### Page 2 of 24

exhibits antifeeding properties for surface

- feeding insects. TPTH is not currently registered for

residential uses.

The toxicity and exposure databases are adequate to support human health risk assessment and make safety findings under FQPA. An immunotoxicity study is required for registration review under the new data requirements for pesticides (40 CFR § 158). Once this study has been received and reviewed the toxicological endpoint selection and uncertainty factors may be re

evaluated.

The most recent HED human health risk a ssessment was completed in September of 1999 as part
of a revised Re

- registration Eligibilit y Decision Document (RED) . At that time, the risk

assessment was reevaluated with respect to the Food Quality Protection Act (FQPA) and addressed the susceptibility of infants and children. No dietary risk from food

- only was identified. However, using d rinking water levels of comparison (DWLOCs) , dietary risk from drinking water were found to exceed the level of concern for chronic (cancer and non

- cancer) dietary exposures

. Several occupational handler scenarios were identified as being of concern.

HED may consider updating risk assessments during registration review to re flect current dietary and occupational exposure policies . In addition, any updated assessment may include potential changes resulting from updated toxicology endpoints and uncertai nty fa ctors for TPTH

.

Introduction

TPTH is a List A reregistration chemical and was the subject of a Registration Standard dated 4/11/84, its associated Guidance Document dated 9/84, and a Reregistration Standard Update

dated 3/18/92. Due to its high toxicity, it was put under Special Review (PD1) in 1985 (50 FR1107 on 1/9/85)

. In September 1999, the RED was issued ; TPTH remained in Special Review status at the time of RED completion and was closed out of Special Review in 2001 . As part of 1999 RED, an HED human health risk assessment was completed and tolerance s were re

evaluated in accordance with the FQPA of 1996 . A number of data gaps in product and residue chemistry and toxicology were also identified in 1999 RED and DCI’s were issued. Since th en toxicological and residue chemistry studies have been submitted. Except for the i mmunotoxicity study ( Guideline Number: 870.7800) the toxicology data base is complete. The submitted residue chemistry studies are under review ; t he guideline requirement s for those studies are still

considered data gaps

. 

### The last risk assessment was conducted as part of the RED in 1999.

TPTH is a fungicide registered for use on pecans, potatoes and sugar beets. In addition, the

states of MN and ND have eight Section 24C, Special Local Need Registrations for use on sugar beets

. TPTH is used to control ea rly and late blight on potatoes, leaf spot on sugar beets, scab and several other diseases on pecans. In addition to its fungicidical activity, TPTH exhibits

antifee ding properties for surface

- feeding insects. To lerances are listed in 40 CFR §180.236 for the combined residues of the fungicide triphenyltin hydroxide (TPTH) and its monophenyltin (MPTH) and diphenyltin (DPTH) hydroxide and oxide metabolites, expressed i n terms of parent TPTH, in or on pecans ( at 0.05 ppm) , potatoes (at 0.05 ppm) and sugar beets (tops at 10.0 ppm

and roots at 0.05 ppm ), milk (at 0.06 ppm), fat (at 0.2 ppm), kidney (at 2.0 ppm), liver (at 4.0

### Page 3 of 24

ppm) and meat (at 0.5 ppm) of cattle, goat, horse and sheep, and hog’s fat (at 0.3 ppm), hog’s meat (at 0.06 ppm) and hog’s meat byproduct (at 0.3 ppm).

TPTH is manufactured by members of the TPTH Task Force (AgrEvo, Elf Atochem and Griffin)

and formul ated both as a wettable powder in a water

- soluble pack and as a flowable concentrate requiring a closed mixing/loading system. These products may be applied as broadcast foliar applications using ground or aerial equipment and by chemigation (potatoes only ). Reregistration of TPTH is being supported only for agricultural uses; it is not supported for residential, aquatic or forestry uses. Based on the registered use patterns, there is a potential for dietary (via food and water) and occupational e xposures to TPTH

. The structure, chemical names, and other identifiers for TPTH may be found in the chemical identity table attached to

this document.

Hazard Identification/Toxicolog y

HED issue d a revised RED in 1999, which identified several toxicology data gaps (Levy, 1999). In response to Registrant comments

, HED placed the developmental Immunotoxicity study in

reserve

. A lthough there are risks of concern for TPTH related to the immune system in fetal and/or neonatal rats, no acceptable guideline or validated protocol exist ed for a developmental immunotoxicity study at the time (Doherty, 2001). Nevertheless, HED recommended that TPTH be assessed for potential immunotoxicit y using the new immunotoxicity testing guideline (870.7800) that includes: the antibody plaque

- forming cell (PFC) assay or ELISA test and the Natural Killer (NK) cell activity assay

.

In response to the Agency’s DCI, the Registrant has submitted a s erie s of studies which includes acute and subchronic neurotoxicity studies (MRID 45 299901 and 45546001) and a Developmental Neurotoxicity ( DNT ) study (MRID 46055701) accompanied by a milk secretion assay in lactating rats (MRID 45890101). These studies have b een reviewed and incorporated into the update d subchronic, chronic and other toxicity profile table (attached ) . HED will revisit the toxicological points of departure (PODs) , uncertainty factors an d the FQPA safety factor for dietary, and occupational exp osure assessments during the registration review process

.

With these evaluated new data, the toxicity database for TPTH is nearly complete. An immunotoxicity study is still required in accordance with the 2007 revised toxicology data requirement for con ventional pesticide registration (40 CFR Part 158).

TPTH is highly toxic, consistently inducing marked to severe toxicity via the oral, dermal or inhalation routes (Toxicity Categories II, II and I, respectively). It is also corrosive to the eyes

and mod erately toxic to the skin but not a dermal sensitizer.

TPTH belongs to a class of chemicals (organo tins) known to be immunotoxic. The primary

treatment

- related effects of TPTH via oral exposure are related to immunotoxicity and include:

decreased leukoc ytes and immunoglobulins in rats and mice following both subchronic and chronic exposures. Decrease d spleen weights have also been observed in rats and mice fed diets containing TPTH for 28 days.

