[Federal Register Volume 63, Number 87 (Wednesday, May 6, 1998)]
[Rules and Regulations]
[Pages 24955-24963]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-12037]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300655; FRL-5789-4]
RIN 2070-AB78
Hydrogen Peroxide; Exemption From the Requirement of a Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This document establishes an exemption from the requirement of
a
[[Page 24956]]
tolerance for residues of the antimicrobial pesticide hydrogen peroxide
up to 120 ppm, in or on raw agricultural commodities, in processed
commodities, when such residues result from the use of hydrogen
peroxide as an antimicrobial agent on fruits, tree nuts, cereal grains,
herbs, and spices. Ecolab, Inc. requested this exemption under the
Federal Food, Drug, and Cosmetic Act, as amended by the Food Quality
Protection Act of 1996 (Pub. L. 104-170).
DATES: This regulation is effective May 6, 1998. Objections and
requests for hearings must be received by EPA on or before July 6,
1998.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-300655], must be submitted to: Hearing
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St.,
SW., Washington, DC 20460. Fees accompanying objections and hearing
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to:
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees),
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and
hearing requests filed with the Hearing Clerk identified by the docket
control number, [OPP-300655], must also be submitted to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. In person,
bring a copy of objections and hearing requests to Rm. 119, CM #2, 1921
Jefferson Davis Hwy., Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e-mail) to: [email protected]. Copies of objections and
hearing requests must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. Copies of objections and
hearing requests will also be accepted on disks in WordPerfect 5.1/6.1
file format or ASCII file format. All copies of objections and hearing
requests in electronic form must be identified by the docket control
number [OPP-300655]. No Confidential Business Information (CBI) should
be submitted through e-mail. Electronic copies of objections and
hearing requests on this rule may be filed online at many Federal
Depository Libraries.
FOR FURTHER INFORMATION CONTACT: By mail: Marshall Swindell, Product
Manager 33, Antimicrobials Division 7510W, Office of Pesticide
Programs, Environmental Protection Agency, 401M St., SW., Washington,
DC 20460. Office location, telephone number, and e-mail address: 2800
Crystal Drive, 6th Floor, Arlington, VA, 22202, 703-308-6341, e-mail:
[email protected].
SUPPLEMENTARY INFORMATION: In the Federal Register of January 14, 1998
(63 FR 2235) (FRL-5759-7), EPA, issued a notice pursuant to section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e)
announcing the filing of a pesticide petition (PP) 7F4834 for tolerance
by Ecolab, Inc., 370 Wabasha Street, St. Paul, MN 55102. This notice
included a summary of the petition prepared by Ecolab, Inc., the
registrant. There were no comments received in response to the notice
of filing.
Subsequently, the proposed tolerance exemption was amended to
delete meat, meat by-products, poultry, milk, and eggs. This was done
because at the low proposed use concentrations, no residues of
toxicological concern are expected on any animal feeds that may be
exposed to hydrogen peroxide. Therefore, no residues of toxicological
concern are anticipated either in animals that may consume these feeds,
or in associated animal by-products.
In addition, the proposed tolerance exemption was amended to
include a maximum residue limit of 120 ppm for hydrogen peroxide. This
limitation was added because of Agency concerns that a high use
concentration could result in measurable residues of hydrogen peroxide.
Residue data will be needed to increase or remove this limitation.
I. Risk Assessment and Statutory Findings
New section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a
tolerance or an exemption from the requirement of a tolerance (the
legal limit for a pesticide chemical residue in or on a food) only if
EPA determines that the tolerance or exemption from the requirement of
a tolerance is ``safe.'' Section 408(b)(2)(A)(ii) defines ``safe'' to
mean that ``there is a reasonable certainty that no harm will result
from aggregate exposure to the pesticide chemical residue, including
all anticipated dietary exposures and all other exposures for which
there is reliable information.'' This includes exposure through
drinking water and in residential settings, but does not include
occupational exposure.
Section 408(b)(2)(C) requires EPA to give special consideration to
exposure of infants and children to the pesticide chemical residue in
establishing a tolerance and to ``ensure that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to the pesticide chemical residue. . . .''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. First, EPA determines the
toxicity of pesticides based primarily on toxicological studies using
laboratory animals. These studies address many adverse health effects,
including (but not limited to) reproductive effects, developmental
toxicity, toxicity to the nervous system, and carcinogenicity. Second,
EPA examines exposure to the pesticide through the diet (e.g., food and
drinking water) and through exposures that occur as a result of
pesticide use in residential settings.
A. Toxicity
1. Threshold and non-threshold effects. For many animal studies, a
dose response relationship can be determined, which provides a dose
that causes adverse effects (threshold effects) and doses causing no
observed effects (the ``no-observed effect level'' or ``NOEL'').
Once a study has been evaluated and the observed effects have been
determined to be threshold effects, EPA generally divides the NOEL from
the study with the lowest NOEL by an uncertainty factor (usually 100 or
more) to determine the Reference Dose (RfD). The RfD is a level at or
below which daily aggregate exposure over a lifetime will not pose
appreciable risks to human health.
An uncertainty factor (sometimes called a ``safety factor'') of 100
is commonly used since it is assumed that people may be up to 10 times
more sensitive to pesticides than the test animals, and that one person
or subgroup of the population (such as infants and children) could be
up to 10 times more sensitive to a pesticide than another. In addition,
EPA assesses the potential risks to infants and children based on the
weight of the evidence of the toxicology studies and determines whether
an additional uncertainty factor is warranted.
Thus, an aggregate daily exposure to a pesticide residue at or
below the RfD (expressed as 100% or less of the RfD) is generally
considered acceptable by EPA. EPA generally uses the RfD to evaluate
the chronic risks posed by pesticide exposure. For shorter term risks,
EPA calculates a margin of exposure (MOE) by dividing the estimated
human exposure into the NOEL from the appropriate animal study.
