Page | 2

Executive Summary

The Antimicrobial Division ( AD ) Regist ration Review Team ha s evaluated the status
of the human health assessments for the active ingredient Tetrakis (hydroxymethyl) phosphonium sulfate (THPS) (PC Code 129058 ) for the purposes of registration review

. THPS was first registered in 1995 and a Registration Eligibility Decision (RED) document has not yet been initiated . A RED is not require d for chemicals registered after November 1, 1984. This document examines the hazard and exposure databases for the registered antimicrobial uses and the applicable human health risk a ssessments the Agency expects to conduct. The antimicrobial use categories for THPS include material preservatives uses, and the industrial processes and water systems uses

THPS is also used to control bacteria, fungi, and algae in industrial and/or

comm ercial recirculating cooling systems, industrial process water, heat transfer systems, oil field operations, oil and gas pipelines, drilling muds, and packer fluids as well as a preservative in water based coatings, pigments, and slurries. There are curre ntly 15 registered products. The concentration of active ingredient is between 20% and 78%.

THPS is most often used as a microbiocide/slim ic ide that is used to control bacteria, fungi, and algae in the manufacture of paper and paperboard products and ad hesives that

do not contact food

. However, some e nd use product s can also be used on emulsions that are applied to food

- contact paper and paperboard

. Therefore, indirect dietary exposure to food could be expected based on the use. An FDA clearance was no t identified. Although likely to be infrequent, dietary exposures via drinking water may occur and assessments

will be needed based on release to surface water from recirculating cooling towers. Upon receipt and review of the environmental fate data the A gency anticipates requiring, the Agency will determine the need for a down

- the

- drain drinking water assessment.

The Agency has reasons to believe that THPS may be a formaldehyde releaser (see D383030 for additional details)

. According to a recent EPA revi ew (D383030), t he formula of this chemical is such that it is likely to release formaldehyde because it contains hydroxymethyl group, which is an essential part which will produce formaldehyde , and the degradation products in aquatic medium are t rihydroxym ethyl

p hosphine (THP) molecules which are formed by releasing two formaldehyde ( HCHO )

molecules

.

The Agency does not have the emissions (e.g. air chamber) data to estimate potential

concentrations of formaldehyde released in to air under various condition s

. The Agency will likely need further data to determine the extent of the THPS degrad ation i n air to
form formaldehyde and THP

. If EPA identifies that THPS is in fact a formaldehyde releaser, EPA may also need to develop additional inhalation risk assess ments to assess the contribution of formaldehyde on the overall aggregate risk from all sources

.

There are no pesticide food use tolera nces for the active ingredient for these indoor

nonfood uses nor are any tolerances needed since the paper and paperbo ard use is supported by FDA under Section 409 of the Federal Food, Drug, and Cosmetic ActPage | 3

(FFDCA). However, exemptions and regulations for food additives under Section 409 of the Federal Food, Drug, and Cosmetic Act (FFDCA) do not relieve the registrant of meeting the standard under Section 408 as amended by the Food Quality Protection Act (FQPA). “Under Section 408, a determination of safety for residues of a pesticide that may be in food is required, and as defined in Section 408(b)(2)(ii), “that there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for

which there is reliable information.”

The primary source of informatio n for this assessment is the Agency risk assessments and supporting documents to support registration, which were finalized in 1995. The purpose of this screen is to determine whether sufficient data are available to support registration review, identify applicable exposure scenarios, and to report whether new human health assessments are needed to support the registration review process.

Anticipated Data Needs The Antimicrobial Division (AD) anticipates the need for additional human health data

for T HPS

.

A 90

- day i nhalation toxicity study (Series 870.3465) will be needed.

Risk Assessments

The Agency will conduct several risk assessment for THPS. The risk assessments are

outlined below:

Occupational exposures to THPS are likely a result of exp osures from open pour and pump liquid exposures to mixer/loaders.

