 

<COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (1/1/2006)>

<EPA Antimicrobials Division contact: [insert name and telephone number
with area code]>

 

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<TEMPLATE:>

<Sensible Life Products>

<[Insert petition number]>

	EPA has received a pesticide petition ([insert petition number]) from
<Sensible Life Products (Div. of LBD, Ltd.)>, 34-7 Innovation Drive,
Ontario, Canada L9H7H9, proposing, pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR part 180 to establish an exemption from the requirement of
tolerance for residues of thymol (as present in thyme oil) in or on food
when the pesticide is used as a hard surface disinfectant.

	Pursuant to section 408(d)(2)(A)(i) of FFDCA, as amended, Sensible Life
Products has submitted the following summary of information, data, and
arguments in support of their pesticide petition.  This summary was
prepared by Sensible Life Products and EPA has not fully evaluated the
merits of the pesticide petition.  The summary may have been edited by
EPA if the terminology used was unclear, the summary contained
extraneous material, or the summary unintentionally made the reader
conclude that the findings reflected EPA's position and not the position
of the petitioner.

<A. Residue Chemistry>

<	1. Plant metabolism.   NA-REMOVE>

<	2. Analytical method. Since this petition is for an exemption from the
requirement of a tolerance, an analytical method is not required.  >

<	3. Magnitude of residues. Thymol residues on food that may contact
hard surfaces treated with thymol-based disinfectant have not been
quantitatively determined, but are anticipated to be low.  The
Incidental Dietary Residential Exposure Assessment Model (IDREAM)
developed by the American Chemistry Counsel’s Biocide’s Panel in
cooperation with EPA was used to estimate exposure potential.  

IDREAM can be used to predict the worst-case estimate of thymol that may
be transferred from the treated surface to food, exposure based on
typical amounts of food that come into contact with surfaces treated
with disinfectants, and potential exposures from food consumption
patterns of different population groups.  Using this model, it is
estimated that the worst-case amount of thymol that may be transferred
from a treated food contact surface to food is 4.6 mg assuming there is
not a potable water rinse (contrary to label instructions) and total
(100%) transfer of any thymol residue from the treated surface to the
food.  

Continuing to use these same conservative assumptions (no rinse and 100%
transfer of any residues), acute and chronic dietary exposure estimates
for population subgroups were calculated using IDREAM.  In both cases
(acute and chronic exposure scenarios), the population subgroup
“Children 1-2 yrs” had the highest potential exposure.  Based on the
low oral toxicity of thymol, it is assumed that the FQPA safety factor
would be set to 1.0, thus only the uncertainty factor of 100x (10x each
for intra- and interspecies variability) would likely be applied to a
repeated dose animal study NOAEL to derive reference dose levels (RfDs).
 For chronic dietary exposure, such a repeated dose study NOAEL would
have to be less than 0.872 mg/kg/day in order for the exposure estimate
to exceed 100% of the chronic RfD.  Similarly, the acute NOAEL would
have to be lower than 1.4 mg/kg/day for acute exposure to exceed 100% of
the acute RfD.

No chronic oral toxicity studies have been conducted by the registrant,
however, according to EPA’s review of the public literature, no
harmful effects were observed for rats dosed with thymol for 19 weeks at
667 mg/kg/day.  Further, the acute oral LD50 in the rat and guinea pig
is 980 mg/kg and 880 mg/kg, respectively.   It is apparent that the oral
toxicity observed for thymol is low and the worst-case exposure levels
from use of thymol in a disinfectant to treat food contact surfaces is
negligible in comparison and presents no basis for concern.

>

<B. Toxicological Profile>

<	1. Acute toxicity. Thymol toxicity data reported in the open
literature cite acute oral> LD50 values of 980 milligrams/kilogram
(mg/kg) and 880 mg/kg for the rat and guinea pig, respectively (Sax,
1984).  These acute oral toxicity values correspond to Toxicity Category
III.  The Material Safety Data Sheet (MSDS) of technical grade thyme oil
cites human health effects as irritating when exposed by inhalation,
dermal, or eye contact and estimates a human ingestion LD50 at 2 g of
the synthetic thymol.  Based upon an estimated thymol dermal toxicity
LD50 of greater than 2,000 mg/kg, the dermal toxicity would be Toxicity
Category III.