Commonly, EPA finds MOEs lower than 100 to be unacceptable. This 100-
fold MOE is based on the same
[[Page 24957]]
rationale as the 100-fold uncertainty factor.
Lifetime feeding studies in two species of laboratory animals are
conducted to screen pesticides for cancer effects. When evidence of
increased cancer is noted in these studies, the Agency conducts a
weight of the evidence review of all relevant toxicological data
including short-term and mutagenicity studies and structure activity
relationship. Once a pesticide has been classified as a potential human
carcinogen, different types of risk assessments (e.g., linear low dose
extrapolations or MOE calculation based on the appropriate NOEL) will
be carried out based on the nature of the carcinogenic response and the
Agency's knowledge of its mode of action.
2. Differences in toxic effect due to exposure duration. The
toxicological effects of a pesticide can vary with different exposure
durations. EPA considers the entire toxicity data base, and based on
the effects seen for different durations and routes of exposure,
determines which risk assessments should be done to assure that the
public is adequately protected from any pesticide exposure scenario.
Both short and long durations of exposure are always considered.
Typically, risk assessments include ``acute,'' ``short-term,''
``intermediate term,'' and ``chronic'' risks. These assessments are
defined by the Agency as follows.
Acute risk, by the Agency's definition, results from 1-day
consumption of food and water, and reflects toxicity which could be
expressed following a single oral exposure to the pesticide residues.
High end exposure to food and water residues are typically assumed.
Short-term risk results from exposure to the pesticide for a period
of 1-7 days, and therefore overlaps with the acute risk assessment.
Historically, this risk assessment was intended to address primarily
dermal and inhalation exposure which could result, for example, from
residential pesticide applications. However, since enaction of the Food
Quality Protection Act of 1996 (FQPA), this assessment has been
expanded to include both dietary and non-dietary sources of exposure,
and will typically consider exposure from food, water, and residential
uses when reliable data are available. In this assessment, risks from
average food and water exposure, and high-end residential exposure, are
aggregated.
High-end exposures from all three sources are not typically added
because of the very low probability of this occurring in most cases,
and because the other conservative assumptions built into the
assessment assure adequate protection of public health. However, for
cases in which high-end exposure can reasonably be expected from
multiple sources (e.g. frequent and widespread homeowner use in a
specific geographical area), multiple high-end risks will be aggregated
and presented as part of the comprehensive risk assessment/
characterization.
Since the toxicological endpoint considered in this assessment
reflects exposure over a period of at least 7 days, an additional
degree of conservatism is built into the assessment; i.e., the risk
assessment nominally covers 1-7 days exposure, and the toxicological
endpoint/NOEL is selected to be adequate for at least 7 days of
exposure. (Toxicity results at lower levels when the dosing duration is
increased.)
Intermediate-term risk results from exposure for 7 days to several
months. This assessment is handled in a manner similar to the short-
term risk assessment.
Chronic risk assessment describes risk which could result from
several months to a lifetime of exposure. For this assessment, risks
are aggregated considering average exposure from all sources for
representative population subgroups including infants and children.
B. Aggregate Exposure
In examining aggregate exposure, FFDCA section 408 requires that
EPA take into account available and reliable information concerning
exposure from the pesticide residue in the food in question, residues
in other foods for which there are tolerances, residues in groundwater
or surface water that is consumed as drinking water, and other non-
occupational exposures through pesticide use in gardens, lawns, or
buildings (residential and other indoor uses).
Dietary exposure to residues of a pesticide in a food commodity are
estimated by multiplying the average daily consumption of the food
forms of that commodity by the tolerance level or the anticipated
pesticide residue level. The Theoretical Maximum Residue Contribution
(TMRC) is an estimate of the level of residues consumed daily if each
food item contained pesticide residues equal to the tolerance. In
evaluating food exposures, EPA takes into account varying consumption
patterns of major identifiable subgroups of consumers, including
infants and children.
The TMRC is a ``worst case'' estimate since it is based on the
assumptions that food contains pesticide residues at the tolerance
level and that 100% of the crop is treated by pesticides that have
established tolerances. If the TMRC exceeds the RfD or poses a lifetime
cancer risk that is greater than approximately one in a million, EPA
attempts to derive a more accurate exposure estimate for the pesticide
by evaluating additional types of information (anticipated residue data
and/or percent of crop treated data) which show, generally, that
pesticide residues in most foods when they are eaten are well below
established tolerances.
Percent of crop treated estimates are derived from federal and
private market survey data. Typically, a range of estimates are
supplied and the upper end of this range is assumed for the exposure
assessment. By using this upper end estimate of percent of crop
treated, the Agency is reasonably certain that exposure is not
understated for any significant sub-population group. Further, regional
consumption information is taken into account through EPA's computer-
based model for evaluating the exposure of significant sub-populations
including several regional groups, to pesticide residues. For hydrogen
peroxide, based on the lack of any residues of toxicological concern,
it is unlikely that significant exposure through the proposed use would
occur to any sub-population although sensitive sub-populations may
exist (eg.,catalase deficient individuals).
II. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), EPA has reviewed the
available scientific data and other relevant information in support of
this action, EPA has sufficient data to assess the hazards of hydrogen
peroxide and to make a determination on aggregate exposure, consistent
with section 408(b)(2), for an exemption of a requirement for a
tolerance for residues of hydrogen peroxide up to 120 ppm, in or on raw
agricultural commodities, in processed commodities, when such residues
result from the use of hydrogen peroxide as an antimicrobial agent on
fruits, tree nuts, cereal grains, herbs, and spices. EPA's assessment
of the dietary exposures and risks associated with establishing the
tolerance follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the
[[Page 24958]]
sensitivities of major identifiable subgroups of consumers, including
infants and children. The nature of the toxic effects caused by
hydrogen peroxide (H2O2) are discussed below.
