According to the conclusions made in the SI DS Initial Assessment Report (SIAR), benzyl alcohol, benzoic acid and its sodium and potassium salts can be considered as a single category regarding human health, as they are all rapidly metabolized and excreted via a common pathway
within 24-hours.

In addition, sodium benzoate and benzoic ac id, both considered by US Food and Drug Administration (FDA) as Generall y Recognized as Safe (GRAS) ch emicals were included since potassium benzoate would react identically. In addition, the US FDA has approved potassium
benzoate as a food additive based on its similarity to sodium benzoate

Executive Summary

Landis International, on behalf of Whitmire Micro-Gen, submitted two petitions (7E7241 and 8E7333) requesting exemptions from tolerance for residues of potassium be nzoate when used as an inert ingredient (preservative) in pesticid e formulations applied pr e- and post-harvest under 40 CFR 180.910 and applied to animals under 40 CFR 180.930. A Notice of Filing for each petition was published in th e Federal Register.

Potassium benzoate is an appr oved food preservative similar in structure and r eactivity to the more widely used and classified by US FDA as GRAS, sodium benzoate. Both are salts of benzoic acid. Perhaps as a result of potassium benzoate’s similarity to sodium benzoate, few toxicological studies on it were found. Because al l benzoates, and in particular benzoic acid and sodium benzoate, react similarly, they were used as surrogates in the developmen t of this profile.

Available data suggest that the acu te toxicity of potassium benzoate is negligible, having an oral median lethal dose (LD 50 ) of >10,000 milligrams per kilogram body weight (mg/kg bw). Acute dermal and inhalation toxicity is low as indicated by the >2000 mg/kg bw LD 50 and >12.2 milligrams per liter (mg/L) median lethal concentration (LC 50 ) of benzoic acid. Sodium benzoate was not irritating to the skin and induced only slight eye irritation in rabbits. Sodium
benzoate and benzoic acid were non- sensitizing in animal tests but showed a very low incidence of sensitization in humans patch te sted. Both sodium benzoate and benzoic acid are known to induce non-immunogenic contact reacti ons, and that is the likely explanation for the low positive

response.

Sub-acute, sub-chronic and chronic toxicity data also indicate th at potassium benzoate should be relatively nontoxic. Oral and de rmal studies had a no observed adverse effect level (NOAEL)

≥ 2000 mg/kg bw and the inhalation study had a NOAEL > 25 milligrams per cubic meter (mg/m 3 ). Sodium benzoate was not carcinogenic in a lifetime mouse feeding study and there is no indication that potassium benzoate should be neurotoxic. Genotoxicity studies indicate the benzoates are not mutagenic; however chromosoma l aberration studies gave ambiguous results. Benzoic acid did not induce repr oductive toxicity in a four-gen eration study. In the human body under normal physiological conditions, potassium benzoate changes from the ionized form to the
undissociated benzoic acid. Benz oic acid and its salts are ra pidly absorbed by mammals, conjugated with glycine, and rapi dly excreted in the urine as hi ppuric acid. There is no reported accumulation of benzoate in the body. However, th e ability to conjugate benzoic acid depends upon adequate liver function and nutritional supply of glycine. All data indicates that potassiumbenzoate is relatively non-toxic as are the other benzoates. No toxicity would be expected from potassium benzoate when used at low concentrations in pesticides.

No developmental toxicity studie s are available in the database. However, no systemic toxicity was observed at doses up to 750 mg/kg/day in a four-generation reproductive study with benzoic acid. In addition, no systemic toxicity was obs erved in the laboratory animals at high doses (>2000 mg/kg/day) of potassium benzoate and benzoates indicating relatively low hazard potential. In terms of hazard, there are low c oncerns and no residual uncertainties regarding prenatal and/or postnatal toxicity. Based on this information, there is no concern at this time for increased sensitivity to infants and children to potassium benzoate when used as an inert ingredient in pesticide formulations and a safety factor analysis ha s not been used to assess risk. For the same reason, EPA has determined that an a dditional safety factor is not needed to protect the safety of infants and children.

Residues of concern are not anticipated for di etary exposure (food and drinking water) or for residential exposure from the use of potassium be nzoate for the proposed use pattern as an inert ingredient in pesticide products . EPA expects aggregate exposure to potassium benzoate to pose no appreciable dietary risk give n that the data on potassium be nzoate show a lack of any systemic toxicity and a lack of any appa rent reproductive or developmental effects.

There is limited environmental fate and ecotoxic ity data available for potassium benzoate, but
the fate and occurrence of benzoic acid have been well studied. The available data indicate that these compounds are expected to be readily biodegr adable in the environment and of low toxicity to fish, aquatic organisms, mammals and birds. The Agency believes that benozoic acid and the
benzoate salts will not cause unreasonable adverse effects on the environment.

Taking into consideration all available informa tion on potassium benzoate, EPA has determined that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to potassium benzoate when used as an inert ingr edient in pesticide formulations applied pre-and post-harvest and ap plied to animals, when considering dietary exposure and all other non-occupational sources of pesticide exposure for which there is reliable information. Therefore, the establishment of an exemption from tolerance under 40 CFR 180.910 and 40 CFR 180.930 for residues of potassium benzoate (CAS Reg. No. 582-25-2) when used as an inert ingredient in pre- and post-harvest and animal applications in pesticide formulations, can be considered assessed as safe under section 408(q) of the FFDCA.

