UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFice OF

CHEMICAl. SAFETY AND

POLLunON PREVENTION

10/19/10

MEMORANDUM

SUBJECT:

FROM:

TO:

THRU:

INTRODUCTION

Benzoic acid. Human Health Effects Scoping Document for

the Registration Review Decision. PC Code: 009101. CAS

No.: 65-85-0. Reg. Review Case No.: 5107. DP Barcode:

D382191.

William J. Hazel, Ph.D., Chemist /2./1 ""-l"tl.'4

Risk Assessment and Science Support B;;;~ft, ~SS Antimicrobials Division (7510P)

Seiichi Murasaki, Chemical Review Manager

Regulatory Management Branch II (RMBII)

Antimicrobiais Division (7510P)

Nader Elkassabany, Ph.D., Chief

Risk Assessment and Science Support Bra

Antimicrobials Division (7510P)

The Antimicrobials Division (AD) of EPA's Office of Pesticide Programs (OPP)

has evaluated the status of the human health assessments for Benzoic acid.

Benzoic acid is an antimicrobial pesticide used as a preservative of food-grade

lubricating oils in industrial facilities. The team examined the hazard and

exposure databases for Benzoic acid to determine whether the current use

pattern, science policy, or database adequacy has materially affected the overall

risk picture.

EXECUTIVE SUMMARY

This is the Human Health Effects Scoping Document for the Benzoic acid

Registration Review Decision. A Reregistration Eligibility Decision (RED) has

never included Benzoic acid. Although a 2007 RED was issued for Benzoic acid

and derivatives (Case 4013), Benzoic acid was not addressed because, in this

case, antimicrobial uses were omitted. The first approval date for a product

containing the active ingredient (ai) Benzoic acid was 7/1/87 but, prior to
2

12/22/05, no products containing this ai remained registered. On this day in 

2005, however, a new product containing this ai was again registered. In such 

situations, the Agency treats the ai as a new active ingredient and, as such, 

Benzoic acid was assigned a new case number, Case 5107.

Benzoic acid is an antimicrobial pesticide in one end-use product (EP) named 

MICROL Preservative registered to Petro-Canada Lubricants Division (EPA Reg. 

No. 82076-1). This EP is formulated as a soluble concentrate/solid (SC/S) 

product containing 99.98% Benzoic acid. As there is no registered 

manufacturing-use product containing Benzoic acid, the SC/S is produced via an 

integrated formulation system; therefore, this EP is the proper material to use to 

satisfy data requirements calling for the TGAI as test substance.

The SC/S product is registered solely to preserve food-grade lubricating oils used 

in commercial food-handling establishments. The product may be added at 

≤1.0% relative to the amount of mineral oil in the lubricant. FDA has established 

regulations that limit the amount of mineral oil in food to 10 ppm (21 CFR 

178.3570). As a result, the maximum residue of Benzoic acid allowed in food 

from this use is 0.1 ppm. The FDA has classified Benzoic acid (21 CFR 

184.1021) and sodium benzoate (21 CFR 184.1733) as Generally Recognized as 

Safe (GRAS). FDA has also set an upper limit of benzoic acid or sodium 

benzoate as direct food-additives in certain foods at ≤0.1% (1000 ppm) by weight 

of the finished food (21 CFR 150.141, 21 CFR 150.161, and 21 CFR 166.110).

FDA also has cleared benzoic acid for use as a component of coatings for food 

contact surfaces (21 CFR 175.300) and as a component of high-temperature 

laminates for food contact surfaces (21 CFR 177.1390). EPA has granted 

exemptions from the requirement of a tolerance for use of benzoic acid as an 

inert ingredient (preservative) in pesticide formulations (40 CFR 180.910 and 40 

CFR 180.930). Human dietary exposure to residues of Benzoic acid from 

pesticidal sources, however, is expected to be minimal compared to the direct 

food-additive uses regulated by FDA.

Use of Benzoic acid to preserve food-grade lubricants for equipment in 

commercial food-handling establishments is an indoor use. Discharges or 

disposal of treated lubricant into aquatic environments is expected to be minimal. 

As a result, this EPA-registered use is not likely to result in contamination of 

drinking water. Thus, human dietary exposure to residues of Benzoic acid in 

drinking water is not expected. Therefore, a dietary (drinking water) risk 

assessment is not required.

