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EXECUTIVE SUMMARY

The Antimicrobials Division (AD) Registration Review Team has evaluated the status 

of the human health assessments for tri-n-butyl tetradecyl phosphonium chloride (TTPC)

(registration review case 5111). One active ingredient (PC Code 128824) and three

registered products exist in the TTPC case. TTPC is a quaternary phosphonium liquid 

biocide approved for use as an end-use product for control of algae, slime-forming 

bacteria, sulfate-reducing bacteria and fungi in industrial process water treatments (Use 

Site Category VIII). TTPC is delivered to industrial process waters using closed metered 

delivery systems; open pouring is prohibited. Examples of TTPC uses include water 

treatment in recirculating cooling water and process waters, heat exchange water systems, 

air washing systems, evaporative coolers, brewery pasteurizers, can warmers, hydrostatic 

sterilizers and retorts, pulp/paper/paperboard systems (non-food contact paper and 

paperboard manufacture of brown paper, sheet for corrugated board, Kraft paper, 

newsprint and similar paper), enhanced oil recovery systems (non-marine/non-estuarine 

use), oil and gas production transmission pipelines and systems, gas storage wells and 

systems, hydro-testing of pipelines and tanks, pipeline pigging and scraping operations 

and oil and gas well drilling and maintenance fluids. A petition for a new product use to 

control microbial growth in waters and on pipe surfaces in fire protection systems was 

recently submitted to the Agency on July 12, 2011. Although this is a new use, AD does 

not believe this use will change our conclusions on data needs or risk assessments for this 

human health registration review.

EPA examined the hazard and exposure databases for the TTPC case to determine 

whether changes in science policy or deficiencies in the databases materially affected the 

overall risk picture. TTPC was first registered as a pesticide in 1989. A Reregistration 

Eligibility Decision (RED) document has not been issued for TTPC since this chemical 

was registered after November 1, 1984. As part of the registration review process, the 

Agency reviewed the existing human health toxicology and exposure data from its initial 

registration in 2007, and the existing open literature. 

On October 18, 2005, the Antimicrobials Division’s Toxicity Endpoint Selection 

Committee (ADTC) identified toxicological endpoints for non-dietary exposure scenarios.

On September 7, 2007, AD developed an occupational exposure assessment for TTPC for 

registration (D340885 and D340886). 

As a result of the closed mixing/loading, PPE, and low volatility, additional 

occupational handler assessments are not anticipated as needed for registration review. 

Dermal and inhalation post-application risks for water-treatment uses are likely to be 

minimal based on dilution, limited exposure contact, and low volatility. The labels for 

TTPC state that use is for industrial applications. Therefore, no residential assessments 

will be needed.

A dietary exposure assessment is not anticipated based on label restrictions specifying 

that TTPC is used on non-food applications. AD believes the concentration of TTPC in 

the drinking water will be minimal. However, EPA will make a determination at a later 

date whether or not a drinking water assessment is needed later based on the applicable 
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environmental fate data that AD required in the recent Environmental and Ecological 

Effects Scoping Document (D394379).

Section 1. Chemical Identity

TTPC is a quaternary phosphonium that is soluble in water, has a low water/octanol 

partition coefficient (Log Kow), has a low vapor pressure and exhibits a low melting point. 

The active ingredient exists as a white solid at room temperature. Although it is not likely

to be bioaccumulative in aquatic organisms, TTPC does not biodegrade in water and is 

stable in aqueous medium photolytically. TTPC is likely to be a persistent chemical in 

aqueous and soil media. No data are available for its binding capability to soils; however, 

since it is ionic in nature, TTPC is not likely to bind strongly with soils (D394379).

Table 1. Chemical Identity

Common 

Name

Tri-n-butyl tetradecyl phosphonium chloride

Synonyms none

PC Code 128824

CAS registry 

number

81741-28-8

Registration 

Review Case 

No.

