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 to2

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

Benzoic acid is an a ntimicrobial pesticide in one end

- use product (EP) named MICROL Preservative registered to Petro

- Canada Lubricants Division (EPA Reg. No. 82076

- 1 ). Th is EP is formulated as a soluble concentrate/ solid ( SC/ S ) product contain ing 99.98 % Benzoic acid

. As t here 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

.

T he 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 amou nt of mineral oil in the lubricant. FDA has established regulations that limit the amount of mineral oil in food to 1 0 ppm (21 CFR 178.3570). As a result, the maximum residue of B enzoi c acid allowed in food from this use is 0.1 ppm. The FDA has classifi ed B enzoic 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 la minate s for food contact surfaces (21 CFR 1 77.1390 )

. EPA has granted exemption s 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

.

U se of Benzoic acid to preserve food

- grade lubricants for equipment in commercial food

- handling e stablishments 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 exposur e to residues of Benzoic acid in drinking water is not expected. Therefore, a dietary (drinking water) risk assessment is not required.

T he SC/S label clearly states that the product is for use only in industrial settings. Therefore, residential exposur e is not expected and assessment of resi dential risk i s not planned as part of the Benzoic acid Registration Review at this time

.
The only potential source of exposure that could contribut e to the aggregate exposure to Benzoic acid is the dietary source , largely the direct food

- additive

use s which have already been classified as GRAS by the FDA. A quantitative3

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

reasons:

T he hazard from, and exposure to, Benzoic acid are expected to be minimal from registered pesticidal uses

. Benzoic acid is natural ly

- occurr ing in humans and many of the foods humans consume, especially fru i ts. The long history of safe human use of this compound as a flavoring agent and preservative in foods and bever ages, pharmaceuticals, cosmetics, personal care products, etc. at concentrations several orders of magnitude higher than th ose use d in food

- grade lubricants

. Once animals are exposed, Benzoic acid is rapidly metabolized by conjugation with glycine in the l iver forming hippuric acid which is rapidly excreted in the urine.

Dermal and inhalation exposure s of o ccupational applicator s are likely during open

- pour loading and mixing of the SC/S with food

- grade industrial lubricants as well as while applying the l ubricant 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 recommen ded 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 availabl e 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

a cid 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 requir ing that handlers wear protective eye covering are sufficient to prot ect workers from the eye irritation effects of exposure to Benzoic acid

.
The primary source s of information for this assessment w ere a 2004 submission from Petro

- Canada Specialty Products and Fluids (MRID 46432703) to support registration of MICROL Pr eservative , 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 review ed

. 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 R eview, and to report why the Agency feels it may be app ropriate to conduct new risk assessments under the R egistration R eview process

.4

Section 1. Chemical Identity

Table 1.1 Chemical Identity Common Name Benzoic acid C hemical N ame Benzenecarboxylic acid , benzeneformic acid Empirical Formula C 7 H 6 O 2 M olecular Weight 122.12 PC Code 009101 CAS R egistry N umber 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 1 22.4 ° C and boils at 2 49 .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 (pK a ) 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, pK o/w , of 1. 87 . T he density at 2 5 ° C is 1. 32 g /cm 3

.

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 toxicit y of Benzoic acid and sodium benzoate are considered to be interchangeable because both will exist as benzo ic 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 toxi city (Toxicity Category III in rat), acute dermal toxicity (Category I V 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 t echnical 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 severa l authors including the World Health Organization ( WHO ; 2 000). 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 th e 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 als o 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 Benzoi c acid a t 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 o n 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 benzoa te at 2% of the diet). At 3750 mg/kg/day, changes in serum cholinesterase occurred. A t 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 Fl uids (MRID 46432703) to support registration of MICROL Preservative excerpts the summary of a 28

- day rat inhalation toxicity study conducted by Ve lsicol 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 c oncentrations (25, 250, and 1200 mg/m 3 air), increased incidence of interstitial fibrosis and inflammatory cell infiltrate were observed in lungs and trachea; although higher than the incidence in untreated6

control animals, no direct dose

- dependence was ev ident. At the two highest doses, upper respiratory tract irritation and decreased absolute kidney weights were elicited in females. At 1200 mg/m 3

, one of ten rats of each sex died, body weight gain decreased in both sexes, platelet count decreased in mal es 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, s odium benzoate appeared to have no maternal tox icity, 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 1 993 IRIS assessment, t he only chronic oral dosing data available involve administration of B enzoic 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 m onths 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/k g/day); at a dose of 1.0% in the diet (50 0 mg/kg/day) there were no signs of toxicity or adverse reproductive effects (IRIS, 1993)

