UNITED STATES 

### ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460



### MEMORANDUM

D ate: 9 / 3 / 15



### SUBJECT: Ferbam Scoping Document OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

PC Code: 03480 I

D ec i s i on No.: 506261

Petitio n No. : NA DP Barcode: 427923

Regis t rat i o n No. : 45728-7

Ri sk Assessment Type: Single Chemical Aggregate

TXR No.: NA Regu l a t o r y Act i o n : R e gi s tration Review

Case No.: 2180

CAS No.: 14484-64-1

40 CFR: §180.114 MR ID No. : NA



### FR O M: Jessica Kidwell

, Risk Assessor

### ~~ Kelly O ' Rourke

, Occupational/R idential Expo ure Assessor

## ~""7**<[)~ ~**  Hannah Pope-Varsalona

, PhD

, Toxicolog

Thurston Morton

, Chemist/Dietary Assessor

, Risk Assessment Branch IV

Health Effects Division (7509P)



### TH R OUGH: Charles Smith

, Acting Branch Chief

Risk Assessment Branch IV

Health Effects Division (7509P)



### TO: KJme Nguyen, Risk Manager Reviewer

Thomas Moriarty, 

### RMS I

Risk Management and Implementation Branch 1

Pesticide Reevaluation Division (7508P)

Attached is the Health Effects Division ' s (HED ' s) scoping document for the fungicide ferbam

(also known as ferric dimethy l d i thiocarbamate) for purposes ofregistration review.

Exec u t i ve S u mmary

HED has considered the available risk assessments for ferbam and its toxicity

, exposure and

usage databases

, as well as the most current EPA science and assessment policies. HED

performed thi s evaluation in order to determine the scope of work necessary to support the

estab l ished tolerances and existing registrations dur i ng registration review. The primary sources

of information for thjs evaluation were the most recent comprehensive HED human health risk

assessments (D304864

, D304868

, and D304867) conducted to support the 2005 USEPA

Registration E ligibility Decision (RED) for ferbam (EPA-HQ-OPP-738-R-05

- 009).Ferbam/034801 Scoping Document Final

Page 2 of 39 Ferbam [ferric dimethyldithiocarbamate] is a broad spectrum fungicide registered for treatment

of disease in fruit trees, small fruits

, and berries

. Registered food uses include apple, citrus fruit,

cranberry, mango, nectarine, peach, and pear. It is used to prevent crop damage in the field and is

also applied prior to harvesting in order to prevent fruits from deterioration in storage or

transport. Dietary, drinking water, and occupational exposures are the relevant scenarios for

exposure to ferbam. There are no residential uses of ferbam

.

No guideline studies are available for subchronic dermal toxicity, inhalation toxicity,

reproducti ve toxicity, neurotoxicity, immunotoxicity, mutagenic and carcinogenic effects.

Available toxicity/metabolism studies from the open literature on ferbam were compared with

data for other dimethyldithiocarbamates, primarily ziram and thiram. A comparison of available

rat metabolism data among these dimethyldithiocarbamates suggests that all these compounds

either dissociate or reduce into dimethyldithiocarbamate anions and are metabolized to carbon

disulfide and dimethylamine. The Hazard and Science Policy C ouncil (HASPOC) met on

January 8, 2015 to discuss the need for a ferbam immunotoxicity study and on April 30, 2015 to

discuss the need for several other ferbam toxicity studies ( subchronic dermal toxicity, inhalation

toxicity, reprodu ctive toxicity, neurot oxicity, mutagenic and ca rcinogenic effects). Based on a

Weight of Evidence approach

, which includes the consideration that ziram and thiram both have

complete enough toxicity databases from which missing toxicological information from ferbam’s

toxicity pr ofile can be bridged, waivers were granted for all the aforementioned study

requirements. Based on this bridging decision, the ferbam toxicity database, combined with that

of thiram and ziram, is considered to be complete for risk assessment.

I n the non

- guideline studies submitted for ferbam, the primary target organs appear to be the

nervous system, thyroid, and reproductive system. Strong evidence of peripheral neurotoxic

effects was also reported for ziram and thiram. Two open literature non

- guideline rat two year

chronic toxicity/carcinogenicity studies with ferbam showed no evidence of carcinogenicity.

Ziram was classified as “suggestive of carcinogenicity, but not sufficient to assess human

carcinogenic potential ” with n o quantification of human carc inogenic risk (i.e., a non

- linear RfD

approach is adequate to account for all chronic toxicity, including carcinogenicity )

. Thiram is

classified as “not likely to be carcinogenic to humans.” Based on the bridging data

, the cancer

classifications of thiram and ziram are protective of any potential carcinogenic effects of ferbam.

N o quantification of cancer risk is required for ferbam. Due to the bridging of toxicity studies

from thiram

, in addition to the available ferba m data

, there is little concern for quantitative or

qualitative susceptibility effects for ferbam in rats following in utero pre

- and post natal

exposures. The FQPA safety factor (SF) for ferbam was reduced to 1X.

The current common moiety plant method wo uld likely include all the residues of toxicological

concern. The qualitative nature of the residue in plants and livestock is considere d to be

adequately understood. Ferbam residues convertible to CS 2 are the residue of concern for

tolerance expression an d/or risk assessment in plants, livestock, rotational crops and drinking

water

. Field trial data for apple and grape remain outstanding ( GDCI

- 034801

- 26275). However,

optional bridging studies for ferbam, ziram and thiram on apple and grape could be submit ted.

Tolerances for cherry and grape are established

, however, these uses are not on the label. TheFerbam/034801 Scoping Document Final

Page 3 of 39 registrant has indicated they are not supporting cherry and grape uses. If these uses are not

supported the grape residue field trials will not be required

.

The acute and chronic dietary risk estimates for food and drinking water combined are below

HED’s level of concern (i.e., <100% of the a cute and chronic population adjusted doses (PADs) )

for the general U.S. population and all population subgroups. A new dietary exposure and risk

assessment will be conducted since the endpoints /PODs may be updated to reflect current

policies and significant change s have occurred with the drinking water models since the last

dietary exposure analysis in 2005. New drin king water models are currently being utilized which

were not in use for the 2005 dietary exposure assessment

. In addition

, t he assessment will use the

newest version of DEEM and reflect updated consumption information.

U.S. tolerances are not numerically compatible with Codex or Canadian MRLs. The tolerance

residue levels will be examined during registration review to determine if further harmonization

can be achieved. Tolerances for the dimethyl dithiocarbamates (thiram, ziram

, and ferbam) and

the ethyle nebis

- dithiocarbamates (EBDCs) are being converted to being expressed as carbon

disulfide equivalents, since it is difficult to distinguish among the various pesticides by analytical

methods alone. HED has recommended that all tolerances for dithiocarbamat es, including

ferbam be converted to be expressed as carbon disulfide, so that the tolerance expression will be

compatible with Codex. Ferbam tolerances are in CS 2 equivalents currently, however, the

expression needs updated.

While there are no residentia l uses of ferbam, residential bystander exposures resulting from off

site transport (i.e., spray drift or volatilization) may occur as a result of occupational applications

of ferbam

. The need for spray drift and volatilization risk assessments for ferbam will be

examined during registration review

.

The previous occupational exposure assessment completed for the RED covered all exposure

scenarios relevant to ferbam (Daiss, R, 12/30/2004, D291030 )

. Although no occupational

handler or post

- application risks of concern were identified with use of appropriate personal

protective equipment (PPE)

, a revised assessment of occupational exposure was conducted as a

result of a later submission of a developmental neur otoxicity study (DNT) on thiram

, which

identified post

- application risks of concern ( Daiss, R. 10/11/2005, D304867 ). U pdated

occupational exposure and risk assessments will be necessary as part of registration review to

reflect revised toxicological endpoi nt selection and current HED policy regarding exposure

assessment methodology.

Chemical Use Profile

Ferbam [ferric dimethyldithiocarbamate] is a broad spectrum fungicide registered for treatment

of disease in fruit trees, small fruits and berries

. Registered food uses include apple, citrus fruit,

cranberry, mango, nectarine, peach, and pear. Ferbam is a fine, black, free

- flowing powder

which decomposes at 180 ° C and has a density of 1.36 g/mL at 20 ° C and vapor pressure of <8.6 x

10

- 7 Torr. Ferbam ha s low solubility in water (120 ppm) and is soluble in acetone, acetonitrile,Ferbam/034801 Scoping Document Final

Page 4 of 39 chloroform, and pyridine. Ferbam tends to decompose upon exposure to heat and moisture with

prolonged storage.

The nomenclature and physiochemical properties of ferbam are presen ted in Table 2.1 of

Appendix 2.

Hazard Identification/Toxicology

No guideline studies are available for subchronic dermal toxicity, subchronic inhalation toxicity,

reproductive toxicity, acute and subchronic neurotoxicity, immunotoxicity, or mutagenic or

carcinogenic effects. Available toxicity/metabolism studies from the open literature on ferbam

w ere compared with data for other dimethyldithiocarbamates, primarily ziram and thiram. A

comparison of available rat metabolism data among these dimethyldith iocarbamates suggests

that all these compounds either dissociate or reduce into dimethyldithiocarbamate anions and are

metabolized to carbon disulfide and dimethylamine. The Hazard and Science Policy Council

(HASPOC) met on January 8, 2015 to discuss the n eed for an immunotoxicity study (TXR No.