Ecolab, Inc. has requested a waiver of all toxicology testing
requirements for hydrogen peroxide. This includes waivers for all
acute, 90-day sub-chronic, chronic, oncogenicity, developmental,
reproductive, mutagenicity, neurotoxicity and metabolism requirements
for hydrogen peroxide. Ecolab's rationale for waivers in each of these
areas is similar, and are summarized by the following four arguments:
1. Available data at the Agency are sufficient to estimate the
potential human health hazard of the end use product.
2. Hydrogen peroxide is generally recognized as safe (GRAS)
according to the Food and Drug Administration (21 CFR part 178) when
used on food-processing equipment, utensils, and food contact articles.
3. Based on the chemical reactivity of this compound and its
unstable nature, conduct of long term or metabolism studies would be
extremely difficult and unreliable.
4. The published Reregistration Eligibility Document for Peroxy
Compounds (Case 4072, December, 1993), has waived all further
toxicology testing requirements for peroxy compounds.
The Agency has reviewed the data waivers requested and concurs that
no generic toxicology testing will be needed for hydrogen peroxide for
the following reasons.
1. Hydrogen peroxide is highly reactive and short lived because of
the inherent instability of the peroxide bond (i.e., the O-O bond).
Agitation or contact with rough surfaces, sunlight, organics and metals
accelerates decomposition. The instability of hydrogen peroxide to
exist as itself, along with detoxifying enzymes found in cells (eg.,
catalase, glutathione peroxidase), makes it very difficult to find any
residues of hydrogen peroxide in or on foods (at proposed use levels),
by conventional analytical methods.
The proposed food contact applications also utilize very low
concentrations of hydrogen peroxide. Therefore, food residues are
expected to be short-lived, based on half-lives for hydrogen peroxide
as short as about 4 minutes under certain conditions. Residues are not
of toxicological concern because hydrogen peroxide decomposes rapidly
into oxygen and water. The Agency has no toxicological concern with
oxygen and water.
2. There are acceptable acute generic data referenced in the
Reregistration Eligibility Document for Peroxy Compounds (December
1993, Case 4072). Hydrogen peroxide was found to be corrosive and
severely irritating to the eyes, skin, and mucous membranes but only
when high concentrations were used. The proposed use patterns are
expected to result in a lack of any residues of toxicological concern.
3. A waiver was granted for all the remaining toxicology testing
requirements because of the reasons given above, and because there is
an extensive data base assembled by the Agency's Office of Water.
Although the Office of Water's data does show toxicological effects in
experimental animals only at high concentrations, the Agency is not
concerned because of the rapid decomposition of hydrogen peroxide into
oxygen and water.
Therefore, the lack of any residues of toxicological concern and
the existence of toxicological effects only at high dose levels in
experimental animals minimizes any concern for exposure to the very low
doses that may be present as a result of the proposed uses.
The Agency also recognizes that commercially available 3% hydrogen
peroxide solutions have been used for many years for personal and
medical uses. The use directions for some of these products state that
these 3% solutions can be used as a sanitizing mouthwash. Other food
contact and medicinal uses for hydrogen peroxide include applications
for wines and liquors (artificial aging), dentrifices, sanitary
lotions, and pharmaceutical preparations.
The long use history of hydrogen peroxide and weight of empirical
evidence and experimental data has led the FDA to put hydrogen peroxide
on the GRAS list when used on food processing equipment, utensils, and
food contact articles (21 CFR 178). Potential symptoms of acute
overexposure to medium or high concentrations of hydrogen peroxide
include irritation of eyes, nose and throat, corneal ulceration,
erythema, vesicles on skin, and bleaching of hair.
The following is a summary of the existing generic data base for
acute, subchronic, chronic, mutagenic, developmental, reproductive, and
carcinogenic effects of hydrogen peroxide in mammalian test animals.
These data show that significant toxicological effects of hydrogen
peroxide in mammalian test systems are measurable only at high doses.
The proposed food contact use patterns are not expected to result in
residues of toxicological concern due to the rapid decomposition of
hydrogen peroxide into oxygen and water. The following generic acute
toxicology data for hydrogen peroxide were cited in the 1993 RED for
hydrogen peroxide. The subchronic, chronic, carcinogenicity,
developmental, and reproductive toxicology, along with the mutagenicity
data are summarized from the Office of Water data base.
1. Acute studies-- i. A study on mice showed an acute oral
LD50 of 2,000 milligrams/kilogram (mg/kg).
ii. A study on rats showed an acute dermal LD50 of 4,060
mg/kg.
iii. A study on mice showed an acute inhalation LC50 of
227 ul/L.
iv. An eye irritation study on rabbits produced severe irritation.
v. A dermal irritation study on rabbits showed hydrogen peroxide
was corrosive.
2. Subchronic exposure-- i. Weanling Osborne-Mendel rats were
exposed to a 0.45% (560 mg/kg/day) aqueous solution of hydrogen
peroxide in drinking water for 3 weeks. When corrected for differences
observed in water intake between control and treated rats, there were
no significant differences observed in absolute and relative organ
weights of the kidney, spleen, heart, or testes. A NOEL of 560 mg/kg/
day was determined, although a lowest-observed-effect level (LOEL) was
not.
ii. Young male Holtzman rats were administered doses of 0, 500,
1,000, or 1,500 mg/kg/day hydrogen peroxide in water for 8 weeks.
