### Thir am/ 07980 I Human Health Risk A ssess m e nt 0 42 4590 & 

### 042459 1



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

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM

Date: Fe bru ary 24, 20 1 5



### SUBJECT: Thiram. Human Health Risk Assessment for th e Import Use ofThiram o n Avocado, PP # 4 E8250 and Banana

, PP # 4 E 8268.

PC Cod e: 07 980 1 DP No

. : 04 2 4 590 & 

### 0424591
Decision No.: 488085 & 

### 489958 Regi st ration No

. : NA
Petition No.: PP#4E8250, PP#4E8268 Regulatory Action: Tolerance

, no registrat i on Risk Assessment Ty pe : Single C h e mical

, A ggregate C ase No.: 012 2

TXR No .: NA

. CAS No.: 137- 26-8

MRIDNo.: NA 

### 40CFR: § 18 0.132 

# r

FROM: Thur s t o n G

. Morton,

# ist/Ri**sk** Assessor

# ~ Kell y O ' Rour ke, O RE 

### Yr(.,.**~** 

### Sue Hummel , C hemist Marquea King

, PhD, Toxicologist

Risk Assess m ent Branch IV, H ealt h Ef fects Di vis ion (7509 P ) /



### T HROUGH : E li ssa Reaves

, Branch C hief

# ~~**~----** Risk Assessment Branch IV/H ealt(Effects Division (7509 P)



### TO : Dris s Benmh eno l

Ra c h e l Holl oma n , Br anch Chief Fungic i de Bran c h

, Re g i s tration Division (7505P)



### 1.0 Executive S ummary

Taminco

, Inc.

, submitted petitions p ropos in g tol er an ces for residues ofthiram on banana at 0.8

ppm and avocado at 8.0 ppm , both expressed as thiram. C urrentl y, tolerances for residues of

thiram are expressed as carbon disulfide. No U. S. regi stra tion i s propo se d. An 

### ea rlier p et ition

for residues of thiram on avocado (PP # lE782 3, D405 132, G. Otakie, 9119 / 12) was withdrawn

du e to l ack of sto r age stability data; whic h h ave been i n cl uded in the cu rr e nt submission. An



### earli er pe t iti o n for re sid ue s of thiram o n banan a (6 E 7144

, D36 5 442, G. Kramer

, 6/9/09) r es ulted

in a time-limited to ler ance du e to an inadequat e number of field trials for thiram on banana

,

w hi c h was exte nded in PP # 4E8243, 0418114

, W

. Cutchin

, 2 / 18 / 20 14 ). The r equ i red fi el d trial

dat a have been includ e d in th e cu rrent s ubmi ss ion

. The t o leran ces to b e established are ba se d on th e u se ofth e OECD To l erance Ca lcul a tion Procedures. A diet ary exp os ure assessment h as been

Pa ge 1 

### of20Thiram/07980 I Human Health Risk Assessment 0424590 & 0424591



### conducted for the avocado and banana uses outside the U.S

. (D423339, T. 

### Morton, 12/18114).

There are no residue chemistry issues which will preclude is suance of a toleranc e for residues of

thiram of 0.5 ppm (expressed as CS2) on banana, nor issuance of a tolerance for residues of

thiram of 10 ppm (expressed as CS2) on avocado, with no U.S. registration

. No additional data

are needed.

HED conducted an updated dietary risk assessment to support the requested uses. No dietary

risks of concern were identified. The acute and chronic dietary risk estimates for food and drinking water are below RED's leve l of concern (i.e., <100% of the acute and chronic population adjusted doses (PADs)) for the general U.S

. population and all population subgroups.

The acute dietary exposure at the 95 1 h 

### exposure percentile was 1.9% ofthe aPAD for the general

U .S. population and 62% of the aPAD for females 13-49 years old, the population subgroup with

the highest percent 

### aP AD.Chronic dietary exposure for the general U.S

. population was 13% of

the cP AD and 70% of the cP AD for children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure to thiram. Thiram is classified as "Not Likely to be Carcinogenic to Humans" based on lack of ev idence for carcinogenicity in mice or rats; therefore, a quantitative cancer risk assessment is not required.