0057106) and on April 30, 2015 to discuss the need for several studies ( subchronic dermal

toxicity, inhalation toxicity, reproductive toxicity, neurotoxicity, or mutagenic and carcinogenic

effects ) (TXR No. 0055029 ) of ferbam. Based on a Weight of Evidence approach which includes

the consideration that ziram and thiram both have complete enough toxicity databases from

which missing toxicological information from ferbam’s toxicity profile can be bridged, waivers

were granted for all the aforementioned study requirements. Due to this toxicology bridging

decision, the ferbam toxicity database, combined with that of thiram and ziram, is considered to

be complete for risk assessment. The data requirements for ferbam are li sted in Appendix 1,

Table 4.

I n the non

- guideline studies submitted for ferbam, the primary target organs appear to be the

nervous system, thyroid, and reproductive system. Neurotoxic affects were seen in four separate

subchronic and chronic studies i n ra ts and mice where effects included abnormal motor activity,

spinal paralysis, cystic lesions in cerebral cortex and cerebellum, collapsed cranium, decreased

life span and mortality starting at 23 mg/kg/day. Strong evidence of peripheral neurotoxic effects

was also reported for ziram and thiram. In three separate ziram studies, ataxia, salivation,

lacrimation, impaired gait, abnormal posture

, inhibition of brain cholinesterase, brain neurotoxic

esterase, and increased motor activity were identified. Toxicity studies for thiram identified

unusual gait, hind leg abnormalities that developed into paralysis and atrophy of hind legs in

female rats, lethargy, reduced startle response, and no tail pinch response among other altered

activities reported. Thyroid anomalies following ferbam exposure included squamous metaplasia

at 32 mg/kg/day. Reproductive affects were demonstrated in two rat studies and were manifested

as decreased implantations and fetuses, increased reabsorptions, and increased relative testes

weight for males.

Two open literature rat two year chronic toxicity/carcinogenicity studies with ferbam showed n o

evidence of carcinogenicity

. Ziram was classified as “suggestive of carcinogenicity, but not

sufficient to assess human carcinogenic potential” based on the occurrence of benign tumors

(hemangiomas) and preputial gland adenomas in male rats by the Cancer Assessment ReviewFerbam/034801 Scoping Document Final

Page 5 of 39 Committee (CARC) in 2002 (TXR No. 0051541 )

. No quantification of human carcinogenic risk

was determined for ziram b ecause the Agency discerned that using a non

- linear approach (i.e.

RfD) is adequate to account for all chronic toxicity, including carcinogenicity. Thiram, is

classified as “not likely to be carcinogenic to humans.” Based on bridging, the cancer

classifica tions of thiram and ziram are protective of any potential carcinogenic effects of ferbam.

No quantification of cancer risk is required for ferbam.

N o quantitative or qualitative susceptibility is evident in fetuses of ra ts exposed to ferbam in

utero

. The decrease in fetal body weight and developmental anomalies were reported at the same

dose which produced decreased body weight changes, number of implants, and increased

percentage of resorptions and mortality effects in dams. Also, in a three

- generatio n reproductive

toxicity study in rat

, no fetal susceptibility effects were reported, i.e., no fetal as well as maternal

to xic effects at 12.5 mg/kg/day. However, a quantitative susceptibility was evident in a mouse

developmental toxicity study. The develop mental anomalies (increased incidences for thick atrial

wall, thin ventricular wall, hydroureter, hydronephrosis, slight

- or marked

- collapsed cranium,

extraossification of supraoccipitals and malaligned sternebrae) were noticed in mice dosed at 228

mg/kg/ day that produced no maternal toxic effects. Further, in another rat reproduction study a

qualitative susceptibility is evident in pups expos ed to ferbam during lactation. Decreased pup

viability, survival and the reduced pup body weights were reported at a dose which produced

decreases in maternal body weight and food consumption during both gestation and lactation

periods. For thiram, there is no evidence for increased susceptibility following in utero exposures

to rats or rabbits and following pre

- and post

- natal exposures to rats for two generations. There is

low concern for the increased susceptibility seen in the developmental neurotoxicity toxicity

study for thiram since the dose response is well defined and this endpoint is used for assessing

the ac ute dietary risk for ferbam for the most sensitive population

. This endpoint is also

protective of the developmental effects seen in the nonguideline ferbam mouse study and the

offspring effects seen in the ferbam reproduction study

. Due to the bridging of studies from

thiram, there is little concern

, as stated above, for quantitative or qualitative susceptibility effects

for ferbam in rats following in utero pre

- and post natal exposures. The refore, the FQPA safety

factor (SF) for ferbam was reduced to 1X.

In a submitted non

- guideline metabolism study, rats were administered [ 35 S]ferbam via oral

gavage. At the only dose tested (10 ml/kg), absorption was quantifiable but incomplete in the

gastrointesti nal tract. At the latest time point analyzed, 24 h, the highest absorption levels were

recorded. Sixty

- one percent of radioactivity had been absorbed via the gastrointestinal tract, of

which 17% was excreted in the feces, 23% in the urine, 18% in expired a ir, 2% in the brain, and

1% in bile (Hodgson et al., 1975). The same study showed that [ 14 C]ferbam administered via

oral gavage crossed the placenta of pregnant rats, was secreted into the milk of lactating rats,

absorbed by the pups, and excreted in the urine of the pups (Hodgson et al., 1975). None of the

dithiocarbamates appear to accumulate in tissue (Liesivuori and Savolainen, 19 94).

In the scientific literature, dithiocarbamates block the conversion of dopamine to epinephrine and

norepinephrine cau sing the inhibition of catecholamine neurotransmitter synthesis in humans

. Transmission of nerve impulses involving norepinephrine are involved in the regulation of

gonadotropin releasing hormone (GnRH), responsible for release of follicle

- stimulating horm oneFerbam/034801 Scoping Document Final

Page 6 of 39 and luteinizing hormone (LH) (reviewed in Cecconi et al., 2007). Dimethyldithiocarbamates

have been shown to dissociate from their metal particles and possess chelating properties. As

chelators, these compounds have the potential to interact and interf ere with sulfhydryls and

macromolecules (Fishbein, 1976 and Miller, 1982). A disruptive role for dithiocarbamates has

also been identified in the nitric oxide synthase (reviewed in Cecconi et al., 2007).

The acute, subchronic, and chronic toxicity profile tables for ferbam

, thiram and ziram are

included in Appendix 1, Table s 1 and 2. Toxicity endpoints, points of departure (PODs), and

uncertainty/safety factors (UF/SFs) were selected for oral, dermal, and inhalation exposure

pathways for the Human H ealth Risk Assessment conducted in 2005 (D304864), and these are

shown in Appendix 1, Table 3. It should be noted that t hiram toxicity studies were selected for

all of the ferbam endpoints. The toxicological doses/endpoints selected for ferbam risk

assessm ent have not been changed since the Reregistration Eligibility Documents (RED) in 2005

(D304864) with the exception of two endpoints, the acute dietary (females 13

- 49 years old) and

short and intermediate

- term dermal. There was a revised assessment of diet ary and occupational

exposure as a result of submission of a developmental neurotoxicity study (DNT) on thiram

(D304867). The DNT NOAEL of 1.4 mg/kg/day was selected for the acute reference dose for

women of reproductive age and for short and intermediate term dermal as it protective against

neurotoxic effect seen in offspring at 3.7 mg/kg/day. The point of departure selected for these

populations is conservative and is expected to be protective against the susceptibility seen in the

thiram DNT study and th e ferbam mouse developmental and 2

- generation reproduction rat

studies

.

Conclusions: The toxicity database for ferbam is considered complete for risk assessment when

bridged with ziram and thiram. The HASPOC determined that a subchronic dermal study, 28

- day

inhalation study, chronic toxicity / carcinog enicity study, mutagenicity battery, acute and

subchronic neurotoxicity stud ies

, and immunotoxicity study are not required at this time based

on the consideration that the ferbam toxicity database will be bridged with that of thiram and

ziram. During registration review, the endpoints and safety factors for risk assessment will be

updated to reflect current policies.

Residue Chemistry

HED has use d available ferbam

- specific meta bolism studies as well as ziram and thiram

metabolism studies to satisfy the ferbam plant metabolism requirements for two crops and to

characterize ferbam for risk assessment purposes. The metabolism and toxicity data support

translation of ziram and thira m field trial data for dietary exposure assessment. A number of lines

of evidence suggest that the dithiocarbamate fungicides are largely interconvertible and

toxicologically equivalent to each other. Strong support for the equivalence of ferbam and thiram

comes from a series of environmental fate studies that indicate that ferbam in dilute aqueous

solutions ( ≤ 50 ppm) is rapidly converted (half

- lives of minutes) to thiram and the anion of

dimethyldithiocarbamic acid (DCC). Other fate studies also show that ziram is also converted to

thiram and DCC anion, and thiram itself forms DCC anion over time. Furthermore, based on the

ziram grape and thiram apple metabolism studies, the current common moiety plant method (i.e.,

everything converted to CS 2 ) would likel y include the residues of the metabolites ofFerbam/034801 Scoping Document Final

Page 7 of 39 toxicological concern. The qualitative nature of the residue in plants is considered to be

adequately understood. Ferbam residues convertible to CS 2 are the residue of concern for

tolerance expression and/or ris k assessment in plants, livestock, and rotational crops. These

same residues of concern are the residues of concern in drinking water for risk assessment.

Given the similar use patterns and environmental fate profile for ferbam, ziram and thiram, HED

will translate field trial data for all fruit crop groups from ziram and/or thiram to ferbam provided

that three acceptable bridging studies in diverse geograph ical locations for each commodity (with

two side

- by

- side field trials each using ferbam, ziram and thiram at identical application rates

and methods, PHI’s, etc.) are submitted for apple, peach and grape; and those studies indicate

residues are comparable for the different fungicides. Acceptable bridging studies have been

submitted for peach. Field trial data for apple and grape remain outstanding ( GDCI

- 034801

- 26275). However, optional bridging studies for ferbam, ziram and thiram on apple and grape

could b e submitted. Tolerances for cherry and grape are established however, these uses are not

on the label. The registrant has indicated they are not supporting cherry and grape uses. If these

uses are not supported the grape residue field trials will not be r equired.