Increased mortality was noted at the high dose. Increased incidence of
dental caries and pathological changes in the periodontium were also
noted at the mid and high dose. A LOEL of 500 mg/kg/day was determined,
but a NOEL was not established.
iii. Male and female C57BL/6N, DBA/2N, and BALB/cAnN mice were
given hydrogen peroxide at 0, 0.1, or 0.4% in drinking water for 30 or
60 days. Equivalent doses (assuming water intake of 150 ml/kg/day) were
0, 150, or 600 mg/kg/day. The high dose resulted in erosion of the
glandular stomach in 29% of mice treated for 30 days and in 40% of mice
treated for 60 days. Duodenal lesions, but no frank nodules, were also
observed at the high dose. A LOEL of 600 mg/kg/day was determined, but
due to the lack of data reported at the 150 mg/kg/day dose, a NOEL
could not be definitively assigned.
3. Chronic exposure-- i. Wistar rats were administered 30 or 60 mg/
kg/day hydrogen peroxide for 100 days by oral intubation. After 100
days, decreases in plasma protein, hematocrit, and plasma catalase were
observed. Administration
[[Page 24959]]
of the same dose levels in feed had no effects. A NOEL of 30 mg/kg/day
could be determined from this study.
ii. Three-week old mice (strain not specified) were administered
0.15% hydrogen peroxide in drinking water for 35 weeks, presumed
equivalent to 150 mg/kg/day. Degenerative changes in the liver and
kidney, as well as inflammation, irregularity and slight necrosis of
the stomach wall were observed. The LOEL was determined to be 150 mg/
kg/day in this study, but a NOEL was not identified.
iii. Male and female C57BL/6N mice were administered 0, 0.1, or
0.4% hydrogen peroxide in drinking water for up to 700 days. Doses of
0, 150, and 600 mg/kg/day were calculated based on assumed intake of
150 mL/kg/day water. The gastrointestinal tract was examined over the
course of the study through serial sacrifice at time points between 90-
700 days. Gastric lesions consisting of erosion and hyperplastic
nodules were detected in the stomach and duodenum after 1-2 years
exposure. The LOEL was determined to be 150 mg/kg/day from this study.
4. Carcinogenicity-- i. Gastric carcinogenesis was investigated in
male Wistar rats. Twenty-one rats received the initiator MNNG in
drinking water for 8 weeks at 100 mg/L, while uninitiated rats (10
animals) received plain drinking water. After 8 weeks, both groups
received 1% hydrogen peroxide in drinking water from week 8 through
week 40. Two other groups (30 and 10 rats, respectively) were chosen as
initiated and uninitiated controls. Surviving rats were sacrificed and
necropsied at 40 weeks. Erosion and ulceration along the limiting ridge
of the fundic mucosa was observed. Initiated rats showed an increased
incidence of adenomatous hyperplasia in this stomach area. There were
no adenocarcinomas induced in the stomach or duodenum. Papillomas of
the forestomach were induced by hydrogen peroxide alone.
ii. Three month old Syrian hamsters were administered either: twice
weekly applications of 30% hydrogen peroxide in the left buccal pouch,
twice weekly buccal application of 0.25% 9,10 dimethyl-1,2-
benzanthracene with either 30% or 3% hydrogen peroxide (hydrogen
peroxide applied on a different day than the DMBA), or DMBA only.
Buccal pouches were examined for tumor development at 19 and 22 weeks
after sacrifice. No epidermoid carcinomas were observed after 22 weeks
of treatment with hydrogen peroxide alone. All three groups receiving
DMBA treatment did develop tumors. The tumors in the group receiving
the 30% hydrogen peroxide and DMBA were reported to be more anaplastic
with deeper penetration of tissue. It was concluded that hydrogen
peroxide may augment oral carcinogenesis induced by DMBA.
iii. Male and female weanling C57Bl/6J mice were administered 0,
0.1, or 0.4% hydrogen peroxide in drinking water for up to 108 weeks.
Erosion of the glandular stomach was observed in 20% and 42% of dosed
mice at the 0.1% and 0.4% dose levels, respectively, compared to 4% in
controls. Duodenal nodules were observed in treated mice and were
classified into hyperplasia, adenoma, and carcinoma. Hyperplasia was
significantly increased at the 0.1% and 0.4% dose levels (40% and 62%
of treated mice respectively), as was the incidence of duodenal
carcinoma, observed in 5 of 99 high dose animals, 1 of 101 low dose
animals, and absent in controls.
iv. Various strains of mice (C57Bl/6N, DBA/2N, BALB/c) were exposed
to 0.4% hydrogen peroxide in drinking water over their lifetime.
Appearance of duodenal lesions (plaques and nodules) was noted in all
strains after 90 days of treatment. Temporary withdraw of hydrogen
peroxide produced apparent reversibility in C57BL/6N mice only after 30
days of no treatment. After 150 days of treatment, C57BL/6N mice
appeared to have an increased incidence of duodenal lesions relative to
the other two strains. After 420-740 days of treatment, the incidence
of duodenal carcinoma was 0, 1%, and 5% in control, low, and high dose,
respectively. This study did not present concurrent control data, and
used varying numbers of mice for examination at the various time
points. Therefore, results from this study are considered equivocal.
v. Strains of mice differing in catalase activities of the
duodenum, blood, and liver (in order of decreasing activity: C3H/HeN,
B6C3F1, C57BL/6N, C3H/C) were given a solution of 0.4% hydrogen
peroxide in drinking water for approximately 6 months. The duodenum was
examined for the incidence and total lesions in each strain.
Approximately 18-22 mice per strain were examined. The data suggested
that the number of duodenal lesions per mouse and total incidence was
inversely correlated wi th catalase activity.
vi. Recent experimental evidence (Upham, et al., Carcinogenesis
18(1): 37-42, 1997) has implicated hydrogen peroxide in the inhibition
of gap junctional intercellular communication in rat liver epithelial
cells (a significant step in production of tumors). These recent data
lend support to the above studies in the implication of high levels of
hydrogen peroxide as a promotor of tumorigenesis. The International
Agency for Research in Cancer (IARC) has designated hydrogen peroxide
as not classifiable as to carcinogenicity, based on the data noted
above.