5111

Structure

Vapor 

Pressure

3.75E-8 mm Hg at 39oC

Section 2. Toxicology

Acute Toxicity

TTPC purified grade active ingredient (PGAI) exhibits low acute oral and dermal 

toxicity (Toxicity Category III) and is corrosive to the eye (Toxicity Category I). An 

acute inhalation toxicity study for the TTPC PGAI was waived and Toxicity Category I 

assigned for inhalation. A formulated manufacturing-use product/end-use product 

(BELLACIDE 350, 50% TGAI) shows low acute oral toxicity (Toxicity Category III); 

however, it is acutely toxic via the dermal route (Toxicity Category I) and is highly 

irritating and corrosive to the eyes and skin (Toxicity Category I). The BELLACIDE 350

formulation (50% a.i.) was negative for dermal sensitization in the Guinea pig 

maximization test.
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Table 2. Acute Toxicity Data for TTPC 

Purified Grade Active Ingredient (PGAI) and BELLACIDE 350 (50% a.i. EP/TGAI) 

Guideline Number

Study Type

MRID 

Number Results Toxicity 

Category

81-1 Acute oral toxicity 00133040 LD50 = 611 mg/kg (M+F) (PGAI) III

00133041 LD50 = 1002 mg/kg (M+F) 

(BELLACIDE 350, 50% a.i. EP/TGAI)

81-2 Acute dermal toxicity 00133042 LD50 = 4000 mg/kg (M+F) (PGAI) III

00133043 LD50 = Not Determined (ND); Animals sacrificed due 

to severe necrosis (M+F) (BELLACIDE 350, 50% a.i. 

EP/TGAI)

I 

(severe skin 

irritation)

81-3 Acute inhalation 

toxicity

Waived --- (PGAI) I

Pilot Study 

(No MRID)

LD50 < 0.1mg/mL; severe pulmonary irritation and 

pneumonitis 

(BELLACIDE 350, 50% a.i. EP/TGAI)

81-4 Acute eye irritation 00133044 Corrosive, Primary Irritation Index (PII) = 102.7 

(mean unrinsed and rinsed eyes) (PGAI)

I

00133045 Corrosive, primary irritation index (PII) = 60.2 (mean 

unrinsed) and 55.0 (mean rinsed eyes)

(BELLACIDE 350, 50% a.i. EP/TGAI)

81-5 Acute dermal 

irritation

00133046 Corrosive, extreme irritation, 

Primary Irritation Index (PII) = 7.7 

(BELLACIDE 350, 50% a.i EP/TGAI)

I

81-6 Skin sensitization 46333002 Non sensitizer (BELLACIDE 350, 50% a.i. EP/TGAI) NA

M = males; F = females; NA = not applicable

Subchronic Toxicity

In a 90-day drinking water study (MRID 41367301) conducted in the rat, TTPC 

produced significantly reduced body weights (up to 22% in males and 18% in females), 

various clinical signs (hunched posture, brownish discoloration on the muzzle and neck, 

prolapsed penis, piloerection, rough fur, foaming salivation, mucous salivation, and 

vaginal discharge), and significantly reduced food and water consumption at the LOAEL 

of 300 ppm (27.2 mg ai/kg/day for males and 32.2 mg ai/kg/day for females). The 

NOAEL established in this study is 100 ppm (8.66 mg ai/kg for males and 11.3 mg ai/kg 

for females). This study is classified acceptable-guideline for an oral subchronic toxicity 

study [OPPTS 870.3100] and is adequate for risk assessment purposes.

Prenatal Developmental Toxicity

In a prenatal rat developmental toxicity study (MRID 00133048, 40680704, 

46721703), gavage administration of TTPC resulted in decreased body weight, body 

weight gain and food consumption in maternal animals at the LOAEL of 60 mg ai/kg/day. 

The maternal toxicity NOAEL is 30 mg ai/kg/day. The developmental toxicity NOAEL 

established in this study is 10 mg ai/kg/day based on the increased incidence of 

incomplete ossification of the fifth sternebrae in fetuses observed at the LOAEL of 30 mg 

ai/kg/day (in the absence of maternal toxicity). This study is classified acceptable-
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guideline for a prenatal developmental toxicity study in rats [OPPTS 870.3700] and is 

adequate for risk assessment purposes.