I. Background

Landis International, on behalf of Whitmire Micro-Gen, submitted a petition (7E7241) requesting an exemption from tolerance for residues of potassium benzoate when used as an inert ingredient (preservative) in pesticide formulations app lied pre- and post-harvest under 40 CFR 180.910. EPA published the Noti ce of Filing for this petition in the Federal Register on February 6, 2008 (73 FR 6964). Landis Internat ional, on behalf of Whitmire Micro-Gen, submitted at second petition (8E7333) requesting and exemption from tolerance for residues of potassium benzoate when used as an inert ingred ient (preservative) in pesticide formulationsapplied to animals under 40 CFR 180.930. EPA publis hed a Notice of Filing for this petition in the Federal Register on June 4, 2008 (73 FR 31862). Two comments were received in the docket for Petition #7E7241, however they are unrelated to potassium benzoate and the Agency believes they were placed in this docket in error by th e commenters. There were no comments received in response to the notice of filing for Petition #8E7333.

This document provides an assessment of the ri sk to human health and the environment for potassium benzoate when used as an inert ingred ient in pesticide formulations and was based on information provided by the submitter and information available in the public literature. It was
also based on the OECD/SIDS Assessment for benz oates. According the conclusions made in the SIDS Initial Assessment Repor t (SIAR), benzyl alcohol, benz oic acid and its sodium and potassium salts can be considered as a single category regarding human health, as they are all rapidly metabolized and excreted via a common pathway within 24-hours.

II. Substance Identity
A. Potassium Benzoate TABLE 1. Substance identity POTASSIUM BENZOATE Chemical abstracts service registry number (CAS RN) 582-25-2

Other names Benzoic acid, potassium salt

DP #
PC Code

Chemical formula C 7 H 6 O 2 · K SMILES (ChemIDplus Lite) c1(ccccc1)C(=O)[O-].[K+]

Chemical structureB. Surrogate Chemicals for Potassium Benzoate

TABLE 2. Substance Identity for Pota ssium Benzoate Surrogate Chemicals (*)

Chemical Name Chemical Formula CAS No. Structure
Benzoic Acid C7-H6-O2 65-85-0

Sodium Benzoate C7-H5-Na-O2 532-32-1

Calcium Benzoate C7-H6-O2.1/2Ca 2090-05-3Ammonium Benzoate C7-H6-O2.H3-N 1863-63-4

• ChemIDplus Lite

III. Use Information

A. Pesticide Uses

Potassium benzoate is currently approved for use as an inert ingredient in nonfood use pesticide products.

B. Other Uses

Potassium benzoate is currently used as a preser vative in pharmaceutical and cosmetic products. It is also used as a preservativ e in human foods such as syrups , jams, jellies, prepared salads, tomato based products, margarine, olives , pickles, condiments and carbonated and noncarbonated beverages. (MRID 47180107) It is al so listed as generall y recognized as safe (GRAS) by the U.S. Food and Dr ug Administration (FDA). (MRID 47180106)

IV. Physical and Chemical Properties

Table 3 contains the physical and chemical properties of potassium benzoate. Since suitable data for potassium benzoate were ofte n lacking, data for sodium benzoate, which is expected to be similar, were substituted when insufficient data were found.TABLE 3. Physical and chemical properties

Parameter Potassium benzoate Source Appearance White powder MRID 47180104

Molecular wt. 160.12 ChemID Melting point ( o C)* 330.6 EPI Suite 4.0 Boiling pt. (1013hPa,

o C) 464.9 EPI Suite 4.0

Density 0.72/0.73 g/cm 3 MRID 47180107 Vapor pressure (hPa)* <0.001 EPI Suite 4.0 Log Kow* -2.269 EPI Suite 4.0 Water solubility (mg/L) 5.56E5 EPI Suite 4.0 * No data available for potassium benzoate , but expected to be similar to sodium
benzoate

V. Human Health Assessment

Toxicological Discussion

Few studies on the acute, sub-acute , sub-chronic, chronic, devel opmental and mutagenicity of potassium benzoate were available for review. Because of potassium benzoate’s similarity to sodium benzoate and benzoic acid, these studies have been included to build any data gaps for toxicological assessment.

Toxicological Data

A. Acute Toxicity

Acute toxicological data on potassium and sodium benzoate and on benzoi c acid are summarized
in Table 4.

TABLE 4. Acute toxicity studies

Study Type Potassium Benzoate (CAS No. 582-25-2)

Chemic

al Species/
strain Results Tox. Category Reference

Acute oral Benzoic
acid Rat LD 50 = 2565 mg/kg III IRDC #163- 282, 1974

Acute oral Benzoic
acid Mouse LD 50 = 2250 mg/kg III BRL#9348,
1979

Acute oral Sodium
benzoate Rat LD 50 = 3140 mg/kg III Loeser, 1977- A; Deuel et

al., 1954TABLE 4. Acute toxicity studies

Study Type Potassium Benzoate (CAS No. 582-25-2)

Chemic

al Species/
strain Results Tox. Category Reference

Acute oral Sodium
benzoate Rat LD 50 = 4070 mg/kg III Smyth & Carpenter,
1948

Acute oral Potassiu

m benzoate Rat

Mouse Guinea pig LD 50 ≥ 10,000 mg/kg

LD 50 ≥ 10,000 mg/kg

LD 50 ≥ 10,000 mg/kg IV KravetsBekkerIvanov a, 1970

Acute
dermal Benzoic
acid Rabbit LD 50 > 2000 mg/kg III IRDC#163-
282 1974

Acute
inhalation Benzoic
acid Rat LC 50 >12.2 mg/L/4hours IV IRDC#163- 282, 1974
Skin
irritation Benzoic
acid Rabbit Not irritating IV IRDC#163- 282, 1974

Skin
irritation Sodium
benzoate Rabbit Not irritating IV RCC
NOTOX Study No.

