UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

 WASHINGTON, D.C. 20460 

OFFICE OF PESTICIDES AND TOXIC SUBSTANCES 

MEMORANDUM

DATE: February 1, 2010 

SUBJECT: Preliminary Human Health Assessment for the Registration Review of Menthol. 

 Registration Review Case #: 4063 

 PC Code: 051601 

 CAS #: 1490-04-6 and 2216-51-5 

 Chemical Class: Biochemical 

FROM: Angela L. Gonzales, Biologist 

Biochemical Pesticides Branch 

Biopesticides & Pollution Prevention Division (7511P) 

TO: Colin Walsh, Regulatory Action Leader 

 Biochemical Pesticides Branch 

Biopesticides & Pollution Prevention Division (7511P) 

ACTION REQUESTED 

The following is a preliminary human health assessment for the biopesticide Menthol in support 

of the development of the Registration Review Work Plan. 
 

 

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RECOMMENDATIONS AND CONCLUSIONS 

Executive Summary

Based on the available data and information, the Agency does not foresee the need for new data 

or for a new human health risk assessment. All data requirements per 40 CFR 158.2050 have 

been fulfilled for the active ingredient. Hazard and exposure data and information as well as 

Agency risk assessments on this chemical were evaluated against current safety standards 

established by the Agency’s scientific policies and regulations and it was determined that there is 

no need to conduct an additional human health risk assessment. The active ingredient is of low 

toxicity and exposure is expected to be minimal based on known use patterns and personal 

protection equipment (PPE) requirements. Additionally, humans are exposed to menthol in a 

variety of products, including medications, foods, and personal care products. There is 

reasonable certainty that no harm will result to the general population from the products 

containing the active ingredient when they are used according to label instructions. 

 

I. Background 

Currently, there are two end-use products that are registered containing the biochemical. The 

first product contains menthol (CAS # 1490-04-6, contains the unspecified isomers of menthol) 

as the only active ingredient, and is used to control tracheal mites in over-wintering honey bee 

hives. The second product contains L-menthol (CAS # 2216-51-5) along with two other active 

ingredients, and is used to control varroa mites in honey bees. Both chemicals fall under this 

registration review case. 

Menthol occurs naturally in a variety of plants, especially in mint. It is found in a variety of 

products, including foods and beverages, cigarettes, medications, and personal care products. 

The four most commonly used isomers of menthol are L-menthol (CAS # 2216-51-5), Dmenthol (CAS #15356-60-2), D/L-menthol (racemic, CAS # 89-78-1) and a mixture of 

unspecified isomers of menthol (CAS # 1490-04-6). There is no appreciable difference in the 

toxicological properties of these isomers. (Menthol TRED, 2004) Two of these isomers are 

used as registered pesticides and are mentioned above. 

Menthol is also approved as an inert ingredient in nonfood-use pesticide products. It is approved 

by the Food and Drug Administration (FDA) as a synthetic flavoring substance for use as a food 

additive (21 CFR 172.515). Menthol is considered to be Generally Recognized as Safe (GRAS) 

by FDA for food-use as an essential oil or natural extractive (21 CFR 182.20). (Menthol TRED, 

2004). 

II. Toxicity Profile 
 

 

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Available toxicity data as required by 40 CFR 158.2050 regarding menthol are summarized 

below in Table 1. 

Table 1. Menthol (051601) 

Study Type/OPPTS Guideline LD50/LC50/Results Toxicity 

Category

Source

Acute Oral Toxicity/OPPTS 870.1100 L-menthol: 

3400 and 4380 mg/kg (mouse); 

940, 2615, and 3300 mg/kg (rat) 

D/L-menthol: 3100 mg/kg (mouse); 

 2602, 2900 and 3,180 (rat) 

III Menthol TRED, 

2004

Acute Dermal Toxicity/OPPTS 870.1200 D/L-menthol: 

> 5,000 mg/kg (rabbit) 

IV Menthol TRED, 

2004

Acute Inhalation Toxicity/OPPTS 870.1300 Acute toxicity data are not available. 

See discussion below. 

