- body weight ratios.

### Thiram

/079801 Human Health Risk Assessment D412465

Page 20 of 21 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4200 Carcinogenicity

(mouse) 42313401 (1992)

Acceptable/guideline M: 0, 15, 150, or 300 ppm F: 0, 15, 300

, or 600 ppm M: 0, 2.5, 24, and 57 mg/kg bw/day F: 0, 3.1, 57

, and 112 mg/kg bw/day NOAEL = 1 5 ppm (M/F: 2.5/3.1 mg/kg bw/day). LOAEL (M) = 150 ppm (24 mg/kg bw/day. LOAEL (F) = 300 ppm (57 mg/kg/day), based on decreases in mean body weight and mean

bod y

- weight gain , anemia, and non

- neoplastic lesions in the eyes, non

- glandular stomach and urinary bladder.

No evidence of carcinogenicity.

870.4300 Combined chronic

toxicity/ carcinogenicity (rat) 42157601 (1991)

Acceptable/guideline 0, 30, 150, or 300 ppm (0, M: 0, 1.5, 7.3

, and 14.7 mg/kg bw/day F: 0, 1.8, 8.9

, and 18.6 mg/kg bw day NOAEL = 30 ppm (M/F: 1.5/1.8 mg/kg/day).

LOAEL = 15 0 ppm (M/F: 7.3/8.9 mg/kg/day), based on changes in hematology, clinical chemistry, incidences of bile duct hyperplasia

and reduction in mean body

- weight gain

.

No evidence of carcinogenicity.

870.5300 In Vitro

Mammalian Gene Mutation Assay in

V79 Chinese

Hamster Cells at the HPRT Locus) 00160621 (1986)

Acceptable/guideline

0.001

- 56.0 μg/mL (±S9) No evidence of mutagenicity with or without

metabolic activation.

870.5375 In Vitro

Mammalian Cytogenetics (Chromosomal Aberration Assay

in Chinese Hamster Ovary Cells) 40510901 ( 1987)

Acceptable/guideline 0.56, 1.0

, or 2.4 μg/mL (

- S9) 1.8, 5.6

, or 18.0 μg/mL (+S9) Significant dose

- related increases in

chromosomal aberrations with and without metabolic activation. Classified as a clastogen.

870.5395 Mammalian

erythrocyte

micronucleus test 40510902 (1987)

Acceptable/guideline 38, 189, or 377 mg/kg Administration of 38, 189, or 377 mg/kg thiram did not cause a significant increase in the frequency of micronucleated polychromatic erythrocytes (MPEs) harvested from male and

female mice.

870.5550 UDS in Primary

Rat Hepatocytes/Mam

malian Cell 00156064 (1985)

0.03, 0.1, 0.3, 1.0, 3.0

, or 10.0 μg/mL Did not induce DNA repair.

870.6200a Acute neurotoxicity

screening battery 45589101 ( 1993)

Unacceptable/non

guideline 0, 10, 25, 60

, or 150 mg/kg bw NOAEL = 10 mg/kg.

LOAEL = 25 mg/kg, based on decreases in food consumption in males and females.

870.6200a Acute neurotoxicity

screening battery 42912401 ( 1993)

Acceptable/guideline 0, 5 , 150

, or 600 mg/kg

bw BMDL 10 = 64.94 mg/kg

. LOAEL = 150 mg/kg, based on FOB effects at 21/2 hours post

- dosing; reduced motor activity at 31/2 hours, and at 7 and 14 days post

treatment.

### Thiram

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Page 21 of 21 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Thiram

.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.6200b Subchronic

neurotoxicity

– feeding study in

rats 43012701 (1993)

Acceptable/guideline 0, 30, 125 or 500 ppm (0/0, 1.74/2.04, 7.26/8.07, and 28.63/31.82 mg/kg bw/day [M/F]) NOAEL = 30 ppm ( 1.74/2.04 mg/kg/day [M/F])

. LOAEL = 125 ppm ( 7.26/8.07 mg/kg/day [M/F]), based on increased numbers of rearing events and elevated incidences of hyperactivity

in females at weeks 8 a nd 13.

870.6300 DNT 46455201 (2004) Acceptable/guideline 0, 20, 45

, or 90 ppm 0, 1.4, 3.7

, or 7.2 mg/kg bw/day Maternal NOAEL = 45 ppm (3.7 mg/kg/day). LOAEL = 90 ppm (7.2 mg/kg/day), based on decreased body weight, body

- weight gain , and

food consumption, clinical signs of toxicity, and FOB findings

. Offspring NOAEL = 20 ppm (1.4 mg/kg/day. LOAEL = 45 ppm (3.7 mg/kg/day) based on increased locomotor activity in females on

PND17

.

870.7485 Metabolism and

pharmacokinetics (rat) No DERs or MRIDs could

be located Rats (6 male + 6 female) were dosed orally for 14 days with unlabelled thiram at 2 mg/kg bw then with [ 14 C]thiram at 2 mg/kg bw on day 15 (Nomeir and Markham, 1990). Expired air and

excreta were collected for a further 96 hours and then the animals were slaughtered for

tissue collection. Approximately 33

- 35% of

the administered 14 C was eliminated in the

uri ne, 2.6

- 5.3% in the feces and 47

- 48% in the expired air. The nature of the volatile 14 C was not investigated in detail, but 75

- 85% of it was collected in a KOH trap suggesting CO 2 , or COS, with the remainder collected in a reagent

for CS 2 . Norris (1991) identified by HPLC the

metabolites in the urine of the rats from the single dose study of Gay (1987) and the multiple dose study of Nomeir and Markham (1990). There were no sex differences in the metabolism but the proportions of some of the

metabolites d epended on the dosage level and the time after dosing. [www. fao.org /docrep/W5897E/w5897e5a.htm]

870.7800 Immunotoxicity

(mouse) 48646401

Acceptable/guideline

0, 15/17.5, 150, or 450

ppm

(0, 3, 25, 74 mg/kg/day) Systemic NOAEL = 450 ppm (74 mg/kg/day, the highest dose tested). Systemic LOAEL was not established.

Under conditions of this study, the Immunotoxicity NOAEL = 150 ppm (25 ppm) Immunotoxicity LOAEL= 450 ppm (74 mg/kg/day) based on treatment related

decreases in anti

- SRBC antibody response.