014658

Eye
irritation Benzoic
acid Rabbit Highly irritating I RCC
NOTOX Study No. 0847/10864,

1988 Eye
irritation Sodium
benzoate Rabbit Not irritating IV Loeser, E.,
1977-B

Eye
irritation Sodium
benzoate Rabbit Slightly irritating III RCC
NOTOX Study No. 014669, 1988
Skin
Sensitizatio

n Benzoic
acid Guinea pig Draize method – not sensitizing BRL #9347,
1979

Skin
Sensitizatio

n Benzoic
acid Guinea pig Maximization test – not sensitizing Gad, 1986

Skin
Sensitizatio

n Benzoic
acid Human Patch test – occasionally positive Rademaker& Forsyth,

1989;
Forsbek & Skog, 1977TABLE 4. Acute toxicity studies

Study Type Potassium Benzoate (CAS No. 582-25-2)

Chemic

al Species/
strain Results Tox. Category Reference

Skin
Sensitizatio

n Sodium
benzoate Human Patch test 5/2045 patients positive Brasch, J., et al., 1993

Skin
Sensitizatio

n Sodium
benzoate Human Nonimmunologic contact
urticaria Nethercott,

J.R. 1984

The acute toxicity studie s of sodium benzoate and benzoic aci d suggest the toxicity of potassium
benzoate would be low. No firm conclusion can be made on the sensitiz ing potential of potassium benzoate. S odium benzoate and benzoic acid were n o n- sensitizing in animal tes ts but showed a very low incidence in humans patch tests. Both sodium benzoate and benzoic acid are known to induce non-immunogenic contact reactions, and this maybe the likely explanation for the low positive responses shown above. No additio nal acute toxicity data or study reports were
available for review other than those descri bed in Table 4 supplied by the applicant or by
OECD/SIDS 2001.

B. 28-Day Oral Toxicity

In a 28-day feeding study, groups of ten rats/s ex/dose were fed diets containing 0, 760, 3800, or 7600 ppm benzoic acid (equivalent to 0, 65, 324.1, and 647.5 mg/kg bw/day, respectively)(BioFax, 1973). No clinical signs of toxicity were observed during the study and no grossly
observable lesions were noted at necropsy

. Under the study conditions u tilized, it is concluded that the NOAEL is 647.5 mg/kg/day, the highest dose tested (HDT).

C. 21-Day Dermal Toxicity

In a 21-day dermal toxicity study, groups of f our male and four female New Zealand white rabbits were treated with 0, 100, 500, or 2500 mg benzoic acid/kg bw/day (IRDC #163-675, 1981). Very slight dermal irritation was noted on one high-dose rabbit. No other treatmentrelated effects were noted on behavior, appe arance, body weight, body weight gain, hematology, clinical chemistry, organ weights or survival . The NOAEL for the study was the high-dose, 2500 mg/kg bw/day. A lowest observed adverse effect level (LOAEL) was not identified.

D. Four-week Inhalation Toxicity

In an inhalation toxicity study, groups of 10 Spra gue-Dawley rats/sex/dose were exposed to an
aerosol dust of benzoic acid at concentrations of 0, 25, 250, or 1200 mg/m 3 six hours/day, five days/week, for four weeks (IRDC 163-676, 1981). Average particle size for the study was 4.7 μm. During the study, one high-dose male and one high-dose female died. The body weight of high-dose rats was decreased at th e end of the study. The absolute and relative liver weight of high-dose males and the absolute and relative lung/trachea weight of high-dose females weredecreased. No treatment-related effects on body weight in mid-dose rats were found, although the absolute and relative kidney we ight of female rats was decrea sed. The upper respiratory tract of mid- and high-dose male and female animals show ed an increased incidence of interstitial cell infiltration and fibrosis, although the incidence was unrelated to dose. No treatment-related
effects were noted in low-dose rats. Based on decreased kidney weight and upper respiratory tract irritation, the LOA EL for the study was 250 mg/m 3 . The NOAEL was 25 mg/m 3

.

E. Sub-chronic Toxicity

In sub-chronic oral toxicity studies of sodium benzoate and benzoic acid on rats and mice, no
treatment-related effects were f ound when the test materials were administered at concentrations

≤ 1% (Collier et al., 2007). At higher concentr ations, treatment decreased food intake, and growth. The same authors reported in another study there was a significant decrease in weight gain in mice treated with 80 mg be nzoic acid/kg bw/day for three m onths and in rats treated with 8% sodium benzoate for 90 days. No other details were provided.

F. Chronic Toxicity

In a 72 week study, 20 male and 30 female Wistar rats were fed a diet containing 1.5% benzoate for 72 weeks (equivalent to 1125 mg/kg bw/da y, Marquardt 1960). A reduced food intake, growth retardation, and increased mortality were noted (15/50 treated vs. 3/25 control). No further details were provided.

In another 72-week study, groups of 10 male an d 10 female Wistar rats were fed a diet containing 40 mg sodium benzoate/kg bw/day (S htenberg and Ignat’ev, 1970). Other than an increase in mortality of 25%, no other treatment-related effects were reported. No other details were provided.