Thymol is corrosive to the rabbit eye and skin and is reported to not be
a dermal sensitizer based on guinea pig data.  Thymol is readily
absorbed from the gastrointestinal tract and is essentially excreted in
the urine as a glucuronate and sulfate conjugate of the parent compound.
 Based on this literature, all acute toxicity data requirements have
been found acceptable.

<	2. Genotoxicty. According to EPA reviews of the open literature,
thymol is not mutagenic in Salmonella, but gives statistically
significant positive results in an Unscheduled DNA synthesis, a Sister
Chromatid Exchange test, and a cell transformation test with Syrian
hamster embryonic cells.  Multiple malformations were noted when thymol
is injected into the air bubble or yolk sac of embryonic chickens. 
Dosing of rats with thymol in the feed at 667 mg/kg body weight/day
highest dose tested) for 19 weeks did not produce any harmful effects. 
Based on review of data available in the open literature, EPA has
consistently concluded that there is no basis for concern.

>

<<	3. Reproductive and developmental toxicity.   Thymol is a normal
constituent of the human diet and a component of many non-pesticidal
consumer products currently marketed in the United States.  Further, it
is generally recognized as safe by the FDA (21 CFR § 182.20) and listed
as a food additive by the FDA (21 CFR § 175.515; synthetic flavoring
substances and adjuvants).  Based on review of this information and data
available in the open literature, EPA has consistently concluded that
there is no basis for concern.>  	

	4. Subchronic toxicity.   According to EPA’s reviews of the public
literature, no harmful effects were observed in rats dosed with Thymol
in the feed for 19 weeks at 667 mg/kg body weight/day.  In A/He mice,
Thymol did not increase the incidence of spontaneous lung tumors with
repeated intra peritoneal injection for 24 weeks at a dose of 6000 mg/kg
body weight.   Based on review of data available in the open literature,
EPA has consistently concluded that there is no basis for concern.

>

<	5. Chronic toxicity.  Thymol is a normal constituent of the human diet
and a component of many non-pesticidal consumer products currently
marketed in the United States, and is generally recognized as safe by
the FDA (21 CFR § 182.20) and is listed as a food additive by the FDA
(21 CFR § 175.515; synthetic flavoring substances and adjuvants). 
Based on review of this information and data available in the open
literature, EPA has consistently concluded that there is no basis for
concern.>

<	6. Animal metabolism.  Thymol is a normal constituent of the human
diet and a component of many non-pesticidal consumer products currently
marketed in the United States, and is generally recognized as safe by
the FDA (21 CFR § 182.20) and is listed as a food additive by the FDA
(21 CFR § 175.515; synthetic flavoring substances and adjuvants). 
Based on review of this information, EPA has consistently concluded that
there is no basis for concern.>

<	7. Metabolite toxicology. NA-REMOVE>

<	8. Endocrine disruption. According to EPA’s reviews of the public
literature, no effects were seen in the thymus, spleen, lymph nodes,
white cell counts, red cell counts, hemoglobin counts, or hematocrits
following the dosing of rats with 1,000 or 10, 000 mg/kg of food grade
Thymol for 19 weeks.  EPA has consistently concluded that the findings
of this literature search do not provide evidence to suggest that Thymol
affects the immune system, functions in a manner similar to any know
hormone, or that it acts as an endocrine disruptor.  Further, thymol
does not belong to a class of chemicals known or suspected of having
adverse effects on the endocrine system.  Therefore, there is no
evidence that thymol has any effect on the endocrine function.  

>

<C. Aggregate Exposure>

<	1. Dietary exposure. >

<	i. Food.  Thymol is a component of many non-pesticidal consumer
products currently marketed in the United States.  It is listed as a
food additive by the Food and Drug Administration (21 CFR 172.515;
synthetic flavoring substances and adjuvants) and is considered
Generally Recognized As Safe or GRAS (21 CFR 172.515, 182.10, and
182.20).  Based on the public literature, there is no basis for concern.
>

<	ii. Drinking water.   No drinking water exposure is expected from the
pesticidal use of thymol, which is confined to its use as a disinfectant
on hard non-porous surfaces.    Thymol has been approved for food use by
FDA as a direct food additive and has shown relatively low toxicity. 
Even if exposure through drinking water were to occur, the exposure
would be far less than the exposure from consumption of thymol thru the
diet.  Therefore, no risk is anticipated.  Based on this information,
there is no basis for concern.

