Thiram/07980 I Human Health Ri s k Assessment



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , 

### D.C. 20460 OFFIC E OF C HE MICA L SAFETY AND POLL UTI O N PREVE N T I ON 

### MEMORANDUM Date : May 2 1 , 20 1 5 D42738 3



### SUBJECT: T hir a m. Revised Human H ealt h Ri sk Assessment for the Import Use ofThiram on Avocado, PP#4E8250 and Banana , PP#4E8268.
PC Code: 07980 I DP No.: 0 4273 83 Deci s io n No.: 488085 Regi st ra t ion No.: NA Peti t ion No.: PP# 4E8250 Re g ul ator y Actio n : Tol eran ce , n o r eg is tration Ri s k Assess m e n t Type: S in g le Chemical, Aggregate Case No.: 0122 TXR No.: NA CAS No.: 137-26-8 MR ID No.: NA 40CF R: § 180.132 d 

### FROM : Thurston G. Morton , Chemist/Risk Assessor

# '.(;J.:;....-- Kelly O ' Rourke , ORE

### )t.J~ 

### IY/, 

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### Risk Assessment Branch IV , Hea lth Effects Di vision ( 7509P ) / THROUGH: Charles S mith , Branch Chief 

## C_**~** Ri s k Assessment Branch IV/ Health E ffects Division (7509 P )

- TO: Driss B e nmh e nol Rachel Ho ll oman, Branch C hi ef Fung icide Branch , Registration Divi s ion (7505 P) 1.0 Exec u tive S umm ary Taminco , Inc. , s ubmitted petitions proposing tol e rances for residues of thiram on banana at 0.8 ppm and avocado at 8.0 ppm , both expressed as thiram. Currentl y, tolerances for residues of thiram are expressed as ca rb on di s ulfide. No U. S. registration is proposed. A n earlier petition for residue s ofthiram on avocado ( PP# 1E78 23, D405132, G

. Otakie, 9/ 1 9112) was withdrawn due to lack of sto rag e s tab i l ity data ; which hav e been included in the current s ubmi ss ion

. An e arlier petition for resi du es of thiram on banana ( 6E7 l 44 , D365442 , G. Kramer , 

### 6 1 9 1

09) re s ult ed in a time

- limited toleranc e due to an inad eq u ate number of field trials for thiram on banana , which was extended in PP #4E8243, D418114 , W. C utchin , 2118/ 2014). Th e required field trial data ha ve been included in the current submission. T he to lerances to b e established are based on the use of the OECD Tole rance Calcu lati on Proc ed ures . A revised dietary ex p os ure assessment ha s been conducted for the avocado and banan a u ses outside the U.S. ( D4 2 7 3 82 , T. Morton, 5/ 2 1/15) to correct langua ge on what residu es were used in the dietary exposure assessment. Pag e 1 

### of 20Thiram/07980 I Human He alth Ri sk Assessme nt 04 2 7383
There are no residue chemistry issues which will pre clude i ss uan ce of a tol erance for residu es of thiram of 0.5 ppm (expr essed as CS2) o n banana , no r issuance of a tolerance fo r residues of thiram of 10 ppm (ex pressed as CS2) on avocado, with no U .S. r eg istration

. No ad ditiona l d a ta are nee d e d

. H ED co nduct ed a n updated dietary ri sk assess m e nt to s upport the requested uses. No di etary ri sks of conce rn were identified. The acute and chronic dietary risk est imates fo r food and drinking water a re be low H E D 's leve l of concern (i.e., < l 00% of the acute and chronic p o pu lation adju s te d dos es (PADs)) for th e ge neral U.S. population and all population s ub gro up s . The acute dietary exposu re at the 

### 95th exposu re percentile was 

### 1.9% of the a P AD fo r the general U.S. population and 61 % of th e a PAD for females 13-49 years old , the popul a ti on subgro up wit h the hi g he s t percent a PAD. C hronic diet ar y ex po s ure fo r th e general U .S

. popul a tion was 1 3% of the c PAD and 70% of th e cPAD for childr e n 1 -2 years o ld , the popu lat io n s ub g roup with the hi g hes t estimated c hronic d ie tary exposure to thiram . T hiram i s cla ss ified as " Not Likel y to be Carc in oge ni c to Humans " based on lack of evi den ce fo r carc in ogen ic i ty in mice o r rats ; therefore , a quantitative cancer ri s k assessment i s not requi red. Thiram is not avai lable fo r sa le or us e b y homeown e r applicator s; th e refore , the re are no resident ial h a ndl e r ex p osure sce nario s app li cab le to thiram. Ho weve r , there i s potential for reside ntial post-application dermal exp os ure from treated go lf co ur se g reen s and tees. Residential ex po su r es re s ultin g from derma l contact with thiram-treate d turf were pre vio u s ly assessed for children 6 to < I I ye ar s old , children l l to < 16 years o l d , and adu l t s. The d e rma l marg i n s of ex p os ur e (MOEs) for th e pop u latio n s assessed ran ge d from 850 to 

### I 000, which did not 

### fa ll below the level of co nc ern of I 00

. Inh a lation post-application exposures fo r go lf co ur ses were not assessed si nce inhalation ex posures are thought to be negli g ibl e in o utdoor post-application sce narios. HED a l so conducted updated aggregate risk assessme nt s , and no aggregate risks of concern were id en tifi e d. Acu te and chronic aggregate ri sk assessme nt s take int o acco unt exposu r e estimates from dietary co n s umption of thiram (food and drinkin g water). As refe renced above, both the acute and chronic d ietary ri s k est imate s a r e not of concern to HED ( < 100 % aPAD and cPAD). In agg r egati ng s ho rt/intermed iate -term ri sk , the Age ncy rou tinel y combines back ground chronic die t ary exposure (foo d + water) w ith s ho rt- an d inte rm ediate-term residential expos ure (dermal o nl y , in the case of this assess m e nt). T he co mbin ed ex p os ur e ma y then b e u sed to ca lculate an MOE for ag g regate risk

. U s ing the go l fe r sce nario for ad ul t male s , adult females , and chi l dre n 

### > 6 yea rs o ld , combined with th e a pp l icab le s ubpopu lation with th e g reat es t di e tar y expos ur e , the total short/interme diat e-term food and residen tial aggregate MOEs are 570 , 540 , and 280 , respectively. As these MO Es are g reater than the target LOC of l 00 , th e short- and intermediateterm agg regat e ri s ks are not of concern. 

### A n updat e d occ up a tion a l e xpo s ur e a nd ri s k a ssess m e nt i s not r e quired t o s upport th e r eq u este d imp o rt u ses .

Page 2 of 20Thiram/07980 I Human Health Risk Assessment 0427383


### 2 .0 HE D R ec omm e nda t ion s HED concludes that there are no risk issues that wou l d preclude granting a tole rance for residues of thiram of 0

. 50 ppm (expressed as CS2) o n banana , nor issuance of a tolerance for residues of thiram of 10 ppm (expressed as CS 2) on avocado, with no U
. S. reg i stration. No add i t iona l data are needed. Specific tolerance recommendations are d i scussed in section 2.2. 

### 2.1 D a ta D efi ci e nci es Tox icology: 

### No new toxicity data are required to support this petition. A previously identified tox icity data gap with respect to immunotox icity (O PP TS 870.7800) has bee n resolved

. An immunotoxic ity study in mice has been subm itted (M RJD 4864640 1 ). The HASPOC dete rm ined that a 28-day inhalation tox i c i ty study with neurotox icity parameters in rats is required. Therefore, a 1 

### OX database uncertainty factor will be retained for the inhal ation route
. An inhalation study i s required for any future reg i strat ion action that i nvo lves an updated inha lation assessment. However, the cholinesterase activity screening assay was wai ved by th e HASPOC and is not required at this time. 