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

residen tia l post-application dermal exposure from treated golf course greens and tees. Residential

exposures resulting from dermal contact with t hiram-treated turf were previously assessed for

children 6 to < 11 years old, children 1 1 to <16 years old, and adults. The dermal margins of

exposure (MOEs) for the populations assessed ranged from 850 to 1000, which did not fall

belo w the level of concern of 100. Inhalation post-application exposures for go lf courses were

not assessed since inhalation exposures are thought to be negligible in outdoor post-application

sce narios.

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 drinking water). As referenced above, both the

acute and chronic dietary risk estimates are not of concern to HED ( <1 00% aP AD and cP AD). In aggregating short/intermediate-term risk

, th e Agency routinely combines background chronic dietary exposure (food + water) with short- and intermediate-term residential exposure (dermal only, in the case of this assessment). The combined exposure may then be used to calculate an MO E for aggregate risk. Using the golfer scenario for adult males, adult females, and children >6

years old, combined with the app licable subpopulation with the greatest dietary exposure, the

total short/intermediate-term food and residential aggregate MOEs are 570, 540, and 280, respectively. As these MOEs are greater th an the targ e t LOC of 100, the short- and intermediateterm aggregate risks are not of concern.



### An updated occupational exposure and risk assessment is not required to support the requested import uses

.

Page 2 of20Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 3 of 20 2.0 HED Recommendations

HED concludes that there are no risk issues that would preclude granting a tolerance for residues

of thiram of 0.5 0 ppm (expressed as CS 2 

### ) on banana, nor issuance of a tolerance for residues of thiram of 10 ppm (expressed as CS 2 

### ) on a vocado, with no U. S. registration. No additional data are needed. 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 870.7800) has been resolved. An immunotoxicity study in mice has been submitted (MRID 48646401). The HASPOC determined

that a 28

- day inhalation toxicity study with neurotoxici ty parameters in rats is required. Therefore, a 10X database uncertainty factor will be retained for the inhalation route. An inhalation study is required for any future registration action that involves an updated inhalation assessment. However, the choli nesterase activity screening assay was waived by the HASPOC and is not required at this 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 pro posed 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 origi nal 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 0.50 ppm supports the banana use pattern and a tolerance of 10 ppm supports the avocado import use

. A summary of tolerance recommendations is presented in Table 2.2. 2 . The

recommended tolerance s were derived with the aid of the OECD toleranc e calculation procedure.

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

. T he current thiramThiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 4 of 20 tolerance expression is not in accord with this guidance. The tolerance expression should read:

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

thiram.

The above recommendatio n 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), including 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 conver tible to carbon disulfide , expressed as carbon

disulfide , in or on the commodity.

Table 2.2.2 . Tolerance Summary for Thiram

.

Commodity Proposed Tolerance (ppm thiram) Recommended

Tolerance (ppm

CS 2 ) Comments;

[Correct Commodity Definition]

Banana 0. 8 0.5 0 OECD Tolerance Calculation procedures recommend 0.7 ppm thiram. (The conversion factor is 0.63x, resulting in a recommendation of 0.5 ppm as CS 2 )*

Avocado 8 10 OECD Tolerance Calculation procedures, using the residues found at a 3 day PHI
recommend 15 ppm thiram. (The conversion factor is 0.63x, resulting in a recommendation of 10 ppm as CS 2 ) *A CODEX MRL of 2 ppm as carbon disulfide has been established, based on mancozeb use on banana



### 2.2. 3 Revisions to Petitioned

- For Tolerances

Tolerance proposals for raw agricultural commodities were changed to be based on the OECD Tolerance Calculation Procedures, and to express the residue as carbon disulfide to harmonize with CODEX. A revised Section F is needed with the changes in tolerance expressio n and
tolerance levels.

2.2. 4 International Harmonization

The Codex Alimentarius has established maximum residue limits (MRL), for “total dithiocarbamates, determined and expressed as “ mg carbon disulfide per kg” in banana of 2 mg/kg, from the use of mancozeb on banana. CODEX has not established any MRLs for carbon disulfide from the use of thiram on avocado or banana. U.S. tolerances are currently established
and expressed as carbon disulfide. The tolerance expression is now compatible with CODEX.Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 5 of 20 2.3 Label Recommendations

No label revisions are required.