5. Developmental and reproductive toxicity. Three older studies on
the developmental and reproductive effects of hydrogen peroxide are
available. These data indicate no apparent developmental or
reproductive effects observed from administration of hydrogen peroxide
at concentrations up to 1% (1000 mg/kg).
6. Mutagenicity-- i. In a standard plate incorporation assay,
hydrogen peroxide (concentrations not stated) was weakly mutagenic to
strains TA98, TA97, and TA1537 for frame shift mutations and to strain
TA102 for oxidative mutations, but was not mutagenic to strains TA100
and TA1538.
ii. Using isolated hepatocytes from Female Fischer rats, hydrogen
peroxide was incubated at concentrations from 0.01 to 1.0mM for 1 hour
at 37 degrees Celsius. Overt cytotoxicity was observed at 1mM. A
concentration dependent increase in single strand DNA breaks was
observed at all other exposure levels. No double strand DNA breaks or
DNA cross-links were observed.
iii. In a human bronchial epithelial cell system, nucleic acid
synthesis was observed to be significantly decreased after exposure to
hydrogen peroxide at 1.2mM for six hours followed by a cell growth
period of 7-9 days. At 100 m, single strand DNA breaks and DNA-protein
cross links were observed, with single strand breaks predominating. DNA
strand breakage has also been observed in other test systems (hamster
V79 cells and bovine pulmonary artery and aortic endothelial cells).
iv. Cell killing and DNA damage were examined in Chinese hamster
fibroblast cells (V79-379A). After incubation of cells with 1-100 mM
hydrogen peroxide at ice cold temperatures for 10 or 20 minutes, single
strand breaks were observed at 1 mM hydrogen peroxide. Double strand
breaks and cell killing were observed at higher (10mM) concentrations
of hydrogen peroxide.
B. Toxicological Endpoints
1. Acute toxicity. The Agency has concluded that for the proposed
food contact uses, no apparent toxicity endpoint exists to suggest any
evidence of significant toxicity from a one-day or single-event
exposure.
2. Short - and intermediate - term toxicity. The Agency has
concluded that
[[Page 24960]]
for the proposed food contact uses, no apparent toxicity endpoint
exists to suggest any evidence of significant toxicity from short and
intermediate term exposure.
3. Chronic toxicity. A RfD for hydrogen peroxide has not been
established because of its short half life and lack of any residues of
toxicological concern. As discussed in the December 1993 Reregistration
Eligibility Document for Peroxy Compounds, and in this final rule,
under the proposed and existing dietary related use patterns (i.e., raw
and processed agricultural commodities, food processing equipment in
breweries, wineries, and beverage plants), there is expected to be a
lack of any residues of toxicological concern.
4. Carcinogenicity. The Agency believes that based on the known
chemistry of peroxy compounds, toxic effects occur as a result of
species formed either during spontaneous decomposition or enzymatic
conversion of the peroxy bond (i.e., O-O bond). These effects occur
only after long term administration of high dose levels, where the
parent compound is continually present. Available data show that
hydrogen peroxide rapidly breaks down into oxygen and water. Because of
this rapid decomposition, the Agency does not expect residues of the
parent compound on the treated comodities.
Based on the proposed use concentrations for hydrogen peroxide, and
data indicating a lack of residues of concern on food, exposure to
hydrogen peroxide under the proposed food contact use concentrations is
not likely to result in any adverse clinical effects, including
promotion of carcinogenisis. This conclusion is supported by the rapid
decomposition of hydrogen peroxide into oxygen and water, which are not
of toxicological concern, and the existence of specific enzymes in the
human body (i.e., catalase and glutathione peroxidase) which also can
break down hydrogen peroxide.
C. Exposures and Risks
1. From food and feed uses. An exemption from the requirement of a
tolerance is being established (40 CFR 180.1197) for the residues of
hydrogen peroxide) up to 120 ppm, in or on a variety of (raw
agricultural commodities, in processed commodities, when such residues
result from the use of hydrogen peroxide as an antimicrobial agent on
fruits, tree nuts, cereal grains, herbs, and spices.
There are no existing food or feed use tolerances or exemptions
from the requirement of a tolerance in title 40 of the CFR for hydrogen
peroxide. The following 21 CFR tolerances and/or exemptions from
tolerances are noted:
Under 21 CFR 184.1366, hydrogen peroxide is GRAS when used on milk
intended for use in cheese making (maximum treatment level of 0.05%),
whey, during preparation of modified whey by electrodialysis methods
(maximum treatment level of 0.04%), dried eggs, dried egg whites, and
dried egg yolks, tripe, beef feet, herring, wine, starch (maximum
treatment level of 0.15%), instant tea, corn syrup (maximum treatment
level of 0.15%), colored cheese whey (maximum treatment level of
0.05%), wine vinegar, and emulsifiers containing fatty acid esters
(maximum treatment level of 1.25%).
Under 21 CFR 178.1010, hydrogen peroxide is approved for use as a
sanitizing solution for use on food processing equipment and utensils,
and on dairy processing equipment. It is also approved for use in
sterilizing polymeric food-contact surfaces.
Under 21 CFR 173.315, hydrogen peroxide is approved for use in
washing or to assist in the lye peeling of fruits and vegetables.
Risk assessments were conducted by EPA to assess dietary exposures
and risks from hydrogen peroxide as follows:
i. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a one day or single exposure. No acute exposure and risk assessment
is applicable because no acute toxicological effects of concern are
anticipated with the proposed food contact uses for hydrogen peroxide.
This is due to the lack of any residues of toxicological concern as a
result of the automatic and rapid decomposition of hydrogen peroxide
into oxygen and water.
ii. Chronic exposure and risk. Residues of hydrogen peroxide are
not expected to remain on the surface of materials which it contacts.