### Chem istry: None ORE: 

### None 

### 2 .2 Tol e ranc e C on s id e ration s 2 . 2 . 1 E nforcement A nal y tic a l Me th o d A colormetri c analytical method is avai l able to enforce the proposed to l erances. The Pestic i de Analytical Manual (PAM) Vo l. II li sts Method I , II , III , IV , and A for the determination of dithiocarbamate residues in/on plant commodities. These me thods are based on t he decomposition of dithiocarbamates with release of CS2. Using the se method s, the 

### CSi is swept through a trap to remove any H2S and into a reaction tube containing a so l ution of copper acetate and an amine

. A co l ored copper dithiocarbamate complex is formed and its absorbance read as a measure of the original dithiocarbamate. The stated l im i t of detection (LO D ) for Meth od I is 0.5- 4.0 ppm. Thiram may be detectab le using PAM I multiresidue methods without F lorisi l cleanup , but is not detected when Florisil cleanup is used

. 

### 2 .2 .2 Rec o mm e nd e d T ol e ra nc es A tol erance of 0.50 ppm supports the banana use pattern and a to le ran ce of I 0 ppm s upports the avocado import use. A summary of tol eranc e recomme ndati ons is presented in Tab l e 2.2.2. The recommended tolerances were derived with the ai d of the OECD tol erance calc ul ation procedu r e. I n 2009 HED issued guidance on tolerance expressions (S. Knizn er, 2009). The current thiram Page 3 of 20Thiram / 07980 I Human H ealth Ri sk Assessment 0427383


### tolerance express ion is not in acco rd with thi s guidance. T he tolerance exp ression s hould read: To lerances for residues of the fungicide thiram (tetramethyl thiuram disulfide), includin g it s metabolites and degradates , in or o n the commodities are listed in the table below. Compliance with the tolerance levels specified is to be determined by measuring only thiram. The above recommendat ion is an interim solution until tolerances for dithiocarbamates are converted to being expressed as carbon di su lfide. When thi s occurs, the tolerance expression should read: Tolerances are estab li shed fo r r es idu es of fungicide thiram (tetramethyl thiuram disulfide), includin g it s metabolites and degradates , in or on the commodities in the table below. Comp l iance with the tolerance levels specified below i s to be determined by measu rin g only tho se thir am residue s convertible to carbon disulfide , exp ressed as carbon disulfide , in or on the commodity.
Tab le 2.2.2

. Tolerance S umm a r y for Thi ram . Proposed Tolerance Recommended Co mments ; Commodity (pp m thiram ) Tolerance (ppm [Correct Commodity Definition] CS 2) Banana 0.8 0.50 OECD Tol eran ce Calculatio n procedur es recommend 0.7 ppm thiram. (The conversion factor is 0.63x, resultin g in a recommendation of 0.5 ppm as CS 2 )* Avocado 8 10 OEC D Tolerance Ca lculation procedures, using the re sidues found at a 3 day PHI recommend 15 ppm thiram. (The conversion factor i s 0.63x, resulting in a reco mmendation of I0 ppm as CS 2) *A CODEX MRLof2 ppm as carbon disulfide ha s been estab li shed , based on mancozeb use on banana 

### 2.2.3 

### Re v i s i o n s t o Petitioned-For Tolerances Tolerance proposal s for raw agricultural co mm odities were c hanged to be based on the OECD Tolerance Ca lculation Procedures , and to express the residu e as carbon disulfide to harmoni ze with CODEX. A revised Section Fis needed with the change s in to lerance expression and tolerance leve ls. 2.2.4 

### International H a rmoni zat io n The Codex Alimentarius has estab l ished maximum residue l imits (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 estab l ished any MRLs for carbon disulfide from the use of thiram on avocado or banana. U.S. tolerances are curTently established and expressed as carbon disulfide. The tol erance expression is now compatible with CODEX.

Page 4 of 20Thiram/07980 I Human Health Risk Assessment 0427383


### 2.3 Label Recommendations No label revisions are req uired

. 

### 3.0 Introdu ction 3.1 C hemical Identity Thiram is a dimethyl dithiocarbamate fungic ide used to prevent crop damage in the field and to protect harvested crops (apples, peaches , and strawberr i es) from deterioration in storage or transport. It 

### i s also used as a seed protectant (e.g

. , small- seeded vegetabl es, lar ge-seeded vegetables, cereal grains, other seeds, conifero u s seeds, cotton seed, ornamenta l seeds, and soybeans) and as a turf protectant from fungal diseases.

TABL E 3 .1. Test Com pound Nomencl a ture
. Compound Cll3 s I J N s c1-4 H

1 C s N s CH. Common name Thiram IUPAC name tetram ethy lthiuram d is ul!id e CJ\S name tetramethylt hiopcroxydicarbonic diamide CAS registry number 1 37-26

- 8 End -u se products (EPs) used in Banguard 42 PLUS (37.0% ai SC) or Banguard 60 (52.6% ai SC) residue !ield study


### 3.2 Physical/Chemical C haracte ri st ic s TABLE 3.2

. Ph ys icoc hemi ca l Properties o f th e Tec hni ca l Grade of Thiram

. Parameter Value Reference Melting range 142-150°C Rev ised Thiram Product and Density 0.32-0.35 g/ mL Residue C hem is try Chapters Water so lubili ty at 20-25 °C 0.00165 g/ 100 mL for th e RED Document , 12

/ 1 6/ 03. Solvent solubility at 20

- 25 ° C petroleum ether (0.0005 g/100 mL), benzene (4.12 g/ 100 mL), acetone (6 .97 g/ 100 ml). xy l e ne (0.9 1 g/ 100 mL). and methanol (0.184 g/ 1 00 mL) Vapor pressure 1.6-1.8 x I 0 · 5 Torr at 25 ° C Dissociation constant, pK. No t app licable Octano l / water partition coefficient, P ow 39.5-54.1


### 3.3 Pesticide Use Pattern A summary of the proposed end- u se product is presented in T able 3.3.

Page 5 of 20Thiram / 07980 I Hum an Hea lth Ri sk Assessme nt 0427383

Table3.3

. S umm a r y o f Directions for Use ofThiram Max. No. Max. A ppli c. Timin g; Formulation App l ic. App lic

. Seasonal PH I Use Dir ectio n s and Ty p e; a nd Eq uip

. !EPA Reg. No. I Rat e, p e r A pp li e. ( d ays) Limitation s kg a i / ha Seaso n Rate ( kg a i / ha) Avocado 80% WDG Use a 6-7 day interval roliar broadcast [T hiram 80 2.4 3 7.2 0 b e twee n applications. W G) Banana 42%SC Us e a 5- 7 day interval Foliar broadcast 1. 26 10 12 .6 0 between application s . [Banguard 42]