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 D424590 & D424591



### Page 6 of 20 Table 3. 3. Summary of Directions for Use of Thiram

Applic. Timing; Type; and Equip. Formulation

[EPA Reg. No.] Applic.

Rate, kg ai/ha Max. No.

Applic.

per Season Max.

Seasonal Applic.

Rate (kg ai/ha) PHI

(days) Use Directions and

Limitations

Avocado

Foliar broadcast 80% WDG

[Thiram 80 WG] 2.4 3 7.2 0 Use a 6

- 7 day interval between applications.

Banana

Foliar broadcast 42% SC

[ Banguard 42] 1.26 10 12.6 0 Use a 5

- 7 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.pdf

. 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 pol icy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns 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 Survey/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 cat egorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when

conditions or circumstances warrant. Whenever appropriate, non

- dietary e xposures based on home use of pesticide products and associated risks for adult applicators and 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 that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4 .0 H azard C haracterization a nd 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 the data requirement. The toxicity data base is inadequate

, however, for the inhalation route of exposure. At this time, however, there is no residential inhalation exposure from thiram.Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 7 of 20 The Hazard and Science Policy Council (HASPOC) met on June 6, 2013 to discuss the need for

a 28

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

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 Toxicological Effects

Thiram has been sh own 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 system. In a non

- guideline study publishe d 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 g uideline 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 urinary system are the target organs

fo r 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 susce ptibility 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 “ N ot
L ikely to be C arcinogenic to H uman s ” b ased 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 acute

- 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 apparen t 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 exposu res. There was no evidence of increased susceptibility following in uteroThiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 8 of 20 exposure to rats or rabbits or following pre

- and post natal exposures to rats. There is evidence of quantitative susceptibility in the DNT study. However, t here is low concern for the enhanced susceptibility seen in the DNT study because clear NOAELs/LOAELs were establi shed for the offspring 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 database.

4.2.1 Completeness of the Toxicology Database

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

- day inhalation toxicity study with neurotoxicity parameters in rats is required (TXR No. 0056685)

. Therefore, a 10 X 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 co ncern for the enhanced susceptibility seen in the DNT study because: 1) clear NOAELs/LOAELs were established for the offspring effects; 2) the dose

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

- 49 years old )

. Consequently, there are no residual uncertainties for pre

- and post

- natal toxicity.

4.2.4 Residual Uncertainty in the Exposur e Database

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

- exposure assessment was performed using maximum percent crop treated (%CT) provided by BEAD, tolerance, the highe st 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 av erage estimated % CT. Estimated drinking water

concentrations were used. An updated worker exposure and risk assessment is not required to
support these petitions

.Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 9 of 20 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 To xicological Doses and Endpoints for Thiram for Use in Dietary and Non

Occupational Human Health Risk Assessments.

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, inci dences of bile duct hyperplasia, and

reduction in mean body

- weight gain from the chronic toxicity/carcinogenicity rat study in conjunction with

elevated cholesterol 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/079801 Human Health Risk Assessment D424590 & D424591



### Page 10 of 20 Table 4.3.1 . Summary of To xicological Doses and Endpoints for Thiram for Use in Dietary and Non

Occupational Human Health Risk Assessments.

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 offspri ng 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 of 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

Avocado. Avocado data have been reviewed previously (48342101, D389505, G. Otakie

, 2/2/2012). Three field trials for thiram on avocado were conducted in Michoacan, Mexico. Initially the three trial locations were determined to be a single trial because the trials were conducted close together with few distinguishing characteristics. This decision was later
reconsidered. In the three trials, three foliar applications of the 80% WG formulation of thiram
at a total rate of 6.42

- 6.43 lb ai/A (7.20

- 7.21 kg ai/ha), residues of thiram, determined as CS 2, 

### and expressed as thiram, were 1.1

- 3 .4 ppm (per trial average residue of 2.3 ppm) in/on avocado
whole fruit at a 0

- day PHI. Residues of thiram were below the LOQ (<0.05 ppm) in/on avocado pulp harvested at a 0

- day PHI. A decline study was conducted, but no discernible pattern of
decline wa s seen. Adequate field trial data had already been submitted for avocado. However, the field trials show higher residues at a 3 day PHI than at the 0 day PHI. The data from the 3 day PHI have been entered into the OECD tolerance calculation spreadsheet, which is found in the appendix to this review. This results in a tolerance estimate of 15 ppm expressed as thiram,Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 11 of 20 which requires a 10 ppm tolerance expressed as carbon disulfide.