. IRIS ( 200 3) reported that a screening

- level review conducted in August 2003 by an EPA contractor of the more recent toxicol ogy literature for Benzoic acid did not identify any critical new studies available since the 1993 IRIS assessment

.
Carcinogenicity

IRIS (19 89 ) classified Benzoic acid as Group D (not classifiable as to human carcinogenicity). The basis for this classific ation was that t here 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 b enzo ate 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 o f 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. A nother 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 inciden c es 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 Bionetic s, 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 As sessment 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. N o 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 as sociated with embryotoxic and fetotoxic effects as well as malformations. H owever, the authors suggested that the effects on the dams and fetuses at ≥ 4% d ietary levels were caused by reduced maternal feed intake, leading to ma lnutrition. 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. D ifferences in8

ph armacokinetics between oral and i ntraperitoneal 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 ha s not been tested directly. However, in a four

- generation rat study, no adverse effects on f ertility 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, 200 0).

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 u sed as supportive evidence in the assessment of the hazards associate d 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 d ensity, or on the percentag e 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 i nduce changes in the numbers of corpora lutea, impl antations, live or dead f etuses, or resorptions, implantation ratio, sex ratio, external or internal malformations, or placental weight. Fetal weights were significantly reduced at t he highest dose (Ishiguro et al., 1993).

Benzyl alcohol at 550 mg/kg / day by gavage on days 6

- 15 of p regnancy 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 t he 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 Ame s tests and in one DNA damage

a ssay with different Salmonella typhimurium strains in the presence or absence9

o f metabolic activation (McCann et al., 1 975; 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

a berrations, 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 1 0 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 so dium 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 166.1 10). 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 clea red 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 use s 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 ha rvest (40 CFR 180.910). EPA has also granted an exemption for use of benzoic acid as an inert ingredient (preservative) in pesticide formulations applie d to animals (40 CFR 180.930). Human dietary exposure to residues of Benzoic acid from pesticidal sour ces, while expected, will be minimal compared to the direct food

- additive uses , pharmaceutical use, cosmetic uses, and naturally

- occurring residues (especially in fruits)

. Thus, a10

quantitative assessment of dietary (food) risk has not been deemed necessar y 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 envi ronments 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 (drinki ng 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 f or the Benzoic acid Registration Review at this time

.

Section 5. Aggregate Risk

The only potential source of exposure that could contribut e 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 pe sticidal 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, cosmeti cs, 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 l iver 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 l ubricants. 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. Howev er, 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 r at 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 th e 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 stud ies and particle size distribution have been received. Label instructions requiring that handlers wear protective eye covering are sufficient to prot ect 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 Disrupt ion

As required under FFDCA section 408(p), EPA has developed the Endocrin e 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 endocri ne 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 wit h 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 deter mine 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 pot ential 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 t he 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 pest icide 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 toxic ology studies will be needed for registration review. However, the following product chemistry and exp osure 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. 2 700) Descriptions of Human Activity (GLN 875.2800)

Risk Assess ment Needed

Inhalation risks to occupational handlers open

- pouring and mixing the Benzoic acid EP in to food

- grade lubricant s in manufacturing facilities

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

Guideline Number: 830

. 7520 Study Title: Particle siz e 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 processi ng facility equipment. M ost (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 do es 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 common ly

- used method. Open

- pouring of a powder results in puff

- back of dust particles which may be inhale d 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 mil ling (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 d epend 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 require s that respiratory PPE be worn. The absorption, distrib ution, 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 b efore it passes through the liver which is the site in w hich benzoic acid is metabolized (conjugated) to expedite excretion. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decision s without th ese data?

The Agency used its best professional judgment based on its years of ex perience 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 si ze 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 decis ion

- 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 represen tative of commercial scenarios

. Th ese 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.14

Guideline Number: 875.2700 Study Title: Product Use Information (Indoor) Rationale for Requiring the Data
Product use information is a narrative description of wh ich, when, and how food

- grade lubricant s

are preserved when the product is actually a pplied; it is not a field study. A description of how the SC/S B enzoic acid product is used will provide a comprehensive, realistic assessment of its potential applications and resulting handler exposure. D es cription s 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 B enzoic acid will be exposed (temperatures, pH’s, etc.); (iv) the rate of degradation of B enzoic acid ; etc. These will provide a comprehensive, realistic assessment of potential occupational exposures. Therefore, these data are required.

Product use information permits E PA 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 signi ficant 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.ep a.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 decision s without th ese 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 overestim ated 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 re fine 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 e nable 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 

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