### 3

. 4 

### Co n s id e rati on of E n viro nment a l Ju s tice P o t e ntial areas of env ironm e ntal justice concerns, to th e extent po ss ible , were considered in thi s hum an health ri sk assessmen t , in accordance w ith U.S. Exec uti ve Order 1 2898, "Fe deral Actions to Add ress Environmental Ju s ti ce in Minority Popul at io n s and Low-Income Populations , " ( http ://epa.gov/ co mplianc e/ ej / resources/ policy/exec o rd e r 12898.pdf). As a part of every pe s ticide risk assess m ent, OPP considers a large var ie ty of co n s um e r s ub groups accord in g to well-established procedures. In line with OPP polic y , HED estimates ri s ks to popu lat io n subgro up s from pesticide expos ures th at are based on patterns of th at su bgrou p ' s foo d and water co n su mption , and ac ti v iti es in and around the hom e that in vo l ve pesticide u se in a res id entia l se ttin g. Extensive data o n food conswnption patterns are comp il e d by the U S DA under t he Nati o nal Hea lth and Nutr iti on S urve y / What We Eat in America (NHANES / WW E I A) and are used in pe s ti c id e ri s k assessments for all registered food uses of a pest icide. These data are analyzed and cat ego rized by s ub gro up s based on age and ethnic grou p . Additionally , OPP is ab le to assess dietary ex posure t o s maller , spec ialize d subgroups and ex po s ure assessments are p e r formed wh e n conditions or c ircum stances warrant. Whenever appropriate, non-dietary expos ures b ased o n hom e u se of pesticid e product s and associated risks for adult app li cators and for to ddl e rs , yo uth s , and adults e nterin g or playing o n treated areas postapp l ication are eva lu ated. Furth e r co n s id e rati o n s are c urre ntl y in deve lopment as O PP has committed r eso urces and ex perti se to the deve lopment of specia li ze d software and mod e ls that consider exposu r e to bystanders and farm workers as well as li festy le and traditional di e tary pattern s among s pe c ifi c subgro up s. 4.0 

### Haz a rd C har a cteriz ation and Do se- Respon se Assessment Thi s assessme nt includes a summary of the prior assessme nt ( M e mo, G

. Kramer , 0 365442 , 6/ 9 / 2009). T he toxicity d a tabase fo r thiram is co n si de r ed a dequ ate to su pp ort the curre nt p etition w hich eva lu ates ora l and d e rm al route s of exposure. H E D also n o tes that an immunotoxicit y s tud y has b ee n s ubm itted and s atisfies th e data r equi r e ment. The tox icit y datab ase is inadequ ate, however, for th e inhalation route of exposure. At th i s tim e, how eve r, the re i s no res identi a l inh a lation expos ure from thiram.
Page 6 of 20Thiram/07980 I Human Health Ri s k A ss ess ment D427383



### The Hazard and Science Policy Counc i 

### I (HASPOC) met on June 

### 6, 2013 to discuss the need for a 28-day inh a lation toxicity study with neurotoxicity measurements and a cho line sterase activity screening assay (TXR No. 0056685). Based on a Weight of Evidence approach , the HASPOC concluded that a 28 -d ay inhalation toxicity study with neurotoxicity parameters in rats is required. Therefore , a 

### 1 OX database uncertainty factor is required for all inhalation exposure risk ass e ssments. However , a cholinesterase activity screening assay is not required at this time. 4.1 Summary of Toxicological Effects Thiram has been shown to cause neurotoxicity fo ll owing acute and subchronic exposures. In the acute and subchronic neurotoxicity studies submitted , neurotoxicity is characterized as l ethargy, reduced and/ or tai l 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 bra in weights or in the histopathology of the nervous system. 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 guide line studies submitted to the Agency

. In addition , no adverse effects on the developing fetal nervous system were seen in a ONT study

. The chronic toxicity profile for thiram indicates that the live r , blood , and urinary system are the target organs for this chemical in mice , rats , and dogs. There is no evidence for increased susceptibility following 

### in ut ero e xposures to rats or rabbits and follow ing 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 Htimans " based on lack of evidence for carcinogenicity in mice or rats. There are no mutagenic/ genotoxic concern s w ith th iram. The avai labl e toxicologica l databas e for thiram suggests that this chem ical has a low to moderate acute
- toxicity profile. Thiram is readily absorbed ( via the ora l route) , distributed , extensive ly metabolized and eliminated primarily in the exp ired a ir and urine ofrats following single or repeated oral administrations. Within 24 hours of administration of the compound , a high amount of radioactivity was e liminated as expired air ( 14 

### C0 2, carbamy l su l fide , and carbon disulfide). The parent compound was not detected in the urine. Fecal metabolites were not evaluated due to the low reco very of radioactivity in the fec e s. There is no apparent sex- or dose-related difference in the distribution , metabolism , or excretion of 1 4 

### C-thiram

. Bioaccumulation of 14 

### C-thiram in ti s sues 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 , the FQPA safety factor for thiram is reduced to IX. The recommendation of 1 X is based on the fo ll owing considerations. The toxicological database for thiram is comp lete with acceptab l e neurotoxicity , developmental , and reproductive toxicity studies. Thiram has been shown to cause neurotoxicity fo ll owing acute Page 7 of2 0Thiram/07980 I Human Health Risk Assessment 0427383
and subchronic exposures. T here was no evidence of in creased susceptibility following 

### in ute ro exposure to rats or rabbit s or following pre-a nd post natal exposures to rats. There is evidence of quantitative susce ptibility in the ONT s tud y. However , there is low concern for the enhanced susceptib ility seen in the ONT study because clear NOAELs/LOAELs were established for the offsp r ing effec t s, the dose-response is well defined, and th e dose/ endpoint is used for acute dietary risk for the most se nsitive population (females 13-49 years o ld ). Co n se quently , there are no residual uncertainties for pre- and post-natal toxicity. There are no r es idu a l un certainties in the thiram expos ure databas e. 

### 4 .2.1 Completeness of the Toxicology Database For this petiti on, the toxicolo gy database for assessing sensitivity and susceptibi lity is complete. Ho wever , based on a Weight of Evide n ce approach, the HASPOC concluded that a 28-day inhalati o n toxicity study with neurotoxicity parameters in rats is required (TXR No. 0056685). Therefo re , a 

### 1 OX databa se uncertainty factor i s required for all inhalation exposure risk assessments. A cholinesterase activity screen ing assay is not required at this tim e. 

### 4.2.2 Ev idenc e of Neurotoxicity Although s igns of neurotoxicity were observed jn the databa se for thiram, there are no residual concerns s ince clear NOAELs were established and the POO s are protective of any neurotoxicity. In additi on , no adverse effects on the developing fetal nervou s system were seen in a ONT study

. 

### 4.2.3 Ev id e n ce of Sens itivity/S usceptibility in the Developing or Young Animal There was no evi dence of increased susceptibility following 

### in utero exposure to rats or rabbit s or fo ll owing pre-and post natal exposures to rats. There is ev id e nce of quantitative susceptibility in the O NT study. Off sp rin g effects ( increa sed locomotor activity in females o n PND 17) occurred at a lower dose than maternal effects ( increased numb er of rearing eve nts and e levated incidences of hyperactivity in females at weeks 8 a nd 1 3). T he re i s lo w co n cern fo r the enhanced susceptibi li ty seen in the ONT study because: 1) clear NOAELs/ LOAELs were established for the offspring effects; 

### 2) the dose-response is well defined; 

### 3) behavioral effect of concern were observed only in femal es on o ne evaluation time period; and 

### 4) the NOAEL is u sed for acute dietary risk for the mo st sens iti ve popu lation s ubgroup (fema le s 13-49 years o ld ). Consequently, there are no re s idual unc e rtainties 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 probabilistic acute dietary

- exposure assessment was performed u s ing max imum percent crop treated (%CT) provided by BEAD , tolerance, th e high es t residue found during field-trial s , distribution of field trial r es idue s, Federal Drug Administration (FDA) monitoring data for apples , a nd empirica l p rocessing factors. A re fined chronic d ie tary-expo s ur e assessme nt was performed using tolerances and average est imated %CT. Estimated drinking water concentrations were used. An updated worker exposure and risk assessment is not required to Page 8of20Thiram/07980 I Human Heal th R i sk Assessment 04 27383



### support these petiti ons . 

### 4

. 3 T oxicity En dpoin t a nd Poin t of De p arture Se lection s A s ummary of the most updated toxico logical endpoi nts and doses chosen for the rele va nt expos ure scenarios for human ri sk assessme nt can be found in the 