Therefore, the risk from dietary exposure is expected to be negligible.
No chronic exposure and risk assessment is applicable because no
chronic toxicological effects are anticipated with the proposed food
contact uses for hydrogen peroxide. This is due to the lack of any
residues of toxicological concern as a result of the automatic and
rapid decomposition of hydrogen peroxide into oxygen and water.
2. From drinking water. Although the proposed food contact uses for
hydrogen peroxide acid may result in transfer of minor amounts of
residues to potential drinking water sources, no risk assessment is
warranted because of: (i) the rapid degradation of hydrogen peroxide
into oxygen, and water, and (ii) these degradates are not of
toxicological concern. Information from the EPA Office of Water also
indicates that when used for potable water disinfection, no residues of
hydrogen peroxyide acid are present by the time the water is pumped
through a distribution system.
3. From non-dietary exposure. Hydrogen peroxide is currently
registered by EPA for a wide variety of uses including: agricultural
premises and equipment; food handling/storage establishments premises
and equipment; commercial, institutional and industrial premises and
equipment; residential and public access premises; medical premises and
equipment; materials preservation; and industrial processes and water
systems.
Hydrogen peroxide is also approved for a variety of medicinal uses
including sanitization of scrapes, cuts, and burns to human and animal
skin, and as a human oral sanitizing mouthwash. It is also used by
medical doctors for general cleansing and sanitization of surgical
areas of the body after operations. Hydrogen peroxide use in homes is
medicinal and exposures are expected to be infrequent and at extremely
short topical duration. The Agency does not know of all approved or
actual uses for hydrogen peroxide. However, non-dietary exposures are
not expected to pose any quantifiable added risk because of a lack of
any significant residues of toxicological concern.
4. Cumulative exposure to substances with common mechanism of
toxicity. Section 408(b)(2)(D)(v) requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency
consider ``available information'' concerning the cumulative effects of
a particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.''
The Agency believes that ``available information'' in this context
might include not only toxicity, chemistry, and exposure data, but also
scientific policies and methodologies for understanding common
mechanisms of toxicity and conducting cumulative risk assessments. For
most pesticides, although the Agency has some information in its files
that may turn out to be helpful in eventually determining whether a
pesticide shares a common mechanism of toxicity with any other
substances, EPA does not at this time have the methodologies to resolve
the complex scientific issues concerning
[[Page 24961]]
common mechanism of toxicity in a meaningful way.
EPA has begun a pilot process to study this issue further through
the examination of particular classes of pesticides. The Agency hopes
that the results of this pilot process will increase the Agency's
scientific understanding of this question such that EPA will be able to
develop and apply scientific principles for better determining which
chemicals have a common mechanism of toxicity and evaluating the
cumulative effects of such chemicals. The Agency anticipates, however,
that even as its understanding of the science of common mechanisms
increases, decisions on specific classes of chemicals will be heavily
dependent on chemical specific data, much of which may not be presently
available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
The Agency does not at this time have data specifically either to
support, or to refute a common mechanism of toxicity for peroxy
compounds (i.e., hydrogen peroxide, peroxyacetic acid). The Agency
believes that based on the known common chemistry of peroxy compounds,
toxic effects occur as a result of species formed either during
spontaneous decomposition or enzymatic conversion of the peroxy bond
(i.e., O-O bond). These effects occur only after long term
administration of high dose levels, where the parent compound is
continually present. Although a common mechanism of toxicity may or may
not be inferred, the Agency's concerns for cumulative risk is mitigated
by the lack of residues of the parent compound (hydrogen peroxide) at
proposed use levels, and by the rapid decomposition of the parent
compound into products which are not of toxicological concern (i.e.,
oxygen and water). As data become available, the Agency may require
further studies on the peroxy compounds to determine whether a
cumulative risk assessment is warranted.
EPA does not have, at this time, available data to determine
whether hydrogen peroxide has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk
assessment. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
hydrogen peroxide does not appear to produce toxic metabolites. For the
purposes of this exemption from the requirement of a tolerance, EPA has
not assumed that hydrogen peroxide has a common mechanism of toxicity
with other substances.
D. Aggregate Risks and Determination of Safety for U.S. Population
1. Acute, short- and intermediate- term risk. The Agency has
concluded that no endpoint exists to suggest any evidence of
significant toxicity from acute, short term or intermediate term
exposures from the proposed food contact uses of hydrogen peroxide.
Short- and intermediate-term aggregate exposure takes into account
chronic dietary food and water (considered to be a background exposure
level) plus indoor and outdoor residential exposure.
The Agency concludes that there is a reasonable certainty of no
harm for acute, short term, and intermediate risk from aggregate
exposure to hydrogen peroxide under the proposed use concentrations.
2. Chronic risk. Residues of hydrogen peroxide are expected to
dissociate rapidly on the surface of materials which it contacts.
Therefore, the chronic risk from dietary exposure is expected to be
negligible. No chronic exposure and risk assessment is required because
no chronic toxicological effects are anticipated with the proposed food
contact uses for hydrogen peroxide. This is due to the lack of any
residues of toxicological concern as a result of the automatic and
rapid decomposition of hydrogen peroxide in air into oxygen and water.
The Agency concludes that there is a reasonable certainty of no
harm for chronic risk from aggregate exposure to hydrogen peroxide
under the proposed use concentrations.
E. Aggregate Cancer Risk for U.S. Population
Available data suggest that hydrogen peroxide acts as a promoter of
carcinogenisis at relatively high doses (in excess of 600 mg/kg) after
chronic administration in drinking water to experimental animals.
Epidemiological reports indicate that the major effect from accidental
ingestion of high doses of hydrogen peroxide in humans (i.e., 1,000 mg/
kg) is acute and severe clinical toxicity, which in a few cases
resulted in death.