OECD/SIDS 2001 reported the effects of sodium benzoate in a 90-day study with male and female Sherman rats given diets containi ng 0, 640, 1280, 3145, or 6290 mg/kg bw/day in a study reported by Deuel (1954). No treatm ent-related effects were found at ≤ 3145 mg/kg bw/day. Pathological lesions (not otherw ise described) were found in th e liver and kidneys of high-dose rats. The NOAEL for the study was 3145 mg/kg bw/day.

G. Carcinogenicity

Groups of 50 male and 50 female five-week ol d Swiss Albino mice we re provided drinking water containing 2% sodium benzoate for life (Toth, 1984). Based on an average daily consumption of 6.2 mL and 5.9 mL for males and females, respectively, the dose of sodium benzoate was equivalent to 6200 mg/kg bw/day and 5960 mg/kg bw/day, respectively. These mice were compared to a control group of 100 ma le and 100 female mice th at received distilled
water. Both treated and contro l mice were monitored daily, body weights were recorded weekly, and gross pathological changes recorded. The mice we re either allowed to die or were sacrificed moribund. Complete necropsies were done and the liv er, spleen, kidneys, bla dder, thyroid, heart, pancreas, testes, ovaries, brain, na sal turbinates, lungs, and other organs with grossly observable pathological changes were examined microscopi cally. Treatment with sodium benzoate had noeffect on survival or the incidence of tumors . The study author concluded “To date sodium benzoate has been generally recognized as safe (GRAS) as a food additive, although its lifelong action has not been investigated. The present experi ment is apparently the fi rst to fill the gap and supply needed proof that the compound is harmless in so far as its long-term tumorigenic effect
is concerned.”

H. Neurotoxicity

No neurotoxicity studies were lo cated. Acute, sub-chronic and chronic toxicity studies do not
indicate a neurotoxic effect would occur.

I. Genotoxicity

Benzoic acid was not mutagenic in Ames test s both with and without metabolic activation (EGG# 580-192-1-78, 1978) and was negative without metabolic activation in a Sister Chromatid Exchange assay with human lymphocytes (Jansson, 1988; Tohda, 1980). A chromosomal aberration study using CHL cells and without metabolic activation gave ambiguous results (Ishidate, et al., 1984). A recombination assay with Bacillus sublilus H17 and M45 was positive (reported with minimal documentation in an abst ract, Nonaka, 1989). Sodium benzoate was not mutagenic in Ames tests, either with or without metabolic activation (Ish idate, et al., 1984) and was negative in a cytogenetic assay using ana phase preparations of cultured human embryonic lung cells without metabolic activation (FDA PB 245453, 1974). An Escherichia coli reverse mutation assay was also negative both with and without metabolic activ ation (Prival, 1991). However a cytogenetic assay using CHL cells was positive without metabolic activation (Ishidate, et al, 1984; Ishidate & Odashirna, 1977) and Sister Ch romatid Exchange assays using Chinese hamster cells or human lymphocytes were positive without metabo lic activation (Abe & Saski, 1977; Xing & Zhang, 1990). Sodium and pota ssium benzoate were positive in a recombination assay with Bacillus sublitus HI7 and M45 (reported with minimal documentation Nonaka, 1989, Ishizaki & Ueno, 1989). The genotoxicity da ta suggest that sodium and potassium benzoate and benzoic acid are negative in Ames point mutation assays but that these chemicals may induce adverse effects on chromosomes since th e data were equivocal. It should be noted that benzaldehyde and benzyl acetate were negative in chromosomal studies.

J. Reproductive Toxicity

In a four-generation study, groups of 20 rats/sex/ dose were fed diets containing 0% 0.5%, or 1% benzoic acid (equivalent to 0, 375, or 750 mg/kg bw/day ( Kieckebusch & Lang

, 1960). No treatment-related effects on growth, body weight , body weight gain, food consumption or feed efficiency were found. No treatment-related eff ects were found on reproduction or lactation, and no effects were found on organ weight. No trea tment-related histopat hological effects were identified. The NOAEL for the study was the hi gh-dose, 750 mg/kg bw/day. A LOAEL was not
identified.K. Developmental Toxicity

No developmental toxicity studies were locat ed, although the four-gener ation reproductive study indicates developmental effects are unlikely.

L Human Studies

Other than the patch testing studies , no human studies were identified.

M. Metabolism and Pharmacokinetics

The metabolic scheme for potassium benzoate is shown below (JECFA 1997). In the human body under normal physiological conditions, potassium benzoate changes from the ionized form to the undissociated benzoic acid. The major elimination pathway involves the rapid conjugation of benzoic acid with glycine to form hippuric aci d which is then excreted in the urine. Some benzoic acid is glucuronidated and also eliminated in the urine.

In studies of male with ma le B6C3F1 mice and Fischer 344 rats treated orally with 14 C-benzyl acetate, the compound was readily absorbed from th e gastrointestinal tract of both species, and
about 90% of the total dose was recovered as ur inary metabolites within 24 hours. A small proportion (0.3-1.3%) of the total dose was excreted in the feces. N one of the benzyl acetate was eliminated via the lungs. Analysis of tissues of animals sacrificed 24 hours after oral administration of labeled compound showed no radioactiv ity, indicating that elim ination was virtually complete. The relative amount of benzyl aceta te absorbed, metabolized, and excreted was unaffected by the size or number of the doses. Rep eated treatment of rats with benzyl acetate at 500 mg/kg bw/day for 14 days followed by a si ngle dose of radiolabeled compound did not change the clearance pattern. More than 90% of the radiolabel in the urine was present as hippuric acid, with minor amounts as benzyl alcohol and benzylmercapturic acid (up to 4%); no unchanged benzyl acetate was found (benzoyl gluc uronide was not measured). No evidence of
saturation or reduction of metabolic ca pacity in either species was found

.