### 2009 risk assessment (Memo , G. Kramer , 

### 0 365 442 , 6 / 9

/ 2009). The endpoint summ ary table i s includ e d be low

. Ta bl e 4.3.1. S u mmary of Tox ico log i ca l D oses a nd E n d p o in ts for Thir a m fo r U se in Di eta r y a nd No nOcc u patio n a l Hum a n H ea lt h Ri sk A ssess m e n ts.
Ex p o s ur e/ U n ce r ta in ty/ FQ P A R ID, P AD , LOC for Stud y a nd Tox i co log i ca l Sce n ar io Po D SFs R i s k Assess m e n t Effects Acute Acute Neurotoxicity S tud y - Dietary BMDL1 0 = Rat (General 64.94 UF A= !O x Acute RID = 0.6494 MRID 429 12401 P opu lation) mg/kg UFH = IOx m g/kg/day L OA E L = 1 50 mg/kg/ d ay based FQPA S F = I x on FOB effects ( lethargy , lower a PAD = 0.6494 temperature , reduce d s tartl e mg/k g/day response , no tail

-pinch response) , reduced moto r act i v ity , and reduced brain weight s . Acute NOAEL = UF " = !O x De v. Neurotoxicity Study

- Rat Dietary 1 .4 mg/kg UFH = I Ox Acute RID = 0.0 14 MRJD 46455201 (Females FQPA SF = Ix mg/k g/day LO AE L = 3

. 7 mg/kg/ day based 13-49 year s aPAO = 0.0 14 on incr eases in motor ac tivi ty o ld) see n in fema le offspring on mg/kg/day PND 1 7
. Chronic UFA= !O x Chronic RID = 0.015 Co-critical: I ) Combined Dietary UF11 = ! Ox mg/kg/d ay C hronic (A ll FQ PA SF = Ix To xicity/ Ca rcinogen ic ity Study population s ) c PAD = 0.0 1 5 - Rat and 2) C hr on ic Oral mg/kg/day Toxicity-D og NOAEL = LOAEL = 7.3 mg/k g/day based 1. 5 mg/kg o n changes in h ema tol ogy , cl inic a l c he mi stry , in cidences of bile duc t hyperplasia, and reduction in mean body-weight gai n from the chronic t ox ic ity/ carcinogenicity r at study in conjunction wit h eleva ted cholesterol leve ls and incre ased liver we ig hts re p orted in the C hron ic Oral Toxicity Study in Dogs at a LOAE L = 7 .23 mg/kg/day Short- and Intermediate -Tenn No inc ide ntal ora l res id e nti a l ex po sure . In c id e nta l O r a l



### P age 9o f 2 0Thiram/07980 I Hum a n H ealth Risk Assessme n t D427383

Table 4.3. 1. S umm a r y o f Toxi co lo g ical Dos es a nd Endpo in ts fo r Thir a m for U s e in Di etary and NonO ccupationa l Hum a n Health Ri s k Ass ess me nt s . Expo s ur e / Unce rtai nty/ FQPA RID , PAD , LOC for Stud y a nd Toxicological Sc enario PoD SFs Ri s k A ss es s m ent Effect s Short

- Tem1 NOAEL = UFA= IOx R esidential L OC for Dev. Neurotoxici t y Study

- Rar Dermal (I- UF11 = IOx MOE = 100 MRJD 46455201 30 days) 1.4 FQ P A S F = Ix mg/kg/d ay ( D e rm a l-ab so rpt io n Oc c up ati o nal L OC fo r LOAEL = 3.7 m g/kg/day based factor= 1%) MOE = 100 on increases in moto r activi ty seen in female offspring on PND 17. I nt

ermed i ate NOA EL UFA = !Ox R esiden ti al LOC for Dev. Neu rotoxicity Study

- Rat -Te rm = 1 .4 UF11 = IO x MOE = 1 00 MRID 4645520 I De rma l (I to mg/ k

g/day FQ P A S F = Ix LOAEL = 3.7 mg/kg/day based 6 months) (Dermal

- absorption Occupational LOC for on increases in motor activity fac tor = 1%) MOE = 100 seen in female offspri ng on PN D 17. Short- a nd I ntermediate Current assessment does not warran t an inhalation assessment. -Term I nhalation Cance r ( oral , de rm al, "Not Like ly to be Ca r c in oge ni c to Hum a ns" inhalation) Point of Departure (PoD) = A data point or an estimated point tha t is derived from observed dose-response data and used to mark the beginning of extrapolation to determine ri sk associated with lower environmen tally re l evant human exposures. NOAEL = no observed adverse effec t leve l. L OAE L = lowes t obse rved ad ve rse effect l evel. UF = un certa in ty factor. UFA = ext ra po lati o n from an im al to hum an ( intr aspecies). UF H = po tential variati on in sens iti v ity among members of the hu man population (interspec ies). FQPA SF = FQPA Safe ty Factor. PAD = populationadjus tcd dose (a = acute , c =chronic). RfD = reference dose. MOE = marg in of exposure. LOC = level of concern.



### 5.0 Dietary Expos ur e a nd Risk Assess ment 5

. 1 Food Residue Profile Avoca do. Avocado d ata have b ee n r ev iewe d prev io u s ly (4 8 3 4 2 101 , 0 3 89 505, G

. Otaki e, 2/2/2 01 2). Three field tri a ls fo r thiram o n av ocad o we re c onducted in Mich oacan , M ex ico. In i ti a ll y th e thr ee tri al locati ons we re de t e rmi ne d to b e a s in g le tr ia l bec au se t he tri al s we re co nduc t ed close t oge th e r w ith f ew di stinguis hing c haracteristics. This decision was later recons ide re d

. In th e three tria ls, three fo li ar a pp l ica tio n s of th e 80% WG fo rmul a ti on of t hi ram at a t o ta l ra te of6 .4 2 -6.4 3 lb a i/A( ?. 2 0

- 7 .2 1 kg ai / ha), r es idue s o fthiram , d e te rmined as CS2

. and ex presse d as thira m , w e r e l.1 -3.4 ppm (pe r trial average res idu e of 2.3 ppm ) in/o n av o cado who le frui t at a 0- d ay PHI. Resid u es of thi ram we re be l ow the LOQ (<0.05 ppm) in/on avocado pulp harvested at a 0

- day P HI. A decli ne s tud y was co nducted, but no d iscernib le pattern of d ecl ine was see n . A d eq u a t e fi e ld tri al da ta had a lready b ee n s ubmi tted fo r avoca do . H oweve r, the fi e ld tri a ls s how hi g h e r res idue s at a 3 d ay PHI th a n at th e 0 d ay PHI. Th e d ata from th e 3 day PHI h ave bee n e nte red int o th e O EC D to le rance calc ulatio n s pread s hee t , w hi c h i s fo und i n the append ix to thi s rev iew. T hi s resu lt s in a toler ance esti m ate of 15 p pm expresse d as thir am.
Page 10 of 20Thiram/07980 I Hu man Health Risk Assessment 0427383


### which requires a 10 ppm tolerance expressed as carbon disulfide

. Banana
. Previously submitted data. Banana data were submitted previously (MRID 4699230 I , D372408, G. Kramer , 9/13 / 2007). Banguard 42 (an SC formu l ation) was used in the trials

. Nine trials were conducted in Co lumbi a ( 1 ), 

### Costa Rica (3), Ecuador (3) , Honduras (I) , and Mexico (I). Ten app li cations 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 app li cations. Decline studies were included w ith some of the trials

. Residues of thiram tended to increase and then decrease with time

. Banana. New data. The locations for the additiona l banana fie ld trials will be considered adequate , based on the explanation provided. The banana fie ld 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 tria l s at PHis l onger 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 the OECD tolerance calcu l ation 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, resu lting in a to l erance needed of0

. 50 ppm. 5.2 

### Water Residue Profile The Environmental Fate and Effects Division has previously assessed residues 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 avocado. EFED provided estim ated drinking water concentrations (EDWCs) in their memo entitl ed
" Environmental Fate and Ecological Effects Assessment and Characterization Chapter for the Thiram Registration Eligib ili ty 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 (Pest icide 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 0.0478 ppm for acute and 0.0025 ppm for chron ic ) were incorporated in DEEM-FCIDrn into the food categories " water , direct , a ll sources" and " water, indirect , all sources" for the dietary assessments.

