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Executive Summary

The Antimicrobial Division (AD) Registration Review Team has 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 required 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 assessments 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 

commercial 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 currently 15 

registered products. The concentration of active ingredient is between 20% and 78%. 

THPS is most often used as a microbiocide/slimicide that is used to control bacteria, 

fungi, and algae in the manufacture of paper and paperboard products and adhesives that 

do not contact food. However, some end use products 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 not 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 Agency 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 review (D383030), the 

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 trihydroxymethyl

phosphine (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 conditions. The Agency 

will likely need further data to determine the extent of the THPS degradation in 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 assessments to assess 

the contribution of formaldehyde on the overall aggregate risk from all sources.

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

nonfood uses nor are any tolerances needed since the paper and paperboard use is 

supported by FDA under Section 409 of the Federal Food, Drug, and Cosmetic Act 
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(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 information 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 THPS. 

A 90-day inhalation 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 exposures 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 preservative in paints, thus 

triggering the need for occupational 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 likely 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 registration 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.
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The Agency expects to conduct an aggregate risk assessment that will include 

residential, dietary and drinking water exposures.

Section 1. Chemical Identity

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 (hydroxymethyl)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 studies have been 

submitted since the first registration.
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Acute Toxicity

The 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 assigned 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 

category 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 at doses of 25, 250, or 500 

mg/kg/day (MRID 422363-10). Due to severe irritation at the application sites, all midand 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 effect 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 irritation study which concluded the 

compound was non-irritating (Toxicity Category IV

Inhalation Toxicity

There are no inhalation toxicity studies available. A 90-day inhalation toxicity study 

(Series 870.3465) will likely be needed to assess aerosolized exposure of paint. Note that 

this toxicity may not be 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, paper board and oil field operations.

Developmental Toxicity

In a prenatal developmental toxicity study (MRID 422364-14) of rats, THPS was

administered by gavage to 3 groups of 24 rats/dose at dose levels of 15, 30 and 60

mg/kg/day, respectively, from gestation days (GD) 6 to 15. Maternal toxicity was noted 

in the 30 mg/kg/day and 60 mg/kg/day groups in the form of salivation and brown 
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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 an 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.

Mutagenicity

The Agency identified several mutagenicity studies. The studies all did not indicate 

that THPS was mutagenic. The mutagenic battery included two acceptable in vitro

ames tests (MRID 44135505 and MRID 46659908) (GDLN 870.5100), two acceptable 

in vitro mammalian cell gene mutation studies (MRID 44135502 and MRID 44135504) 

(GDLN 870.5300), and two acceptable in vitro cytogenetics tests in Chinese hamster 

ovaries (MRID 42236318 and MRID44135503) (GDLN 870.5375). In addition, an in 

vivo unscheduled DNA synthesis test in rat hepatocytes(MRID 4223617 and 43312201)

(GDLN 870.5550) and a gene mutation study in Salmonella and E. Coli (MRID 

42236316) (GDLN 870.5140) were also submitted.

 

Chronic/Carcinogenicity

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

administration 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 hyperplasia 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 the 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 focal 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 significantly 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 1 
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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 were no significant effects 

observed in offspring at any dose level tested in this study. 

Toxicology of Formaldehyde 

Since the release of formaldehyde may be associated with the use of THPS, the 

exposure and risk associated with the formaldehyde released 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 approach 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 IRIS 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 formaldehyde emissions from pressed wood. As discussed 

in the Response to Public Comments on the Formaldehyde Preliminary Risk 

Assessment (EPA, 2009) the following disclaimer was provided for the non-cancer 

formaldehyde inhalation endpoint that was selected by OPP 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 been 

subjected to an interagency review or external peer review. Because of time 

constraints imposed by statutory deadline, OPP could not consider all available peerreviewed science (for example, the intentional human dosing toxicity studies). Thus, 

this value 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 

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

decision (D257896 and D281630) and EPA concluded that dietary risks were acceptable. 