Since THPS is also formulated into preservative coatings, pigments and slurries, the Agency also assumed that THPS is an in

- can preservat ive in paints, thus triggering the need for occupat ional and residential risk assessments from the application of paint (e.g. brush/roller, and airless sprayer) is expected. If formaldehyde is present in sufficient quantities in THPS formulated paint, then an inhalation post

- application assessment would li kely be needed to assess the inhalation risks of formaldehyde EPA will likely reevaluate the indirect food uses (e.g. paper and paperboard, water based coatings, pigments, etc.) and will conduct a new acute and chronic dietary assessment during registratio n review. Since the product is used in commercial recirculating cooling water systems, the Agency anticipates that the effluent wastewater could discharge directly to surface water. As a result, the Agency would need to model environmental concentrations in the surface water and develop a drinking water human health risk assessment. During registration review, the Agency anticipates that additional environmental fate data will also be needed [see Environmental Fate and Ecological Assessment (D383030)] to assess the need to conduct a down the drain drinking water human

health risk assessment.Page | 4 The Agency expects to conduct an aggregate risk assessment that will include residential, dietary and drinking water exposures.

Section 1. Chemical Identit y

The available data indicates that THPS is practically insoluble in water, soluble in commercial solvents, and has low vapor pressures (~1E

- 5 mm Hg)

. Table 1 presents the identity of THPS

.

Table 1

. Chemical Identity of THPS

Common

Name Tetrakis (hydro xymethyl)phosphonium sulfate (THPS)

CAS name Tetrakis (hydroxymethyl)phosphonium sulfate

PC Code 129058 CAS registry

number 55566

- 30

- 8

Registration

Review Case

No. 5034

Structure

Section 2. Toxicology

The Agency reviewed the toxicity database for THPS

. Most of the available data was submitted during the initial registration in 1995. No new toxicity s tudies have been

submitted since the first registration.Page | 5

Acute Toxicity

T he acute toxicity data are considered adequate for reregistation and for registration

review. According to Agency records , the combined acute LD50 is 575 (519

- 637) mg/kg

and is as signed as oral toxicity category III (MRID 4382001). The acute dermal LD50 is >2000 mg/kg and is assigned as a dermal toxicity category III (MRID 42236306). The acute inhalation LC50 is 0.591mg/L(combined) and is assigned as an inhalation toxicity

catego ry III (MRID 46659905). THPS is a primary eye irritant and the toxicity category assigned is toxicity category I for eye irritation (MRID 46659906). However, it should be noted that it is rated toxicity category IV for dermal irritation (MRID 46659907). THPS is classified as a strong dermal sensitizer in the guinea pig (MRID 43282003). ). However, EPA noted in their review (D257896), that “THPS is a significant eye irritant, and, although it does not display dermal irritation after a single exposure, a 28

- day dermal toxicity in rats (MRID 42236310) has demonstrated significant dermal irritation after five applications of the technical test material (75% a.i.).

Sub

- chronic Toxicity

Dermal Toxicity

A 28

- day dermal range

- finding rat study was conducted a t doses of 25, 25 0, or 500 mg/kg/day (MRID 422363

- 10). Due to severe irritation at the application sites, all mid

and high

- dose animals were euthanatized after 4

- days of treatment . At 25 mg/kg/day there was a 25% reduction in male body weight, an effec t which may be due to primary toxicity or could have been a secondary effect due to dermal irritation. The dermal

irritation induced included moderate to severe erythema and edema. Additional dermal

tests were waived based on the irritation effects for the mid and high dose level rats

.

EPA noted in their review that this finding was inconsistent with the results of the acute dermal toxicity study (Toxicity Category III) , which indicated that the LD50 was >2,000 mg/kg and also the primary dermal irritatio n study which concluded the compound was non

- irritating (Toxicity Category IV

Inhalation Toxicity

There are no inhalation toxicity studies available. A 90

- day i nhalation toxicity study ( Series 870.3465) will likely be needed to assess aerosolized exposu re of paint

. Note that

this toxicity may not b e necessary if the use of THPS in water based coatings, pigments

, slurries are not used in paints and the registrant can demonstrate that THPS will not be aerosolized in the other occupational uses for paper, p aper board and oil field operations.

Developmental Toxicity

In a prenatal developmental toxicity study (MRID 422364

- 14) of rats, THPS was admin istered by gavage to 3 groups of 2 4 rats/dose at dose levels of 15, 30 and 60 mg/kg/day, respectively, from g estation day s (GD) 6 to 15. Maternal toxicity was noted

in the 3 0 mg/kg/day and 60 mg/kg/day groups in the form of salivation and brownPage | 6

staining , liver mottling, body weight gain, and pale livers. At the high dose, severe distress, body weight gain, liver mottling was also noticed. Evaluation of developmental toxicity in the progeny of the high dose female rats revealed a decrease in body weight of the liter, and a n increase in the number of fetuses born with extra thoracolumbar ribs. The

maternal NOAEL is 15 mg/kg/day

In another prenatal developmental toxicity study (MRID 41615002 ) in rabbits

, THPS

was administered orally at 6, 18, and 60 mg/kg/day from days 6

- 15 of gestation. There was an increase incidence of external/malformation s in high dose rats. These include eye abnormalities, limb malformations, and cardiac malformations. The increase in skeletal variations was significantly increased. The maternal and developmental NOAEL was 18 mg/kg/day.

