Document ID: EPA-HQ-OPP-2009-0900-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-03-31T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 		     WASHINGTON, D.C. 20460

 ADVANCE \d61 	OFF		ICE OF PREVENTION,

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.  

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),
D-menthol (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

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.

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
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

	 

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