Enforcement Method

A colorimetric analytical method is available to enforce the proposed tolerances. The Pesticide

Analytical Manual (PAM) Vol. II lists Method I, II, III, IV, and A for the determination of

dithiocarbamate residues in/on pla nt commodities. These methods are based on the

decomposition of dithiocarbamates with release of CS 2 . Using these methods, the CS 2 is swept

through a trap to remove any H 2 S and into a reaction tube containing a solution of copper acetate

and an amine. A colored copper dithiocarbamate complex is formed and its absorbance read as a

measure of the original dithiocarbamate. The stated limit of detection (LOD) for Method I is 0.5

- 4.0 ppm. Ferbam is only partially recovered using FDA multiresidue m ethods.

D ietary Exposure and Risk

The most recent dietary (food and water) exposure assessment was conducted in 2005 ( R . Daiss,

3/3/ 2005

, D 291049

, ) and the revised dietary and drinking water assessment (R, Daiss,

10/11/2005

, D304867, ) usi ng the Dietary Exposure Evaluation Model (DEEM

- FCID  , Version

2.03), and the Lifeline Model Version 2.0 which use food consumption data from the USDA’s

Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998. Tier II

estimated drinking water concentratio ns used in the analyses were calculated by EFED using the

PRZM/EXAMS surface water model (J. Melendez, 8/19/04

, D293028 ).

A refined probabilistic acute dietary

- exposure assessment was performed using maximum

percent crop treated, average field

- trial res idue values for blended commodities, distribution of

field trial residues, and empirical processing factors. For the chronic dietary exposure analysis,

average field trial residues and average percent crop treated (CT) were used. Empirical

proc essing fac tors were also used. Dietary risk estimates were determined considering exposures

from food plus drinking water using EDWCs for surface water sources provided by EFED.Ferbam/034801 Scoping Document Final

Page 8 of 39 The acute dietary risk estimates for food and drinking water combined are below HED’s level of

concern (i.e., <100% of the aPAD) for the general U.S. population and all population subgroups.

Using DEEM

- FCID, acute dietary exposure at the 99.9 th exposure percentile is estimated at

0.0075 mg/kg bw/day for the general U.S. population (15% of the aPAD) and 0.2090 mg/kg

bw/day (42% of the aPAD) for children 1

- 2 years old, the population subgroup with the highest

% aPAD dietary exposure to ferbam. The revised DEEM model acute dietary exposure estimate

for the population subgroup females 13

- 49 ye ars old is 44% of the aPAD.

The 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 DE EM

- FCID software, dietary exposure is estimated at

0.0001 mg/kg bw/day for the general U.S. population (<1% of the cPAD) and 0.0002 mg/kg

bw/day (<1% of the cPAD) for children 1

- 2 years old, the population subgroup with the highest

estimated chronic dietar y exposure to ferbam.

Conclusions for Residue Chemistry, Enforcement Method, and Dietary Exposure and Risk : Field

trial data for apple and grape remain outstanding ( GDCI

- 034801

- 26275). However, optional

bridging studies for ferbam, ziram and thiram on apple and grape could be submitted. Tolerances

for cherry and grape are established however, these uses are not on the label. The registrant has

indicated they are not supporting cherry and grape uses. If these uses are not supported

, the grape

residue fi eld trials will not be required. A new dietary exposure and risk assessment will need to

be conducted if there are changes to the ferbam toxicological endpoints/ PODs or UFs or

significant changes to the EDWCs. The assessment, if conducted, will use the new est version of

DEEM and reflect updated consumption information.

Residential Exposure

The re are no registered residential uses for ferbam ; therefore, a residential exposure assessment

is not needed for registration review.

Residential bystander exposur es resulting from off

- site transport (e.g., spray drift or

volatilization) may occur as a result of applications of ferbam

. The potential for spray drift will

be quantitatively evaluated for each pesticide during the Registration Review process which

ensures that all uses for that pesticide will be considered concurrently. The approach is outlined

in the revised (2012) Standa rd Operating Procedures for Residential Risk Assessment (SOPs)

–

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of

Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to

drift

. In terms of volatilization, the Agency has developed a Volatilization Screening Tool and a

subsequent Volatilization Screening Analysis

( http://www.regulations.gov/#!d ocketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific

inhalation toxicological studies) or further analysis is required for ferbam

.Ferbam/034801 Scoping Document Final

Page 9 of 39 Conclusions: There are no residential uses registered for ferbam ; therefore, a residential

exposure a ssessment is not necessary during registration review. The need for spray drift and

volatilization risk assessment for ferbam will be examined during registration revi ew

.

Aggregate Risk Assessment

I n accordance with the Food Quality Protection Act ( FQPA )

, H ED must consider and aggregate

pesticide exposures and risks from three major sources: food, drinking water, and residential

exposures. The aggregate risk assessment evaluates the combined risk from dietary exposure

(food and water) and any non

- occupational (residential) uses

. However, since there are no

residential uses for ferbam

, the ferbam aggregate risk assessment includes only dietary exposure

(food an d water). See dietary exposure assessment discussed above.

Occupational Exposure

Occupational handler and post

- application exposures are expected based on the registered

agricultural uses of ferbam

. Ferbam is currently formulated as a water dispersible granule. The

application rates range from 2. 7 lb ai/A to 4. 6 lb ai/A, and may be applied via chemigation

, groundboom, air blast sprayer, and mechanically

- pressur ized hand wand ; aerial application is

prohibited

. Occupational exposure scenarios applicable to ferbam range from short

- term (1 to 30

days) to intermediate

- term (30 days to six months) duration

.

The occupational handler assessments indicate that

, for the currently registered uses, all o f the

potential exposure scenarios result in dermal and inhalation margins of exposure ( MOEs) greater

than or equal to the LOC of 100 with baseline clothing attire consisting of long pants, long

sleeved shirt and shoes plus socks

. The current label require s the addition of gloves and a

respirator for airblast application

.

Several levels of post

- application exposure activities have been evaluated, ranging from “low

exposure ” activities such as weeding and scouting in immature plants to very high exposure

activities such as harvesting or thinning fruit from trees. Adequate d islodgeable foliar residue

(DFR) data for ziram, which has a similar chemical structure and properties, are available for

apples and grapes. These data wer e used to assess all scenarios ; additional DFR data are not

needed at this time. Although t he short

- and intermediate

- term post

- application assessment

conducted for the RED indicate d that MOEs reach the LOC of 100 on the day of application

, a

revised assessment was conducted as a result of a later submission of a DNT study on thiram

, which identified post

- application risks of concern ( Daiss, R. 10/11/2005, D304867)

. The

restricted entry interval (REI) on the current label is 24 hours.

Conclusions : The occupational exposure datab ase is adequate to support the registration r eview

of ferbam

. A new occupational exposure and risk assessment will need to be conducted if there

are changes to the ferbam toxicological PODs or UFs or significant changes to current policies

and exposure assessmen t methodology.Ferbam/034801 Scoping Document Final

Page 10 of 39 Public Health and Pesticide Epidemiology Data

For this evaluation, both the OPP Incident Data System (IDS) and the Centers for Disease

Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH)

Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) d atabases were

consulted for pesticide incident data on the active ingredient ferbam ( Recore, S. and Evans, E.

7/9/2015

, D427982 )

. The purpose of the database search is to identify potential patterns in the

frequency and severity of the health effects attri buted to ferbam exposure. There were no

incidents reported in the IDS involving ferbam. A review of SENSOR

- Pesticides 1998

- 2011

identifies 19 cases, stemming from 15 events , involving ferbam. Of these, nine cases are single

a

. i

. , one case was a self

- harm a ttempt by ingestion and was removed from th e analysis. Of the

eight remaining single a

. i

. cases, four cases were moderate in severity and four cases were low in

severity. Ferbam is not included in the Agricultural Health Study (AHS).

Conclusions: Based on the low (or no) frequency and severity of incident cases reported for

ferbam to both IDS and SENSOR

- Pesticides, there does not appear to be a concern at this time

that would warrant further investigation. The Agency will continue to monitor the incident

information and if a concern is triggered, additional analysis will be included in the risk

assessment.

Tolerance Assessment and International Harmonization

U.S. permanent tolerances are established under 40 CFR § 180.114 for the registered uses of

ferbam in/on a number of commodities. Codex, Mexican, and Canadian maximum residue limits

(MRLs) for residues of ferbam have been established for some of the same commodities which

have tolerances in the United States. Mexico adopts U.S. tolerances and/or Codex MRLs for its

export purposes. While residue definitions are compatible with Codex, and expressed as carbon

disulfide, some U.S. tolerances are not numerically compatible with Codex or Canadian MRLs.

The current tolerance residue levels will need to be ree valuated once the additional field trial

data are submitted. International harmonization will also be considered at the same time. See

Appendix 2, Table 2. 2

.

The tolerance expression for ferbam has been reviewed and should be updated as follows based

on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09). The tolerance

expression should read: Tolerances are established for residues of the fungicide ferbam ( ferric

dimethyldithiocarbamate ), 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 ferbam residues convertible to carbon disulfide, expressed as carbon

disulfide, in or on the commodity.

A copy of the International Residue Limit Status (IRLS) sheet is attached to this memorandum.Ferbam/034801 Scoping Document Final

Page 11 of 39 Table 1 . Tolerance Summary for Ferbam.