Although a dietary risk assessment has been done during registration, EPA will likely 

reevaluate the indirect food uses (e.g. paper and paperboard, water based coatings, 
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pigments, etc.) 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 infrequent, dietary exposures via drinking water may occur in the 

event of a down-the-drain discharge. The contaminated water could pass through 

wastewater treatment facilities into the drinking water or may be discharged directly to 

surface water which is later treated. However, 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

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 

and develop a drinking water risk assessment. 

Section 4. Occupational/Residential 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 applications 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 preservative 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, the 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 and 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 based 
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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 exposure assessment assumptions. If label prohibitions on paint 

use are put into effect then the Agency anticipates that painting exposure data will not be 

necessary.

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

inhalation occupational and residential post-application exposure assessment to the 

degradate formaldehyde. Other inhalation post-application exposures to THPS or from 

formaldehyde for uses such as oil drilling are expected to be minimal. Dermal postapplication exposures for water-treatment and other material preservation uses such paper 

manufacturing or oil drilling 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 assessments 

(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 wastewater 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 for 
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painting. The Agency expects to conduct residential handler risk assessments for these 

scenarios and the Agency is likely to conduct risk assessments only of short-term 

duration (1-30 days).

* Note that if the material preservatives used in coatings, pigments 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 10-3Pa 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 Agency 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 data 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 exposure values. Dermal post-application exposures for uses such as watertreatment 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, postapplication 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 

information concerning exposures to pesticide residues in food and drinking water, and 

non-occupational pesticide exposures. Food exposures of concern are not anticipated as a 

concern based on the fact that THPS is not expected to be introduced into the food; there 

are no food use tolerances, no registered food uses and no indirect food uses. 

The Agency expects that it will need to conduct a residential assessment to examine 

application exposure to paint. In addition, a dietary assessment will also be conducted 

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

expects to conduct an aggregate risk assessment that will include residential, dietary and 

drinking water exposures.

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to 

establish, modify, or revoke a tolerance, the Agency consider "available information” 
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concerning the cumulative effects of a particular pesticide's residues and "other 

substances that have a common mechanism of toxicity.” EPA has not 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 adverse 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 include 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 

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 registration 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), THPS 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 produced 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 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 

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 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. THPS 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 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. Incidents
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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 Division (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 anticipates that a 90-day inhalation 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)

Inhalation 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 identified 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 875.2700) 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 meeting 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 slimicide in paper/paperboard at a maximum 
Page | 13

use level of 84 mg/kg in the pulp slurry. The additive may also be added to water, 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 paper and paperboard products cannot exceed 

84 ppm.

Section 10. Overall Conclusions

The Agency reviewed the hazard and exposure databases for THPS and anticipates

that additional toxicology and exposure data will be needed. In addition, the Agency 

anticipates 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 assessment. Depending on the outcome of the review and 

acceptance of the new exposure and toxicological data, the Agency anticipates the need

to 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, the EPA also anticipates that dietary and 

aggregate assessments will be needed to ensure that THPS registration review case meets

the safety standards established by FFDCA, as amended by FQPA. 

Section 11. Reference 

D383030. Summary of the Tetrakis (hydroxymethyl) 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 12, 2011.

D257896. Tetrakis (hydroxymethyl) 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 Inhalation Toxicity Study 

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 which 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 applications. In 

addition, an 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 inhalation 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 rat. 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, inhalation, 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 assessment 

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.
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Appendix B: Exposure Guideline 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 scenarios 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 the 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: Inhalation 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 

inhalation 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 inhalation 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 data 
Page | 16

are warranted. 

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 airless 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 potential 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 report 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 impact 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.

Guideline 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 provide 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 Data
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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 during residential and occupational use.

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

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: 875.2500

Study Title: Inhalation Exposure

Rationale for Requiring the Data

The post application 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 bystanders. 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 Number: 875.2700

Study Title: Product Use

Rationale for Requiring the Data
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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 application 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 comprehensive, 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) in March 1998. (The draft guideline is available at 

http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm.). The guideline for applicator 

product use information should 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 during 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 types 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: 875.2900 

Data Requirement: Data Reporting 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. 

This 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