>

<	2. Non-dietary exposure. The potential for non-dietary exposure to
thymol residues for the general population, including infants and
children, is limited because of the low concentrations of thymol used in
hard surface disinfectants and removal of most resultant residues by
potable water rinsing following use.  Thymol is a normal constituent of
the human diet as a component of thyme and thyme oil, which are commonly
used as direct food additives.  While there exists a great likelihood of
prior exposure for most, if not all, individuals to thymol and thyme
oil, any increased exposure due to its use as a hard surface
disinfectant would be negligible.  Thyme, which contains thymol, is a
pesticide active ingredient for the control of aphids on ornamental
plants.  Thyme and thyme oil are considered minimum risk pesticides, and
are exempted as active ingredients under FIFRA 40 CFR 152.25(f).  Based
on this information, there is no basis for concern.

>

<D. Cumulative Effects>

<	Thymol does not appear to produce a toxic metabolite produced by other
substances.  Compared to other currently registered active ingredients,
thymol has a novel mode of cellular action, and no indication of toxic
effects of thymol would be cumulative.  Data to determine whether thymol
has a common mechanism of toxicity with other substances is not
available at this point, and therefore EPA has not assumed that thymol
has a common mechanism of toxicity with other substances.  Based on this
information and use pattern, there is no basis for concern.  

>

<E. Safety Determination>

<	1. U.S. population. The IDREAM Tier 1 (worst case) assessment with the
highest concentration of thymol (as present in thyme oil) being 0.23%
estimates that a maximum of 4.6 mg of thymol could potentially be
transferred into food that has come into contact with the treated
surfaces.  The maximum value of incidental dietary ingestion for a small
child (15 kg b.w.) would be 0.31 mg/kg b.w./day of thymol.  However,
this estimate is high (overly conservative) because the calculation does
not take into account reduction of potential residues by the performance
of the potable water rinse step as directed by the product label for
treatment of food contact surfaces.

Exposure calculations in a Tier 2 assessment of the IDREAM demonstrated
that residues of thymol are not expected to be present on food contact
surfaces at levels of concern for any population group, even without
consideration of further reduction of residues by a potable water rinse.
 The Tier 2 assessment uses a default level (1 mg/cm²) of product
residue taken directly from the FDA Guidelines for Sanitizing Solutions,
which is generally considered to be a worst-case estimate to address
possible uses of sanitizing solutions in all food contact uses.  The
acute and chronic exposure values in a Tier 2 assessment are the
estimated likelihood of exposure to selected U.S. subpopulations (i.e.,
children – 1 to 2 years of age; children – 3 to 5 years of age;
adults – 13+ years of age; and females – 13 to 49 years of age)
based on calculations from published study data and from compiled
datasets obtained from USDA’s Continuing Survey of Food Intakes by
Individuals (1994-1998) and the National Health and Examination Survey. 
The highest estimated potential dietary exposures to
disinfectant-related residues of thymol were in the 1 to 2 year old
children subpopulation subgroup – 0.009 mg/kg/day for chronic exposure
and 0.014 mg/kg/day for acute exposure.  These estimates are considered
high as they do not account for the reduction in potential residues from
the required potable water rinse step.   Based on these potential
dietary exposure estimates, the use of thymol hard surface disinfectants
on hard surface food contact surfaces is not likely to result in
residues levels of any toxicological significance and there is no basis
for concern.  >

<	2. Infants and children. According to the information/data submitted
and other information available to the Agency, there is reasonable
certainty that no harm will result from aggregate exposure to residues
of thymol to the U.S. population, including infants and children, under
reasonable circumstances, when hard surface disinfectants containing
thymol are used in accordance with the product label directions.  

As summarized above, potential incidental dietary exposure to thymol
used in hard surface disinfectants was estimated using Tier 1 and Tier 2
IDREAM assessments.  Even though these calculations do not take into
account reduction of potential residues by the potable water rinse step
as directed by the product label for treatment of food contact surfaces,
these assessments provided confirmation that potential thymol residues
on food contact surfaces are well below any level of concern.

In addition, there is a long history of the use and presence of thyme,
thyme oil, and thymol in the diet with no known adverse effects.  Based
on worst case exposure calculations, the low toxicity potential of
thymol, and its historical presence in food with no known adverse
effects, it is reasonable to conclude that no harm will result from
exposure to thymol on a hard surface treated with a disinfectant.

>

<F. International Tolerances>

<	According to the World Health Organization, thymol residues in food
are safe to consumers at up to 50 mg/kg.  Under the European Union
regulation Nr. 2377/90, thymol is in group II of the non-toxic
veterinary drugs which do not require a MRL.

>