Table 5.2. E DW Cs for Use in the Human-Health Ri sk Assessment. An nu a l App Rate SC IGROW PRZM/EXAMS* PRZM/EXAMS* PRZM/EXAMS* ( lbs concentration Acute EEC non-cancer ca n cer chronic Cro p ai/acre/v r) foob) foob) c hroni c EEC foob) EEC fnnb) Turf farm 146.6 0.84 47.8 2.5 2.2 

### * Index Reservoir e nvironment


### Page 11 of2 0Thiram/07980 I Human Health Risk Assessment 04 27383


### 5 .3 Di etary Ri sk Assess m ent 5.3.1 De s cripti o n of Residue Data Used in Dietary Assessment A partially refined probabi li stic acute dietary-exposure assessment was performed using l 00 %CT , average residue of field

- trial residue values for blended commodities , distribution of field trial residues , h i ghest pulp residues, and empirical processing factors. Avocado and banana pulp residues, along w i th average field trial residues for apples , peaches and strawbe rri es and 100 % crop treated (CT) were u sed for the chronic dietary exposure ana lysis for all crops. Empirica l processing factors were also used. 

### 5.3.2 Percent C rop Treated Use d in Di etary Assess m ent Percent crop treated was set at 100 % for the acute and chronic dietary exposure analyses. 

### 5.3.3 Acute Dietary Risk Assess ment A partially refi ned probabilistic acute dietary-exposure assess ment was performed u s in g 100 %CT, average re s idue of field-trial residue values for blended commodities , distribution of field trial residues , highest pu lp re s idues , and empirical processing factors. Dietar y ri s k estimates were determined considering exposures from food plus drinkin g water using E DWCs for surface water sou rc es provided by EFED. Th e acute dietary risk estimates for food and drinking water combined are below HED ' s level of concern (i.e. , < 100% of the aPAD of0.6494 mg/kg bw/ day) for the general U.S. population and all population subgroups (including fema l es 13-49 years old; aPAD of 0.014 mg/kg bw/ day). Us in g DEEM-FC ID , acute dietary exposure at the 95 111 

### exposure percentile is estimated at 0.0 12002 m g/ kg bw / day for the general U.S. population (1.9% of the aPAD) and 0.008595 mg/kg bw / day (6 1 % 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 a r e summari zed in Table 5.3

. 3.

Page 12 of 20Thi r am / 07980 I Hum an Health Ri sk Assessment D427383

T ab le 5 .3.3. R esu lt s of A c ut e Di eta r y Ex p os u r e a n d Ri sk An a l ys is for Thir a m (Foo d + Wat e r ). 95•h P e r ce nti le

Popu l ati o n a PAD Expo s ur e S ubg r oup ( m g/k g/ d ay) ( m g/k g/d ay) %a PAD Gene r a l U.S. Population 0.6494 0.0 12002 1.9 I 

## - All lnfant s 

# I (< I year old) 0.6494 0.027109 4.2 Children 1-2 years old 0.6494 0

. 0 435 0 3 6.7 C hildren 3

- 5 years old 0.6494 0.0 32302 5. 0 C hildren 6- 12 yea r s old 0.6494 0.018667 2.9 Youth 13-19 years old 0.6494 

### ! 0.009851 1.5 Adu lts 20-49 

# I years old 0.6494 0.007907 1.2 Ad ults 50

- 99 yea rs old 0.6494 0.008705 1.3 Females 13- 49 ye ars o ld 0.0 14 0

. 008595 6 1 •T he values for the hi g h es t ri s k popu lat ion for eac h percentile are bolded. 

### 5

. 3 .4 

### C hroni c Di et ary Ri s k Ass e ss m e nt Th e partially refin ed c h ron ic di e tary risk es tim ates for food and water co mbin ed are below H EO's le ve l of co nc e rn (i.e

. , < 100 % of the cPAO of0.0 15 mg/kg b w / day) fo r th e ge neral U.S

. popu lation and all popu lat io n s ubgroups. Usi ng the D EEM -FC ID softwa re , d ie tary ex posure is est imated at 0.00 1 999 mg/kg bw/ day for the general 

### U.S. popu l ation ( 1 3% of the cPAD) and 0.010557 mg/kg bw / day ( 70 % of th e cP A D ) for ch i ld ren 1-2 years o ld , th e pop ul atio n s u bg roup with the highe s t es ti m ated chronic d ietary exposure t o t h iram. The estimated ex po s ures/ risk s for food and drinkin g water a r e s ummarized in Tab l e 5.3.4. T ab le 5.3.4. S umm a r y of C hr o n i c Di etary Ex p os ur e a nd Ri s k fo r Thira m (Food + W a t e r ). Age Group cPAD ( m g/k_g/day) Ex posure ( mg/k _g/da y) %c PAD Ge ne ral U.S. Pooulation 0.015 0.001999 13 A ll Infants ( < l year o ld ) 0.015 0.005387 36 C hildren 1-2 yea r s o ld 0.015 0

. 0105 57 7 0 C hildren 3

- 5 years o ld 0.015 0.006870 46 C hildren 6- 1 2 years o ld 0.015 0.003359 22 Youth 13-19 yea r s old 0.015 0.001413 9.4 Adults 20-49 years old 0.015 0.001077 7.2 Adults 50

- 99 y ears old 0.015 0.001421 9.5 Females 13

-49 years old 0 .01 5 0.001186 7.9 • The va lu es for the highest ex po se d popu lati on is bo ld ed. 

### Page 13 of 20Thiram / 07980 I Hum an Health Ri s k Assessment 0427383



### 5 . 3.5 Ca ncer Di e tary Ri s k Assessment 

### Thiram is class ified as "Not Likely to be Ca r c in ogen ic to Hum ans " based on lack of ev idence for carcinogenicity in mice or rat s; therefore , a quantitativ e cancer risk assess ment is not required 

### (0 2639 48 ). 6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

### Thiram is not available for sale or use by homeowner appl icators; therefore , there are no re s id e nti al handler exposure s cenarios applicable to thiram. Howe ve r, there is potential for re s id ential po s t-application derma l exposure from treated golf cours e greens and tees. Residential exposu res resultin g from derma l contact with thiram-treated turf we r e previou s ly as sesse d for children 6 to < 11 

### years old , c hildren 11 to < 16 years o ld , and adult s. When use is r es tricted to g r ee ns and tee s, the duration of exposu r e is I hour to r e flect the anticipated tim e a pl aye r would be s pending in contact with those area s. T he dermal margins of exposure ( MO Es) for th e populations assessed ranged from 850 to I 000 , wh ich are above the target MOE of 100 and , therefore , not of concern (Tab le 6.0). I nhalation post
- application exposure s for golf cour ses were not a ssesse d since inh alation expo s ures are thou ght to be ne g li g ible in outdoor postapplication sce narios.