### Page 4 of 24

In developmental toxicity studies, evidence of possib le developmental toxicity was only seen in the presence of definitive maternal toxicity in the rat or at levels higher than doses causing maternal toxicity in the rabbit. Nevertheless, in a multigenerational reproductive toxicity study, offspring toxicity (primarily the F 2 

### offspring), manifested as decreased litter size and decreased liver and spleen weights, was observed at a dose ~3 X lower than the dose causing overt toxicity (decreased body weight) in the F 0 

### , F 1 

### and F 2 

### maternal animals.

Rat toxicity via the dermal or inhalation routes in subchronic studies consisted of local skin irritation at all tested doses (< 5.0 mg/kg/day) for 21 days or death and lung and respiratory irritation and edema up to 2 mg/kg/day (0.002 mg/mL). In 1990, TPTH was class ified as a group

B2

– Probable Human Carcinogen, by the HED Carcinogenicity Peer Review Committee, based on pituitary and testicular tumors in rats and liver tumors in mice (Sjoblad, 1990). This conclusion was reviewed by the Scientific Advisory Panel, an d the original classification was retained. The Q 1 

### * of 1.83 (mg/kg/day) - 1 

### remains in place and was used in the carcinogenicity risk assessment. There is, however, little support for a mutagenic concern associated with these

tumors. All toxicity endpoint s (cancer and non cancer) will be revisited during registration review to ensure they are consistent with current HED policies.

In the acute rat neurotoxicity study, clinical signs, associated with adverse effects on neurobehavior were: palpebral closure, piloerection, excessive grooming, and increased activity on handling; the peak response occurred within 4

- 6 hours of dosing. Decreased total and ambulatory motor activity was also seen in both sexes following subchronic exposure. In the DNT, the materna l animals exhibited neurotoxicity at doses that were not neurotoxic in the pups. TPTH is related to test substances (particularly trimethyl and triethyl tin) that are known to be neurotoxic and are often used as positive controls in neurotoxicity studies.

In several metabolism studies, the biliary route was identified as the most important in excretion

of 113 

### SN from TPTH. Most of the label (80

- 100%) was recovered in the feces; little remained in the tissue (≤0.5%). After 24 hours, the kidneys, liver, e pididymis and the brain had the most

label. After 7 days, very little labeled test substance remained in the tissue [highest content was in the liver: (0.1356 μg equivalents/gm in males and 0.1612 μg equivalents/gm in females)]. The major metabolites of TPTH, which are the same in plants and animals, are diphenyl and monophenyl tin. Both of these metabolites are of toxicological concern. In the milk secretion study in rats, which accompanied the DNT study, only as much as 0.10 μg/mL of total TPTH or

its metabolites were found in samples from lactating rats 30 minutes after a single oral dosing or 6 hours after multiple dosing for 10 days. It is of note that the Agency for Toxic Substances and Disease Registry list inorganic or metallic tin as not very t oxic due to its poor gastrointestinal absorption (ATSDR, 2005)

.

A dermal absorption factor (DAF) of 10%, which was derived from a comparison of the rabbit oral and dermal developmental toxicity test LOAELs, was used for the cancer risk assessment.

### Page 5 of 24

Conclusions: The toxicity database for TPTH is complete except for an immunotoxicity study, which is required under the 2007 revised 40CFR Part 158 Toxicology Data Requirements.

Considerable amounts of new data have been received and reviewed since the 1 999 DCI

. T he Point of Departures, endpoints, the uncertainty factors and FQPA Safety Factors for TPTH (see

Table 7A and 7B ) will be reevaluated during registration review based on the review of this outstanding data as well as all of the currently available data.

Residue Chemistry a nd Dietary Exposure

As part of the 1999 RED, a human health risk assessment was completed, tolerances were re

evaluated in accordance with the FQPA of 1996 , and a number of data deficiencies in residue

chemi stry were identified

. The guideline requirements for those studies are still data gaps, but

studies have been submitted and are under review. The submitted studies will be evaluated on their adequacy to fulfill data requirements for guideline 860.1340

, residue analytical method for plant s (MRID 45531201 ) and animal commodities (MRID 45350302 & 4531202 ) ; guideline

860.1380

, storage stabil ity (MRID 45350303 & 45603101 ) ; and guideline 860.1360,

mul t iresidue method s (Morales, J., 2007)

. HED will complete the review of the submitted studies and make decisions during the registration review process.

The qualitative nature of the residue(s) of TPTH in plants and animals has been adequately

identified/characterized and is understood. The residues of concern for registered food uses do

not nee d revision. HED ROCKS, after studying the BEAD report on new available studies, also confirmed that the residue of concern (parent only) in water does not need revision (S callon, E., email, 8/9/2012). The current tolerance expression as listed in the 40 CFR §180. 236 has not been updated to reflect current HED policies. The tolerance expression will need to be revised during the registration review process.

Dietary risk estimates for exposures to TPTH in food and drinking water were calculated in 1999 and do not reflect current policies and practices. The previous dietary exposure analysis was conducted on food only, and the risk from water was evaluated separately using the DWLOC method. A dietary exposure assessment agg regating food and water in a quantitative analysis , using potentially new toxicological endpoints may need to be conducted.

HED conducted a revised refined acute and chronic (non

- cancer and cancer) dietary risk analyses for TPTH using the Dietary Exposure Evaluation Model (DEEM TM 

### ) in 1999. The refined dietary risk assessment utilized anticipated residues (ARs), processing factors and percent crop treated (%CT) information for meat and milk ( Levy, S., 8/20/99).

The d ietary risk estimates from exposures to food only were below the Agency’s levels of

concern for the U.S. general population and all population subgroups for acute and chronic

exposures. At the 99.9th percentile exposure, a cute d ietary exposure from food only was less

than 34% of t he acute Population Adjusted Dose (aPAD) with the most highly exposed population subgroup being females 20+ years old, not pregnant, not nursing . Chronic (non

cancer) dietary exposure from food

- only was less than 4% of the chronic Population Adjusted

Dose (cPAD) with the most highly exposed population subgroup being children, 1

- 6 years old

.

### Page 6 of 24

Chronic ( cancer) dietary exposure from food

- only was 1.1 x 10 - 6 

### for the general US population.

Two othe r scenarios were investigated f o r chronic (cancer) dietary expo sure. In one scenario which included only meat and milk, the carcinogenic risk estimate was 9.4 x 10 - 7 

### for the general US population. In the third scenario which excluded sugar beet commodities and meat and milk, the carcinogenic risk estimate was reduce d to 8.7 x 10 - 8 

### for the general US population. HED previously used drinking water levels of comparison (DWLOCs) to assess the exposure to TPTH in drinking water and concluded that the risk from exposure to residues in drinking water was above the level of concern for chronic (cancer and non

- cancer) dietary exposures

.