The SC/S label clearly states that the product is for use only in industrial settings. 

Therefore, residential exposure is not expected and assessment of residential 

risk is not planned as part of the Benzoic acid Registration Review at this time.

The only potential source of exposure that could contribute to the aggregate 

exposure to Benzoic acid is the dietary source, largely the direct food-additive 

uses which have already been classified as GRAS by the FDA. A quantitative 
3

assessment of dietary risk has not been deemed necessary for the following 

reasons:

The hazard from, and exposure to, Benzoic acid are expected to be 

minimal from registered pesticidal uses.

Benzoic acid is naturally-occurring in humans and many of the foods 

humans consume, especially fruits.

The long history of safe human use of this compound as a flavoring agent 

and preservative in foods and beverages, pharmaceuticals, cosmetics,

personal care products, etc. at concentrations several orders of magnitude 

higher than those used in food-grade lubricants.

Once animals are exposed, Benzoic acid is rapidly metabolized by 

conjugation with glycine in the liver forming hippuric acid which is rapidly 

excreted in the urine.

Dermal and inhalation exposures of occupational applicators are likely during 

open-pour loading and mixing of the SC/S with food-grade industrial lubricants as 

well as while applying the lubricant to food-handling equipment. The low dermal 

hazard, the label requirement that gloves be worn, and the rapid rate of excretion 

are expected to render the dermal exposure route of minimal concern. Therefore, 

occupational dermal risk is not recommended for assessment. However, 

quantitative occupational inhalation risk assessments are expected to be needed 

as Benzoic acid is a crystalline solid and as the SC/S may be loaded via the 

open-pour method. A 28-day rat inhalation toxicity study is available that is 

expected to be considered adequate for occupational inhalation risk assessment. 

The Agency will attempt to locate this study, add it to our databases, and have it 

scientifically evaluated for use during the risk assessment stage of the Benzoic 

acid Registration Review. Modeling will be used to estimate worker inhalation 

exposure once the product use study and particle size distribution have been 

received. Label instructions requiring that handlers wear protective eye covering 

are sufficient to protect workers from the eye irritation effects of exposure to 

Benzoic acid.

The primary sources of information for this assessment were a 2004 submission 

from Petro-Canada Specialty Products and Fluids (MRID 46432703) to support 

registration of MICROL Preservative, the 1993 EPA/IRIS report, and the 2000 

and 2002 WHO assessments. No new toxicity data for Benzoic acid have been 

submitted to the Agency since 1993 although the 1981 inhalation toxicity study 

noted above does not appear to have yet been reviewed. The purpose of this 

scoping document is to determine whether sufficient data are available to support 

registration review, whether new human health assessments are needed to 

support Registration Review, and to report why the Agency feels it may be 

appropriate to conduct new risk assessments under the Registration Review 

process.
4

Section 1. Chemical Identity

Table 1.1 Chemical Identity

Common Name Benzoic acid

Chemical Name Benzenecarboxylic acid, benzeneformic acid

Empirical Formula C7H6O2

Molecular Weight 122.12

PC Code 009101

CAS Registry Number 65-85-0

Registration Review Case No. 5107

Chemical Structure:

Benzoic acid is a colorless crystalline solid at room temperature with no odor or 

with a slight benzaldehyde-like odor. It melts at 122.4 °C and boils at 249.2 °C. 

It is somewhat soluble in water (0.34 g/100 ml at 25 °C), very soluble in methanol 

and ethanol, and of low solubility in hexane. The dissociation constant (pKa) is 

4.19 at 25 °C. The vapor pressure is 7 x 10-4 mmHg at 25 °C. Benzoic acid has 

an octanol/water partition coefficient, pKo/w, of 1.87. The density at 25 °C is 1.32

g/cm3.

Section 2. Toxicology

The toxicity database for Benzoic acid appears to be adequate to permit the 

Agency to conduct a hazard characterization for this Registration Review. 

Studies testing the oral toxicity of Benzoic acid and sodium benzoate are 

considered to be interchangeable because both will exist as benzoic acid in the 

stomach. No additional toxicity data are expected to be needed at this time. A 

1981 28-day rat inhalation toxicity study has not yet been reviewed but is 

expected to be adequate for occupational inhalation risk assessment purposes.