Mutagen i city

T he Agency identified several mutagenic ity studies . The studies all did not indicate that THPS was mutagenic. The mutagenic battery included two acceptable in vitro

ames test s ( MRID 44135505 and MRID 4 6659908 ) (GDLN 870.51 0 0)

, two acceptable

in vitro mammalian cell gene mutation studies (M RID 44135502 and MRID 44135504) (GDLN 870.5300), and two acceptable in v itr o cytogenetics test s in Chinese hamster

ovaries (MRID 42236318 and MRID 44135503) (GDLN 870.5375) . In addition

, an in

vivo unscheduled DNA synthesis test in rat hepatocytes (MRI D 4223617 and 43312201) (GDLN 870.5550) and a gene mutation study in Salmonella and E. Coli (MRID 42236316) (GDLN 870.5140) w ere also submitted

.

Chronic/ Carcinogenicity

A National Toxicology Program (NTP) study dosed rats and mice with oral gavage

a dministration at doses 0, 5, 10 mg/kg/day of THPS for 104 weeks. Liver effects such as cytoplasmic vacuolation was noted in both male and female rats and cystic degeneration

of the liver were noted in male and female mice . Other effects noted were hyper plasia of the bone marrow, leukemia , adenomas of the anterior pituitary, focal hyperplasia in the adrenal medulla. The NTP concluded there was no evidence of carcinogenicity

.

Reproduction

The submitted study ( MRID 45320801 and MRID 45615801) examined th e effect of THPS on reproduction and fertility in rats at dose levels of 0, 1.0, 7.5, and 15.0 mg/kg over two generations. Organ weights were affected at the 15 mg/kg/day dose level, and included an increase in liver weight for P generation females and F1 generation males and females. The increase in liver weight corresponded with histopathological alterations at the 15 mg/kg/day dose level, which included periportal hepatocyte enlargement, periportal hepatocyte vacuolation, bile duct proliferation, and f ocal hepatocyte necrosis. These effects were observed also at the 7.5 mg/kg/day dose and were considered

treatment

- related, as there was a dose

- response between the 7.5 and 15.0 mg/kg/day dose

levels. Reproductive performance and fertility were not signi ficantly affected in parental animals of either generation. Although viability index was in the range of 70

- 80%, this value is not atypical for the rat. The NOAEL assigned for systemic effects was 1Page | 7

mg/kg/day , based upon the histological alterations of the liver observed in both parental generations at the 7.5 mg/kg/day dose. The reproductive toxicity NOAEL is provisionally determined to be > 15 mg/kg/day, and the reproductive toxicity LOAEL is provisionally determined to be > 15 mg/kg/day, as there wer e no significant effects observed in offspring at any dose level tested in this study.

Toxicology of Formaldehyde

Since the release of formaldehyde may be a ssociated with the use of THPS , the exposure and risk associated with the formaldehyde release d as a result of registered

THPS uses must be assessed. The characterization of formaldehyde toxicity and the selection of endpoints for risk assessment were included in the Formaldehyde RED

.

At the time of the RED, there was uncertainty regarding the a pproach for the assessment of the cancer risks and it was anticipated that these uncertainties would be resolved upon completion of the IRIS update for formaldehyde. As an interim measure, the cancer risks were presented as range based on the existing IR IS unit risk and the

results of CIIT model runs.

There were also uncertainties regarding the selection of the non

- cancer endpoint because an evaluation of formaldehyde was also being conducted by OPPT and NCEA to evaluate a petition regarding formalde hyde emissions from pressed wood. As discussed

in the Response to Public Comments on the F ormaldehyde Preliminary Risk

Assessment (EPA, 2009) t he following disclaimer was provided for the non

- cancer formaldehyde inhalation endpoint that was selected by OP P for use in the RED:

OPP developed the formaldehyde inhalation noncancer toxicological endpoint used in this RED through the established reregistration process, which includes stakeholder consultation and public comment. However, the result has not bee n subjected to an interagency review or external peer review. Because of time constraints imposed by statutory deadline, OPP could not consider all available peer

reviewed science (for example, the intentional human dosing toxicity studies). Thus,

this v alue should be considered an interim value, developed solely for the purposes of this determination and subject to future revision and subsequent peer review and should not be used in other contexts as EPA's opinion of the best available science on

the non

- cancer effects of formaldehyde.