In one human study, a man given 6, 9, 13.9 34.7 and 69.3 mM sodium benzoate showed complete elimination of the compound within 10-14 hours. No accumulation was apparent (WHO, 1974)Benzoate Metabolism

N. Toxicity Endpoint Selection and Levels of Concern

Potassium benzoate is not toxic by the oral, derm al, or inhalation routes. Once absorbed, it is readily metabolized and excrete d. No toxicity endpoint of concern was iden tified in the available toxicity studie s. Lung irritation in the inhalation study was likely due to an irritation effect of the high-dose used while decreased kidney weights in the same study, without microscopic correlates, were not considered treatment-related. No toxicity was observed in subchronic studies in rats and mice at doses of 1% (equivalent to 1000 mg/kg/day) and or above. No
adverse effects in rats in a chronic stu dy at 1125 mg/kg/day, no tumors in mice at 5900 mg/kg/day, and no reproductive eff ects at 750 mg/kg/day, the highest dose tested. No systemic toxicity was observed via dermal route at doses up to 2500 mg/kg/day in rabbits. The quantitative risk assessment for the dietary and residential exposure is not necessary since no endpoint of concern was identifi ed in the available database.

VI. Special Considerations for Infants and Children

In general, Section 408(b)(2)(c) of FFDCA provi des that EPA shall appl y an additional tenfold (10x) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the da tabase on toxicity and exposure
unless EPA determines based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the Food Quality Protection Act (FQPA) safety factor (SF). In applying this provision, EPA either retainsthe default value of 10x or uses a different additiona l safety factor when re liable data available to EPA support the choice of a different factor.

No developmental toxicity studie s are available in the database. However, no systemic toxicity was observed at doses up to 750 mg/kg/day in a four-generation reproducti ve study. In addition, no systemic toxicity was observed in the labora tory animals at high doses (>2000 mg/kg/day) of potassium benzoate and benzoates indicating relatively low hazard potential. There was no evidence of clinical sign s of neurotoxicity, therefore a deve lopmental neurotoxicity study is not required. In addition, no evidence of immunotoxicity is available in the database; therefore an immunotoxicity study is not required. In terms of hazard, there are low concerns and no residual uncertainties regarding prenatal and/or postnatal toxicity. Based on this information, there is no concern at this time for increased sensitivity to infants and children to potassium benzoate when used as an inert ingredient in pesticide formulations and a safety factor analysis has not been used to assess risk. For the same reason, EPA has determined that an additional safety factor is not needed to protect the safe ty of infants and children.

VII. Endocrine Disruptors

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar 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 ap proach to making the statutorily required
determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.
This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.
This list should not be construed as a lis t of known or likely e ndocrine disruptors.

Potassium benzoate was not among the group of 58 pesticide active ingredie nts on the initial list
to be screened under the EDSP. Under FFDCA sec. 408(p) the Agen cy must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/

.VIII. Exposure Assessment

A. Aggregate Exposure In examining aggregate exposure, the Federa l Food, Drug, and Cosmetic Act (FFDCA) section
408 directs EPA to consider available informati on concerning exposures from pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

The primary route of exposure to potassium benz oate from its use as an inert ingredient in pesticide products would most likely be thr ough consumption of f ood to which pesticide products containing it have been applied, and po ssibly through drinking water (from runoff). Residential (dermal and inhalation) exposures from home garden uses are possible. Metabolism data indicates that potassium be nzoate would be rapidly absorbe d, metabolized, and excreted. It should also be noted that US FDA has approve d potassium benzoate as a food preservative.

No hazard was identified for the acute and chronic dietary assessment (food and drinking water), or for the short, intermediate, and long term re sidential assessments, and therefore no aggregate risk assessments were performed.

B. Cumulative Exposure

Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when c onsidering whether to establish, modify, or revoke a tolerance, the Agency consider “ava ilable information” concerning the cumulative effects of a particular pesticid e's residues and “other substances that have a common mechanism of toxicity.”

EPA has not found potassium benzoate to share a common mechanism of toxicity with any other substances, and does not appear to produce a toxi c metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that potassium benzoate does not have a common mechanism of toxicity with other substances. For information regarding
EPA's efforts to determine which chemicals ha ve a common mechanism of toxicity and to
evaluate the cumulative effects of su ch chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative

.

IX. Environmental Justice Statement

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions
to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-estab lished procedures when applicab le. In line with OPP policy,ARIA/HED estimates risks to popul ation subgroups from pesticid e exposures that are based on patterns of that subgroup’s food and water c onsumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups base d on age, season of the year, ethnic group, and region of the country. Additionally, OPP is ab le to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate , non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for childre n (three to less than six years old), youths, and adults entering or playing on treated areas post-application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and mode ls that consider exposure to bystanders and farm workers as well as lifesty le and traditional dietary patterns among specific subgroups.