Commodity Current Tolerance (ppm CS 2 )

Apple 4.0

Cherry 4.0

Cranberry 4.0

Fruit, citrus, group 10 4.0

Grape 4.0

Nectarine 4.0

Peach 4.0

Pear 4.0

Mango 4.0

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 Lo w

- Income

Populations," http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order

_12898.pdf

. The Office of Pesticide Programs (OPP) typically considers the highest potential

exposures from the legal use of a pesticide when conducting human health risk assessments,

including, but not limited to, people who obtain drinking water from sources near agricultural

areas, the variability of d iets within the U.S., and people who may be exposed when harvesting

crops. Should these high exposures indicate potential risks of concern, OPP will further refine

the risk assessments to ensure that the risk estimates are based on the best available infor mation.

Cumulative Risk Assessment

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of

chemicals sharing a common mechanism of toxicity. At a September 2001 meeting of the

Federal Insecticide, Fungicide, and Ro denticide Act (FIFRA) Scientific Advisory Panel (SAP) it

was determined that there was insufficient evidence to suggest that f erbam shares a common

mechanism of toxicity with other chemical substances (dithiocarbamates). The basis for this

conclusion is de scribed in detail in the HED document, “The Determination of Whether

Dithiocarbamate Pesticides Share a Common Mechanism of Toxicity” (12/1/2001). The

document can be found on EPA’s website

at http://www.epa.gov/oppsrrd1/cumulative/dithiocarb.pdf

.Ferbam/034801 Scoping Document Final

Page 12 of 39 Human Studies

The 2005 RED and supporting risk assessment s relied in part on data from studies in which adult

human subjects were intentionally exposed to a pesticide or other chemical

. These data, which

include studies from Pesticide Handler Exposure Database (PHED) 1.1; the Agricultural Handler

Exposure Task Force (AHETF) database; and the Agricultural Reentry Exposure Task Force

(ARTF) database, ar e (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that

review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics

review may have included review by the Human Studies Review Boar d. Descriptions of data

sources, as well as guidance on the ir use, can be found at the Agency website 1

.

Risk Assessment Updates and Data Deficiencie s

• Additional f ield trial data for apple and grape were required in the DCI ( GDCI

- 034801

- 26275)

, unless acceptable bridging studies for ferbam, ziram and thiram on apple and

grape are submitted and ferbam labels are amended to match the use patterns in the field

studies. HED will translate field trial data for all fruit crop groups from ziram and/or

thiram to ferbam, provided three acceptable bridging studies in dive rse locations (with

two side

- by

- side field trials each using ferbam, ziram, and thiram at identical application

rates and methods, PHIs, etc) are submitted for apple and grape; and indicate that

residues are comparable for the different fungicides and furt hermore that the use

directions for ferbam are revised to be the same as the use on the proposed translated

data. The bridging study would not be required to use all three fungicides for all three

crop groups if the registrant does not propose to transla te from both ziram and thiram to

ferbam for any individual crop group. Tolerances for cherry and grape are established

however, these uses are not on the label. The registrant has indicated they are not

supporting cherry and grape uses. If these uses are not supported the grape residue field

trials will not be required.

• Updated exposure and risk assessments will be conducted if there are any significant

changes to ferbam toxicological endpoints, points of departure, Food Quality Protection

Act safety factor or other uncertainty factors, standard operating procedures, or exposure

data models or assumptions.

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and

http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.htmlFerbam/034801 Scoping Document Final

Page 13 of 39 Ref erences

Banijamali, A.; Gay, M.; Kehoe, D. et al. (1990) Elimination and Distribution of Thiram

Following Nine Week Sub

- Chronic Administration in Rats (Multiple Dose Treatment): Lab

Project Number: 87114: 8850: 8850

- 1. Unpublished study prepared by Hazlet on Labs, Inc.;

Uniroyal Chem., Inc. and Analytical Dev. Corp. 151 p. (also MRID 42235702).

Cecconi S., Paro R., Rossi G., Macchiarelli G. (2007) The effects of the endocrine disruptors

dithiocarbamates on the mammalian ovary with particular regard to manc ozeb. Current

Pharmaceutical Design , 13, 2989

- 3004.

Daiss, R. 12/30/2004. D291030.Occupational Exposure Assessment and Recommendations for

the Reregistration Eligibility Decision (RED) for Ferbam.

Daiss, B. 3/3/2005. D291049. Revised Ferbam Acute and Chronic Dietary Exposure

Assessments for the Reregistration Eligibility Decision

.

Daiss, R. 4/19/2005. D304864. Revised Ferbam HED Risk Assessment for Reregistration

Eligibility Document (RED). B. Daiss.

Daiss, R. 10/11/2005. D304867. Revise d Addendum to the Risk Assessment Recommendations

for the Reregistration Eligibility Decision (RED) for Ferbam.

Fishbein L. (1976) Environmental health aspects of fungicides. Dithiocarbamates. J. Toxicol.

Environ. Health , 1, 713

- 735.

Haworth, S., Lawlor, T, Mortelmans, K, Speck, W & Zeiger, E. (1983) Salmonella mutagenicity

test results for 250 chemicals. Environ. Mutagenesis , Suppl. 1,3

- 142

Hodge, H.C.; Maynard, E.A.; Downs, W.; et al. (1952) Acute and short

- term oral toxicity tests of

ferric dimethyldithiocarbamate (ferbam) and zinc dimethyldithiocarbamate (ziram). J

. Amer

. Pharm

. Ass

. , Scientific Ed. XLI(12): 662

- 665. Also i n unpublished submission received Dec 25,

1962 under PP0393; submitted by E.I. du Pont de Nemours & Co., Inc., Wilmington, Del.;

CDL:090425

- B) ( a lso MRID 00083232)

.

Hodge, H.C.; Maynard, E.A.; Downs, W.L.; et al. (1956) Chronic oral toxicity of ferric

dimethyldithiocarbamate (ferbam) and zinc dimethyldithiocarbamate (ziram). J. Pharm.

Experim. Thera

. 118(2):174

- 1 81. (Also i n unpublished submission received Dec 25, 1962 under

PP0393; submitted by E.I. du Pont de Nemours & Co., Inc., Wilmington, Del.; CDL: 090425

- A)

( a lso MRID 00083231).

Hodgson, J.R., Hoch, J.C., Cassles, T.R., Helion, D.O., and Lee, C.C. (1975) M etabolism and

disposition of ferbam in the rat. Toxicol. Appl. Pharmacol. , 33

, 505

- 513.Ferbam/034801 Scoping Document Final

Page 14 of 39 Kidwell, J. 2/6/2003. TXR No. 0051541. Ziram: Second Report of the Cancer Assessment

Review Committee.

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

Lee C., Russel J., Minor J. (1978) Oral toxicity of ferric di

- methyl dithiocarbamate (ferbam) and

tetramethylthiuram disulfide (thiram) in rodents. J. Toxicol. Environ. Health , 4, 93

- 106 ( a lso

MRID 00143817).

Leshin, J. 4/30/2015. TXR No. 0057106

. Ziram and Ferbam: 4 Summary of Hazard and Science

Policy Council (HASPOC). Recommendations on the Requirement of an Immunotoxicity Study.

Leshin, J

. 8/14/2015

, TXR No. 0055029 Ferbam: Summary of Ha zard and Science Policy

Council (HASPOC) Meeting of April 30, 2015: Recommendations on the Need for a

Subchronic Dermal, 28

- day Inhalation, Chronic Toxicity/Carcinogenicity, Mutagenicity, and

Acute and Subchronic Neurotoxicity Studies.

Liesivuori, J. and Savolainen, K. (1994) Dithiocarbamates. Toxicology , 91, 37

- 42

McGregor, D.B., Brown, A, Cattanach, P., Edwards, L, McBride, Do, Riach, C. & Caspaiy, WJ.

(1988) Responses of the L5178Y tk+ /tk

- mouse Iymphoma cell forward mutation assay: III. 72

coded chemicals. Environ. M ol. Mutagenesis , 12, 85

- 154

Miller D.B., (1982) Neurotoxicity of the pesticidal carbamates. Neurobehavioral Toxicology and

Teratology , 4, 779

- 787.

Otakie, G. December 16, 1999; HED Metabolism Assessment Review Committee ad hoc Meeting

of 12/09/ 99. Ziram/Ferbam Metabolism. Chemical Nos. 034805 and 034801. Barcodes D261844

and D261846.

Otakie, G. 3/3/2005. D291050. Revis ed Ferbam Residue Chemistry Considerations for

Reregistration Eligibility Decision.

Otakie, G. 3/24/2011. D384363. Thiram Spotrete F Fungicide (EPA Reg. No. 45728

- 26)

Amendment to Add Use on Peaches; and Reregistration Data

- Magnitude of the Residue of

Ferbam, Thiram, and Ziram in Peaches

- Dithiocarbamate Fungicide Formulation Bridging Study.

Occupational Exposure Assessment and Recommendations for the Reregistration Eligibility

Decision (RED) for Ferbam. R. Diass. 12/30/2004. D291030.

Recore, S. and Evans, E. 7/9/2015. D427982. Ferbam: Tier I (Scoping) Review of Human

Incidents and Epidemiology.Ferbam/034801 Scoping Document Final

Page 15 of 39 Short, R.; Russel, J.; Minor, J.; et al. (1976) Developmental toxicity of ferric

dimethyldithiocarbamate and bis(dimethylthiocarbamoyl)disulfide in rats and mice. Toxicol.

Appl. Pharmacol.

, 35:83

- 94 (a lso MRID 00143816)

.