Acute Toxicity

The TGAI (99.98% SC/S) Benzoic acid exhibits low to moderate acute oral 

toxicity (Toxicity Category III in rat), acute dermal toxicity (Category IV in rabbit), 

and acute inhalation toxicity (Category IV). The TGAI was slightly irritating to 

rabbit skin (Category III) and was not a dermal sensitizer of guinea pigs. 

However, the technical was severely irritating to the eyes (Category I) (MRID 

46432703).
5

Absorption and Metabolism

Benzoic acid is rapidly and efficiently absorbed through the digestive tract to the 

extent that complete absorption has been considered likely by several authors 

including the World Health Organization (WHO; 2000). Absorption through the 

skin is less than complete. A number of animal species were found to dermally 

absorb between 25% in pigs and 89% in rhesus monkeys. Whether orally or 

dermally absorbed, benzoic acid is rapidly conjugated with glycine in the liver 

forming hippuric acid which is rapidly excreted. If the glycine pool is insufficient, 

remaining Benzoic acid may be glucuronidated and excreted; small amounts of 

unchanged Benzoic acid may also be excreted (WHO, 2000).

Subchronic Toxicity

Oral. The 2000 WHO hazard assessment summarized a number of short-term 

oral toxicity studies (published 1948-1993) in cats, rats, and mice; cats were the 

most sensitive species. In cats treated with Benzoic acid at 100-200 mg/kg/day 

for 15-23 days, no adverse effects were observed. At 300-420 mg/kg/day for 3-4 

days, behavioral effects, degenerative effects on the liver, kidneys, and lungs, 

and death (50%) were induced in cats.

In rats, no adverse effects were observed after having been treated with Benzoic 

acid or sodium benzoate at up to 1100 mg/kg/day for 7-35 days. Doses from 

1800-2300 mg/kg/day caused such effects as reduction in relative liver and 

kidney weights, absolute spleen weight, relative and absolute thymus weight, and 

20-50% mortality. Higher doses (4-5% of the diet or 3000-6700 mg/kg/day) 

resulted in 80-100% mortality within 11-28 days.

In mice treated in the diet or drinking water, no effects were observed at 3000 

mg/kg/day (sodium benzoate at 2% of the diet). At 3750 mg/kg/day, changes in 

serum cholinesterase occurred. At 4500 mg/kg/day, hypersensitivity, reduced 

liver and kidney weights, altered serum cholesterol and phospholipids, enlarged 

hepatocytes, and 60% mortality occurred. At 6000 mg/kg/day, 75% mortality 

resulted and, at 12000 mg/kg/day (sodium benzoate at 8% of the diet), there was 

100% mortality within 3 weeks.

Dermal. A dermal toxicity study is not currently available.

Inhalation. The 1993 IRIS assessment reported that inhalation toxicity studies 

were not available. A 2004 submission from Petro-Canada Specialty Products 

and Fluids (MRID 46432703) to support registration of MICROL Preservative 

excerpts the summary of a 28-day rat inhalation toxicity study conducted by 

Velsicol Chemical Corp. (1981) and used by the World Health Organization 

(WHO) in their 2000 hazard assessment. Rats were exposed 6 hr/day and 5 

days/week. The mass median aerodynamic diameter of the Benzoic acid dust 

aerosol was 4.7 μ. At all treatment concentrations (25, 250, and 1200 mg/m3

air), increased incidence of interstitial fibrosis and inflammatory cell infiltrate were 

observed in lungs and trachea; although higher than the incidence in untreated 
6

control animals, no direct dose-dependence was evident. At the two highest 

doses, upper respiratory tract irritation and decreased absolute kidney weights 

were elicited in females. At 1200 mg/m3, one of ten rats of each sex died, body 

weight gain decreased in both sexes, platelet count decreased in males and 

females, absolute and relative liver weights decreased in males, and 

trachea/lung weights decreased in females. This study is not known to have 

been reviewed by OPP. If not, a thorough scientific evaluation of this study will 

be conducted and, if adequate, it will be used in occupational inhalation risk 

assessments.

Chronic Oral Toxicity

EPA’s Integrated Risk Information System (IRIS) conducted a review of data 

available to assess chronic toxicity of Benzoic acid (last revised 7/1/93). This 

was based mainly on a 1973 FDA study titled “Evaluation of the Health Aspects 

of Benzoic Acid and Sodium Benzoate as Food Ingredients” (Report No. 

SCOGS-7. NTIS PB-223837/6). 

