### UNITED STATES ENVIRONM **ENTAL 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.2



### 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 Profile3



### 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 LD 50 /LC 50 /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.4

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 Developm ental/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 LC 50 

### 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 that5



### 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