Section 3. Dietary Assessment

Dietary

A dietary risk assessment was conducted during registration to examine the indirect

food use exposures for food contact paper and paper board . According to the dietary risk

assess ment, THPS fulfilled the FIFRA/FQPA requirement of no harm” a registration

decision (D257896 and D281630 ) and EPA concluded that dietary r isks were acceptable. Although a dietary risk assessment has been done during registration, EPA will likely

reevaluat e the indirect food use s (e.g. paper and paperboard, water based coatings,Page | 8

pigments, et c .) and exposures and toxicological endpoint and conduct a new acute and

chronic dietary assessment during registration review.

Drinking Water

Since THPS is used in industrial process water, heat transfer systems, oil field operations, oil and gas pipelines, drilling muds, and packer fluid, the Agency expects that

it could migrate to groundwater and surface water and then on to drinking water

. Although likely to be i nfrequent, dietary exposures via drinking water may occur in the

event of a down

- the

- drain discharge. The c ontaminated water could pass through wastewater treatment facilities into the drinking water or may be discharged directly to

surface water which is later treated . Howeve r, at this time there are no environmental fate data to determine whether THPS can pass through wastewater treatment facilities into drinking water or migrate into residential groundwater wells as a result of its current use

patterns. Upon receipt and review of the environmental fate data the Agency anticipates requiring, the Agency will determine the need for a down

- the

- drain drinking water

assessment.

In addition, since the product is used in commercial recirculating cooling water

s ystems, the Agency anticipates that the effluent wastewater could discharge directly to surface water. As a result, t he Agency would need to model environmental concentrations and develop a drinking water risk assessment

.

Section 4 . Occupational /Reside ntial Exposure

An occupational and/or residential exposure assessment is required for an active ingredient if (1) certain toxicological criteria are triggered and (2) there is potential exposure to handlers (mixers, loaders, applicators, etc.) during use or to persons entering treated sites after application is complete. For THPS , the Agency needs to select toxicological endpoints before a risk assessment can be conducted. The Agency also anticipates needing to conduct occupational dermal and inhalation risk assessments once

the needed exposure data has been submitted, reviewed, and accepted by the Agency.

Based on the available use information, AD concludes that there is potential exposure to occupational handlers from open pour/pump liquid applicati ons for the uses in industrial processes and water systems uses and material preservative uses . In addition,

since THPS is found as a material preservative in water based coatings, pigments and slurries, EPA typically assumes that THPS could also be used as an in

- can preserv ative in paints even though this application is not stated in the existing registered labels

. The Agency will need to confirm whether or not the manufacturer of paints is allowed. Currently the label does not prohibit this use. Thus, th e Agency will need to assess this

use. If painting use is prohibited, the Agency anticipates that this data will not be needed

.

Until the labels prohibit the paint use , the Agency will assume THPS could be used on paints. Therefore, both occupational a nd residential application techniques typically associated with painting exposures (pump/pour liquids, brush/roller, and airless sprayer)

will be assessed using the labeled rates typically used to preserve the water basedPage | 9

coatings, pigments, and slurries

. AD will assess residential handler exposure to paints assessing applications to brush/roller and airless sprayer.

Product use data provided by the registrant will be useful to clarify whether THPS

added to water based coatings, pigments, and slurries are later formulated into paints. Based on product use data, the Agency may later decide to refine the risk assessment
scenarios and to refine ex posure assessment assumptions. If label prohibitions on paint use are put into effec t then the Agency anticipat es that painting exposure data will not be

necessary

.

If a painting situation exists, t he Agency anticipates that there also may be a potential

inhalation occupational and residential post

- application exposure assessment to the degrad ate formaldehyde. Ot her inhalation post

- application exposures to THPS or from formaldehyde for use s such as oil drilling are expected to be minimal. Dermal post

application exposures for water

- treatment and other material preservation uses such paper manufacturing or oil dril ling are likely to be minimal for THPS or formaldehyde.