X. Environmental Fate

There is limited environmental fate data availa ble for potassium benzoate, but the fate and
occurrence of benzoic acid have been well stud ied. For this assessment, sodium, potassium, calcium and magnesium salts were considered equivalent with resp ect to their environmental fate and ecotoxicity. The physical and chemical properties for these salts varied slightly, but are not expected to impact their behavior or toxicity in the environment. The benzoate salts are highly water soluble and readily dissociate into the an ion (benzoic acid) and cation (sodium, potassium, calcium, magnesium and ammonium ion). Theref ore, the environmental fate and effects of benzoic acid salts are closely rela ted to that of benzoic acid an d the free cation. Table 4 provides environmental fate and chemical properties for be nzoic acid and representative molecules of the salts. (US EPA, 2003)

TABLE 5. Properties and Envi ronmental Fate of Benzoic Acid and Selected Salts (**)
Property Benzoic Acid Sodium Benzoate Benzoic Acid,
Ammonium Salt Water Solubility (mg/L @ 25 C) 3400 (M) 5.56E05 (M) >1.0E06 (E)

Vapor Pressure (mm Hg 25 C) 7E-04 (M) 3.67E-09 (E) 2.65E-07 (E)

Henry’s LawCoefficient (atmm3/mole) 3.8E-08 (M) 1.09E-07 (E) 5.2E-16 (E)

Biodegradation Primary: hours-days Ultimate: days-weeks Primary: hours-days Ultimate: days-weeks Primary: hours-days Ultimate: days-weeks Log Kow 1.87 (M) -2.27 (E) -1.33 (E) Koc (mL/g) 14 (E) 14 (E) 99Hydrolysis Halflife @ pH 7 (days) No hydrolizable functional groups No hydrolizable functional groups 52 days** Table 5 adopted from US EPA Memorandum: “Benzoic Acid and Be nzoate Salts: Health Effects Division Science Assessment Documen t for

Tolerance Reassessment.”
Estimates performed with EPI Suite 4.0 show pot assium benzoate woul d biodegrade quickly. Most partitioning, based on Fugacity Level III, would occur with water (27.7%) and soil (72.2%)
with none into air or sediment.

XI. Ecotoxicity

According to EPA’s 2003 document, “Benzoic Acid and Benzoate Salts: Health Effects Division
Science Assessment Document for Tolerance Reassessment:”

“Estimated toxicity indicates that benzoic acid is the most toxic of the substances
reviewed in this assessment. Table 6 lists th e estimated toxicity for several species based on predictive modeling for acute and chronic endpoints for all compounds. Based on the environmental fate profile of benzoic acid a nd its salts, exposures from label uses are unlikely to reach concentrations necessary to elicit effects in aquatic organisms. Using laboratory rat data as a surroga te for terrestrial wild mammals and birds, benzoic acid and its salts do not appear to be very toxic and adverse effects from labeled uses is not expected. “

Table 6: Ecotoxicity of Benz oic Acid and Selected Salts Property Benzoic Acid Sodium Benzoate Benzoic Acid,
Ammonium Salt Fish (96-h LC50; mg/L) 1200 >1.0E06 1.4E05 Daphnid (48-h LC50; mg/L) 1274 8.8E05 1.2E05 Green Algae (96-h EC50; mg/L) 790 4.3E05 61172 Fish (30-day Chronic, mg/L) 151 71380 10486 Fish (SE)(96-h LC50, mg/L) 258 32047 6374 Mysid Shrimp (96h LC50, mg/L) 380 >1.0E06 4.3E05 Green Algae (96-h Chronic; mg/L) 73 3646 893

Earthworm (14-day LC50; mg/kg dry weight) 8238 18317 9081

** Table 6 adopted from US EPA Memorandum: “Benzoic Acid and Be nzoate Salts: Health Effects Division Science Assessment Documen t for

Tolerance Reassessment.”

Estimated ecotoxicity data were provided by running the EPI Suite 4.0 model and obtaining values for acute fish LC50s, acute daphnid LC50s and acute algae EC50s. Most values for potassium benzoate are derived fr om sodium benzoate since they behave similarly. Overall, potassium benzoate is non-toxic to aquatic orga nisms and the octanol/water partition coefficient indicates a low potential for bioaccumulation. Valu es derived from EPI Suite 4.0 are provided in
Table 7.TABLE 7. Ecotoxicity of Potassium benzoate Organism Duration/Endpoint Potassium benzoate MRID
Fish 96 Hours LC 50 7.05 E5 mg/L EPI Suite 4.0 Fish 14-day LC 50 6.65 E5 mg/L EPI Suite 4.0 Daphnid 48 Hours LC 50 2.11 E5 mg/L EPI Suite 4.0 Green Algae 96 Hour EC 50 15,716 mg/L EPI Suite 4.0 Fish 30-day ChV 55,150 mg/L EPI Suite 4.0 Daphnid ChV 12,462 mg/L EPI Suite 4.0 Green Algae ChV 2947 mg/L EPI Suite 4.0

XII. Risk Characterization

Landis International, on behalf of Whitmire Micro-Gen, submitted two petitions requesting exemptions from tolerance for residues of potassi um benzoate when used as an inert ingredient (preservative) in pesticide formulations applied pre- and post-harvest and applied to animals. A Notice of Filing for each petition was published in the Federal Register

Potassium benzoate is an appr oved food preservative similar in structure and r eactivity to the more widely used and classified by US FDA as GRAS, sodium benzoate. Both are salts of benzoic acid. Perhaps as a result of potassium benzoate’s similarity to sodium benzoate, few toxicological studies on it were found. Because al l benzoates, and in particular benzoic acid and sodium benzoate, react similarly, they were used as surrogates in the developmen t of this profile.