Based on the 1993 IRIS assessment, sodium benzoate appeared to have no 

maternal toxicity, fetal toxicity, or teratogenicity in mice, rats, hamsters, or rabbits 

when given orally (Food and Drug Research Labs, Inc., 1972). The highest 

doses tested were 175 mg/kg/day in mice and rats, 300 mg/kg/day in hamsters, 

and 250 mg/kg/day in rabbits. 

Also from the 1993 IRIS assessment, the only chronic oral dosing data available 

involve administration of Benzoic acid to rats and mice (Shtenberg and Ignat'ev, 

1970; Ignat'ev, 1965; Marquardt, 1960). A dose of 40 mg/kg/day for 17 months 

was associated with decreased resistance to stress in mice and possibly with 

reduced food and water intake in rats after 18 months (Shtenberg and Ignat'ev, 

1970). However, another report from this laboratory (Ignat'ev, 1965) indicated 

that 80 mg/kg/day in rats for 18 months was not associated with adverse effects 

on body weight, survival, or gross or microscopic pathology.

Other long-term dietary studies (Marquardt, 1960) showed decreased food intake 

and body weight in rats fed benzoic acid at 1.5% in the diet (750 mg/kg/day); at a 

dose of 1.0% in the diet (500 mg/kg/day) there were no signs of toxicity or 

adverse reproductive effects (IRIS, 1993). 

IRIS (2003) reported that a screening-level review conducted in August 2003 by 

an EPA contractor of the more recent toxicology literature for Benzoic acid did 

not identify any critical new studies available since the 1993 IRIS assessment.

Carcinogenicity

IRIS (1989) classified Benzoic acid as Group D (not classifiable as to human 

carcinogenicity). The basis for this classification was that there were no human 

cancer studies available and animal bioassays were deemed inadequate.
7

Nevertheless, IRIS (1989) summarized the animal studies. In an inadequate 

lifetime mouse study (Toth, 1984), male and female animals were dosed at 2% 

sodium benzoate in the drinking water (equivalent to Benzoic acid at about 3500 

mg/kg/day). Histopathologic examinations of all mice included 11 organs and all 

gross lesions. The treatment had no apparent effect on survival or tumor 

incidence. As part of a five-generation reproduction study, Shtenberg and 

Ignat'ev (1970) administered test compounds in a paste in daily doses of 40 

mg/kg benzoic acid combined with 80 mg/kg sodium bisulfite in a paste before 

feeding an unspecified basic diet to mice for 17 months. Another group received 

benzoic acid only; no further details were given. Malignant tumors (not otherwise 

specified) occurred in 8/100 treated mice and 1/8 mice in the third generation of 

the treated group. Tumor incidences were not reported for untreated mice. 

Dinerman and Ignat'ev (1966) reported that a 3-month exposure to 0.2% benzoic 

acid in the diet increased the susceptibility of mice to the development of 

carcinomas following intraperitoneal inoculation with Erlich ascites carcinoma 

cells. Tumors developed in 62/90 (68.8%) of benzoic acid-treated mice and in 

16/49 (32.6%) of the control mice. Benzoic acid and sodium benzoate have 

been tested for mutagenicity or genotoxicity in prokaryotes (McCann et al., 

1975), eukaryotes (Litton Bionetics, Inc., 1974), and several mammalian test 

systems (Litton Bionetics, Inc., 1974, 1975; Oikawa et al., 1980). No positive 

results have been reported.

Reproductive and Developmental Toxicity

Developmental Toxicity

A 2000 Concise International Chemical Assessment Document (CICAD) 

summarized available developmental and reproductive toxicity studies testing 

Benzoic acid and sodium benzoate. CICAD s are jointly prepared by WHO, UN, 

and the International Labour Organization. The subject CICAD is referred to 

here as WHO (2000). For sodium benzoate, several teratogenicity studies are 

available that have been performed with different species. No effects were seen 

in dams or offspring of rats, mice, rabbits, or hamsters given oral doses of up to 