Based on the proposed use concentrations for hydrogen peroxide, and
data indicating negligible residues on food, exposure to hydrogen
peroxide under the proposed food contact use concentrations is not
likely to result in any adverse clinical effects, including promotion
of carcinogenisis. This conclusion is supported further by the rapid
decomposition of hydrogen peroxide into oxygen and water, which are not
of toxicological concern, and the existence of specific enzymes (i.e.,
catalase and glutathione peroxidases) for breakdown of hydrogen
peroxide.
The Agency concludes that the cancer risk for the U.S. population
from aggregate exposure to hydrogen peroxide is negligible under the
proposed food contact use concentrations.
F. Aggregate Risks and Determination of Safety for Infants and Children
Safety factor for infants and children. In assessing the potential
for additional sensitivity of infants and children to residues of
hydrogen peroxide, EPA considered data from developmental and
reproductive toxicity studies available from the scientific literature
and summarized by the Office of Water. The developmental toxicity
studies are designed to evaluate adverse effects on the developing
organism resulting from maternal pesticide exposure during gestation.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre-and post-natal toxicity and the
completeness of the database, unless EPA determines that a different
margin of safety will be safe for infants and children.
Margins of safety are incorporated into EPA risk assessments either
directly through use of a MOE analysis or through using uncertainty
(safety) factors in calculating a dose level that poses no appreciable
risk to humans. In either case, EPA generally defines the level of
appreciable risk as exposure that is greater than 1/100 of the NOEL in
the animal study appropriate to the particular risk assessment. This
100-fold uncertainty factor/margin of exposure is designed to account
for inter-species
[[Page 24962]]
extrapolation and intra-species variability.
In the case of the proposed food contact uses for hydrogen
peroxide, because of the lack of any residues of toxicological concern,
a NOEL was not identified for risk assessment purposes, and the
uncertainty (safety) factor approach was not used for assessing any
risk level by hydrogen peroxide. For the same reason, an additional
safety factor to protect infants and children is unnecessary.
Additionally, based on the following conditions, no increased
susceptibility to infants or children is expected to occur.
1. Three older studies on the developmental and reproductive
effects of hydrogen peroxide are available. The data from these studies
indicates that no apparent developmental or reproductive effects were
observed from administration of hydrogen peroxide at concentrations up
to 1% (1,000 mg/kg).
2. Hydrogen peroxide is highly reactive and short lived because of
the inherent instability of the peroxide bond (i.e., the O-O bond).
Agitation or contact with rough surfaces and metals accelerates
dissociation. The proposed food contact applications utilize very low
concentrations of hydrogen peroxide (i.e., ppm). Food residues are
expected to be short-lived and are not expected to accumulate. This is
because hydrogen peroxide dissociates rapidly in air into oxygen and
water. The Agency has no toxicological concern with oxygen and water.
3. A waiver was granted for all the remaining toxicology testing
requirements because of the reasons given in items a and b above, and
because there is an extensive data base assembled by the Agency's
Office of Water showing toxicological effects in experimental animals
only at high concentrations, which are not expected with the proposed
use patterns.
4. The Agency also recognizes that commercially available 3%
hydrogen peroxide solutions have been used for many years for personal
and medical uses. The use directions for some of these products state
that these solutions can be used as a sanitizing mouthwash. The long
use history of hydrogen peroxide and weight of empirical and
experimental data has led the FDA to put it on the Generally Recognized
As Safe (GRAS) list when used on food processing equipment, utensils,
and food contact articles (21 CFR part 178).
Therefore, because of the rapid decomposition of hydrogen peroxide
residues into degradates that are of no toxicological concern (i.e.,
oxygen, water), the Agency concludes that there is a reasonable
certainty of no harm for infants and children from exposure to hydrogen
peroxide under the proposed food contact use concentrations.
III. Other Considerations
A. Endocrine Disruption
EPA is required to develop a screening program to determine whether
certain substances (including all pesticides and inerts) ``may have an
effect in humans that is similar to an effect produced by a naturally
occurring estrogen, or such other endocrine effect...'' The Agency is
currently working with interested stakeholders, including other
government agencies, public interest groups, industry and research
scientists in developing a screening and testing program and a priority
setting scheme to implement this program. Congress has allowed three
years from the passage of the FQPA (August, 1999) to implement this
program. At that time, the EPA may require further testing of this
active ingredient and end use products for endocrine disrupter effects.
There is no current evidence to suggest that hydrogen peroxide acts in
a manner similar to any known hormone or that it acts as an endocrine
disrupter.
B. Analytical Enforcement Methodology
Because an exemption from the requirement of a tolerance is being
granted for hydrogen peroxide, an enforcement analytical method is not
needed. However, an adequate analytical method (designated QATM 202 by
Ecolab, Inc., a redox titration procedure) is available in the interim.
Because of the long lead time from establishing a tolerance or
exemption of the requirement of a tolerance to publication of the
enforcement methodology in the Pesticide Analytical Manual., Volume II,
the analytical method is being made available to anyone interested in
pesticide enforcement when requested from Norm Cook, Antimicrobials
Division (7510W), Office of Pesticide Programs, US Environmental
Protection Agency, 401 M Street, SW., Washington, DC 20460. Office
location and telephone number: 2800 Crystal Drive, 6th Floor,
Arlington, VA 22202, 703-308-6411.
C. Magnitude of Residues
Residues of hydrogen peroxide are short lived on treated crops and
are not expected to bioaccumulate in livestock and/or poultry that
consume treated feedstuffs. Because of the lack of any residues of
toxicological concern, the Agency has waived this data requirement.
D. International Residue Limits
There are no Codex Alimentarius Commission (Codex) Maximum Residue
Levels (MRLs) for hydrogen peroxide.