Conclusions: A dietary exposure assessment aggregating food and water together in one quantitative analysis , using new er version of DEEM which utilizes newer consump tion data and revised population subgroups may need to be conducted. In addition, any updated assessment may include potential changes resulting from updated toxicology endpoints

.

Residential Exposure

There are no current or pending residential uses associated with TPTH ; therefore, a residential exposure assessment was not performed nor required during re re gistration review. Since there are no currently registered residential uses for TPTH , it is not anticipated that a residential assessment will need to be conducted during registration review.

Aggregate Risk Assessment

An aggregate risk assessment may be conducted at the time of registration review to incorporate current policies reg arding aggregation of exposures from different dietary routes (drinking water and food) using the newer version of DEEM which utilizes newer consumption data and revised population subgroups . In addition, any updated assessment may include potential chang es resulting from updated toxicology endpoints

.

Occupational Exposure

TPTH , is a restricted use contact fung icide registered for sug ar beets, potatoes, and pecans. Some of the pests controlle d by TPTH include cerc ospora leaf spot on sugar beets, early and late blight, and suppression of the Colo rado potato beetle on potatoes, and scab, brown leaf spot, downy spot, powdery mildew, liver spot, sooty mold and leaf blotch on pecans.

TPTH is formulated as a technical product (96 % active ingredient or a.i. ), a wettable powder in

water

- soluble bags (80 % a.i.), and a flowable (l iquid) concentrate (40 % a.i.). T he registered products may be applied by ground sprayers and by aerial application. Chemigation is prohibited except for application on potatoes.

### Page 7 of 24

Occupational Handlers In the last risk assessment completed in September 1999 (S. Levy and J. Doherty, D258270), the occupational exposure and risk estimates were conducted for short

- and intermediate

- term dermal and inhalation exposure for both priv ate an d commercial applicators. Long

- term worker exposure is not expected. HED determined 10 major exposure scenarios for occupational handler exposure. Several occupational handler scenarios exceeded HED level of concern (MOEs < 100) at baseline personal pro tective equipment. These scenarios were then assessed with engineering controls that are currently on the labels as well as typical rates . The resulting MOEs for two scenarios ( mixing and loading liquids and wettable powder for aerial and/or chemigation application) still exceeded HED’s level of concern (MOEs < 100) for dermal

exposure. Mixing and loading liquids for sugar beet aerial application scenario was mitigated t o

a MOE of 170 with applied typical application. However, even with applied typical application rates for mixing and loading wettable powder for aerial and/or chemigation application to the three crops the risks of concern were not able to be mitigated.

Cancer risk estimates for seven scenarios yielded risks ranging from 8.8 E

- 5 to 1.4 E

- 4 for commercial applicators. Cancer risk estimates ranged from 3.6 E

- 6 to 9.1 E

- 5 for private

growers. MOEs were mitigated with engineering controls currently on the la bels. Cancer estimates at baseline for commercial application of spray with ground

- boom and air

- blast sprayer

range d from 1.4 E

- 04 to 8.3 E

- 5 while private application MOE ranged from 4.4 E

- 5 to 4.3 E

- 6.

No new uses have been registered since the last risk as sessment was completed for TPTH; however, other parameters have changed. Reco mmended unit exposures for occupational handler assessments have generally been derived only from Pesticide Handlers Exposure

Database ( PHED )

. However, recently both the ORETF and AHETF have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/science/handler

- exposure

- data.html ). As more reliable data become available (such as that from the AHETF and ORET F), the Agency will continue to replace existing data. N ew exposure monitoring data will be inc o rporated , as necessary, during

r egistration r eview.

Post

- Application Exposure Results There are multiple potential sources of dermal exposure to individuals performing post

appli cation activities in previously

- treated TPTH fields. Two studies (MRID 43557401 and MRID 4257801) were submitted and previously reviewed d uring the last risk assessment. MRID 43557401 is a reentry study of pecan workers while MRID 4257801 is a dislodgeable foliar

residue study on potatoes and peanuts. T he studies resulted in exposure values that were then used as surrogate data for several post application exposure scenarios instead of generic tr ansfer

coefficient values. The post

- application assessment indicates that for pecan harvesting, MOEs

exceed 100 on day zero of application. Cancer risk estimates were greater than 1.0 E

- 4 until day 7 to 30 after application depending on field site. MOEs for potato maintenance w ere greater than 100 on day zero while sugar beets was greater than 100 on day two of application. Cancer risks

were less than 1.0 E

- 04 two days after application for both potatoes and sugar beets. The studies may have to be reevaluated due to their age and change s/updates in exposure frequencies and durations. In addition, the Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task

### Page 8 of 24

Force. If new policies or pro cedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for TPTH

.

Recommended unit exposures for occupational handler assessments have generally been derived only from PHE D. However, recently both the ORETF and AHETF have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/ science/handler

- exposure

- data.html ). As more reliable data become available (such as that from the AHETF and ORETF), the Agency will continue to replace existing data. N ew exposure monitoring data will be incorporated , as necessary, during Registration Review.

The restricted entry interval (REI) is based on the acute toxicity of triphenyltin hydroxide

technical material. TPTH has been noted to be a potential eye irritant. TPTH is classified as toxicity category II for oral and derma l, and I for inhala tion routes. The current reentry interval (REI) is 48 hours for all crops ; this REI appears to be adequate.

Residential bystander inhalation exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of TPTH. The Agency is in the process of evaluating these types of exposures and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation

exp osure into the Agency's risk assessments

. The need for a bystander inhalation risk

assessment for TPTH should be examined during registration review.

Conclusions : Due to recent occupational exposure science policy updates, existing occupational

handler and post

- application scenarios may have to be reassessed to support registration review. These updates include changes to data sources and default assessment inputs for both occupational handler an d post

- application assessments. T he assessment may also ne ed to be updated to reflect any p otential changes to PoDs or new uncertainty factors for TPTH. In addition, new typical application rates and daily acreage supplied by BEAD (T. Chandgoyal, 06/25/12) could also result in changes to the risk estimates.

P ublic Health and Pesticide Epidemiology Data

A memo written in 2012 (S. Recore, 07/19/2012, D 466848) outlined any incidents r eported with

the chemical TPTH. Based on the low frequency and severity of incident cases reported for TPTH, there does not appea r 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.