U. S. EPA. September 2005. Reregistration Eligibility Decision for

Ferbam. http://www.regulation.gov/ ID: EPA

- HQ

- OPP

- 738

- R

- 05

- 009Ferbam/034801 Scoping Document Final

Page 16 of 39 

### Appendix 1Ferbam/034801 Scoping Document Final

Page 17 of 39 Table 1. Acute Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID Results MRID Results MRID Results

870.1100 Acute

Oral 40561501 LD 50 > 5000mg/kg

(m/f)

Category IV 41340401 a

42429301 b

43701301 a LD 50 =320 mg/kg (M&F)

LD 50 = 381 mg/kg (M)

LD 50 = 267 mg/kg (F)

Category II

LD 50 >2000 mg/kg (M&F)

Category III

LD 50 =2068 mg/kg (M&F)

LD 50 = 2719 mg/kg (M)

LD 50 = 2060 mg/kg (F)

Category III 00153548 LD 50 =2.6 g/kg

Category III

870.1200 Acute

Dermal 40561502 LD 50 >4000 mg/kg

(m/f)

Category III 41340402 a LD 50 > 2000 mg/kg (M &

F)

Category III 00147099 LD 50 ≥ 2.0 g/kg

Category III

870.1300 Acute

Inhalation 41508101 LC 50 = 0.4 mg/L,

Category II 41442001 a LC 50 =0.07 mg/L (M&F)

LC 50 =0.08 mg/L (M)

LC 50 = 0.06 mg/L (F)

Category II 00152556 LC 50 ≥ 0.1 mg/L

Category II

870.2400

Primary Eye

Irritation 40561503 Slight eye irritant

Category III 41643001 a

41454401 b Severe irritation

Category I

Severe irritation

Category I 00147100 Moderate eye irritant

Category II

870.2500

Primary Skin

Irritation 40561505 Very slight to slight

dermal irritant

Category IV 41643002 a

41454602 b Not a dermal irritant

Category IV

Not a dermal irritant

Category IV 00147101 Very slight dermal irritant

Category IV

870.2600 Dermal

Sensitization 40561504 Weak dermal

sensitizer 41643003 a Moderate dermal sensitizer;

30% sensitization rate 00153068 Moderate dermal sensitize

a Technical b 76% formulationFerbam/034801 Scoping Document Final

Page 18 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

870.3100 90

- day

Oral Toxicity

(rodent) MRID 00143817

(Lee et al., 1978)

Acceptable/Non

guideline

0, 23, 66, 109, 331

mg/kg/day (m)

13 weeks/CD Rats NOAEL = 23 mg/kg/day

LOAEL = 66 mg/kg/day

based on decreased body

weight gain and food

consumption

At 109 and 331 mg/kg/day,

increased mortality (30%

between 3 rd and 5 th week

for109 mg/kg/day and

100% in less than 1 week

for 331 mg/kg/day),

histopathological changes

(golden pigmentation of

reticulo endothelial cells)

in spleen and mesentric

lymph nodes were seen. 42450301 (1992)

Acceptable/guideline

0, 100, 300, 1000

ppm

M: 0, 7.4, 21.4, 67.8

mg/kg/day

F: 0, 8.8, 24.2, 76.9

m g/kg/day

(Rat) NOAEL = M: 7.4,

F: 8.8 mg/kg/day

LOAEL = M: 21.4,

F: 24.2 mg/kg/day

based on decreases

in body weight,

body weight gain,

food consumption,

and minimal

histopathological

changes in the

female liver 40773601 (1988)

Unacceptable/guideli

ne

0, 50 , 500, or 1000

ppm

(0, 2.5, 25, or 50

mg/kg bw/day)

Rat 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

(nonrodent) N/A (requirement fulfilled by subchronic dog

study; see Special Studies) N/A (requirement fulfilled by chronic dog

study) 41503608 (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)

(dog) 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 Waived 41297001 (1989)

Acceptable/guideline

M&F: 0, 100, 300,

1000 mg/kg

(Rabbit) NOAEL = M:

>1000, F: 300

mg/kg

LOAEL = F: 1000

mg/kg based on

decreased body

weight and food

consumption and

clinical chemistry

suggestive of

minimal

hepatotoxicity. A 42642501 (1992)

Acceptable/guideline

0, 250, 500, or 1000

mg/kg bw/day

(rabbit) 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.Ferbam/034801 Scoping Document Final

Page 19 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

LOAEL was not

observed in m ales.

870.3250 90

- day

dermal Waived N/A N/A

870.3465 90/28

- day

Inhalation Waived 47628201 (2001)

[28

- day inhalation

nose only study]

Acceptable/guideline

0.095, 0.318, 1.153,

2.898 μg/L NOAEL = 0.095

μg/L

LOAEL = 0.318

μg/L based on

changes in the

larynx

characterized by

squamous

metaplasia of the

ventrolateral

epithelium,

hyperplasia of the

ventral epithelium,

necrosis of the

ventral cartilage

and subepithelial

inflammatory

infiltration Study required and has been called in.

870.3700a

Developmental Toxicity

(rodent) MRID 00143816

(Short et al., 1976)

Acceptable/Non

guideline

0, 11, 114

mg/kg/day

GD 6

- 15

(rat) Maternal NOAEL = 11

mg/kg/day

LOAEL = 114 mg/kg/day

based on 25% mortality,

decreased body weight

gain of dams, decreased

number. of implants/dam,

fetuses/dam, and

increased. number of

resorptions

Developmental NOAEL =

11 mg/kg/day

LOAEL = 114 mg/kg/day

based on decreased fetal

body weight, 41908701 (1990)

Acceptable/guideline

F: 0, 1, 4, 16, 64

mg/kg/day

(Rat) Maternal NOAEL

= 4 mg/kg/day

LOAEL = 16

mg/kg/day based on

decreased body

weights, reduced

food consumption,

salivation, and

increased water

intake.

Devel opmental

NOAEL = 4

mg/kg/day

LOAEL = 16

mg/kg/day based 00151610 (1978)

Unacceptable/guideli

ne

0, 12.5, 25, 50, or

100 mg/kg bw

(Rat)

40534101; 41498301

(1988)

Acceptable/guideline Maternal NOAEL =

12.5 mg/kg.

LOAEL = 25 mg/kg,

based on reduced body

weight gains and food

consumption.

Developmental NOAEL

could not be

determined.

LOAEL = 12.5 mg/kg,

based on reduced

ossification.

Maternal NOAEL

could not be

determined.Ferbam/034801 Scoping Document Final

Page 20 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

MRID 00143816

(Short et al., 1976)

Acceptable/Non

guideline

0, 23, 228

mg/kg/day

GD 6

- 14

(Mouse) increased incidences of

developmental anomalies

(HDT vs Controls:

unossified sternebrae

20/31 vs 9/76, slightly

collapsed cranium

- 7/31 vs

0/76, malformed cranium

2/35 vs 0/90 ,

hydrocephalus 2/35 vs

0/90, he matoma

- 2/73 vs

0/180 and cleft palate

- 1/35

vs 0/90) were observed

Maternal NOAEL = 228

mg/kg/day

LOAEL = None

Developmental NOAEL

= 23 mg/kg/day

LOAEL = 228 mg/kg/day

based on increased no. of

developmental anomalies

(HDT vs Controls): thick

atrial wall (5/ 88 vs 0/100),

thin ventricular wall (8/88

vs 0/100), hydroureter

(13/88 vs 1/100),

hydronephrosis (26/88 vs

21/100), slight

- (6/96 vs

0/107) or marked

- (1/96 vs

0/107) collapsed cranium ,

extraossification of

supraoccipitals (37/96 vs

16/107) and malaligned

sternebrae (13/96 vs

6/107). diaphragmatic

thinning 0, 7.5, 15, or 30

mg/kg bw

(Rat) 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.Ferbam/034801 Scoping Document Final

Page 21 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

870.3700b

Developmental

Toxicity (nonrodent) N/A 00161316 (1986)

Acceptable/guideline

F: 0, 3, 7.5, 15

mg/kg/day

(Rabbit) Maternal NOAEL

= 3 mg/kg/day

LOAEL = 7.5

mg/kg/day based on

decreased body

weight gain.

Developmenta l

NOAEL = 7.5

mg/kg/day

LOAEL = 15

mg/kg/day based on

increased incidence

of resorptions and

post

- implantation

loss. 40444702(1987)

Acceptable

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

40, or 80 mg/kg bw

(range

- finding)

(Rabbit)

40577301 (1987)

Acceptable

0, 1, 2.5, or 5mg/kg

bw

(range

- finding)

(Rabbit)

42223601 (1992)

Acceptable

0, 1, 5, or 10 mg/kg

bw

(Rabbit) Maternal NOAEL = 3

mg/kg bw/day.

LOAEL = 5 mg/kg/day,

based on decreased

maternal body

- weight

gains.

Developmental

NOAEL was not

determined.

LOAEL was not

determined.

Maternal NOAEL = 5

mg/kg bw/day.

LOAEL was not

determined.

Developmental

NOAEL = 5 mg/kg.

LOAEL was not

determined.

Maternal NOAEL = 10

mg/kg bw/day

LOAEL was not

determined

Developmental

NOAEL = 10 mg/kg

LOAEL was not

determined.