300 mg/kg/day (highest dose tested) during gestation (US FDA, 1972b). In a 

study with rats by Onodera et al. (1978), doses of 4% or 8% via diet (uptake of 

965 or 1875 mg/kg/day) induced severe maternal toxicity (no weight gain or loss 

in body weight, increased mortality) and were associated with embryotoxic and 

fetotoxic effects as well as malformations. However, the authors suggested that 

the effects on the dams and fetuses at ≥4% dietary levels were caused by 

reduced maternal feed intake, leading to malnutrition. The intake of sodium

benzoate in the highest dose group (8%) was lower than that at 2%, where no 

adverse effects were seen. From this study, a NOAEL of about 1310 mg/kg/day 

can be derived. In a study with rats by Minor and Becker (1971), however, 

fetotoxic and teratogenic effects occurred at 1000 mg/kg/day. In this study,

sodium benzoate was administered by intraperitoneal injection. Differences in 
8

pharmacokinetics between oral and intraperitoneal administration may be the 

reason for the higher sensitivity.

Studies performed with eggs of leghorn hens (single injection of ≤5 mg Benzoic 

acid per egg), chick embryo neural retina cells (lowest-observed-effect 

concentration [LOEC] of 34.7 mmol/L), and a chick embryotoxicity screening test 

(single injection of ≤0.1 mg per embryo) gave no indication of embryotoxic or 

teratogenic effects (Verrett et al., 1980; Jelinek et al., 1985; Daston et al., 1995).

Reproductive Toxicity

The reproductive toxicity of Benzoic acid and sodium benzoate has not been 

tested directly. However, in a four-generation rat study, no adverse effects on 

fertility or lactation were observed after dosing with Benzoic acid at ≤1% in the 

diet (about 500 mg/kg/day). Also, no effects on testes occurred in rats in 

response to 4 wk of dosing with Benzoic acid in the diet at ≤650 mg/kg/day or in 

mice dosed with Benzoic acid lifelong in the drinking water at 6200 mg/kg/day 

(WHO, 2000).

As benzyl acetate and benzyl alcohol are practically quantitatively (>90%) 

metabolized to benzoic acid via the benzaldehyde intermediate, data on their 

reproductive toxicity may be used as supportive evidence in the assessment of 

the hazards associated with benzoic acid (WHO, 2000). These studies are 

summarized below.

Dietary benzyl acetate (up to 5% in the diet for 13 weeks) had no effect on the 

weights of the epididymis, cauda epididymis, or testis, on sperm motility or 

density, or on the percentage of abnormal sperm in mice or rats (US NTP, 1993).

Benzyl acetate (0, 10, 100, 500, or 1000 mg/kg/day by gavage on gestation days 

6-15) had no significant effects on maternal health in rats and did not induce 

changes in the numbers of corpora lutea, implantations, live or dead fetuses, or 

resorptions, implantation ratio, sex ratio, external or internal malformations, or

placental weight. Fetal weights were significantly reduced at the highest dose 

(Ishiguro et al., 1993).

Benzyl alcohol at 550 mg/kg/day by gavage on days 6-15 of pregnancy had no 

effect on gestation index, average number of live pups per litter, postnatal 

survival, or pup body weight on days 0 and 3 in CD-1 mice (York et al., 1986), 

while 750 mg/kg/day (days 7-14) induced a reduction in the pup weight and 

maternal weight gain, but no pup mortality or changes in mating or gestation

indices, the total number of resorptions, or the number of live pups per litter 

(Hardin et al., 1987).

Mutagenicity

Benzoic acid tested negative in several Ames tests and in one DNA damage 

assay with different Salmonella typhimurium strains in the presence or absence 
9

of metabolic activation (McCann et al., 1975; Ishidate et al., 1984; Nakamura et 

al., 1987; Zeiger et al., 1988). Only in one recombination assay with Bacillus 

subtilis H17 and M45 was a positive result obtained (Nonaka, 1989). However, 

due to missing experimental details (only results given), the validity of this study

cannot be judged. There was no indication of genotoxic activity (chromosomal 

aberrations, sister chromatid exchange) in tests with mammalian cells (Chinese 

hamster CHL and CHO cells, human lymphoblastoid cells, human lymphocytes) 

without metabolic activation (Oikawa et al., 1980; Tohda et al., 1980; Ishidate et 

al., 1984; Jansson et al., 1988). No in vivo mutagenicity tests were conducted 

using Benzoic acid. However, a number of in vivo studies on sodium benzoate 

were positive.