Banana. Previously submitted data. Banana data were submitted previous ly (MRID 46992301, D372408, G. Kramer, 9/13/2007). Banguard 42 (an SC formulation) was used in the trials. Nine trials were conducted in Columbia (1), Costa Rica (3), Ecuador (3), Honduras (1), and Mexico (1). Ten applications were made at a target rate of 1.26 kg ai/ha, for a total application rate of 12.6 kg ai/ha. Spray oil was used as an adjuvant with the applications. Decline studies were

included with some of the trials. Residues of thiram tended to increase and then decrease with

time.

Banana. New data. The locations for the additional banana field trials will be considered adequate, based on the explanation provided. The banana field trials are considered adequate and support a tolerance for residues of thiram on banana. Higher residues were reported in some, but not all of the field trials at PHIs longer than the proposed PHI of 0 days. The data at the 0 day PHI should be reasonably representative of the residues expected for thiram on banana, so the data from the 0 day PHI were used in th e OECD tolerance calculation procedure, which predicted a tolerance of 0.7 ppm expressed as thiram. This tolerance was then converted to be expressed as ppm carbon disulfide with a 0.63x conversion factor, resulting in a tolerance needed
of 0.5 0 ppm.

5. 2 Water Residue Profile

The Environmental Fate and Effects Division has previously assessed residue s in drinking water from the existing uses of thiram. A new drinking water assessment is not required since requested uses are for import banana and avocad o.

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 monitoring 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 Assessment.

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 environmentThiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 12 of 20 5. 3 Dietary Risk Assessment

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

For the probabilistic acute dietary exposure analysis, field

- trial data were used. Empirical processing factors were also used. In addition, the assessment assumed 100% of the crops were treated with thiram. Avocado pulp residues, and average field trial residues for apples, bananas, peaches and strawberries along with 100% crop treated (CT) were used for the chronic dietary exposure analysis for all crops. Empirical p rocessing factors were also used.

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

Percent crop treated was set at 100% for the acute and chronic dietary exposure analyses.

5. 3 .3 Acute Dietary Risk Assessment

A partially refined probabilistic acute dietary

- exposure assessment was performed using 100% CT, highest residue of field

- trial residue values, distribution of field trial residues, and empirical processing factors . Dietary risk estimates were determined considering exposures from food pl us drinking water using EDWCs for surface water sources provided by EFED.

The acute dietary risk estimates for food and drinking water combined are below HED’s level of concern ( i.e. , <100% of the aPAD of 0.6494 mg/kg bw/day) for the general U.S. popula tion and all population subgroups (including females 13

- 49 years old ; aPAD of 0.014 mg/kg bw/day). Using DEEM

- FCID, acute dietary exposure at the 95 th 

### exposure percentile is estimated at

0.0 12053 mg/kg bw/day for the general U.S. population (1.9% of the a PAD) and 0.0 08637 mg/kg bw/day (62% of the aPAD) for females 13

- 49 years old , the population subgroup with the highest % aPAD dietary exposure to thiram. The estimated exposures/risks for food and drinking water are summarized in Table 5.3.3.

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

Exposure (mg/kg/day) % aPAD

General U.S. Population 0.6494 0. 012053 1.9

All Infants (<1 year old) 0.6494 0. 027189 4.2

Children 1

- 2 years old 0.6494 0.043572 6.7

Children 3

- 5 years old 0.6494 0.0 32295 5.0

Children 6

- 12 years old 0.6494 0.0 18813 2.9

Youth 13

- 19 years old 0.6494 0.0 09850 1.5

Adults 20

- 49 0.6494 0.00 7959 1.2Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 13 of 20 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

Exposure (mg/kg/day) % aPAD
years old

Adults 50

- 99 years old 0.6494 0.00 8760 1.4

Females 13

- 49 years old 0.014 0.008637 62
* The values for the highest risk population for each percentile are bolded.