Hander Exposure

Occupational Handlers

The Agency identified potential occupational handler exposures for THPS from existing registered uses on the label . The potential occupational handler risk a ssessments (both short

- term (1

- 30 days) and intermediate

- term (>30 days) ) by scenario that the Agency expects to conduct during registration review include:

Short

- term and Intermediate

- term Exposures

Mixing/loading liquids for water treatment and wastewa ter systems (closed and open pour) , and oil field operations for short

- term and intermediate

- term dermal

and inhalation exposure ; Mixing/loading liquids for material preservatives in slurries (closed and open pour) such as paper and paperboard or paint for short

- term and intermediate

- term

exposures ; and

Short

- term Exposures *

Application of in

- can preservative in paints (brush/roller and airless sprayer) resulting in dermal and inhalation exposures

.

The methods of direct application include liquid pour and liquid pump

, brush/roller, and airless sprayer of paint

.

Residential Handlers *

Residential handler exposure (dermal and inhalation) can occur through the application of THPS preservative coatings via paintbrush /roller or sprayer application forPage | 10

pa inting . The Agency expects to conduct residential handler risk assessments for these scenarios and the Agency is likely to conduct risk assessment s only of short

- term duration (1

- 30 days).

* Note that if the material preservatives used in coatings, pigmen ts and slurries are prohibited for the use in paint products, the Agency anticipates that these exposures awill not be necessary.

Postapplication Exposure *

Although the vapor pressure of THPS is relatively low ( 1.7 x 10 - 3 Pa at 25 °C [ 1.3E

- 5

torr at 25 °C ] ), the Agency has concerns that THPS can hydrolyze to form formaldehyde.

If this is the case , the Agency anticipates the need to evaluate formaldehyde exposure resulting from the use of THPS treated paints and assess the postapplication inhalation

risk from interior applications involving latex primer/paint. However, the Agency at this time does not have data to ascertain the actual amount of formaldehyde in the preserved paint based on the current lack of hydrolysis data or air monitoring data. The Agen cy will require chamber tests to identify emissions of THPS and formaldehyde. Actual THPS and formaldehyde monitoring data or air chamber studies could be used to refine the exposures and risks estimated in this assessment. Without actual air monitoring da ta or hydrolysis data , AD may need to assume that 100% formaldehyde formation may occur from releases of THPS

. A study is needed to ascertain the actual amount of formaldehyde formation in the preserved paint needed in order to estimate a more

accurate ex posure values. Dermal post

- application exposures for uses such as water

treatment and material preservation are likely to be minimal.

* Note that if the material preservatives used in coatings, pigments and slurries are not used for paint products, posta pplication inhalation assessment of THPS or formaldehyde

emissions resulting from THPS in paint will not be necessary.

Section 5

. Aggregate and Cumulative Exposure

In examining aggregate exposure, EPA takes into account the available and reliable

infor mation concerning exposures to pesticide residues in food and drinking water, and

non

- occupational pesticide exposures

. F ood exposures of concern are not anticipated as a

concern based on the fact that THPS is not expected to be introduced into the food; t here are no food use tolerances, no registered food uses and no indirect food uses.

The Agency expect s that it will need to conduct a residential assessment to examine application exposure to paint

. In addition, a dietary assessment will also be conduct ed

based on indirect food uses and as well as a drinking water assessment

. The Agency expects to conduct an aggregate risk a ssessment that will include residential , dietary and drinking water exposures

.

Section 408(b)(2)(D)(v) of FFDCA requires that, whe n considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information”Page | 11

concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity.” EPA has n ot yet determined

whether THPS has a common mechanism with other compounds , consequently a cumulative assessment will not be performed

.

Section 6 . Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adver se outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These

studies inclu de endpoints which may be susceptible to endocrine influence

, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For

e cological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part

of its registration decision

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

E PA 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 produced by a “naturally occurring estrogen, or other such endocrine effects as

the Administra tor 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 identify 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 will proceed to the next stage of the EDSP where EPA will determine which, if any, of the

T ier 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 establish 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 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. TH PS 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 assay s for THPS. 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/

.

Section 7

. IncidentsPage | 12

There has been one reported human incidents in the OPP database that has been associated with exposure to THPS and appears to be a result of a misuse

.

Section 8 . Anticipated Data Needs

The Antimicrobial Di vision (AD) anticipates the need for additional human health

data for THPS . The Agency expects to need the following toxicology study (utility and rationale provided in Appendix A).

Toxicology Data Needs

AD anticipate s that a 90

- day i nhalation toxicity study (Series 870.3465) will be

needed.