IV. Conclusion
Therefore, the exemption from the requirement of a tolerance is
established for residues of hydrogen peroxide up to 120 ppm in or on
raw agricultural commodities, in processed commodities, when such
residues result from the use of hydrogen peroxide as an antimicrobial
agent on fruits, tree nuts, cereal grains, herbs, and spices.
It should be understood that the Agency may take appropriate
regulatory action, and/or require the submission of additional data to
support the exemption from the requirement of a tolerance for hydrogen
peroxide, if new relevant adverse effects information comes to the
Agency's attention.
V. Objections and Hearing Requests
The new FFDCA section 408(g) provides essentially the same process
for persons to ``object'' to a tolerance regulation issued by EPA under
new section 408(e) and (l)(6) as was provided in the old section 408
and in section 409. However, the period for filing objections is 60
days, rather than 30 days. EPA currently has procedural regulations
which govern the submission of objections and hearing requests. These
regulations will require some modification to reflect the new law.
However, until those modifications can be made, EPA will continue to
use those procedural regulations with appropriate adjustments to
reflect the new law.
Any person may, by July 6, 1998, file written objections to any
aspect of this regulation and may also request a hearing on those
objections. Objections and hearing requests must be filed with the
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of
the objections and/or hearing requests filed with the Hearing Clerk
should be submitted to the OPP docket for this rulemaking. The
objections submitted must specify the provisions of the regulation
deemed objectionable and the grounds for the objections (40 CFR
178.25).
Each objection must be accompanied by the fee prescribed by 40 CFR
180.33(i). If a hearing is requested, the objections must include a
statement of the factual issues on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the requestor (40 CFR 178.27).
A request for a hearing will be granted if the Administrator
determines that the
[[Page 24963]]
material submitted shows the following: There is genuine and
substantial issue of fact; there is a reasonable possibility that
available evidence identified by the requestor would, if established,
resolve one or more of such issues in favor of the requestor, taking
into account uncontested claims or facts to the contrary; and
resolution of the factual issues in the manner sought by the requestor
would be adequate to justify the action requested (40 CFR 178.32).
Information submitted in connection with an objection or hearing
request may be claimed confidential by marking any part or all of that
information as CBI. Information so marked will not be disclosed except
in accordance with procedures set forth in 40 CFR part 2. A copy of the
information that does not contain CBI must be submitted for inclusion
in the public record. Information not marked confidential may be
disclosed publicly by EPA without prior notice.
VI. Public Docket
EPA has established a record for this rulemaking under docket
control number [OPP-300655] (including any comments and data submitted
electronically). A public version of this record, including printed,
paper versions of electronic comments, which does not include any
information claimed as CBI, is available for inspection from 8:30 a.m.
to 4 p.m., Monday through Friday, excluding legal holidays.
The public record is located in Room 119 of the Public Information
and Records Integrity Branch, Information Resources and Services
Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, Crystal Mall #2, 1921 Jefferson Davis Hwy.,
Arlington, VA.
Electronic comments may be sent directly to EPA at:
[email protected].
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer any copies of objections and hearing requests
received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record which
will also include all comments submitted directly in writing. The
official rulemaking record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
VII. Regulatory Assessment Requirements
This final rule establishes an exemption from the requirement of a
tolerance under FFDCA section 408(d) in response to a petition
submitted to the Agency. The Office of Management and Budget (OMB) has
exempted these types of actions from review under Executive Order
12866, entitled Regulatory Planning and Review (58 FR 51735, October 4,
1993).
This final rule does not contain any information collections
subject to OMB approval under the Paperwork Reduction Act (PRA), 44
U.S.C. 3501 et seq., or impose any enforceable duty or contain any
unfunded mandate as described under Title II of the Unfunded Mandates
Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does it require any
prior consultation as specified by Executive Order 12875, entitled
Enhancing the Intergovernmental Partnership (58 FR 58093, October 28,
1993), or special considerations as required by Executive Order 12898,
entitled Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations (59 FR 7629, February 16, 1994),
or require OMB review in accordance with Executive Order 13045,
entitled Protection of Children from Environmental Health Risks and
Safety Risks (62 FR 19885, April 23, 1997).
In addition, since these tolerances and exemptions that are
established on the basis of a petition under FFDCA section 408(d), such
as the exemption in this final rule, do not require the issuance of a
proposed rule, the requirements of the Regulatory Flexibility Act (RFA)
(5 U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency has
previously assessed whether establishing tolerances, exemptions from
tolerances, raising tolerance levels or expanding exemptions might
adversely impact small entities and concluded, as a generic matter,
that there is no adverse economic impact. The factual basis for the
Agency's generic certification for tolerance actions published on May
4, 1981 (46 FR 24950) and was provided to the Chief Counsel for
Advocacy of the Small Business Administration.
VIII. Submission to Congress and the General Accounting Office
Under 5 U.S.C. 801(a)(1)(A), as added by the Small Business
Regulatory Enforcement Fairness Act of 1996, the Agency has submitted a
report containing this rule and other required information to the U.S.
Senate, the U.S. House of Representatives, and the Comptroller General
of the General Accounting Office prior to publication of this rule in
today's Federal Register. This is not a ``major rule'' as defined by 5
U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: April 30, 1998.
Frank Sanders,
Director, Antimicrobials Division, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180-- [AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. Section 180.1197 is added to read as follows:
Sec. 180.1197 Hydrogen peroxide; exemption from the requirement of a
tolerance.
An exemption from the requirement of a tolerance is established for
residues of hydrogen peroxide up to 120 ppm in or on raw agricultural
commodities, in processed commodities, when such residues result from
the use of hydrogen peroxide as an antimicrobial agent on fruits, tree
nuts, cereal grains, herbs, and spices.
[FR Doc. 98-12037 Filed 5-5-98; 8:45 am]
BILLING CODE 6560-50-F