Tolerances and Internationa l Harmonization

US permanent tolerances for TPTH ar e listed in 40 CFR 180. 2 36 and are summarized in the

attached table. The tolerance exp ression for TPTH in 40 CFR § 180.236 should be changed

### Page 9 of 24

according to HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09) as

follows:

Tolerances are established for residues of th e herbicide t riphenyltin hydroxide

, including its metabolites and degradates, in or on the commodities in the tabl e below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of triphenyltin hydroxide (TPTH) and its monophenyltin (MPTH) and diphenyltin (DPTH) hydroxide and oxide

metabolites

, calculated as the stoichiomet ric equivalent of TPTH, in or on the commodity.

The Codex Alimentarius Commission and Canada have not established MRLs for residues of

TPTH

.

Environmental Justice

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

- Income Populations ," http://www.epa.gov/compliance/resources/policies/ej/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 diets within the U.S., and people who may be exposed w hen harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure

that the risk estimates are based on the best available information.

Endocrine Disruption Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxici ty, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturati on, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), TPTH is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect

### Page 10 of 24

produc ed by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to id entify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems wil l proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establi sh a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 6 7 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. TPTH is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

ins, requiring the submission of EDSP screening assays for TPTH. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Cumulative Risk Assessments

At this time, EPA does not have available data to determine whether TPTH has a common

mechanism of t oxicity with other substances. EPA has not made a common mechanism of toxicity finding as to TPTH and any other substances, and TPTH does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U.S. Therefore,

EPA has not a ssumed that TPTH has a common mechanism of toxicity with other substances.

Human Studies

Previous assessments 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 the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with a pplicable ethics requirements. Future assessments will rely on the most current and updated d ata from a variety

of sources. All data used are subject to ethics review pursuant to 40 CFR 26. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.

Data Requirements / Deficiencies

Guideline Number: 870.7800

- Study Title: Immunotoxicity

### Page 11 of 24

References

Author Barcode Date Title Sarah Levy D258010 9/8 / 19 99 TPTH: Revised Acute and Chronic (Non

- Cancer and Cancer) Dietary Exposure Analyses for the HED

Revised Risk Assessment

. Sarah Levy D2 59257 9/21 / 19 99 TPTH (Triphenyltin Hydroxide) : HED Revised Risk Assessment for the Reregistration Eligibility Decision (RED) Document.

Sarah Levey, and

John Doherty D258270 08/31/1999 TPTH: Response to EPA Transmittal of the Preliminary HED Risk Assessment for TPTH, PC Code #083601, DP Barcode: D258270.

Tara Chandgoyal 07/25/2012 BEAD Chemical Profile for Registration Review: Triphenyltin Hydroxide (TPTH) a l s o known as Fe n tin Hydroxide (083601) Kelly

O’Rourke D250108 05/06/1999 Occupational and Resident i al Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document for Triphenyltin Hydroxide (TPTH ) Doherty, J.

and Rowland, J. TXR

012972 11/13/1998 Triphenyltin hydroxide: Report of the Hazard

Identification Assessment Review Committee

Doherty, J. TXR

014509 3/23/2001 Triphenyltin hydroxide: Report of the Hazard

Identification Assessment Review Committee:

Reconsideration on the need for a developmental immunotoxicity study and sustaining the requirement for the developmental neurotoxicity study Sjoblad, R

. TXR No.

0052679 5/24/1990 Peer Review of Triphenyltin hydroxide (TPTH)

### Page 12 of 24

Table 1

- Chemical Identity

Common Name 

### triphenyltin hydroxide

IUPAC name 

### triphenylstannanylium hydroxide

CAS name 

### Stannane, hydroxytriphenyl

PC Code 083601
CAS registry number 76

- 87

- 9 Registration Review

Case No. 0099

Chemical Structure



### TPTH is a fine white powder with a melting point of 118

- 120 C, bulk density of 0.2758 g/mL at 25 C, octanol/water partition coefficient (log Kow) of 3.268, and vapor pressure of < 1x10

- 7 

### torr at 25 C. TPTH is practically insoluble in water (8 ppm), and is moderately soluble in most organic solvents (acetone 70 g/L; benzene 41 g/L; 1,2

- dichloromethane 74 g/L; ether 28 g/L; ethanol 10 g/L; and methylene chloride 171 g/L).

### Page 13 of 24

Table 2

- Summary of US and International Tolerances and Maximum Residue Limits Residue Definition:

US Canada Mexico 1 

### Codex

40 CFR 180.236

C ombined residues of the fungicide triphenyltin hydroxide (TPTH) and its monophenyltin (MPTH) and diphenyltin (DPTH) hydroxide and oxide metabolites, expressed in terms of parent TPTH

. 

### None None

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

US Canada Mexico 1 

### Codex Beet, sugar, roots 0.05 Beet, sugar, tops 10.0
Cattle, fat 0.2 Cattle, kidney 2.0
Cattle, liver 4.0
Cattle, meat 0.5
Goat, fat 0.2 Goat, kidney 2.0
Goat, liver 4.0
Goat, meat 0.5 Hog, fat 0.3 Hog, meat 0.06 Hog, meat byproducts 0.3
Horse, fat 0.2 Horse, kidney 2.0
Horse, liver 4.0
Horse, meat 0.5

Milk 0.06

Pecan 0.05

Potato 0.05 Sheep, fat 0.2 Sheep, kidney 2.0 Sheep, liver 4.0 Sheep, meat 0.5

Com pleted: M. Negussie; 08/17/2012

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

### Page 14 of 24

Table 3

- 

### Summary of Registered Use Patterns and Formulations for Triphenyltin Hydroxide TPTH

Reg No % AI Product Type Application Equipment Use Sites

246640 96 % Technical

Ground spray

and aerial and ( chemigation

allowed on

potato es only) Pecan trees, Potatoes, and/or Sugar

Beets 5514671 96 % Technical

5514672 80 % Wettable Soluble packet

5514684 40 % Flowable Liquid

concentrate

62719443 80 % Water

- dispersible granules in water soluble packets

70506198 96% Technical

70506212 40 % Flowable Liquid

concentrate

1812279 96 % Technical

70506214 80 % Wettable Soluble packet

352699 80 % Wettable Soluble packet



### Table 4

- 

### Status of Required Toxicological Studies

Test 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 21/28

- Day Dermal

................................ ........................ 870.3250 90

- Day Dermal

................................ ............................. 870.3465 90

- Day Inhalation

................................ ......................... yes

yes

yes

no

no 1 yes

yes

yes

--- yes

870.3700 Developmental Toxicity (rodent)

................................ . 870.3700 Developmental Toxicity (nonrodent)