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

The partially refined chronic dietary risk estimates for food and water combined are below HED’s level of concern ( i.e. , <100% of the cPAD of 0.015 mg/kg bw/day) for the general U.S. population and all population subgroups. Using the DEEM

- FCID software, dietary exposure is

estimated at 0.00 1987 mg/kg bw/day for the general U.S. popul ation (13% of the cPAD) and

0.0 10490 mg/kg bw/day (70% of the cPAD) for children 1

- 2 years old, the population subgroup with the highest estimated chronic dietary exposure to thiram. The estimated exposures/risks for food and drinking water are summarized in Table 5. 3 .4.

Table 5.3.4. Summary 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 1987 13

All Infants (<1 year old) 0.015 0.00 5352 36

Children 1

- 2 years old 0.015 0.0 10490 70

Children 3

- 5 years old 0.015 0.00 6827 46

Children 6

- 12 years old 0.015 0.00 3339 22

Youth 13

- 19 years old 0.015 0.00 1405 9.4

Adults 20

- 49 years old 0.015 0.00 1071 7.1

Adults 50

- 99 years old 0.015 0.00 1412 9.4

Females 13

- 49 years old 0.015 0.00 1179 7.9 * 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

resi dential handler exposure scenarios applicable to thiram . However, there is potential forThiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 14 of 20 residential post

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

Res idential exposures resulting from dermal contact with thiram

- treated turf w ere previously

assessed for children 6 to <11 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 thos e areas. The dermal margins of exposure (MOEs) for the populations assessed ranged from 850 to 1000

, which are above the target MOE of 100 and, therefore, not of concern ( 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.

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 conversion 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 expo sure assessment are 5,300; 4,400; and 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 o n day "t" (μg/cm 2 ); CF1 = weight unit 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.Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 15 of 20 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

concer n to HED (<100% aPAD) at the 95 th 

### exposure percentile for the general U.S. population 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. populat ion 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 an 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 dietar y exposure , the total

short / i ntermediate

- term foo d and residential aggregate MOEs are 570

, 54 0, and 28 0

, respectively . As th ese MOE s are above the target MOE of 100 , the short

- and intermediate

- term aggregate risk s are not of concern

. For children < 6 years old, there is no residential exposure, therefore, a short/intermediate 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/o r 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 1071 0.00 14 0.002 471 570


### Adult 6 

### Female 1.4 100 0.01 4 0.00 1179 0.00 14 0.002 579 540

Children 6 >6 years old 1.4 100 0.014 0.00 3339 0.0016 0.00 4939 28 0

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 t his case, only dermal exposure is applicable. S ource of residential exposure values used in aggregate assessment (Table 6.0 ).

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

5 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]

6 Relevant population subgroup with highest exposures (Tables 5. 3 .4 and 6.0).Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 16 of 20 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 chronic dietary risk estimates are not of concern to HED (<100% c PAD) f or 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 not 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 imported uses

.

9.0 Re ferences

Carleton, J. and Jenkins,F. 12/11/03. “Environmental Fate and Ecological Effects Assessment and Characterization Chapter for the Thiram Registration Eligibility Decision Document”

Hummel, S. 12 / 18 /201 4

. D419341

. Thiram on Avocado, PP#4E8250 and Banana, PP#4E8268. 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 Gu idance 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. 2 / 24 /201 5 . D4 23339

. Thiram: Revised Acute and C hronic Dietary (Food and Drinking Water) Exposure and Risk Assessment to Support a Petition For Conversion of the Time

- Limited Banana Tolerance to Permanent and Import use on Avocado.

Rury, K. 6/30/2013 . TXR No. 0056685 . Thiram: Summary of Hazard and Scie nce Policy Council (HASPOC) Meeting of June 6, 2013: Recommendations on the Need for a 28

- day Inhalation Study and Cholinesterase Assessment Screening Assay.Thiram/079801 Human Health Risk Assessment D424590 & D424591



### Page 17 of 20 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/079801 Human Health Risk Assessment D424590 & D424591



### Page 18 of 20 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), bas ed 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 p up 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 D424590 & D424591



### Page 19 of 20 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 body

- 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/079801 Human Health Risk Assessment D424590 & D424591



### Page 20 of 20 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 and 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 adminis tered 14 C was eliminated in the urine, 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 propo rtions of some of the metabolites depended 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.