870.3800

Reproduction MRID 00143816

(Short et al., 1976)

Acceptable/Non

guideline

0, 23, 66,109

mg/kg/day

13 weeks

treatment to males

during premating

(Rat) Systemic NOAEL ( Males )

= 23 mg/kg/day

LOAEL = 66 mg/kg/day

based on decreased body

weight and food

consumption. At HDT,

30% mortality between 2 nd

and 6th week of treatment,

decrea sed body weight and 43935801 (1996)

Acceptable/guideline

0,72, 207, 540 ppm

F 0 males: 0, 5.3,

14.8, 37.5

mg/kg/day

F 0 females: 0, 6.1,

16.8, 42.8

mg/kg/day Parental/Systemic

NOAEL = 14.8

mg/kg/day

LOAEL = 37.5

mg/kg/day based on

reduced body

weights, body

weights gains, and

food consumption 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.Ferbam/034801 Scoping Document Final

Page 22 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

MRID 00143816

(Short et al., 1976)

Acceptable/Non

guideline

0, 15, 51

mg/kg/day

14 days treatment

to females prior to

mating

(Rat)

MRID 00143816

(Short et al., 1976)

Acceptable/Non

guideline

0, 7.6, 41

mg/kg/day (before

birth)

0, 23, 152

mg/kg/day (after

birth)

GD 16 through

PND 21 food consumption were

observed.

Reproductive NOAEL

( Males ) = 109 mg/kg/day

LOAEL = None

Offspring NOAEL = 109

mg/kg/day

LOAEL = None

Systemic NOAEL

( Females ) =None

LOAEL = 15 mg/kg/day

based on decreased food

consumption.

At HDT, decreased body

weight and food

consumption were noticed.

Reproductive NOAEL

( Females ) = 51

mg/kg/day

LOAEL= None

Offspring NOAEL = 51

mg/kg/day

LOAEL = None

Systemic NOAEL

( Females )= 7.6 mg/kg/day

LOAEL = 41 mg/kg/day

based on decreased body

weight and food

consumption in dams

Reproductive

NOAEL( Females ) = N/A

LOAEL = N/A

Offspring NOAEL = 23

mg/kg/day F 1 males: 0, 5.6,

16.7, 42.7

mg/kg/day

F 1 females: 0, 6.3,

18.4, 47.5

mg/kg/day

(rat) in the F 0 and F 1

males and females.

Offspring NOAEL

= 16.8 mg/kg/day

LOAEL = 42.8

mg/kg/day based on

decreased body

weig hts at birth in

F 2 pups and during

lactation in F 1 and

F 2 pups. (rat)

45441203 (1997)

Acceptable/guideline

0, 20, 60, or 180 ppm

(0, 1.4, 4.2, or 12.2

mg/kg bw/day)

(rat) Reproductive NOAEL

was not determined.

LOAEL >180 ppm (8.9

mg/kg/day).

Offspring NOAEL =

180 ppm (11.8

mg/kg/day).

LOAEL = 60 ppm (3.9

mg/kg/day), based on

decreased mean body

weight.

Parental/Systemic

NOAEL = 20 ppm (1.4

mg/kg/day).

LOAEL = 60 ppm (4.7

mg/kg/day) based on

reduced body

- weight

gains during gestation

. Reproductive NOAEL

≥ 180 ppm (12.2

mg/kg/day).

LOAEL was not

determined.

Offspring NOAEL =

20 ppm (1.4

mg/kg/day).

LOAEL = 60 ppm (4.2

mg/kg/day), based on

decreases in pup body

we ight and body

- weight

gain.Ferbam/034801 Scoping Document Final

Page 23 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

(Rat)

MRID 00085454

(Sherman, 1966)

Acceptable/Non

guideline

0, 12.5 mg/kg/day

(m/f)

3 months

treatment during

each generation

(F0, F1, F2)

(Rat) LOAEL = 152 mg/kg/day

based on reduced viability,

lactation indices, and

reduced body weight of the

pups.

Note: Cross feeding

studies indicate reversal

ef

fects. Control pups

nursed by dams in HDT

had poor viability and

growth. Pups from HDT

nursed by control dams

had good viability and

normal body weight.

Systemic NOAEL= None

LOAEL = None

Reproductive NOAEL =

12.5 mg/kg/day

LOAEL = None

Offspring NOAEL = 12.5

mg/kg/day

LOAEL = None

870.4100a Chronic

Toxicity (rodent) MRID 00083231

(1956)

Acceptable/Non

Guideline

0, 1.25, 12.5, 125

mg/kg/day

2 years

ai not specified

(Ex

- Wistar Rats) NOAEL = 12.5 mg/kg/day

LOAEL = 125 mg/kg/day

based on decreased body

weight gain, 100%

mortality, decreased life

span (430 days vs 600

- 700

days) abnormal hindleg

grasping action at 2 or

more months postdosing

and cystic lesions in the 43404201 (1994)

Acceptab le/guideline

0, 60, 180, 540 ppm

M: 0, 2.5, 7.7, 23.7

mg/kg/day

F: 0, 3.4, 10.2, 34.6

mg/kg/day

(CD

- rat)

NTP (1983)

Acceptable/guideline NOAEL = not

established

LOAEL = M: 2.5,

F: 3.4 mg/kg/day

based on

histopathological

findings in various

organs.

NOAEL = M: 22,

F: 26 mg/kg/day N/AFerbam/034801 Scoping Document Final

Page 24 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

MRID 00143817

(Lee et al., 1978)

Acceptable/Non

guideline

0, 8, 32, 80

mg/kg/day (m)

0, 9, 37, 96

mg/kg/day (f)

(CD Rats) cerebral cortex and

cerebellum.

Note: testicular atroph y

was present in mid and

high dose groups, however

not dose dependent.

NOAEL = 8 mg/kg/day

LOAEL = 32 mg/kg/day

based on decreased body

weight, food consumption,

increased relative spleen

weight in both males and

females and increased

relative testes weig ht and

histological changes such

as increased incidence of

squamous metaplasia in

thyroid, and/or severity of

fatty infiltration in the

pancreas in males.

At 96 mg/kg/day, ataxia

which included an unusual

gait, spreading of the hind

limbs and dragging of t he

hind feet was noticed in

1/24 females and partial

paralysis of caudal to the

lumbar region of the spine

during 52

- 53 weeks was

noticed in 2/24 females.

HDT group had increased

relative thyroid weight in

both males and females. 0, 300, or 600 ppm

M: 0, 11, or 22

mg/kg/day

F: 0, 13,or 26

mg/kg/day

(F344 rat)

45770201 (1983)

Acceptable/guideline

0, 20, 200, or 2,000

ppm

M: 0, 0.70, 6.9, or 74

mg/kg/day

F: 0, 0.83, 8.5, or 91

mg/kg/day

(F344 rat) based on lack of

effect.

LOAEL = M: >22,

F: >26 mg/kg/day

NOAEL = M: 0.70,

F:0.83 mg/kg/day

LOAEL = M: 6.9,

F: 8.5 mg/kg/day

based on slight

anemia in females,

decreases in the

absolute and

relative weight of

the crural muscle in

both sexes, atrophy

of the crur al muscle

in both sexes,

increased mucosal

cornification of the

stomach in both

sexes, follicular cell

hypertrophy of the

thyroid in females,

and rhinitis of the

nasal cavity in

females.

870.4100b Chronic

Toxicity (nonrodent) MRID 00083231

(Hodge et al.,

1956) NOAEL = 5 mg/kg/day

LOAEL = 25 mg/kg/day

based on 100% mortality 42823901 (1993)

Acceptable/guideline

0, 50, 185, 700 ppm NOAEL = M: 1.6,

F: 1.9 mg/kg/day 41967901 (1991)

Acceptable/guideline

0, 30, 90, or 250 ppm NOAEL (M) = 30 ppm

(0.84 mg/kg/day).Ferbam/034801 Scoping Document Final

Page 25 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

Acceptable/Non

Guideline 0, 0.5,

5, 25 mg/kg/day

ai not specified

(1 yr Dog) after 5

- 9 months, and

convulsive seizures.

Note: n=1 per sex/group M: 0, 1.6, 6.6, 17.4

mg/kg/day

F: 0, 1.9, 6.7, 20.6

mg/kg/day

(Dog) LOAEL = M: 6.6,

F: 6.7 mg/kg/day

based on decrease

in body weight gain

in the females and

liver histopathology

in males. 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

(dog) 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.

870.4200a

Oncogenicity (rat) MRID 00083231

(Hodge et al.,

1956)

Acceptable/Non

Guideline

0, 1.25, 12.5, 125

mg/kg/day

2 years

ai not specified

(Ex

- Wistar Rat)

MRID 00143817

(1978)

Acceptable/Non

guideline

0, 8, 32, 80

mg/kg/day (m)

0, 9, 37, 96

mg/kg/day (f)

(CD Rat) No evidence of

carcinogenicity

No evidence of

carcinogenicity Same as chronic

toxicity

- CD rat

above (870.4100a).

(CD rat)

Same as chronic

toxicity

- F344 rat

above (870.4100a).

(F344 rat)

Same as chronic

toxicity

- F344 rat

above (870.4100a).

(F344 rat) Evidence of

carcinogenicity

based on

increased incidence

of benign

hemangiomas in

CD male rats at

23.7 mg/kg/day

Evidence of

carcinogenicity

based on

increased incidence

of thyroid C

- cell

carcinoma in male

rats at 22

mg/kg/day

Evidence of

carcinogenicity

based on increased

incide nce of

preputial gland

adenomas in male N/AFerbam/034801 Scoping Document Final

Page 26 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

rats at 74

mg/kg/day.