........................... 870.3800 Reproduction

................................ ................................ yes

yes

yes yes

yes

yes

870.4100 Chronic Toxicity (rodent)

................................ ............. 870.4100 Chronic Toxicity (nonrodent)

................................ ....... 870.4200 Oncogenicity (rat)

................................ ......................... 870.4200 Oncogenicity (mouse)

................................ .................. 870.4300 Chronic/Oncogenicity (mouse)

................................ .... 870.4500 Chronic/Oncogenicity (rat)

................................ ........... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

### Page 15 of 24

Table 4

- 

### Status of Required Toxicological Studies

Test Technical

Required Satisfied

870.5100 Mutagenicity

— Gene Mutation

- bacterial

.................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

............... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5385 Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5395 Mutagenicity

— Micronucleus assay

............................. 870.5550 Mutagenicity

— Other Genotoxic Effects

...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotox. (hen)

................................ .... 870.6100 90

- Day Neurotoxicity (hen)

................................ ......... 870.6200 Acute Neurotox. Screening Battery (rat)

...................... 870.6200 Chronic Neurotox. Screening Battery (rat)

................... 870.6300 Develop. Neuro

................................ ............................ no

no

yes

yes

no 1 ---

--- yes

yes

yes

870.7485 General Metabolism

................................ ..................... 870.7600 Dermal Penetration

................................ ....................... 870.7800 Immunotoxicity yes

no 1

yes yes

yes

no

1 These studies were not required , yet they were submitted and subsequently were reviewed by HED and found to be scientifically acceptable.



### Acute Toxicity

Table 5A

- 

### Acute Toxicity Profile

- Triphenyltin Hydroxide (96%A.I/1981) 1

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute Oral

- rat 00124210 LD 50 = 165 mg/kg (M) 156 mg/kg (F) II

870.1200 Acute Dermal

- rat 00124214 LD 50 = 1600 mg/kg II

870.1300 Acute Inhalation

- rat 00124212 LC 50 =60.3 μg/L I

870.2400 Primary Eye Irritation 00139034 Corrosive I

870.2500 Primary Skin Irritation 00139034 PIS = 2.8 III

870.2600 Dermal Sensitization Several Studies (e.g., 00124216) Negative in the Buehler

assay. Not considered a

sensitizer.

1 All studies classified as ACCEPTABLE or otherwise determined to contain useful data.

### Page 16 of 24

Table 5B

- 

### Acute Toxicity Profile

- Triphenyltin Hydroxide (80%A.I 2003) 1

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute Oral

- rat 45883303 LD 50 = >50 mg/kg (M&F) II

870.1200 Acute Dermal

- rat 45883304 LD 50 = >200 mg/kg (M&F) II

870.1300 Acute Inhalation

- rat 45883305 LC 50 =0 .0 6 mg/L (M&F) I

870.2400 Primary Eye Irritation 45883306 Corrosive I

870.2500 Primary Skin Irritation 45883307 PDII = 3.0

Moderate irritant III

1 All studies classified as ACCEPTABLE or otherwise determined to contain useful data.



### Table 6

- 

### Subchronic, Chronic and Other Toxicity Profile of Triphenyltin Hydroxide

.

Guideline No./Study Type MRID

No.(year)/Classification/Doses: Results

870.3100 Subchronic (13

- Week) feeding in

rats 00157771 (1986)

Acceptable/Guideline 0, 4, 20, 100 ppm; M/F = 0.30/0.35, 1.56/1.72, 7.41/7.85 mg/kg/day NOAEL: < 0.33 mg/kg/day [M & F] (NOTE: Decreased IgG antibodies at this dose)

LOAEL = 7.63 mg/kg/day: decreased body weight and gain and food consumption (M & F).

870.3100 Subchronic (13

- Week) feeding in

mice 00157952 (1986)

Classified as “Useable ” 1
0, 4, 20, 80 ppm; M/F = 0.62/0.88, 3.44/4.12, 18.28/20.64 mg/kg/day No NOAEL or LOAEL was assigned. Observed

effects:

Immunotoxicity: decreases in IgA and IgM antibodies at 4 ppm (M & F).

Systemic: Decreased adrenal weight at 4 ppm (F) and decreased ovary weight and increased liver weight (M & F) at 80 ppm.

870.3100 Subchronic (13

- Week) feeding

- Guinea pig 00086467( 1960)

Unacceptable 0, 2.5, 5, 20, 50 ppm ~0, 0.1, 0.2, 0.4, 2 mg/kg/day NOAEL < 2.5 ppm (estimated to be 0.1 mg/kg/day) (lowest dose tested): decreased leukocyte counts.

870.31150

Subchronic feeding

- dog No valid study. Refer to chronic feeding study below

.

870.3465 Subchronic (90

- day) inhalation

rats 41017701 (1989)

Acceptable/Guideline 0, 0.014, 0.34, 2.0 mg/m 3 (M & F) 0, 0. 86, 0.454, 1.950 mg/m 3 (F) NOAEL = 0.00034 mg/L LOAEL = 0.002 mg/L: deaths and lung and respiratory irritation and edema.

870.3200 00142880 (1985) Systemic:

### Page 17 of 24

Table 6

- 

### Subchronic, Chronic and Other Toxicity Profile of Triphenyltin Hydroxide

.

Guideline No./Study Type MRID

No.(year)/Classification/Doses: Results

21

- day dermal

- rats Acceptable/Guideline

0, 5, 10, 20 mg/kg/day NOAEL > 20 mg/kg/day. No systemic effects at highest dose tested.

Local: NOAEL < 5 mg/kg/day. Local irritation (considered reversible).

870.3700a Developmental toxicity

- rat; one
of several studies 00142878 (1985) 2

0, 0.35, 1.00, 2.80, 8.00 mg/kg/day Maternal toxicity: NOAEL = 1 mg/kg/day; LOAEL = 2.8 mg/kg/day: decreased body weight and food consumption. Developmental toxicity: NOAEL = 2.8 mg/kg/day; LOAEL = 8 mg/kg/day: decreased fetal weight and increased

sterneb rae unossified (Typical response seen at this dose level in other studies). At 8 mg/kg/day, poor pup survival or smaller litter size and less

viable fetuses also seen in other studies.

870.3700b Developmental toxicity

- rabbit/oral 40104801 (1987)

Acceptable/Guideline 0, 0.1, 0.3, 0.9 mg/kg/day Maternal toxicity: NOAEL = 0.1 mg/kg/day; LOAEL = 0.3 mg/kg/day: decreased body weight gain. Developmental toxicity: NOAEL = 0.3 mg/kg/day; LOAEL = 0.9 mg/kg/day: lower fetal body weight and

increased inciden ts of unossified hyoid body

and/or arches.