Table 6
. 0. Residential P o s t-Appl ication Dermal Exposure from Treated Go l f Course Greens and Tees. Wei g ht unit Tran sfe r H ours of Formulation Life s tage T rR1 2 conve rs ion Coefficic nt3 Ex p osure4 Expo s ure s {ug./c m 2 ) fac t or (c m 21h r ) (hr) {m g./day) (m g/ ug) Liquid s 1 Adu lt 1.81 0.001 5,300 I 9.6 Liquid s C hildre n 11 t o 1.81 0.001 4 ,400 I 7.8 < 16 yea rs Liquid s Childr e n 6 to < 11 1.81 0.001 2,900 I 5.3 yea r s o ld I. Liquids i s the repre sentative formulation for fl owable concentrate formulation. 2. Tl'Rt = AR • F • ( 1- Fo)' • CF2 • CF3 where. ITRt = turf transferable r es idu e on day "t" (μ g/c m 2 ): AR = application rate ( 16.3 lb ai / ac rc ); F = fraction ofa i r etai n ed on turf(0.01): Fo = fraction of r esidue that di ss ipate s d ail y (0. 1 ): t

= po s t-application day o n which ex pos ure i s bein g assesse d (0): CF2 = weight unit conversion fac tor ( 4.54 x I08 μg/lb ): and C F3 = a rea unit conversion factor ( 2.4 7 x I

### o ·8 ac r c/cm2 ). 3. The transfer coefficients used for the ·•golfer

.. dermal scenario s were derived using the best available data. I n this case. data collected during a golf course maintenanc e study ( Klonn e and Bruce. 2005 ) was consi dered to provide the best repre sen tati on of the exposures that mi g ht be ex p erienced by go lfers

. The recommended point estimates for use in post-application ad ult, children 11 < 16 years o ld

. and c hildre n 6 < 1 1 yea rs o ld der mal expos ure ru;sess m c nt are 5 .300; 4.400; and 2.900 cm 2 /hr. re spec tiv e ly 4

. For a chemical that has a label restriction for g r ee ns and t ees. a I hour exposure calc ul atio n i s assu m ed. 5. Exposure (mg/ da y) = ITRt •CF ! •TC• ET where

. · rrnt = turf transferable residue on day "t" (μg/ cm 2 ): CF ! = weight unit conversion factor (0.00 I mg/μg) ; TC = tran sfe r coefficient (c m 2 /h r ): and ET = ex pos ure time ( Ihr /day). 

### E*AF 6. Ab so r bed Dose {m g/

kg ·da y), 

### D 

## = w h

ere, E = exposu r e (mg./da y): AF= absorption factor (0.0 I ): 

### BW and 13\.V = body weight (69. 57. and 32 kg for adu lts . children 11 to < 16 yrs a nd children 6 to < I I y rs, r espectively). 7. MOE = POD ( 1 .4 mg.lkg/day) I Absorbed Dose (mg/k g/day). The level of concern (LOC) is I 00. 

### Page 14 of 20 Absorbed Do sc 6 (m

g/kg/day)
0.0014
0.0014 0.0016 Dermal M

OE7

1000 100 0 850Thiram/079801 Human Health Risk Assessment 0427383


### 7.0 Agg r egat e E xpo su r e /Ri s k C h a r ac t eriz a ti o n 7. 1 Ac ute Agg r egat e Ri s k The acute aggregate risk assessment takes into acco unt exposure estimates from d i etary consumption of thiram (food and dr i nking water). The acute dietary risk estimates are not of concern to HED ( < 100% aPAD) at the 95 1 h exposure percentil e fo r the general U.S

. popu l ation and all other population subgroups. Therefore , the acute aggregate risk associated with the proposed uses of thiram is not of concern to HED fo r the general U.S

. popu l ation or any popu lation subgroups. 

### 7 .2 S h ort
- a nd In te rm ed i at e- Te rm Agg r ega t e Ri s k In aggregating short- and intermediate-term risk , the Agency routinely combines background chronic dietary exposure (food + water) with short/intermediate-term resident ial exposure (dermal on ly)

. The combined exposure may then be used to calculate an MOE for aggregate risk. Using the go l fer scenario for adult males , adult fema les , and ch il dren > 6 years old , combined with the applicab le subpop ul ation 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 above the target MOE of 100, the short- and i ntermediate-tern1 aggregate risks are not of concern. For children 

### <6 years old , there i s no reside n ti al exposure, therefore, a short/intermediate term aggregate risk assessme nt is not required for th is population. Table 7.2 summarizes the short/i ntermed i ate-term agg regate exposures to thiram. 

### Table 7. 2 S ho rt-T erm a nd/ o r Intermediate Term Ag gre gate Ri s k C alculation s S h o rt- or Inte rm e di a t e -Term Sce n a rio Max A ve r age Agg r ega t e Foo d a nd R es ide n t i a l Tota l 

### Population NO A E L Lo e• Allo wa bl e W ate r Ex po su r e Ex p os ure MOE (foo d , mg/kg/d ay Ex p os ure 2 Ex po s ur e m g/ k g/ d ay3 m g/kg/ d ay4 wate r , a nd m g/kg/ d ay m 1?/k 1?/ d av r es id en ti a l ) 5 Adult6 Male 1.4 100 0.014 0.001071 0.0014 0.002471 570 Adult6 Female 1.4 100 0.014 0.001179 0.0014 0.002579 540 Children 6 > 6 1.4 100 0.014 0.003339 0.0016 0.004939 280 y ears old 1 The Le vel of Concern (LOC) is bas ed on the I OX for interspecies e xtrapolation , I OX for intraspec ies variations ,

and IX F QPA SF , totaling 100. 2 Maximum Allowable Exposure (mg/k g/day) = NOAEL/LOC 3 Re s idential Exposure = [Ora l e xpo s ure+ Dermal expo s ure + Inhalation Exposure]. In this case , on ly de rmal expo s ure is applicable. Source of residential exposure values used in aggregate asse s sment (Table 6.0). 4 Total Ex po s ure = Avg Food & Water Exposure + Residential Expo s ure 5 Aggre g ate MOE = [NOAEL I (Avg Food & Water Ex posure + Re s idential Expo s ure)] 6 Relevant population s ubgroup with high e st exposures (Tables 5.3.4 and 6.0).

Page 

### 1 5of 20Thiram / 07980 I H uman Health Risk As sess me nt 0427383


### 7.3 C h ro ni c Agg r egat e Ri s k The chronic aggrega te ri s k assessme n t take s into account exposure est imate s from dietary consumption of thiram (foo d and drinki ng water). T he chronic d ietary ri s k estimates are not o f concern to HED 

### (< 100 % c PA D ) for the gene ral U.S. populatio n and all other population subgroups. T herefore , the chro ni c agg regate r isk assoc iated with the pro p osed uses of thiram is n ot of co ncern to H E D fo r the ge neral U .S. p op u latio n or an y p o pu lation s ub gro up s. 

### 8.0 Occ u pati ona l Expo s ure/Risk C haracte r iza t io n An updated worker exposure and risk assessment is not requ ire d to support the requested i mported u ses . 

### 9
. 0 Refe r en ces Carleton . J
. and J enkins.F. 12 / 11 / 03. "E nvironment al Fate and Ecological Effec ts Assessment and C haracterization Chapter for th e Thi ram Reg i stra ti o n Eligibili ty D ecisio n Document'' Humme l , S. 12/1 8 /2014. 0419 34 1. Th iram on Avocado, PP # 4E8250 and Banan a, PP#4E8 26 8

. Summary of Ana ly ti ca l Method s and Residue Data. Kramer , G.a nd Greear. W. 06/ 09/ 2009

. D365442. Thiram i nio n Imp o rt e d Bananas. Revi se d Human Health Ri s k Assessment. Knizn e r . S. 05/ 27/2009. " Interim Guidance on Tolerance Expressions, " EPA Memorandum

. Me n de z , E. 5/ 30/2000. D263948

. H E D D OC No
. 0 14 193. Thira m - Toxico logy D i sc iplin ary Chapte r for the Re registration Eligib il ity Deci s ion Document. Morton. T. 5/2 1 / 20 15

. 04 27382. Thiram : Revi sed Acute and Chron ic Di e t ary (Fo od and Drinking Water) Exposu re and Risk Assessment to S upp ort a P e tition For Co nve rsio n of the Time-Limited Banana Tolerance to Perman e nt and Import u se on Avocado. Rury , K
. 6 / 30/20 13. T X R No. 0056685

. T h iram: S u mm ary of H azard an d Science P o licy Counci l ( H ASPOC) Meetin g of J une 6 , 2013: Recommendat ions on the Nee d for a 28-day Inhalation Study and C holinesterase Assessment Sc re e ning As say.