In a prenatal rabbit developmental toxicity study (MRID 00133047, 40680705, 

46721704); the maternal/developmental NOAELs and LOAELs are 3.75 and 11.25 mg 

ai/kg/day, respectively. Maternal toxicity consisted of decreased body weight gain and 

food consumption. Adverse developmental effects in rabbits included delayed ossification 

of the fore-limb and hind-limb phalangeal nuclei and significantly decreased fetal body 

weight for males. This study is classified acceptable-guideline for a prenatal 

developmental toxicity study in rabbits [OPPTS 870.3700] and is adequate for risk 

assessment purposes. 

Reproduction and Fertility Effects Toxicity

A reproduction and fertility effects toxicity study is not currently required to support 

the registered uses of TTPC containing pesticide products.

Chronic Toxicity

Chronic studies are not currently required to support the registered uses of TTPC 

containing pesticide products. 

Carcinogenicity

A carcinogenicity study is not currently required to support the registered uses of 

TTPC containing pesticide products.

Mutagenicity

The data base for mutagenicity is considered adequate (see Table 3). TTPC 

(BELLACIDE 350, 50% a.i.) was negative for mutagenicity in a reverse gene mutation 

assay with bacteria and in DNA repair assays in rat hepatocytes and human fibroblasts. 

TTPC was also negative for chromosomal aberrations in hamsters in the in vivo

micronucleus assay.

Neurotoxicity

An acute neurotoxicity study with cholinesterase measurements at the peak time of 

inhibition was required in 2007 based on the assumption that TTPC would behave 

similarly to an organophosphate pesticide. Rather, TTPC belongs to a different group of 

chemicals referred to as ionic liquids; specifically TTPC is a quaternary phosphonium 

compound that is manufactured as a liquid pesticide. In addition, the limited clinical signs 

(hunched posture and foaming/mucus salivation) observed in rats administered TTPC for 

90-days via the drinking water occurred only at the highest dose tested (lack of a doseresponse), are not present in other studies (e.g., animals treated with TTPC in acute and 

developmental toxicity studies show no salivation) and may not involve the cholinergic 

system/inhibition of cholinesterase activity (e.g., hunched posture). Therefore, the 
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Agency does not anticipate requiring neurotoxicity/cholinesterase studies conducted with 

TTPC. 

Table 3. Mutagenicity Studies for TTPC

Guideline, Study Type

MRID/Classification

Description of Results

84-2 Reverse Bacterial Gene Mutation

(Ames) Assay

MRID 00133049/Accession No. 252019

Classification: Acceptable

BELLACIDE 350 (50% a.i.) did not cause a mutagenic effect at 

concentrations as high as 127.6 μg/0.1 ml (per plate) using S. 

typhimurium strains TA 98, 100, 1535, 1537 and 1538 with or 

without metabolic activation.

84-2 In vivo Nucleus Anomaly Cytogenetic 

Test in Chinese Hamster Bone Marrow

MRID 40680706

Classification: Acceptable

BELLACIDE 350 (50% a.i.) is not mutagenic since it did not cause 

a dose-related or significant increase in anomalous nuclei when 

given via gavage once daily for 2 days to 6 male and 6 female 

Chinese hamsters at doses of 19, 38, or 76 mg/kg, in the absence of 

metabolic activation.

84-2 Unscheduled DNA Synthesis/Repair 

in Rat Hepatocytes)

MRID 40680707/41185801

Classification: Acceptable

BELLACIDE 350 (49.85% a.i.) is not genotoxic since it did not 

cause DNA damage (lack of increases in grain counts which are

indicative of repair) at doses up to cytotoxic levels of 5 μg/ml in 

the absence of metabolic activation. 

84-2 Unscheduled DNA Synthesis/Repair 

in Human Fibroblasts

MRID 40680708/41185802

Classification: Acceptable

BELLACIDE 350 (49.85% a.i.) is not genotoxic since it did not 

cause DNA damage at the highest 9 μg/ml nontoxic dose in the 

absence of metabolic activation. Test results under conditions of 

no metabolic activation are considered acceptable. However, this 

type of mutagenicity study is satisfied by MRID 40680707.