Occupational and Residential Exposure Data Needs

AD anticipates the need for the following occupational and residential exposure

data for THPS :

Dermal Exposure (Outdoor and Indoor) (GDLN 875.1100 and 875.1200)

I nhalation Exposure (Outdoor and Indoor) (GDLN 875.1300 and 875.1400) Data Reporting and Calculations (GDLN 875.1600) , and
Product Use Information (GDLN 875.1700)

Post Application Exposure Data Needs

If sufficient quantities of THPS degradate are identifi ed in a hydrolysis study, the Agency may also need air monitoring data and will likely call in the following data to examine THPS and formaldehyde inhalation exposure. The studies anticipated as needed would

be:
(GDLN 875.2500 ) Inhalation Exposure
(GDLN 8 75.2700 ) Product Use Information , and
(GDLN 875.2900 Data Reporting and Calculations

.

Section 9 . Tolerances

There are no pesticide food use tolerances for the active ingredient for these indoor nonfood uses nor are any tolerances needed since this use is supported by FDA under Section 409 of the Federal Food, Drug, and Cosmetic Act (FFDCA). However, exemptions and regulations for food additives under Section 409 of the Federal Food, Drug, and Cosmetic Act (FFDCA) do not relieve the registrant of meet ing the standard under Section 408 as amended by the Food Quality Protection Act (FQPA).

It should be noted that a food contact substance notification (FCN No. 955) was submitted by the registrant to FDA on 6/17/2010 to allow THPS at levels not to exceed 400 ppm in water based coatings, starches, pigments, and filler substances. THPS is also

registered by FDA in 21 CFR §176.300 as a slim i cide in paper/paperboard at a m aximumPage | 13

use level of 84 mg/kg in the pulp slurry. The additive may also be added to wate r, which when introduced into the pulp slurry, results in a concentration in the pulp slurry not to exceed 84 mg/kg. The registered labels with paper and paperboard uses state that the concentrations of THPS in the registered p aper and paperboard products cannot exceed

84 ppm.

Section 10 . Overall Conclusions

The Agency reviewed the hazard and exposure databases for THPS and anticipate s that additional toxicology and exposure data will be needed

. In addition, the Agency anticipates additional environme ntal fate data will also be needed [ see Environmental Fate and Ecological Assessment (D383030)] to assess the need to conduct a down the drain drinking water assessment

. Depending on the outcome of the review and acceptance of the new exposure and toxicolo gical data, the Agency anticipates the need

t o conduct new occupational and residential handler assessments . Depending on the outcome of the review and acceptable of new environmental data and water modeling, the Agency anticipates the need to conduct new drinking water assessments for registration

review

. If formaldehyde is present in sufficient quantities in THPS formulated paint

, then an inhalation postapplication assessment would likely be needed to assess the inhalation risks of formaldehyde

. Finally, t he EPA also anticipates that dietary and

aggregate assessment s will be needed to ensure that THPS registration review case meet s the safety standards established by FFDCA, as amended by FQPA.

Section 1 1 . Reference

D383030. Summary of the Tetrakis (h ydroxymethyl) phosphonium sulfate (THPS) Product Chemistry, Environmental Fate, and Ecotoxicity Data for the Registration Review Decision Document. Memorandum from Najm Shamim, U.S. EPA to Eliza Blair, U.S. EPA. January 1 2 , 2011.

D257896 . Tetrakis (hydro xymethyl) phosphonium sulfate (THPS) . Risk assessment for use of the active ingredient in manufacturer of food contact paper. Memorandum from T. McMahon, Ph.D. to M.Swindell, U.S. EPA.Appendix A: Toxicity Guideline Study Justifications

Guideline Numbers : 870. 3465 Study Titles: 90

- day I nhalation T oxicity S tudy Rationale for Requiring the Data The Agency does not have a full picture of the potential effects which THPS could occur as a result of exposure via the inhalation route. The needed study whic h was not previously available would provide insight into concerns regarding toxicity via the inhalation route. It may also provide a toxicity endpoint applicable to an inhalation risk assessment. The Agency previously used an oral toxicological endpoint from a maternal toxicity endpoint from a developmental study and assumed 100% absorption. Inhalation exposure is high for workers who apply paint through airless sprayers and brushes. These applicators would likely to be exposed to aerosols from paint app lications. In addition, a n inhalation study is required to address uncertainties around the inhalation toxicity to refine the Agency’s risk assessment. Currently for inhalation exposures an extra 10 X uncertainty factor is added for a lack of an inhalati on toxicity endpoint. The study may result in a change in how risks are quantified and removal of a 10X uncertainty. The data would allow the Agency to conclude more definitively whether or not there would be any concerns for inhalation toxicity in the ra t. This would provide a more complete hazard characterization of THPS in regards to the potential risks to the U.S. general population.