Section 3. Dietary Exposure

Food Exposure

The SC/S label directs the user to dissolve the product in the mineral oil 

component of food-grade lubricating oils prior to mixing with any other lubricant 

components. The product may be added at ≤1.0% relative to the amount of 

mineral oil in the lubricant. The mineral oil concentration in food is limited to 10 

ppm (21 CFR 178.3570). As a result, the maximum theoretical concentration of 

benzoic acid allowed in food from the preservation of food-grade lubricants used 

in commercial food-handling establishments is 0.1 ppm. The FDA has affirmed 

that benzoic acid (21 CFR 184.1021) and sodium benzoate (21 CFR 184.1733) 

are direct food substances Generally Recognized as Safe (GRAS). FDA has 

also specified requirements for several specific standardized foods each of which 

includes an upper limit of benzoic acid or sodium benzoate as an antimicrobial, 

flavoring agent, or adjuvant at ≤0.1% (1000 ppm) by weight of the finished 

artificially sweetened fruit jelly (21 CFR 150.141), artificially sweetened fruit 

preserves and jams (21 CFR 150.161), and margarine (21 CFR 166.110). Note 

that the 0.1-ppm concentration in food resulting from the preservation of 

lubricants is four orders of magnitude (10,000x) less than the 1000 ppm in food 

as permitted by FDA when benzoic acid is used as a direct food additive.

FDA also has cleared benzoic acid for use as a component of resinous and 

polymeric coatings for food contact surfaces (21 CFR 175.300) and as a 

component of laminate structures for food contact surface uses at high 

temperatures ≥250° F (21 CFR 177.1390). EPA has granted an exemption from 

the requirement of a tolerance for use of benzoic acid as an inert ingredient 

(preservative) in pesticide formulations applied to growing crops or to raw 

agricultural commodities (RACs) after harvest (40 CFR 180.910). EPA has also 

granted an exemption for use of benzoic acid as an inert ingredient (preservative) 

in pesticide formulations applied to animals (40 CFR 180.930). Human dietary 

exposure to residues of Benzoic acid from pesticidal sources, while expected, will 

be minimal compared to the direct food-additive uses, pharmaceutical use, 

cosmetic uses, and naturally-occurring residues (especially in fruits). Thus, a 
10

quantitative assessment of dietary (food) risk has not been deemed necessary as 

part of this Registration Review.

Drinking Water Exposure

Use of Benzoic acid to preserve food-grade lubricants for equipment in 

commercial food-handling establishments is an indoor use. Discharges or 

disposal of treated lubricant into aquatic environments is expected to be minimal. 

As a result, this EPA-registered use is not likely to result in contamination of 

drinking water. Thus, human dietary exposure to residues of Benzoic acid in 

drinking water is not expected. Therefore, a dietary (drinking water) risk 

assessment is not required.

Section 4. Residential Exposure

The SC/S label clearly states that the product is for use only in industrial settings. 

Therefore, residential exposure is not expected and assessment of residential 

risk is not planned for the Benzoic acid Registration Review at this time.

Section 5. Aggregate Risk

The only potential source of exposure that could contribute to the aggregate 

exposure to Benzoic acid is the dietary source, largely the direct food-additive 

uses which have already been classified as GRAS by the FDA. A quantitative 

assessment of dietary (food) risk has not been deemed necessary for the 

following reasons:

The hazard from, and exposure to, Benzoic acid are expected to be 

minimal from registered pesticidal uses.

Benzoic acid is naturally-occurring in humans and many of the foods 

humans consume, especially fruits.

The long history of safe human use of this compound as a flavoring agent 

and preservative in foods and beverages, pharmaceuticals, cosmetics, 

personal care products, etc. at concentrations several orders of magnitude 

higher than those that might result in food from use in food-grade 

lubricants.

Once animals are exposed, Benzoic acid is rapidly metabolized by 

conjugation with glycine in the liver forming hippuric acid which is rapidly 

excreted in the urine.

Section 6. Occupational Exposure

Dermal and inhalation routes of occupational applicator exposure are likely 

during open-pour loading and mixing of the SC/S with food-grade industrial 

lubricants. The low dermal hazard, the label requirement that gloves be worn, 
11

and the rapid rate of excretion are expected to render the dermal exposure route 

of minimal concern. Therefore, occupational dermal risk is not recommended for 

assessment. However, quantitative occupational inhalation risk assessments are 

expected to be needed as Benzoic acid is a crystalline solid, it is somewhat 

volatile (vapor pressure of 7 x 10-4 mmHg at 25 °C), and the SC/S may be loaded 

via the open-pour method. A 28-day rat inhalation toxicity study is available that 

is expected to be considered adequate for occupational inhalation risk 

assessment. The Agency will attempt to locate this study, add it to our 

databases, and have it scientifically evaluated for use during the risk assessment 

stage of the Benzoic acid Registration Review. Modeling will be used to estimate 

worker inhalation exposure once the product use and human activity studies and 

particle size distribution have been received. Label instructions requiring that 

handlers wear protective eye covering are sufficient to protect workers from the 

eye irritation effects of exposure to Benzoic acid.