870.4200b

Oncogenicity

(mouse) N/A 43373701 (1994)

Acceptable/guideline

0, 29, 75, 225, 675

ppm

M: 0, 3, 9, 27, 82

mg/kg/day

F: 0, 4, 11, 33, 95

mg/kg/day

(CD

- 1 mouse)

NTP (1983)

Acceptable/guideline

0, 600, or 1200 ppm

M: 0, 122, or 196

mg/kg/day

F: 0, 131, 0r 248

mg/kg/day

(B6C3F1 mouse) NOAEL = M: 9, F:

11 mg/kg/day

LOAEL = M: 27, F:

33 mg/kg/day based

on decreased

absolute brain

weight in both

sexes and increased

incidence of u rinary

bladder epithelial

hyperplasia and

decreased body

weight gain in CD

1 males. No

evidence of

carcinogenicity

NOAEL = M:196

mg/kg/day; not

established for

females;

LOAEL = M: >196,

F: 131 mg/kg/day

based on increased

incidence of

alvelolar epithelial

hyperplasia in

females

Evidence of

carcinogenicity

based on increased

incidence of

alveolar/bronchiola

r adenomas and of

combined 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.Ferbam/034801 Scoping Document Final

Page 27 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

alveolar/bronchiola

r adenomas or

carcinomas in

female B6C3F1

mice at ≥ 131

mg/kg./day

870.4300

Chronic/Oncogenicity Waived 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

(Rat) NOAEL = 30 ppm

(M/F: 1.5/1.8

mg/kg/day).

LOAEL = 150 ppm

(M/F: 7.3/8.9

mg/kg/day), based on

changes in hematology,

clinical ch emistry,

incidences of bile duct

hyperplasia and

reduction in mean

body

- weight gain.

No evidence of

carcinogenicity.

870.5100

Mutagenicity

– Gene

Mutation

– bacterial Waived 00147462 (1984)

Acceptable/guideline

41642901 (1990)

Acceptable/guideline

Haworth, et al.

(1983)

Acceptable/guideline The test article was

positive for gene

mutation induction

in strain TA100

(±S9).

The test article was

mutagenic when

tested above 50

μg/plate (+S9).

The test article was

positive in strains

TA100 (±S9) and

TA1535 (+S9)

870.5265 Gene

Mutation Waived 00147462 (1984)

Acceptable/guideline The test article was

positive for gene N/AFerbam/034801 Scoping Document Final

Page 28 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

Salmonella/mammali

an activation gene

mutation assay

41642901 (1990)

Acceptable/guideline

Haworth, et al.

(1983)

Acceptable/guideline mutation induction

in strain TA100

(±S9).

The test article was

mutagenic when

tested above 50

μg/plate (+S9).

The test article was

positive in strains

TA100 (±S9) and

TA1535 (+S9)

870.5300

Mutagenicity

– Gene

Mutation

–

mammalian Waived 45806501(1999)

Acceptable/guideline

McGregor, et al.

(1988)

Acceptable/guideline No reproducible

increase in the

mutation frequency

of mouse

lymphoma cells

was seen

The test article was

positive for gene

mutation induction

(

- S9). 00160621 (1986)

Acceptable/guideline

0.001

- 56.0 μg/mL

(±S9)

(V79 Chinese

Hamster Cells at the

HPRT Locus) No evidence of

mutagenicity with or

without metabolic

activation.

870.5375

Mutagenicity

– Cytogenetics

-

Structural

Chromosomal

Aberrations Waived 41287802 (1989)

Acceptable/guideline

Gulati (1989)

Acceptable/guideline There was no

evidence of

structural

chromosomal

aberrations over

background.

The test article was

positive for

chromosomal

aberrations (±S9). 40510901 ( 1987)

Acceptable/guideline

0.56, 1.0, or 2.4

μg/mL (

- S9)

1.8, 5.6, or 18.0

μg/mL (+S9)

(Chromosomal

Aberration Assay in

Chinese Hamster

Ovary Cells) Significant dose

- related

increases in

chromosomal

aberrations with and

without metabolic

activation. Classified

as a clastogen.Ferbam/034801 Scoping Document Final

Page 29 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

870.5395 Mammalian

Erythrocyte

Micronucleus test Waived Proudock, R.L. and

Taylor, K. (1992

Unacceptable

-

maximum tolerated

dose not tested,

dosing regime n not

justified, and non

standard procedures

used. The test article was

negative in the

peripheral blood of

CD

- 1 Swiss mice

fed levels of 25, 75,

225, or 675 ppm for

89 days. 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

Unscheduled DNA

Synthesis in Primary

Rat

Hepatocytes/Mammal

ian Cell Waived 41287801 (1989)

Acceptable/guideline There was no

evidence that

unscheduled DNA

synthesis was

induced. 00156064 (1985)

0.03, 0.1, 0.3, 1.0,

3.0, or 10.0 μg/mL Did not induce DNA

repair.

870.6100a Acute

Delayed

Neurotoxicity (hen) N/A N/A N/A

870.6100b 90

- day

Neurotoxicity (hen) N/A Waived (TXR 0056685)

870.6200a Acute

Neurotoxicity

Screening Battery

(rat) Waived 43362801 (1994)

Acceptable/guideline

M&F: 0, 15, 300,

600 mg/kg NOAEL = not

established

LOAEL = M&F: 15

mg/kg/day based on

ataxia and slight

impairment of gait

in males. 45589101 ( 1993)

Unacceptable/non

guideline

0, 10, 25, 60, or 150

mg/kg bw

42912401 ( 1993)

Acceptable/guideline

0, 5, 150, or 600

mg/kg bw NOAEL = 10 mg/kg.

LOAEL = 25 mg/kg,

based on decreases in

food consumption in

males and females.

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.Ferbam/034801 Scoping Document Final

Page 30 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

870.6200b

Subchronic

Neurotoxicity

Screening Battery

(rat) Waived 43413701 (1994)

Acceptable/guideline

0, 72, 207, 540 ppm

M: 0, 5, 14, 34

mg/kg/day

F: 0, 6, 16, 40

mg/kg/day Systemic NOAEL

= M: 14, F: 16

mg/kg/day

LOAEL = M: 34, F:

40 mg/kg/day based

on decreased body

weight and body

weight gains.

Cholinesterase

NOAEL = M: 14,

F: 6 mg/kg/day

LOAEL = M: 34, F:

16 mg/kg/day based

on brain

cholinesterase

inhibition in both

sexes and brain

neurotoxic esterase

activity in the

males. 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

Developmental

Neurotoxicity (DNT) N/A 43935801 (1996)

Unacceptable/guideli

ne

0, 72, 207, 540 ppm

Maternal gestation:

0, 5, 13, 32

mg/kg/day

Maternal lactation:

0, 11, 30, 79

mg/kg/day Maternal NOAEL

= 13 mg/kg/day

LOAEL = 32

mg/kg/day based on

reduced body

weights and/or

body weights gains,

and decreased food

consumption during

gestation and

lactation.

Offspring NOAEL

= not established

LOAEL = 5

mg/kg/day based on 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 locomotorFerbam/034801 Scoping Document Final

Page 31 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

47900401 (2009)

Acceptable/Non

guideline

0, 72, 207, 540/360

ppm

0, 8.6, 24, 46.6

mg/kg/day increased motor

activity.

Mate rnal NOAEL

= 8.6 mg/kg/day

LOAEL = 24

mg/kg/day based on

decreases in body

weights, body

weight gain, and

food consumption

during gestation

and/or lactation.

Offspring NOAEL

= 8.6 mg/kg/day

LOAEL = 24

mg/kg/day based on

increased

locomotor activity,

decre ased

habituation, and

decreases in body

weights and body

weight gains. activity in females on

PND17

.

870.7485 General

Metabolism Acceptable/Non

Guideline

Hodgson et al.,

1975 and JMPR

(Rat) 40

- 70% of 35 S label

absorbed in 24 h, 23% in

urine, 18% in air, 1% in

bile, <1% small amount in

tissues. CS 2 was the only

compound found in the

expired air.

43% of 14 C in urine, 1.4%

in bile, 0.6% in air (Note:

the label was in the methyl

carbon and this would not

detect CS 2 ) 42391001 (1992)

Unacceptable/guideli

ne

M&F: 15, 352

mg/kg or 15

mg/kg/day

(Rat) The test material

was rapidly

absorbed and

excreted via the

urine and expired

air, and s ignificant

amounts were

excreted in the

feces. Small

amounts were

widely distributed

in the body. 42235701 No DER

(Gay et. al ., 1991)

41503607 No DER

(Norris, 1989)

42235702 No DER

(Banijamali et al.

, 1990)

(Rats) Rats (6 male + 6

female) were dosed

orally for 14 days with

unlabeled 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 collec ted for a

further 96 hours and

then the animals were

slaughtered for tissueFerbam/034801 Scoping Document Final

Page 32 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

Hunt and Gilbert,

1976

Acceptable/Non

guideline

35 S

- Ferbam

(0.45mg/kg)

and 3 H

- Ferbam

(0.74mg/kg)

- Total 1.19 mg/kg

bw, Single oral

dose, One animal

tested

(Sheep)

Hunt and Gilbert,

1976

Unacceptable/Non

- guideline

35 S

- Ferbam

(0.45mg/kg)

Single oral dose,

One animal tested

(Sheep) 14 C

- ferbam crossed the

placenta into the fetus.

In lactating rats, 14 C

radioactivity wa s secreted

into milk, absorbed by

pups and excreted in pups

urine.

35 S

- 12% in urine and 11%

in feces;

3 H

- 62% in urine and 20%

in feces

(majority of label

eliminated in urine at 31

-

47 h and in feces in 18

- 23

h)

14% in urine, 10% in feces

Dimethylami ne and thiram

were not found; Air was

not analyzed

(Note: Dimethylamine

metabolite would not be

expected detected with 35 S

label) 46731701 (2001)

main

Acceptable/Guidelin

e

Series of 8 pilot

studies

15 or 150 mg/kg/day

(main)

See DER for a

listing of studies and

doses

46731702

(comparison study

– in Appendix to

DER) Metabolites were

not identified.