Practical Utility of the Data

How will data be used? An inhalation study may result in changes to the endpoints and how the risks are quantified.

How could the data impact the Agency’s future decision

- making? The study would form the foundation for hazard characterization and toxicity endpoints selection for risk assessment through all exposure routes (oral, inhalat ion, and dermal). The data would allow the Agency to conclude more definitively whether or not there would be any concerns for

inhalation toxicity in rodent species. It is possible that the database uncertainty factor be reduced or removed, resulting in different magnitude of the value of the endpoint used for regulation. . In many cases, toxicity observed via the inhalation route is higher than toxicity observed via oral exposure, which means that the route

- to

- route extrapolation used in the RED risk as sessment
could have resulted in an underestimation of risks from inhalation

. It is particularly important to properly assess inhalation risks for THPS because there is high inhalation exposure for workers applying paints.Page | 15

Appendix B: Exposure Guideli ne Study Justifications

Guideline Numbers: 875.1100 and 875.1200 Study Titles: Dermal Exposure (Indoor and Outdoor) Rationale for Requiring the Data
Note: Dermal exposure data are needed for both residential and occupational uses. The selection of an outdoor versus an indoor site is based on the high end exposure scenario. In almost all cases, repeating an exposure study for the same scenario outdoors and indoors is not necessary.

The potential for dermal exposure is very likely for exposure scenari os involving open pouring liquids and painting applications . The existing CMA data base and PHED for these scenarios are limited in scope for QA/QC and number of monitoring units. EPA presented the need for additional handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that additional data

are warranted.

The criteria for the dermal exposure data are based on the potential for dermal exposure from the labeled uses (e.g., occupational workers using paints and leather working fluids ) and evidence of toxicity. If the toxicological endpoints from THPS are used to assess the risks, there is an endpoint

selected for the dermal route

Practical Utility of t he Data

1. How will the data be used?

The dermal exposure data will be used to assess dermal exposures from open pouring of preservatives and application of paints . For occupational uses, the dermal exposure data will be

used to assess the short

- , and intermediate

- term exposures. The dermal exposure data will be used to determine the accuracy of the dermal risks to both residence and occupational workers.

2. How could the data impact the Agency’s future decision

- making?

If risks warrant mitigation, the dermal exposure data will provide the types of mitigation necessary such as chemical resistant gloves or closed systems for commercial uses, or potential removal of

uses from the label.

Guideline Numbers: 875.1300 and 875.1400 Study Titles: Inhalati on Exposure (Indoor and Outdoor) Rationale for Requiring the Data
Note: Inhalation exposure data are needed for both residential and occupational uses. The selection of an outdoor versus an indoor site is based on the high end exposure scenario (for

in halation the selection is typically indoors). In almost all cases, repeating an exposure study for the same scenario outdoors and indoors is not necessary.

The inhalation exposure route is very important for exposure scenarios such application of paints where aerosols would be generated. In addition, inhalation exposures from application are evident in exposure studies in the Pesticide Handlers Exposure Database (PHED). The significance of these exposures is directly affected by the severity of the inha lation toxicological endpoint of concern. At this point in time, no toxicological data are available to assess the inhalation risk. The existing Chemical Manufacturer Association (CMA) data base and PHED for these scenarios are limited in scope for QA/QC and number of monitoring units. EPA presented the need for additional handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that additional dataPage | 16

are war ranted.

The criteria for the inhalation exposure data are based on the potential for respiratory exposure from the labeled uses (e.g., exposure to application of paints ) and evidence of toxicity. If no toxicological endpoints of concern were identified, then the inhalation exposure data would not be

needed.

Practical Utility of the Data

1. How will the data be used?

The inhalation exposure data would be used to assess the residential short

- term duration of painting with a paint brush/roller and an a irless sprayer. For occupational uses, the inhalation exposure data

would be used to assess the short

- and intermediate

- term as well as pouring a preservative in manufacturing settings, and preservation of leather preservative solutions).

2. How could the data impact the Agency’s future decision

- making?