Page 1 6 o f 20Thiram/079801 H uman Health Risk Assessment D427383 Appendix A. Toxicity Profiles Tab l e A.2.1. Acute Toxicity Profile

- Thir a m. Guideline No. Study Type MRlD(s) Results Toxicity Category 110 0 Acute oral (rat) 00163854 LD so = 2.6 g/kg Ill 1200 Acute dermal 00259250 LD so**2.0** g/kg 111 1300 Acute inha lat ion (rat) 00165855 LC so**0.1** mg/L II 2400 Primary eye irritation (rabbit) 00259250 Moderate eye II irritant 2500 Primary dermal irritation (rabbit) 00259250 Very sl ig ht dermal IV irritant 2600 Dermal sensitization 00153068 Moderate skin N I A sens iti zer
Table A .2. 2. S ub c hronic and C hronic Toxicity and Genotoxicity Profil e - Thiram. G uid e lin e MRID No. (year)/ No. S tud y T y pe C l assificatio n /Doses Results 870.3100 90-Day oral 4077360 I ( 1988 ) NOAE L = co uld not be determined due to lack t ox icity (rat) Unacceptable/guide line of information on stabi li ty. 0 , 50, 500 , or I 000 ppm LOAEL = 25 mg/kg/day , based on decreases in (0 , 2.5 , 25 , or 50 m g/kg body-weight ga in , hematology and c l inical bw/day) chemistrv oarameters. 870.3150 90

- Day oral 46 1503608 (1990) NOAEL = 1.9 mg/kg/day. toxicity (dog) Acceptable/ guide line LOA EL = 6.3 m g/kg/day , based on adverse 0, 75 , 250, or 500 ppm c han ges in cl ini cal chemistry , and decreases in (0 , 1.94- 2.58 , 6.17-7.85 , mean body weight and food consumption. or 10.55-14.69 mg/kg bw /dav) 870.3200 21-Day dermal 4264250 I ( 19 92) NOAEL = 300 mg/kg/day. toxicity (rabb it) Acceptable /g uidelin e LOAEL = I000 mg/kg/day , based on decreases 0,250 , 500 , or 1000 in body-weight gain and food consumption as mg/kg bw/day well as a ltera ti ons in clinical chemistry. 870.3700a Prenatal 00151610 ( 1978) Maternal NOA EL = 12.5 mg/kg. developmental (rat) Unacceptab le / g uid e lin e LOAEL = 25 mg/kg, based on reduced body

0 , 12.5 , 25, 50, or I00 weight gains and food consumption. mg/kg bw Developmental NOAEL cou ld not be detennined. LOAEL = 12

. 5 m g/kg , based on reduced ossification. 870.3700a Prenatal 40534 101 ;41498301 Maternal NOAE L could not b e determined. deve lopmental (rat) (1988) LOAEL = 7.5 mg/kg , based on decreases in Acceptab le /guide! in e body

- weight gain, alopecia, scars, damaged 0 , 7.5, 15, or 30 mg/kg bw d i g its , red

- stai ned paws and excessive sa liv at ion. Dev e l opmental NOAEL = 7.5 mg/kg. LOAEL = 1 5 mg/kg based on retarded growth and rudimentary 13th rib , and reduced oss i ficat io n. 

### Pag e 17 of 20Thiram/07980 I Human Health Risk Assessment 0427383

Tab l e A.2.2

. S ubchroni c and C hronic Toxicity an d Genotoxicity Profile

- T hir am. Guideline No. Stud y Type 870.3700b Prenatal developmental ( rabbit)

- 870.3700b Prenatal developmental (rabbit) 870.3700b Prenatal developm e nt a l ( r abbit) 870.3800 2-Gen. reproduction and fertility effects (ra t)

>----

870.3800 2 -G en. reproduction and fertility effect s (rat)

>------

8 70.4 1 00 C hronic t oxici t y ( I year ; dog) MRLD No
. (yea r ) / C la ss ification /Doses R es u l ts 40444702( 1 987) Materna l NOAEL 

### = 3 mg/kg bw /day. Acceptabl e LOAE L 

### = 5 mg/kg/day , based on decreased 0, I , 3, 5 , 7.5, 10 , 20, 40, maternal body-wei g ht ga in s . or 80 m g/ kg bw D eve lo pmental NOAEL was not determined. (range-finding) LOAEL was not determined. 4057730 I ( 1988) Materna l NOAEL 

### = 5 mg/kg bw/day. Acceptable LOAEL was not determined. 0 , I , 2.5, or 5mg/kg bw D eve lopm e ntal NOAEL 

### = 5 mg/kg.**ranoe-findin g)** **~**___ ,_

LOAEL was not determtned. 4222360 I ( 1992) Materna l NOA EL = I 0 mg/kg bw/day Acceptable LOA EL was not determined 0, I , 5 , or I 0 m g/kg bw D evelopme ntal NOAEL 

### = I 0 mg/kg L OAEL was not determined. 42095901 ( 1991) Acceptable/ guideline 0, 30, 60 , o r 180 ppm ( FO : 0 1 0, 1. 2/1.9, 2.4/ 3.9, or 8.5111 .8 m g/ kg bw / da y [M/F]) (Fl: 01 0, 1. 5/ 2.0, 3.24.3, or 9.2/ 13.4 mg/kg bw / day [M /F)

4544 1203 ( 1997) Acceptable/guideline 0 , 20, 60 , or 180 ppm (0, 1 .4 , 4.2 , o r 12.2 m g/kg bw/day)

4196790 I ( 199 1) Acceptable/g ui de line 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 ~** 



### Page 18 of2 0 Par e nta l/Sys temi c NOAE L = 30 ppm (1.9 ng/kg/day [M!F]). I OAEL = 60 ppm (2.6 / 3.1.7 mg/kg/day [M / F])

ased on decreases in body-weight gain and ood co n s umption. L b fi R e productive NOA EL was not determined. L OAE L > 180 ppm (8.9 mg/kg/day). Off s pring NOA EL = 180 ppm (I 1.8 n g/kg/day)

. I L OAEL = 60 ppm (3.9 mg/ kg/day) , ba se d o n ecrease d mean body weight. d p a r e ntal/S ys tem ic NOA EL = 20 ppm ( 1.4 mg/k g/day). L r OAEL = 60 ppm (4.7 mg/ kg/ day) based on educed body

- weight gains during gestation. Reproductive NOA**EL ~**  1 80 ppm ( 1 2.2 ng/kg/day). I LOAEL was not determined. Off s prin g NOA EL = 20 ppm ( 1.4 mg/kg/day)

. L

OAE L 

### = 60 ppm (4.2 m g/ kg/day) , based on ec reases in pup body weight and body-weight d ain. g



### ---- NOA EL (M) = 30 ppm (0.84 m g/kg/da y). NOAE L ( F ) = 90 ppm (2.54 mg/kg/day). LOAEL (M) = 90 ppm (2.61 mg/kg/day, based

n increased mean choleste r ol levels. 0 LOAEL ( F ) = 250 ppm (7.23 mg/kg/day) , b ased o n increase d mean c hole stero l levels and II