870.3700b Developmental toxicity

- rabbit/dermal 42909101 (1993)

Acceptable/Guideline 0, 1.5, 2.25, 3.0 mg/kg/day Maternal and developmental toxicity: NOAEL and LOAEL > 3 mg/kg/day. No effects at highest dos e tested.

870.3800 Reproductive toxicity

- rat 00162655 (1986)

Acceptable/Guideline 0, 0.5, 18.5, 50 ppm ~0, 0.25, 0.925, 2.5 mg/kg/day Parental toxicity: NOAEL = 0.925 mg/kg/day; LOAEL = 2.5 mg/kg/day: decreased body weight.

Developmental toxicity: NOAEL = 0.25 mg/kg/day; LOAEL = 0.925 mg/kg/day: decreased litter size, liver and spleen weights.

870.4100a Chronic toxicity

–
rat 00080390 (1970)

Acceptable/Nonguideline 0, 0.5, 1, 2, 5, 10 ppm
~0, 0.025, 0.05, 0.1, 0.25, 0.5 mg/kg/day (M & F) NOAEL = 0.1 mg/kg/day; LOAEL = 0.25 mg/kg/day: decreased leukocyte counts (M & F)

870.4100b Chronic toxicity

– dog 40285501 (1987)

0, 2, 6, 18 ppm

Classified as Reserved 0, 0.062, 0.206, 0.562 mg/kg/day (M) 0, 0.071, 0.213, 0.624 mg/kg/day (F) NOAEL and LOAEL > 0.562 mg/kg/day (M) 0.624 mg/kg/day (F). No effects at the highest

dose tested.

870.4200b 41087501 (1989) NOAEL < 0.85 mg/kg/day (lowest dose tested)

### Page 18 of 24

Table 6

- 

### Subchronic, Chronic and Other Toxicity Profile of Triphenyltin Hydroxide

.

Guideline No./Study Type MRID

No.(year)/Classification/Doses: Results

Carcinogenicity

–

mouse Acceptable/Guideline

0, 5, 20, 80 ppm 0.85, 3.50, 15.24 mg/kg/day (M) 0, 1.36, 4.56, 20.16 mg/kg/day (F) based on decreased in immunoglobulins. Particularly IgA and IgM in either males or

females.

Positive for hepatocellular adenomas and

carcinomas. Dose levels considered adequate.

870.4300

Combined chronic toxicity/carcino

genicity

- rat 41085702 (1989)

Acceptable/Guideline 0, 5, 20, 80 ppm 0, 0.3, 1.3, 6.2 mg/kg/day (M) 0, 0.4, 1.6, 6.2 mg/kg/day (F) NOAEL not established. LOAEL <5 ppm (lowest dose tested; 0.3 mg/kg/day, M; 0.4 mg/kg/day, F): deaths in

fem ales and decreases in immunoglobulins (IgG, IgG2a, IgG2c, IgA).

Positive for pituitary and testicular tumors. Dose levels considered adequate

870.5100

Bacterial reverse gene mutation test 00125264 (1981)

Acceptable/Guideline

0.3125

– 5 μg/plate +/

- S9 Salmonella typhimurium strains TA11535, TA1537, TA1538, TA98,

TA100

312.5

– 5000 μg/plate +/

- S9

Escherichia coli strain WP2 uvr A Not mutagenic in S. typhimurium or E. coli ± metabolic activation.

Gene mutation in

yeast 00152224 (1985)

Acceptable/Nonguideline 0, 0.05, 0.1, 0.5, 1.0 μg/mL

– S9 0, 1, 10, 50, 100 μg/mL +S9 Schizosaccharomyces pombe Not mutagenic ± metabolic activation up to cytotoxic concentrations (0.1 μg/mL

– S9; 100 μg/mL +S9)

870.5300

In vitro

mammalian cell gene mutation

test 00152226 (1985)

Acceptable/Guideline L5178Y Mouse lymphoma cells
0, 10, 15, 23, 30, 45, 60, 80, 100, 125, 150 ng/mL

– S9 0, 40, 70, 100, 150, 200, 250, 300, 400, 500, 600 ng/mL +S9 Borderline positive in the presence of S

- 9 mix but negative in absence of S

- 9.

870.5375

In vitro

mammalian

chromosome

aberration test 00152223 (1985)

Acceptable/Guideline Human lymphocytes 0, 0.03125, 0.0625, 0.125, 0.25, 0.5, 1 μg/mL

– S9 0, 0.25, 0.5, 1, 2 μg/mL +S9 Positive for inducing chromosome aberrations ±

S

- 9. Study demonstrates clastogenic property of

TPTH.

870.5385

Mammalian bone

marrow chromosomal

aberration test

in vivo 40371102 (1987)

Acceptable/Guideline

Chinese hamsters 0, 20, 50, 80 mg/kg (single gavage dose) Negative up to a dose that caused overt toxicity to the test animals and cytotoxicity to the bone marrow (80 mg/kg).

870.5395 00152225 (1985) Negative up to a dose (140 mg/kg) causing overt

### Page 19 of 24

Table 6

- 

### Subchronic, Chronic and Other Toxicity Profile of Triphenyltin Hydroxide

.

Guideline No./Study Type MRID

No.(year)/Classification/Doses: Results

Micronucleus

assay
in vivo NMRI

mouse bone

marrow Acceptable/Guideline

0, 35, 70, 140 mg/kg (oral gavage) High dose = 77% of LD 50 toxicity.

870.5450

Dominant lethal assay Sprague

Dawley rats 00125265 (1978)

Acceptable 0, 3, 20, 38, 150 mg/kg; consecutive 5 daily gavage doses and 10 successive matings f or 10 weeks Negative at up to 38 mg/kg/day. At 150 mg/kg/day, high rate of deaths.

870.5575 Mitotic gene conversion assay 00155521 (1985)

Acceptable/nonguideline Saccharomyces cerevisiae D4 0, 0.1, 1, 3, 5 μg/mL

– S9 0, 1, 5, 10, 15 μg/mL +S9 Negative in S. cerevisiae ± S

- 9 metabolic

activation.