Available data suggest that the acu te toxicity of potassium benzoate is negligible, having an oral

LD 50 of >10,000 mg/kg bw. Acute dermal and inhala tion toxicity is low as indicated by the >2000 mg/kg bw LD 50 and >12.2 mg/L LC 50 of benzoic acid. Sodium benzoate was not irritating to the skin and induced only slight eye irr itation in rabbits. Sodium benzoate and benzoic acid were non-sensitizing in animal tests but s howed a very low incide nce of sensitization in humans patch tested. Both sodium benzoa te and benzoic acid are known to induce nonimmunogenic contact reactions, and th at is the likely explanation for the low positive response.

Sub-acute, sub-chronic and chronic toxicity data also indicate th at potassium benzoate should be relatively nontoxic. Oral a nd dermal studies had a NOAEL ≥ 2000 mg/kg bw and the inhalation study had a NOAEL > 25 mg/m 3 . Sodium benzoate was not carcinogenic in a lifetime mouse feeding study and there is no indication that potassium benzoate s hould be neurotoxic. Genotoxicity studies indicate the benzoates are not mutagenic; however chromosomal aberration studies gave ambiguous results. Benzoic acid did not induce reproductive toxicity in a fourgeneration study

. In the human body under normal physiological conditions, potas sium benzoate changes from the ionized form to the undissociat ed benzoic acid. Benzoic acid and its salts are rapidly absorbed by mammals, conjugated with glyc ine, and rapidly excreted in the urine as hippuric acid. There is no reported accumulation of benzoate in the body. However, the ability to conjugate benzoic acid depends upon adequate liver function and nutritio nal supply of glycine.All data indicates that potassium benzoate is relatively non-toxic as are the other benzoates. No toxicity would be expected from potassium be nzoate when used at low concentrations in pesticides.

No developmental toxicity studie s are available in the database. However, no systemic toxicity was observed at doses up to 750 mg/kg/day in a four-generation reproducti ve study. In addition, no systemic toxicity were observed in the labo ratory animals at high doses (>2000 mg/kg/day) of potassium benzoate and benzoates indicating relatively low hazard pote ntial. In terms of hazard, there are low concerns and no residual uncer tainties regarding prenatal and/or postnatal toxicity. Based on this information, there is no concern at this time for increased sensitivity to infants and children to potassium benzoate when used as an inert i ngredient in pesticide formulations and a safety factor analysis has no t been used to assess risk. For the same reason, EPA has determined that an additional safety factor is not needed to protec t the safety of infants
and children.

Residues of concern are not anticipated for di etary exposure (food and drinking water) or for residential exposure from the use of potassium be nzoate for the proposed use pattern as an inert ingredient in pesticide products . EPA expects aggregate exposure to potassium benzoate to pose no appreciable dietary risk give n that the data on potassium be nzoate show a lack of any systemic toxicity and a lack of any apparent developmental effects.

There is limited environmental fate and ecotoxic ity data available for potassium benzoate, but
the fate and occurrence of benzoic acid have been well studied. The available data indicate that these compounds are expected to be readily biodegr adable in the environment and of low toxicity to fish, aquatic organisms, mammals and birds. The Agency believes that benozoic acid and the
benzoate salts will not cause unreasonable adverse effects on the environment.

Taking into consideration all available informa tion on potassium benzoate, EPA has determined that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to potassium benzoate when used as an inert ingr edient in pesticide formulations applied pre-and post-harvest and applied to animals when considering dietary exposure and all other non-occupational sources of pesticide exposure for which there is reliable information. Therefore, the establishment of an exemption from tolerance under 40 CFR 180.910 and 40 CFR 180.930 for residues of potassium benzoate (CAS Reg. No. 582-25-2) when used as an inert ingredient in pre- and post-harvest and animal applications in pesticide formulations, can be considered assessed as safe under section 408(q) of the FFDCA.

References

Abe, S. and Sasaki, M. 1977. J. Nat. Cancer Inst. 58. As cited in OECD/SIDS 2001.

Brasch, J. et al. 1993. Dermatose n. 41:71-76. as cited in OECD/SIDS 2001.

Bio-Fax. 1973. Benzoic acid, Indus trial Bio-Test Laboratories, Inc., Northbrook, IL, Data Sheet
28-4/73. As cited in OECD/SIDS 2001.BRL#9347.1979 (Unpublished study). Dermal sensitiza tion study in Guinea pigs with benzoic
acid. As cited in OECD/SIDS 2001.

BRL#9348.1979 (Unpublished study). Acute oral toxicity in mice administered benzoic acid. As
cited in OECD/SIDS 2001.

Collier, R., Setliff, L.A., Layton, C. 2007. Pota ssium benzoate: Petition for exemption from tolerance. Whitmire Micro-gen, c/o Landis Inte rnational, Inc., P.O. Box 5126, Valdosta, GA

31603-5126

Duel, H.J., Jr., et al., 1954. Food Res. 19:1-12. As cited in OECD/SIDS 2001.

EGG# 580-192-1-78, 1978 (Unpublished). Salmonella/mammalian-microsome plate incorporation mutageneis a ssay of benzoic acid 99.5%. As cited in OECD/SIDS 2001.