1cr

case d li ve r-t o-bod weight ratio s. _JThiram / 07980 I Human Health Risk Assessment 0427383

Tab l e A

. 2

. 2

. S ubchronic and C hronic Toxicity an d Genotoxic i ty P r ofile

- Thiram. Guide li ne MRID No. (yea r )/ No. Study Type C la ss ific at io n /Doses Res u lts 870.4200 Carci n ogenicity 4231340 I ( 1992) NOAEL = 15 ppm (M/ F: 2.5/ 3.1 mg/kg (mouse) Acceptable/gu id eline bw / day). M: 0, 15, 150 , or 300 ppm LOAEL (M) = 150 ppm (24 mg/kg bw/ day

. F: 0, 15, 300 , or 600 ppm LOAEL (F) = 300 ppm (57 mg/kg/day) , based M: 0 , 2.5, 24, and 57 on decreases in mean body we i g ht and mean mg/kg bw/day body-weight gain , anem ia, and non -n eoplastic F: 0 , 3. 1 , 57 , and 11 2 lesions in the eyes, non-glandular stomach and mg/kg bw / day urinary bladder. No evidence of carcinogen ic ity. 870.4300 Combined chronic 42157601 (1991) NOAEL = 30 ppm (M/F: 1. 5 / 1 .8 mg/kg/day). toxicity/ Acceptable/ guide l ine LOAEL = 150 ppm (M/ F: 7.3 / 8.9 mg/kg/day) , carc in ogen ic ity 0, 30 , 150 , or 300 ppm (0, based on changes in hematology , cl ini cal (rat) M: 0, 1.5, 7.3 , and 14.7 chemistry, incidences of bile duct hyperp lasia mg/kg bw/day and reduction in mean body-weight ga in

. F: 0, 1.8, 8.9 , and 18.6 mg/kg bw day No evidence of carc ino genicity. 870.5300 Jn Vitro 00160621 (1986) No evidence ofmutagenicity with or without Mammalian Gene Acceptable/guideline metabolic act ivation

. Mutation Assay in 0.001-56.0 μg/ mL (± S9) V79 Chinese Hamster Ce ll s at the HPRT L ocus) 870

. 5375 Jn Vitro 40510901 ( 1987) S i gnificant dose-related increases in Mamma li an Acceptable/ guide lin e chromosoma l aberrations wit h and without Cytogenetics 0.56 , 1 .0 , or 2.4**~1g/mL** metabolic activation

. Classified as a clastogen. (Chromosoma l (

- S9) Aberration Assay 1.8 , 5.6 , or 18.0 μg/ mL i n Chinese Hamster ( + S9) Ovary Cells) 870.5395 Mammalian 40510902 ( 1987) Admi ni stration of38 , 18 9 , o r 377 mg/kg thiram erythrocyte Accep t able / gu ideline did not cause a significant in crease in the micronucleus test 38 , 189 , or 377 mg/ kg frequency of micronucleated polychromatic erythrocytes (MPEs) harvested from male and female mice. 870.5550 UDS in Primary 00156064 (1985) Did not indu ce DNA repair. R

at 0.03 , 0.1, 0.3 , 1.0, 3.0 , or Hepatocytes/ Mam 10.0 μg/mL malian Ce ll 870.6200a Acute neurotoxicity 45589 101 ( 1993) NOA EL = I0 mg/kg. screening battery Unacceptable/ non- LOA EL = 25 mg/kg, based on decreases in guideline food consumption in males and females. 0 , 10 , 25 , 60 , or 150**mg/k~** bw 870.6200a Acute neurotoxicity 4291240 1 ( 1993) BMDL 1 0 = 64

. 94 mg/kg. screening battery Acceptable/ guide! ine LOAEL = 150 mg/kg, based on FOB effects at 0, 5. 150 , or600 1n g/ kg 21 / 2 hours post-dosing; reduced motor act ivity bw at 3 I / 2 hours , and at 7 and 14 days post
treatment. 

### Page 19 of 20Thiram / 07980 I Hum an Health R is k Assessment 0427 383

Tab le A .2.2. S ubchroni c and C hronic To x icit y and Genotoxicity Profile

- Thiram

. G uid e l in e MRID No. (yea r ) / No. S tud y T ype C lass ifi ca ti o n /Doses R es ults 870.6200b Subchronic 430 1 2701 (1993) NOA EL = 30 ppm (1.74/2.04 mg/k g/day neurotoxicity

- Acceptable/guidel in e [M/F]). feeding s tud y in 0, 30 , 125 o r 5 00 ppm LOAEL 

### = 125 ppm (7.26/ 8.07 mg/kg/day rat

s (0 1 0, 1.74 / 2 .04 , 7.26/ 8.07 , [M / F]) , ba se d on increase d numbers of rearin g and 2 8.6 3 / 3 1 .82 m g/kg eve nt s and elevated incidences of hyperac tivi ty bw/d ay rM / Fl) in fema les at weeks 8 and 13.

- 870.6300 ONT 4645520 I (2004) Ma ternal NOAE L = 45 ppm (3.7 mg/k g/day). Acceptable/ g uideline LOA EL = 90 ppm (7.2 mg/kg/day), based on 0 , 20, 45, or 90 ppm decreased body weigh t , body-we i g ht gain, and 0 , 1.4 , 3.7 , o r 7.2 m g/ kg food co n s umption , clini ca l s i g n s of t oxicity, bw / day and FOB find in gs . Off s pring NOA EL = 20 ppm ( 1 .4 mg/kg/day. LOA E L = 45 ppm (3.7 m g/ kg/ day) based on increased locomotor activity in fema les on PNDl7.



## - 8 70.7485 Me t abo li sm a nd No D E Rs or MRIDs could Rats (6 male + 6 female) were dosed orally for pharmacokin e ti cs be locat e d 14 days with unlab e ll e d thiram at 2 m g/kg bw (ra t) then with [ 14 C)thiram at 2 mg/ kg bw on day 1 5 (No m e ir a nd Markh am, 1990). Expired air and excreta we re collected for a further 96 hours and then the animals were slaughtered for tissue collection. A pproxima te ly 33-35 % of th e adm ini s tered 14 C was e li minated in the urin e, 2.6 -5.3 % in th e f eces and 47-48% in th e expired air. The nature of the volati le 14 C was n ot invest igate d in de tail , but 75 -85 % of it was collec t ed in a KOH trap suggesting C02 , or COS, wi th the remainder co ll ected in a reagent for CS 2

. No rri s ( 1991) identified by HP LC the metabolites in the urine of the rats from the s in g l e do se s tud y of Gay ( 1987 ) and th e mu ltipl e dose s tud y ofNomeir and M arkham ( 1990)

. There were n o sex diff e r

e nc es in the m etabol i s m but the proportions of some of th e metabolites d epe nd ed on the dosage level and the t ime after dosing. [www.fao.or& docree/ W5897E/w5897e5a.htmJ

_ 870.7800 lmmunot ox i c it

y 48646401 Sys t e mic NOAEL 

### = 450 ppm (74 mg/kg/day , th e hi g h es t dose te s ted). ( mou se) Acceptable/ gu ideline Sys te mi c LOA EL was n o t es tabli s hed

. 0, 15 / 1 7.5, 1 50. or 450 Under condi tion s of thi s stu dy , the ppm 

# L lmmun otoxicity NOA EL = 150 ppm (25 ppm ) (0, 3, 25 , 74 mg/ kg/day) lmmun o t oxicity LOA EL = 450 ppm (74 mg/kg/day) ba sed on t rea tm ent related d ec reases in anti-SR B C antibody re seo n se.



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