870.5550

Unscheduled DNA synthesis in

mammalian cells 00155522 (1985)

Acceptable/Guideline Primary rat hepatocytes
0, 0.1, 0.025, 0.05, 0.1, 0.25, 0.5, 1.0, 2.0 μg/mL Negative up to cytotoxic concentrations
(≥ 1.0 μg/mL)

870.6200a

Acute neurotoxicity rat 45350301 (2001)

0, 10, 50, 75, 125 mg/kg, oral gavage Range finder study NOAL & LOAEL not determined. Most common clinical signs (all doses): palpebral closure, piloerection, rocking, lurc hing, swaying when walking, decreased urination and defecation (M& F). Findings occurred in a

dose

- related manner; peak effect observed at 4

- 6 hours for all treatment groups.

870.6200a

Acute neurotoxicity screening battery

rat 45299901 (2000)

Acceptable /Guideline 0, 5, 25, 75 mg/kg (M&F), oral gavage NOAEL = Not established. LOAEL = 5 mg/kg:

Clinical signs of toxicity (excessive grooming, increased activity on handling, and piloerection in both sexes).

870.6200b Subchronic (13 weeks) neurotoxicity screening battery

rat 45546001 (2001)

Acceptable/Guideline 0, 5, 20, 80 ppm dietary 0, 0.4, 1.4, 5.7 mg/kg/day (M) 0, 0.4,1.6, 6.1 mg/kg/day (F) NOAEL = 20 ppm (1.4/1.6 mg/kg/day in M/F)

LOAEL = 80 ppm (5.7/6.1 mg/kg/day in M/F): decreased body weight, bo dy weight gains, and food consumption (M&F). Decreased total and ambulatory motor activity in both sexes

870.6300 Developmental neurotoxicity study

rat 46055701 (2003)

Acceptable/Non

- guideline 0, 1, 2.5, 5 mg/kg/day, oral gavage Maternal

NOAEL = 1 mg/kg/day

LOAEL = 2.5 mg/kg/day: clinical conditions (i.e., pallor, piloerection, red discharge from the vagina, and low body temperature) requiring sacrifice in one animal; these conditions were similar to those seen in dams at the next higher

dose.

Neur otoxicity, manifested as different grades of:

### Page 20 of 24

Table 6

- 

### Subchronic, Chronic and Other Toxicity Profile of Triphenyltin Hydroxide

.

Guideline No./Study Type MRID

No.(year)/Classification/Doses: Results

ease of handling during functional observational battery (FOB), consisting of: reactivity, reduced rearing and activity levels at 5 mg/kg/day.

Offspring

NOAEL = 2.5 mg/kg/day

LOAEL = 5 mg/kg/day: decreased body weight and body weight gain

No adverse neurological effects on motor activity, auditory startle response, learning and memory, brain weights, brain morphology or neuropathology at any dose.

Special Study

Milk secretion study rat 45890101 (2003)

Acce ptable/Non

- guideline 0, 4 mg/kg single oral gavage Milk sampled at 0.5, 1, 3, 6, 24 hours

post

- dosing 0, 4 mg/kg/day for 10 days oral gavage Milk sampled at 6 or 24 hours post

dosing on Days 5 or 10 and on Day15. Systemic effects: No effects of treatment observed on clinical signs, mortality or body weight.

Transfer to milk: No detectable residues found in samples from lactating rats.

Mean concentration

Study Day 5

6 hrs

- Mean conc. parent TP T H = 0.05 μg/mL

Total TPTH (plus metabolite) = 0.06 μg/mL

24 hrs

- parent TPTH below the limit of detection (LOD = <0.02 μg/mL)

Study Day 10

6 hrs

- Mean conc. parent TP T H = 0.09 μg/mL

Total TPTH (plus metabolite) = 0.10 μg/mL

24 hrs

- parent TPTH below the limit of detection; total TPTH = 0.03 μg/mL.

Study Da y 15

No TPTH or its metabolite found in milk.

Data indicate that TPTH is transferred to the milk of lactating dams at the maximum low level of 0.09 μg/mL after receiving multiple daily oral doses of 4 mg/kg/day for 10 days.

870.7485

General

metabolism (several studies 1986 to 1989) Six studies 1986 to 1989:

41387201

41309101

41309102

40029405

40029406

40029407 Acceptable The contributions from six studies combine to meet the general metabolism requirement for

TPTH. The 14 C studies are confounded by t he fact that the labeled phenyl group splits off and the fate of the parent compound is not followed. Thus, the labeled phenyl may be excreted in the urine but this does not represent excretion of

intact TPTH. The 113 Sn labeled TPTH studies

follow the fa te of the tin although this may be as triphenyl, diphenyl or monophenyl or as tin itself. The biliary route is the most important in

excretion of 113 Sn from TPTH. Most of the

### Page 21 of 24

Table 6

- 

### Subchronic, Chronic and Other Toxicity Profile of Triphenyltin Hydroxide

.

Guideline No./Study Type MRID

No.(year)/Classification/Doses: Results

label (80

- 100% in several studies) is recovered

in the feces. Little remains i n tissues (for example, ≤ 0.5%). After 24 hours, the kidneys, liver epididymis and brain had the most label. After 7 days, little remained in the tissues [highest content was in the liver: (0.1356 μg equivalents/gm in M and 0.1612 μg equivalents/gm in F) ]. The major metabolites of TPTH, which are the same in plants and animals, are diphenyl and monophenyl tin. Both of these metabolites are of toxicological

concern.

870.7600 Dermal penetration

rat Several studies 1986 and 1987

00156684

40073001

40198301 Acceptable Studies demonstrate that TPTH adheres to the skin and only a small percentage (<1%) is absorbed in 10 hours. The TPTH remaining on the skin can potentially be absorbed over time. Because of complications involved with

adherence to th e skin, a dermal absorption factor of 10% was derived by comparing the oral and dermal developmental toxicity studies.

870.7800 Special Immunotoxicity Studies (28 days) Dietary Several studies 1982 to 1990

41518200 (1990) Acceptable

Rats 0, 0.07, 0.34 1.71, 3.37, 8.16 mg/kg/day (M)
0, 0.07, 0.37, 1.82, 3.4, 8.32, mg/kg/day (F)

Mice 0, 0.19, 1.00, 4.64, 8.80, 20.21 mg/kg/day (M)
0, 0.23, 1.15, 5.46,10.04, 21.48 mg/kg/day (F)

----------------------------------------------- 40 200301 (1986)

Unclassified

0 , 2.5 mg/kg/day 10 consecutive days (Female Wistar rats); oral gavage In rats (41518200): NOAEL = 1.82 mg/kg/day; LOAEL = 3.4 mg/kg/day: decreases in IgG. At higher doses: decreased spleen weight, white blood cells (WBCs) and circulating lymphocytes.