If risks warrant mitigation, the inhalation exposure data will provide the types of mitigation necessary such as dust mist respirators, full face respirators or closed systems for commercial uses,

or p otential removal of uses from the label.

Guideline Numbers: 875.1600 Study Title: Data Reporting and Calculations Rationale for Requiring the Data For all exposure studies this data need is needed to facilitate the review of the data. The study repor t and all raw data/calculations would be reviewed for the adequacy of the

data.

Practical Utility of the Data

1. How will the data be used?

The data are needed to interpret the dermal and inhalation exposure data collected.

2. How could the data imp act the Agency’s future decision

- making?

This data need is triggered if an exposure study is conducted. It would aid the Agency to make accurate interpretations of the studies to develop an accurate and refined risk assessment and refined mitigation.

Gui deline Numbers: 875.1700 Study Title: Product Use Information Rationale for Requiring the Data Product use information is a description of how the product is actually applied; it is not a field study. A description of how this product is used would pro vide for a comprehensive realistic assessment of its potential applications. The description of the application techniques would be used to define the exposure scenarios to be assessed in the risk

assessment. Practical Utility of the DataPage | 17

1. How will t he data be used?

A complete description of product use would ensure that the risk assessment is inclusive of the types of exposures occurring during residential and occupational use.

2. How could the data impact the Agency’s future decision

- making?

Th e need for a risk assessment as needed under Registration Review would require that the risk assessor understands how the product is applied.

Guideline Number: 875.2 5 00 Study Title: Inhalation Exposure Rationale for Requiring the Data

The post applica tion inhalation exposure may be required if it is determined that the use of these products have the potential to release formadehyde during the product use conditions (e.g., formaldehyde emissions from paint ).

Practical Utility of the Data

1. How will the data be used? The post application inhalation exposure data will be used to assess the residential and/or occupational inhalation risks to formaldehyde emissions from paint if released based on product

use. For example, the use of paint is expected to trigger an inhalation postapplication assessment

2. How could the data impact the Agency’s future decision

- making? The inhalation exposure data will be used to determine the accuracy of the post application inhalation risks to occupational bystander s. If risks warrant mitigation, the inhalation exposure data will provide the types of mitigation necessary such as respiratory protection from respirators or closed systems for commercial uses to potential removal of uses from the label.

Guideline Numb er: 875.2700 Study Title: Product Use

Rationale for Requiring the DataPage | 18

A description of how products containing THPS are used will provide a comprehensive, realistic assessment of its potential applications. Product use information for the post applica tion data is a description of what type of consumer products are treated; it is not a field study (guideline no. 875.2700). A description of what types of consumer products are treated, specifically what types of leather and paints, will provide a compreh ensive, realistic assessment of potential post application exposures. Therefore, these data are required.

Product use information assists EPA to more accurately assess pesticide exposure to applicators by describing how the pesticide is actually used and applied. EPA requires this information because differences in use can translate to significant differences in exposure, and thus in risk.

The guideline for post

- application product use information was presented to the FIFRA Science Advisory Panel (SAP) i n March 1998. (The draft guideline is available at http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm .). T he guideline for applicator product use information sho uld be substantially similar to the one for post

- application.

Practical Utility of the Data

1. How will the data be used?

A complete description of product use would ensure that the risk assessment is inclusive of the types of exposures occurring dur ing residential and occupational use. The listing of the end use consumer products would be used to define the exposure scenarios to be assessed in the risk assessment. For example, if the use for leather is used to make clothes or if the preservative is used in inks then a postapplication assessment may need to be considered.

2. How could the data impact the Agency’s future decision

- making? A complete description of consumer products treated would ensure that the risk assessment is inclusive of the typ es of exposures occurring during residential use. The need for a risk assessment as needed under Registration Review would require that the risk assessor understands how the product is applied.

Guideline Number: 875. 29 00 Data Requirement: Data Reportin g and Calculations
Rationale for Requiring the Data For all exposure studies, these data are needed occupationally and in the residential setting to

facilitate the review of the data.
Practical Utility of the Data

1. How will the data be used?

The study report and all raw data/calculations will be reviewed for the adequacy of the data.

2 . How could the data impact the Agency’s future decision

- making? The data are needed to define and interpret the inhalation and dermal exposure data collected.

T his data need is triggered any time an exposure study is conducted. It would aid the Agency to make accurate interpretations of the studies to develop an accurate and refined risk assessment and refined mitigation.

Sign

- off Date: 02/18/11 DP Barcode No.: D383029