EPI Suite, version 4.0. 2008. Office of Po llution Prevention Toxics, U.S. EPA

FDA.PB 245453, 95S. 1972. Food and Drug Res earch Laboratories, Inc., Teratologic evaluation of FDA 71-37 (sodium benzoate). East Orange, NJ, Food and Drug Administration, Washington, DC. As cited in OECD/SIDS 2001.

Fosbeck, M. and Skog, E. 1977. Contact Derma titis 3:201-205. As cited in OECD/SIDS 2001.

Gad, S.C., et al., 1986. Toxicol. Appl. Phar macol. 84:93-114. As cited in OECD/SIDS 2001.

IRDC#163-282, 1974 (Unpublished study). Acute toxicity studies in rats and rabbits. As cited
in OECD/SIDS 2001.

IRDC #163-675, 1981.(Unpublished study).21-Day dermal t oxicity study in rabbits. As cited in
OECD/SIDS 2001.

IRDC #163-676, 1981.(Unpublished study).4-Week sub- acute inhalation toxicity study of
benzoic acid in rats with amendm ent. As cited in OECD/SIDS 2001.

Ishidate, J., Jr. and Odashima, S., 1977. Mut. Res. 48:337-354. As cited in OECD/SIDS 2001.

Ishidate, M., Sofuni, T., Yoshikawa, K., Haya shi M., et al. 1984. Primary mutagenicity screening of food additives currently used in Ja pan. FdChem Toxic. 22(8):623-636. As cited in
OECD/SIDS 2001.

Ishizaki, M., and Ueno, S.1989. J. Food Hyg.Soc. Japan. 30:447-451. As cited in OECD/SIDS

2001.

Jansson, T. et al., 1988. Mutat. Res. 206:17-24. As cited in OECD/SIDS 2001JECFA. 1997. Joint FAO/WHO Expert Committee on Food Additives. As cited in
OECD/SIDS 2001

Kieckebsch, W. and Lang, K. 1960. Arzneim- Forsch. 10:1001-1003. As cited in OECD/SIDS

2001.

Krevets-Bekker, A.A. and Iva nova, O.P. 1970. Faktroyvnesh, SredyIkhZnachenieZodorov’yaNaseleniya No. 2, 125: in BIBRA Toxicity Profiles, BIBRA International, Great Britain. As cited in OECD/SIDS 2001.

Loeser, E., 1977. Akuteoraletoxizitaet. Baye r AG data. As cited in OECD/SIDS 2001.

Loeser, E. 1977. Untersuchungenzur Haut- und Sc hleimhautvertraeglichkeit. Bayer AG data.
As cited in OECD/SIDS 2001.

Marquardt, P. 1960. Arzneim.-Forsc h 10:1033. As cited in OECD/SIDS 2001.

MRID 47180104. 2007. Potassium benzoate, ph ysical/chemical properties. [URL: http://www.sigma-aldrich.com ]. Whitmire Micro-gen, c/o Landis International, Inc., P.O. Box 5126, Valdosta, GA 31603-5126.

MRID 47180107. 2007. Potassium benzoate, ph ysical/chemical properties [URL: http://www.velsicol.com/asps/ documents/pibs/ProbenzPG.pdf ]. Whitmire Micro-gen, c/o Landis International, Inc., P.O. Box 5126, Valdosta, GA 31603-5126.

Nethercott, J.R., et al. 1984. J. Occ. Med. 26:734-736. As cited in OECD/SIDS 2001.

Nonaka, M. 1989. Environ. Mol. Mutagen. 14:143. As cited in OECD/SIDS 2001.

OECD/SIDS 2001. SIDS Initial Assessment Report for 13 th SIAM (Bern 7 th – 9 th November 2001). Benzoates.

Prival, M.J. et al. 1991. Mutat. Res. 260:321-329. As cited in OECD/SIDS 2001.

Rademaker, M. and Forsyth, A. 1989. C ontact Dermatitis 210, 104-107. As cited in
OECD/SIDS 2001.

RCC NOTOX Primary skin irritati on/corrosion study with natrium benzoate in rabbits (Study No. 014658. RCC NOTOX B.V., s’-Hertogenbo sch. As cited in OECD/SIDS 2001.

RCC NOTOX 1988. Eye irritation/corrosion study of benzoic acid in the rabbit (Study No. 0847/1084). As cited in OECD/SIDS 2001.

RCC NOTOX. 1988. Acute eye irritation/corrosion study with natrium benzoate in rabbits. (Study No. 014669). As cited in OECD/SIDS 2001.Shtenberg, A.J. and Ignat’ev, A.D. 1970. Food. Cosmet.Toxicol. 8:369-380. As cited in
OECD/SIDS 2001.

Smyth H.F., Jr., and Carpenter, C.P. 1948. J. Ind. Hyg. Toxicol. As cited in OECD/SIDS 2001.

Tohda, H. et al., 1980. Cancer Res. 40: 4775-4780. As cited in OECD/SIDS 2001.

Toth, B. 1984. Lack of tumorigenicity of sodi um benzoate in mice. Fund. Appl. Toxicol 4:494-

496.

US EPA. 2003 Memorandum: Benzoic Acid an d Benzoate Salts: Health Effects Division
Science Assessment Document for Tolerance Reassessment.

WHO. 1974. WHO Rood Additives Se ries No. 5., Geneva, Switzerland.

Xing, W. and Zhang, Z. 1990. Mutat. Res. 241:109-113. As cited in OECD/SIDS 2001.