In mice NOAEL = 0.23 mg/kg/day, LOAEL = 1.15 mg/kg/day: decreased spleen weight absolute and relative. At higher doses: decreased IgM, WBC, neutrophils and circulating lymphocytes.

--------------------------------------------------------- - Systemic:

No adverse effects

Immunosuppression: No evidence of increased susceptibility to

T riticella spiralia.

1 Classified on a trial basis by HIARC (see HIARC, 1998).

2 Selected by HIARC as the most representative rat de velopmental studies with TPTH. Initial concerns for hydronephrosis and hydroureter, which were observed in this study, were removed by the data from subsequent studies that did not demonstrate this effect (HIARC, 1998).

### Page 22 of 24

Table 7 A

- 

### Triphenyltin Hydroxide : Summary of Toxicological Doses and Endpoints for Use in Dietary and Non

- Occupational Human Health Risk Assessments.

Exposure

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level

of Concern for

Risk

Assessments Study and Toxicological Effects

Acute Dietary

– Females 13+ NOAEL =

0.3 mg/kg/day UF A = 10

UF H = 10 FQPA SF = 3X Acute RfD =

0.00 3 mg/kg/day

aPAD = 0.001 mg/kg/day Developmental Toxicity Study in

Rabbits (MRID 40104801) LOAEL = 0.9 mg/kg/day based on lower fetal body weight and

increased incidents of unossified hyoid body and/or arches in rabbit

fetuses

Points of Departure not previously selected for this exposure scenario

Chronic Dietary (All populations) NOAEL =

0.1 mg/kg/day UF A = 10

UF H = 10

UF D = 3 a
FQPA SF = 10X Chronic RfD =

0.0003 mg/kg/day

cPAD = 0.00003 mg/kg/day Chronic feeding

– Rats

(MRID 00080390) LOAEL = 0.25 mg/kg/day based on decreased leukocyte counts

Incidental Oral

Short

- Term (1

- 30 days) Points of Departure not previously selected for this exposure scenario

Incidental Oral

Intermediate

- Term (1

- 6 months) Points of Departure not previously selected for this exposure scenario

Dermal Short

Term (1 to 30 days) and

Intermediate

- Term (1 to 6 months) NOAEL = 3

mg/kg/day UF A = 10

UF H = 10 FQPA SF = 10X Residential LOC

for MOE = 100 0 Dermal Developmental toxicity

–

Rabbits (MRID 42909101) Maternal and developmental: LOAEL = >3 mg/kg/day. No effects at highest dose tested.

Dermal Long

Term (> 6 months) Use pattern does not indicate that exposure will be for this interval.

Inhalation Short

Term (1 to 30 days) and

Intermediate

- Term (1 to 6 months) NOAEL =

0.00034 mg/L UF A = 10

UF H = 10 FQPA SF = 10X Residential LOC

for MOE = 100 0 Subchronic Inhalation toxicity

- Rat

(MRID 41011701) LOAEL = 0.02 mg/L based on death and respiratory irritation and edema.

Inhalation Long Term (> 6 months) Use pattern does not indicate that exposure will be for this interval.

Cancer (oral, dermal, inhalation) Oral Q 1 * = 1.83

(mg/kg/day) - 1 TPTH is classified as a B2 Carcinogen, Probable Human Carcinogen based on pituitary

and testicular tumors in rats and liver tumors in mice. A dermal absorption factor of

10% should be used for this risk assessment b . An inhalation absorption factor of 100%

should be used for this risk assessment.

### Page 23 of 24

Table 7 A

- 

### Triphenyltin Hydroxide : Summary of Toxicological Doses and Endpoints for Use in Dietary and Non

- Occupational Human Health Risk Assessments.

Exposure

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level

of Concern for

Risk

Assessments Study and Toxicological Effects

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. UF = uncertainty factor. FQPA SF = Special FQPA safety factor. PAD = population adj usted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of

exposure.

a UF D = Database Uncertainty Factor; HIARC recommended that in addition to the inter

- species extrapolation and the intra

species variation an extra 3X be applied becaus e of the instability of the test material in the diet in the 1970 study (MRID 00080390) and because of the potential for increased mortality in the 1989 study (MRID 41085702) near the LOAEL (Doherty and Rowland, 1998).

b Based on a comparison of the LOAELs from the oral developmental toxicity test in rabbits and the dermal developmental toxicity test in rabbits.

### Page 24 of 24

Table 7B

- 

### Triphenyltin Hydroxide: Summary of Toxicological Doses and Endpoints for Use in Occupational Human Health Risk Assessments.

Exposure

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level

of Concern for

Risk

Assessments Study and Toxicological Effects

Dermal Short

Term (1 to 30 days) and

Intermediate

- Term (1 to 6 months) NOAEL = 3

mg/kg/day UF A = 10

UF H = 10 FQPA SF = 10X Occupational

LOC for MOE =

100 Dermal Developmental toxicity

–

Rabbits (MRID 42909101) Maternal and developmental: LOAEL = >3 mg/kg/day. No effects at highest dose tested.

Dermal Long

Term (> 6 months) Use pattern does not indicate that exposure will be for this interval.

Inhalation Short

Term (1 to 30 days) and

Intermediate

- Term (1 to 6 months) NOAEL =

0.00034 mg/L UF A = 10

UF H = 10 FQPA SF = 10X Occupational

LOC for MOE =

100 Subchronic Inhalation toxicity

- Rat

(MRID 41011701) LOAEL = 0.02 mg/L based on death and respiratory irritation and edema.

Inhalation Long Term (> 6 months) Use pattern does not indicate that exposure will be for this interval.

Cancer (oral, dermal, inhalation) Oral Q 1 * = 1.83

(mg/kg/day) - 1 TPTH is classified as a B2 Carcinogen, Probable Human Carcinogen based on

pituitary and testicular tumors in rats and liver tumors in mice. A dermal absorption factor of 10% should be used for this risk assessment a . An inhalation absorption factor of 100% should be used for this risk assessment.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. UF = uncertainty factor. FQPA SF = Special FQPA safety factor. PAD = population adj usted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of

exposure.

a Based on a comparison of the LOAELs from the oral developmental toxicity test in rabbits and the dermal developmental toxicity test in rabbits.