The test material

was absorbed and

excreted mainly via

the expired air,

urine, and smaller

amounts were

excreted in the

fec es. Small

amounts were

widely distributed

in the body, with

the highest tissue

concentrations

found in the liver,

fat, kidney, spleen,

lung, thyroid, and

adrenals.

Metabolites were

identified. collection.

Approximately 33

- 35%

of the administered 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 (19 87)

and the multiple dose

study of Nomeir and

Markham (1990).

There were no sex

differences in the

metabolism but the

proportions of some of

the metabolites

depended on the dosage

level and the time after

dosing.

[www. fao.org /docrep/

W5897E/w5897e5a.htm

]

870.7600 Dermal

Penetration N/A Same as 21

- day

dermal rabbit

(870.3200) and The test material

was minimally

absorbed Dermal absorption was estimated to be 1%

(D291237, 2003)Ferbam/034801 Scoping Document Final

Page 33 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

rabbit oral

developmental

(870.7600).

870.7800

Immunotoxicity Waived (TXR No. 0057106) Waived (TXR No. 0057106) 48646401 (2011)

Acceptable/guideline

0, 15/17.5, 150, or

450 ppm

(0, 3, 25, 74

mg/kg/day)

(Mouse) 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.

Special studies

28

- Day Oral toxicity MRID 00083232

(Hodge et al.,

1952)

Acceptable/Non

guideline

0, 7.5, 37.5, 188,

375 mg/kg/day

(m/f)

(Ex

- Wistar Rats)

MRID 00083232

(Hodge et al.,

1952)

0, 5, 25

mg/kg/day

Acceptable/Non

guideline NOAEL = None

LOAEL = 37.5 mg/kg/day

based on slight anemia and

decreased body weight.

HDT had 50% mortality

during the third and fourth

week along with anemic

effects.

NOAEL = None

LOAEL = 5 mg/kg/day

based on decreased RBCs

and hemoglobin

Note: n=1/groupFerbam/034801 Scoping Document Final

Page 34 of 39 Table 2. Subchronic and Chronic Toxicology Profiles of Dimethyl Dithiocarbamates

Studies Ferbam Ziram Thiram

MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results MRID /

Classification /

Doses Results

(Dog) Severe vomiting and

malaise at 100 mg/kg/day;

however, no data provided.Ferbam/034801 Scoping Document Final

Page 35 of 39 Table 3. Summary of Toxicological Doses and Endpoints for ferbam for Use in Dietary and O ccupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary

(General Population,

including Infants and

Children) NOAEL= 5

mg/kg/day UF A = 10 x

UF H =10 x

FQPA SF= 1 x Acute RfD = 0.05

mg/kg/day

aPAD = 0.05

mg/kg/day Acute Neurotoxicity Study

– Rat (Thiram; MRID

42912401)

LOAEL = 150 mg/kg/day based on FOB effects (lethargy,

lower temperature, reduced startle response, no tail pinch

response) and reduced motor activity

Acute Dietary

(Females 13

- 49

years of age) NOAEL= 1.4

mg/kg/day UF A = 10 x

UF H = 10 x

FQPA SF= 1 x Acute RfD =

0.014 mg/kg/day Dev. Neurotoxicity Study

– Rat (Thiram; 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/day UF A = 10x

UF H =10x

FQPA SF= 1x Chronic RfD =

0.015

mg/kg/day

cPAD = 0.015

mg/kg/day Combined Chronic Toxicity/Carcinogenicity Study

– Rat

(Thiram; MRID 42157601)

LOAEL = 7.3 mg/kg/day based on changes in

hematology, clinical chemistry, incidences of bile duct

hyperplasia, and reduction in mean body weight gain

Incidental Oral

All Durations Endpoints of concern were not selected for incidental oral exposure scenarios (short and intermediate terms), since there are no

residential uses (e.g., turf) supported for ferbam.

Dermal Short

- Term

(1

- 30 days) NOAEL= 1.4

mg/kg/day UF A = 10 x

UF H =10 x

FQPA SF= 1 x Occupational LOC

for MOE = 100 Dev. Neurotoxicity Study

– Rat (Thiram; MRID

46455201)

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

activity seen in female offspring on PND 17

Dermal

Intermediate

- Term

(1

- 6 months) NOAEL= 1.4

mg/kg/day UF A = 10 x

UF H =10 x

FQPA SF= 1 x Occupational LOC

for MOE = 100 Dev. Neurotoxicity Study

– Rat (Thiram; MRID

46455201)

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

activity seen in female offspring on PND 17

Inhalation

All Durations NOAEL= 1.5

mg/kg/day UF A = 10x

UF H =10x

FQPA SF= 1x UF DB = 10x Occupational LOC

for MOE = 1000 Combined Chronic Toxicity/Carcinogenicity Study

– Rat

(Thiram; MRID 42157601)

LOAEL = 7.3 mg/kg/day based on changes in

hematology, clinical chemistry , incidences of bile duct

hyperplasia, and reduction in mean body weight gainFerbam/034801 Scoping Document Final

Page 36 of 39 Table 3. Summary of Toxicological Doses and Endpoints for ferbam for Use in Dietary and O ccupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Cancer (oral, dermal,

inhalation) Based on bridging, the cancer classifications of thiram and ziram are protective of any potential carcinoge nic effects of ferbam. No

quantification of cancer risk is required for ferbam.Ferbam/034801 Scoping Document Final

Page 37 of 39 Data requirements (40 CFR 158.340) for ferbam are provided in the following table. Use of the 1998

guideline numbers does not imply that the 1998 guideline protocols were used.

Table 4. Toxicology Data Requirements for Ferbam

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21

- Day Dermal

870.3250 90

- Day Dermal

870.3465 90

- Day Inhalation (28

- day) yes

yes

waived*

waived*

waived* yes

yes

-

-

-

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction yes

NA

yes yes

-

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity yes

yes

yes

NA

waived* yes

yes

yes

-

-

870.5100 Mutagenicity

— Gene Mutation

- bacterial

870.5300 Mutagenicity

— Gene Mutation

- mammalian

870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

870.5xxx Mutagenicity

— Other Genotoxic Effects waived*

waived*

waived*

waived* -

-

-

-

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90

- Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

870.6300 Develop. Neurotoxicity (DNT) NA

NA

waived*

waived*

NA -

-

-

-

-

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity yes

NA

waived** yes

-

-

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six

- month Oral (dog) no

yes

no no

yes

no

*TXR No.: XXXXXXX

**TXR No.: 0057106Ferbam/034801 Scoping Document Final

Page 38 of 39 Appendix 2

Table 2.1 Nomenclature and Physical/Chemical Properties Ferbam, Ziram, Thiram

Common name Ferbam Ziram Thiram

Chemical structure

Molecular Formula C 9 H 18 N 3 S 6 Fe C 6 H 12 N 2 S 4 Zn C 6 H 12 N 2 S 4

Molecular Weight 416.5 305.8 240.4

IUPAC name ferric dimethyldithiocarbamate zinc bis(dimethyldithiocarbamate) tetramethylthiuram disulfide

CAS name tris(dimethylcarbamoditioato)iron (T

- 4)

- bis(dimethyldithiocarbamato

S,S’)zinc tetramethylthioperoxydicarbonic

diamide

CAS # 14484

- 64

- 1 137

- 30

- 4 137

- 26

- 8

PC Code 034801 034805 079801

Melting point/range 180 C 226

- 251 C 142

- 150 C

pH of 1% aqueous susp NA 6.9

- 7.5 5% solubility NA

Density or specific

gravity 0.6 kg/l 1.71 g/mL 0.32

- 0.35 g/mL

Water solubility

(20 ° C) 130 mg/L 1.58

- 18.3 mg/L 18 mg/L

Solvent solubility

(20 ° C) soluble in organic solvents with

high dielectric constant, e.g.,

chloroform, pyridine, acetonitrile,

acetone acetone 2.88, methanol 0.22,

toluene 2.33, n

- hexane 0.07 (g/L) ethanol <10, acetone 80, chloroform

230, hexane, dichloromethane 170,

toluene 18, isopropanol 0.7 (g/L)

Vapor pressure at 20 ° C < 8.6x10

- 7 torr < 1 x 10

- 3 mPa 2.3 mPa

Dissociation constant

(pK

a ) NA NA NA

Octanol/water partition

coefficient (K

ow ) K

ow logP

- 1.6 K

ow logP 1.23 K

ow logP 1.73

UV/vis absorption

spectrum NA NA NA

thiram and 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) at 20

- 25 C.Ferbam/034801 Scoping Document Final

Page 39 of 39 Table 2. 2 International Residue Limits

. 

### Ferbam (PC Code 034801; Date of Request xx/xx/xx )

Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition :

US Canada Mexico 2 Codex 3

40 CFR 180.114

Plants: ferbam (ferric

dimethyldithiocarbamate), calculated as

carbon disulfide Ferbam: (OC

- 6

- 11)

- tris(dimethylcarba

modithioato

kS,kS')iron

(calculated as

zineb) ferbam

(ferric

dimethyld

ithiocarba

mate),

calculated

as carbon

disulfide Plant: total

dithio carbamates,

determined as CS2,

evolved during acid

digestion and expressed as

mg CS2/kg.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2

Apple 4.0 7 4 5

Cherry 4.0 7 4 0.2

Cranberry 4.0 7 4 5

Fruit, citrus, group 10 4.0

--- 4 2 Orange, 10 Tangelo and

mandarin

Grape 4.0 7 4 5

Nectarine 4.0 7 4

Peach 4.0 7 4 7

Pear 4.0 7 4 5

Mango 4.0 7 4 2

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP =

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the

fat portion of the sample. MRLs indicated as proposed have not been final ized by the CCPR and the CAC.