Toxicity Endpoint Selection for Human Health Assessments

On October 18, 2005, the Antimicrobials Division’s Toxicity Endpoint Selection 

Committee (ADTC) identified toxicological endpoints for non-dietary, short-term 

(ST)/intermediate-term (IT) incidental oral (residential), dermal (occupational/residential) 

and inhalation (occupational/residential) exposure scenarios. The ST/IT NOAEL selected 

for these non-dietary risk assessments was 8.66 mg/kg/day based on the toxicities 

observed at the LOAEL in the 90 day rat oral toxicity study. The target margin of 

exposure (MOE) for ST/IT exposures via the incidental oral, dermal, routes was set at 100 

based on uncertainty factors (UFs) of 10x for inter-species extrapolation and 10x for intraspecies variation. A default absorption factor of 100% was used for the dermal and 

inhalation exposure risk assessments since no absorption study data are available. For 

short- and intermediate-term inhalation exposure scenarios, an additional UF of 10 was 

applied to the endpoint based on use of an oral endpoint to assess inhalation hazard. 

Consequently, the TTPC target MOE for inhalation was set at 1000 (10x for inter-species 

extrapolation, 10x for intra-species variation, and 10x for extrapolation from an oral 

toxicity study for inhalation risk assessments). 

However, in 2007, the registrant submitted a label amendment application to add two 

new uses to the existing BELLACIDE 350 label as well as new information showing a 

low vapor pressure for TTPC technical grade active ingredient. These actions initiated a 

re-evaluation of the toxicity endpoints, UFs, and target MOEs previously selected for the 
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active ingredient, TTPC. For the proposed new uses of BELLACIDE 350 (50% a.i.), no 

additional toxicity data, application of an additional 10x for inhalation exposures, or 

inhalation risk assessments were required to address use of this product in enhanced oil 

recovery systems and non-food contact pulp and paperboard processing. However, this 

decision (Memorandum: S. Malish to V. Noble, June 31, 2007) does not negate the need 

to assess potential risks for other existing labeled uses of pesticide products containing 

TTPC. 

Anticipated Mammalian Toxicology Data Needs

Initially, the ADTC (Memorandum: T. McMahon to N. Cook, November 5, 2005) 

identified two toxicology data gaps for TTPC; a 28-day repeated-dose inhalation toxicity

study with an associated range-finding study (to assess occupational short-term and 

intermediate-term inhalation risk because of the presumed high vapor pressure of TTPC) 

and an acute neurotoxicity study with cholinesterase measurements at the peak time of 

inhibition (because TTPC was considered an organophosphate pesticide and 

cholinesterase activity was not measured in the available toxicity studies). 

The data gap for a 28-day inhalation toxicity study was negated in 2007 due to (1) a 

correction in the vapor pressure value for TTPC (a low vapor pressure is currently 

reported for TTPC) and (2) removal of the labeled use of BELLACIDE 350 (50% TTPC 

a.i.) in decorative fountains. As for the acute neurotoxicity study with cholinesterase 

measurements data gap, the Agency no longer requires this special study because clinical 

signs (hunched posture and foaming/mucus salivation) were observed in only one toxicity 

study, were not dose-related and/or may not involve the cholinergic system/inhibition of 

cholinesterase activity. 

Although unlikely, dietary exposures to TTPC via drinking water may occur in the 

event of an industrial down-the-drain discharge in which contaminated water could pass 

through waste water treatment facilities into drinking water, be discharged directly to 

surface water that is subsequently treated and/or migrate into residential groundwater 

wells. If the additional environmental fate data as required by the Agency’s registration 

review of TTPC shows this active ingredient and/or any of its’ degradates to be persistent 

in drinking water, additional toxicity studies (e.g., a reproduction and fertility effects 

study, a chronic toxicity study, carcinogenicity studies in two species or tier 1 toxicity 

studies for degradates of toxicological concern) may be required. 

Section 3. Dietary Assessment

Dietary (Food)

According to the existing labels, TTPC may be used as a slimacide for pulp, paper and 

paperboard mills and water systems; however, the label restricts the use to nonfood 

applications and TTPC was not cleared for any indirect food contact use by FDA. As a 

result, no dietary exposure assessment is anticipated to be needed.
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Drinking Water

Although it is expected that drinking water exposures are 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 available environmental fate data to determine whether 

TTPC 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. 