Acute Eye Irritation/OPPTS 870.2400 Slightly irritating; see discussion below III Menthol TRED, 

2004 

Acute Dermal Irritation/OPPTS 870.2500 Moderately irritating III Menthol TRED, 

2004 

Skin Sensitization/OPPTS 870.2600 Not a sensitizer Menthol TRED, 

2004 

90-day Oral/ OPPTS 870.3100 

D/L-Menthol (mg/kg-bw/day) 

Mouse: 

1) NOEL = 560, LOEL = 1100 (based 

on increased incidence of perivascular 

lymphoid hyperplasia and interstitial 

nephritis in females; 

2) NOAEL = 1956 (males), 2386 

(females); LOAEL = 4773 (males), 

3913 (females) (based on reduction in 

body weight gain at highest dose tested 

D/L-Menthol (mg/kg-bw/day) Rat: 

1) NOEL = 750, LOEL = 1500 (based 

on increased incidence of interstitial 

nephritis in male rats only) 

2) NOAEL = 937 (males), 998 

(females); LOAEL = N/A: no effects 

on organ weights, no other adverse 

effects observed at highest dose tested 

(slight increase in severity of 

spontaneous interstitial nephritis in 

males-OECD stated was not an adverse 

effect) 

Menthol TRED, 

2004 

90-day Dermal – rat/OPPTS 870.3250 

Waived due to lack of prolonged 

dermal exposure based on current use 

patterns. Additionally, exposure from 

handling products is mitigated through 

the requirement of chemical resistant 

gloves as PPE. 
 

 

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90-day Inhalation – rat/OPPTS 870.3465 

Waived due to lack of significant 

levels of repeated inhalation exposure 

based on current use patterns. See 

below for more information on 

inhalation toxicity. 

Prenatal Developmental/OPPTS 870.3700 No teratogenic effects observed (mice,

rat, hamster and rabbit studies) 

Menthol TRED,

2004 

Mutagenicity: 

Bacterial Reverse Mutation Test/OPPTS 

870.5100 

Negative Menthol TRED,

2004 

Mutagenicity: 

In vitro Mammalian Cell Assay (mouse 

lymphoma)/OPPTS 870.5300

Negative Menthol TRED,

2004 

Acute Inhalation Toxicity

Acute inhalation studies were not identified by the reviewer. A subchronic inhalation study was 

referenced in the Tolerance Reassessment Progress and Risk Management Decision (TRED) 

document for menthol (2004) which indicated that when rats were exposed to L-menthol vapors 

for 71-79 days, no systemic effects were observed at any dose. Histological observations 

revealed irritant effects on lungs and trachea at the highest dose tested. The exposure 

concentration in the study could not be measured as there was not an adequate analytic method 

available at the time. Exposure concentrations were expressed as weight of menthol vaporized 

divided by the volume of air circulated and determined to be 0.087, 1.148 and 0.259 ppm. 

Because the measurement of exposure concentration is not reliable, an accurate LC50 and/or 

NOEL cannot be derived. The study cannot be used to determine precautionary labeling for the 

same reason. 

At this time, submission of an acute inhalation study is not required. Based on the use patterns 

of the currently registered EPs, significant inhalation exposure of the active ingredient is not 

likely when products are used according to label instructions. Additionally, humans are exposed 

to menthol vapors in a variety of medications, foods, beverages and personal care products. 

Acute Eye Irritation

Based on the information available to the Agency, menthol is considered to be slightly irritating 

to the eye. The active ingredient was historically classified as a severe eye irritant, which was 

based on an eye irritation study where undiluted concentrations of 1% and 5% menthol 

(unspecified isomer, purity and vehicle) were tested using rabbits. No information was provided 

regarding the experiments, the number of animals used, and the individual scores for each 

animal. Only the overall result (severe irritation) was reported in the study. More recent testing 

on four menthol isomers has revealed that the chemicals are slightly irritating to the eye. These 

studies were conducted according to OECD Guideline 405 and the results indicated that 
 

 

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concentrations of 29-64% L-menthol, D-menthol and D/L-menthol in diethylphthalate and 

undiluted menthol liquid were slightly irritating to the eye. 

III. Tolerances 

§ 180.1092 Menthol; exemption from the requirement of a tolerance. 

An exemption from the requirement of a tolerance is established for residues of the pesticidal 

chemical menthol in or on honey and honeycomb when used in accordance with good 

agricultural practice in over-wintering bee hives. 

[74 FR 26535, June 3, 2009] 

 

IV. Incidents 

According to the Incident Data System, there has been one reported incident that was considered 

minor involving a domestic animal. The product was a dog repellant (Dog Away Spray, EPA 

Reg. No. 270-221) which is no longer registered. No other information was provided. No 

incidents have been reported for products containing menthol as an active ingredient for the 

current use patterns. 

V. References 

U.S. EPA Tolerance Reassessment Progress and Risk Management Decision (TRED) for 

Menthol (051601) Issued September, 2004.

 cc: A. L. Gonzales, C. Walsh, BPPD Science Review File 

 A. L. Gonzales, FT, PY-S: 2/01/10