Section 7. Human Incident Reports

No Benzoic acid-specific human poisoning incidents have been reported in the 

OPP incident database.

Section 8. Cumulative Risk

EPA does not have, at this time, available data to determine whether Benzoic 

acid has a common mechanism of toxicity with other substances or how to 

include this pesticide in a cumulative risk assessment. For the purposes of this 

Registration Review, EPA has assumed that Benzoic acid does not have a 

common mechanism of toxicity with other substances.

Section 9. Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine 

Disruptor Screening Program (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.
12

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. This list of chemicals was selected based on the 

potential for human exposure through pathways such as food and water, 

residential activity, and certain post-application agricultural scenarios. This list 

should not be construed as a list of known or likely endocrine disruptors.

Benzoic acid is not among the group of 58 pesticide active ingredients on the 

initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency 

must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future 

EDSP test orders/data call-ins for all pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, 

the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, 

please visit our website: http://www.epa.gov/endo/.

Section 10. Overall Conclusions

Data Needs

The Agency has screened the hazard and exposure databases for Benzoic acid

and does not anticipate that additional toxicology studies will be needed for 

registration review. However, the following product chemistry and exposure data 

are expected to be necessary to conduct occupational inhalation exposure 

assessments.

Particle size distribution of the EP (GLN 830.7520)

Product Use Information – Indoor (GLN 875.2700)

Descriptions of Human Activity (GLN 875.2800)

Risk Assessment Needed

Inhalation risks to occupational handlers open-pouring and mixing the 

Benzoic acid EP into food-grade lubricants in manufacturing facilities.
13

Appendix A. Need for, and Uses of, the Data

Guideline Number: 830.7520

Study Title: Particle size distribution of the end-use product

Rationale for Requiring the Data

The Benzoic acid end-use product (EP) is in the form of a powder of 99.98% purity. Its only 

registered use is the preservation of food-grade lubricants to be used in/on food processing 

facility equipment. Most (or all) of these preserved lubricants are formulated in commercial 

manufacturing facilities by workers who are expected to be exposed for intermediate-term (1-6 

months) or long-term (>6 months) durations. The current label does not specify the loading 

method; this indicates that open-pouring of the powdered EP into the lubricant is permitted and

is, quite likely, the most commonly-used method. Open-pouring of a powder results in puff-back 

of dust particles which may be inhaled by the antimicrobial handlers. Early stages of mixing will 

often continue to generate dust until the benzoic acid dissolves. Typically, a dust/powder 

formulation will be comprised of particles in a distribution of sizes some of which will be inhalable 

and some of which will be respirable. The profile of this particle size distribution will depend on 

the composition of the product (in this case, pure food-grade benzoic acid, USP), properties of 

the product, method of preparation/synthesis, degree of milling (for solids), variation between 

batches, and any physical changes occurring after manufacture (e.g., fine dust generated during 

shipping and handling, further milling done by the formulator/packager, etc.). The magnitude of 

inhalation exposure will depend on the profile of this particle size distribution, the duration of 

exposure, pounds of EP used per day, equipment used, PPE actually worn, etc. Neither the

label nor the supplier’s MSDS requires that respiratory PPE be worn. The absorption, 

distribution, metabolism, and excretion of a compound following exposure via the inhalation route

could be much different than via the oral or dermal routes of exposure. The compound would 

reach the blood before it passes through the liver which is the site in which benzoic acid is 

metabolized (conjugated) to expedite excretion. 

Practical Utility of the Data

1. How did the Agency make its earlier regulatory decisions without these data?

The Agency used its best professional judgment based on its years of experience and general 

use information from the registered product labels and product chemistry data. The assumptions 

made in the past could have overestimated or underestimated exposures and, hence, risks.