Section 4. Occupational/Residential Exposure

TTPC is the active ingredient in three registered products. These products are 

formulated as liquid soluble concentrates for use in industrial processes and water systems 

(Use Site Category VIII). The industrial process and water system category includes uses 

such as recirculating cooling and process water systems, air washers and industrial air 

scrubbing systems, heat transfer systems, pulp and paper and paperboard mills, enhanced 

oil recovery systems, fire protection systems, oil and gas production and transmission 

pipelines and systems, gas storage wells and systems, hydrotesting, pipeline pigging and 

scraping operations, drilling and workover and fracturing fluids.

The end-use products contain 5 to 50% active ingredient (a.i.), the labels of which 

explicitly states that the biocide is to be metered into water via a fully closed system.

Labeling also requires PPE such as coveralls worn over long-sleeved shirt, goggles, face 

shield, chemical resistant gloves and footwear in case of leaks or breaks in the closed 

delivery system.

The Agency did an open literature search and did not identify any relevant exposure 

studies in the existing literature that could be used to supplement the existing Agency 

exposure database. There are minimal potential exposures for closed mixing/loading 

systems. 

The vapor pressure is 3.75E-8 mm Hg at 39oC. As a result of the closed 

mixing/loading, PPE for protection against leaks/malfunctions, and low volatility;

additional occupational handler assessments are not anticipated as needed for registration 

review. Dermal and inhalation post-application risks for water-treatment uses are likely to 

be minimal based on dilution, limited exposure contact, and low volatility. 

The labels for TTPC are for industrial applications and no consumer products are 

treated. Therefore, no residential assessments will be needed. 

Section 5. Aggregate and Cumulative Exposure

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

information concerning exposures to residues in food and drinking water, and non-
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occupational pesticide exposures. EPA does not expect that an aggregate exposure 

assessment will need to be initiated.

Unlike other pesticides for which EPA has followed a cumulative risk approach based 

on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity 

finding as to TTPC and any other substances and TTPC does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of registration review, 

therefore, EPA has not assumed that TTPC has a common mechanism of toxicity with 

other substances. For information regarding EPA’s efforts to determine which chemicals 

have a common mechanism of toxicity and to evaluate the cumulative effects of such 

chemicals, see the policy statements released by EPA’s Office of Pesticide Programs 

concerning common mechanism determinations and procedures for cumulating effects 

from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

Section 6. Incidents

There have been no human incidents reported in any of the OPP databases associated 

with exposure to TTPC. 

Section 7. Anticipated Data Needs

The Antimicrobial Division (AD) does not anticipate the need for any additional 

toxicity or exposure studies for TTPC for registration review. 

Section 8. Tolerances

There are no pesticide tolerances or exemptions from the requirement of tolerance for 

TTPC established by either EPA or FDA. 

Section 9. 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 the 

registration hazard assessment for TTPC, 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), TTPC is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 
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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. TTPC 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 TTPC. 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 10. References

D394379. Tri-n-Butyl Tetradecyl Phosphonium Chloride, Product Chemistry, 

Environmental Fate, and Ecological Effects Scoping Document for Registration Review. 

Memorandum from S.Gowda, W. Erickson, and N. Shamim to E. Blair.

D340885 and D340886. Occupational Exposure Assessment for TTPC: Proposed Label 

Amendments to Add New Use Sites for Bellacide 350 (50% TTPC) and Bellacide 355 

(5% TTPC) Industrial End-Use Products. Memorandum from D. Aviado, U.S. EPA to D. 

Edwards, U.S. EPA. September 10, 2007.

D394470. Tri-n-Butyl Tetradecyl Phosphonium Chloride: Toxicology Chapter/Hazard 

Characterization for the Human Health Assessment Scoping Document for Registration 

Review of TTPC (Case No. 5111). Memorandum from M. Centra, U.S. EPA to N. Mottl 

and E.Blair, TXR No.: 1003219. October 25, 2011.