2. How will the data be used? 

The particle size distribution will permit the Agency to estimate the inhalation exposure of 

commercial loaders open-pouring and then mixing the EP in manufacturing facilities to preserve 

food-grade lubricants formulated. This relatively simple study will determine the percentage of 

dust that is respirable and permit modeled estimation of exposure which, in turn, permits risk 

estimation without the conduct of more expensive occupational inhalation exposure studies.

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

These data, along with the endpoint and point of departure from the 28-day rat inhalation study,

will enable the Agency to conduct route-specific (inhalation) and chemical-/formulation-specific 

(dust profile) risk assessments that are representative of commercial scenarios. These

assessments will permit a determination of which use patterns are expected to result in 

exposures less than the Agency’s level of concern, which ones must be supported by additional 

data, and which ones are likely to have risks of concern that must be mitigated.
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Guideline Number: 875.2700

Study Title: Product Use Information (Indoor)

Rationale for Requiring the Data

Product use information is a narrative description of which, when, and how food-grade lubricants

are preserved when the product is actually applied; it is not a field study. A description of how 

the SC/S Benzoic acid product is used will provide a comprehensive, realistic assessment of its 

potential applications and resulting handler exposure. Descriptions are needed of: (i) what 

specific types of lubricants (viscosity, temperature limits, for what industry, etc.) are treated; (ii)

what stage in the manufacturing process each material is treated; (iii) the conditions to which the 

Benzoic acid will be exposed (temperatures, pH’s, etc.); (iv) the rate of degradation of Benzoic 

acid; etc. These will provide a comprehensive, realistic assessment of potential occupational 

exposures. Therefore, these data are required.

Product use information permits 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 risk. 

The guideline for postapplication 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 postapplication.

Practical Utility of the Data

1. How did the Agency make its earlier regulatory decisions without these data?

The Agency used its best professional judgment based on its years of experience and general 

use information from the registered product labels and product chemistry data. The assumptions 

made in the past could have overestimated or underestimated exposures and, hence, risks.

2. How will the data be used? 

The description of the specific lubricants preserved, application techniques, and physicochemical 

disposition will be used to determine the exposure scenarios and to refine the assumptions to be 

included in occupational inhalation risk assessment. It may also be used for the Agency to 

determine which representative exposure scenarios should be included in any studies triggered 

by apparent risks of concern obtained using more conservative modeled methodologies. 

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

These data will enable the Agency to understand how the EP is applied and to ensure that the 

risk assessment is inclusive of the types of exposures occurring commercially during pesticide 

use. This information will permit a determination of which use patterns are expected to result in 

exposures less than the Agency’s level of concern, which ones must be supported by additional 

data, and which ones are likely to have risks of concern and, therefore, must be mitigated.
Guideline Number: 875.2800

Study Title: DescriDtions of Human Activity

Rationale for Requiring the Data

Very limited worker activity data are available for antimicrobial pesticides, including materials

preservatives used in consumer products such as paint and industrial lubricants. Worker

application parameters are generally defined by the physical nature of the formulation (e.g.,

formula and packaging), by the equipment required to deliver the chemical to the use site, and

by the application rate required to achieve an efficacious dose. Without specific information

regarding such use parameters as amount of pesticide handled and duration of use, risk

assessments would have to be based on professional judgments. Such assessments could

greatly overestimate or underestimate exposure and, hence, risk.

Practical Utiljty of the Data

1. How did the Agency make its earlier regulatory decisions without these data?

The Agency used its best professional judgment, general use information from the registered

product labels, and product chemistry data. The assumptions made in the past could have

overestimated or underestimated exposures and, hence, risks.

2. How will the data be used?

These data will clearly identify such specific parameters as: equipment type(s), formulation(s),

dilutions, treatment frequency and duration, -real-world- PPE used, etc. In high exposure

scenarios such as direct-pour loading in preserved lubricant manufacturing facilities,

metalworking fluid use, and paint applications, these human activity details will enable the

Agency to refine its risk assessments.

3. How could the data impact the Agency's future decision-making?

Descriptions of human activities will allow the Agency to: (i) dismiss certain uses as not being of

concern; (ii) mitigate certain uses of concern; (iii) determine which uses need additional data for

support; (iv) refine its risk assessment and make decisions using fewer assumptions and more

reliable data; etc.

Sign-off Date

DP Barcode No. :

10/19/10

0382191

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