August, 1967
DIMETHRIN
DRAFT
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the one-hit, Weibull, logit or probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to pre.ict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
-------
-Dimethrin
August, 198*7
-2-
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 67239-16-1
Structural Formula
CH3
CH3 C
CH3
O~C~CH
6
CH
/
2,4-Dimethylbenzyl-2,2-dimethyl-3(2-methylpropenyl)-cyclopropane carboxylate
Synonyms
0 ENT 21,170; Chrysantheraumic acid; 2,4-Dimethylbenzylester.
Uses
0 Insecticide for use in ponds and swamps as a mosquito larvicide
(Meister, 1986).
C18«24°2
286.39 (Ambrose, 1964)
Amber liquid
1758C
Properties
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density —-
Vapor Pressure (25°C)
Specific Gravity 0.98
Water Solubility (25°C) Insoluble (further details not provided)
Log Octanol/water Partition —
Coefficient
Taste Threshold —
Odor Threshold
Conversion Factor
Occurrenca
0 No information is available on the occurrence of dimethrin in water.
Environmental Fate
0 No information is available on the environmental fate of dimethrin.
-------
Dimethrin August, 1987
-3-
III. PHARMACOKINETICS
Absorption
0 In a preliminary metabolic study by Ambrose (1964-), four rabbits were
given 5 mL/kg (5 mg/kg) of undiluted dimethrin by intubation. Urine
was collected every 24 hours over a 72-hour period. Identification
of two possible metabolites in the urine indicated that dimethrin was
absorbed. Sufficient data were not available to quantify the extent
of absorption.
Distribution
0 No information on the distribution of dimethrin was found in,the
available literature.
Metabolism/Excretion
0 Information presented by Ambrose (1964) indicates that dimethrin
(5 mg/kg), administered by intubation to rabbits, is metabolized (by
reduction) and excreted in the urine as chrysantheinumic acid and the
glucuronic ester of 2,4-dimethyl benzoic acid. Sufficient information
was not presented to determine if these are the only metabolites of
dimethrin or if any unchanged dimethrin is excreted.
IV. HEALTH EFFECTS
Humans
0 No information on the health effects of dimethrin in humans was found
in the available literature.
Animals
Short-term Exposure
0 The acute oral LDso value of dimethrin for male and female Sherman
rats was reported to be >15,000 mg/kg (Gaines, 1969).
0 Ambrose (1964) conducted an acute oral study in which male and
female albino rabbits (two/sex/dose) and male albino Wistar-CWL rats
(five/dose) were given a single dose of 10 or 15 mL/kg (9.8 or 14.7
mg/kg) of technical-grade dimethrin (98% pure) by gavage. Albino
guinea pigs (four/sex) received a single dose of 10 mL/kg (9.8 mg/kg)
by gavage. No effects were observed in rats or rabbits during a
2-week observation period. (Specific parameters observed were not
identified). In guinea pigs, the only effect reported during a
similar observation period was a refusal to eat or drink for 24 hours
following dosing.
e Ambrose (1964) administered 10 mLAg O-8 mg/kg) of technical-grade
dimethrin (98% pure) to 15 male albino Wistar-CWL rats by gavage,
-------
Dimethrin August, 1987
-4-
5 days per week for 3 weeks. This corresponds to an average daily
dose of 7 mg/kg. No adverse effects, as judged by general appearance,
behavior and growth, were observed. At necropsy, no gross abnormalities
were observed. No histopathological examinations were performed.
Dermal/Ocular Effects
4 Ambrose (1964) conducted a dermal irritation study in which dimethrin
(96% pure) was applied at a dose level of 10 mL/kg (9.S mg/kg) to the
intact or abraded skin of four albino rabbits (two/sex) for a 24-hour
exposure period. No skin irritation was observed immediately after
the removal of the dimethrin or during a 2-week observation period.
0 Ambrose (1964) reported that single or multiple (3 consecutive days)
instillations of 0.1 mL of undiluted dimethrin (98% pure) into the
conjunctival sac of eight albino rabbits caused no visible irritation
or chemosis and no injury to the cornea as detectable by means of
fluorescein staining. When 0.2 mL of dimethrin was applied to the
penile mucosa of five albino rabbits on two occasions 6 days apart,
no irritation or sloughing of the mucosa was observed during a 1-week
observation period.
e Masri et al. (1964) applied 3 mL of undiluted dimethrin to the shaved
back and sides of three albino rabbits 10 times over a 2-week period
(frequency of application not specified). The only reported reaction
was the development of a slight scaliness which disappeared after
cessation of application.
e Ambrose (1964) applied dimethrin (98% pure) to the skin of albino
rabbits (five/dose) 5 days per week for 13 weeks (65 applications).
Doses administered were 0.5 mL/kg undiluted dimethrin or 0.5 mL/kg
of a 50% solution of dimethrin in cottonseed oil (equivalent to
0.25 mL/kg of dimethrin); controls received 0.5 mL/kg of cottonseed
oil only. No evidence of any cutaneous reaction was observed.
Occasionally, a slight, nonpersistent erythema was observed in all
groups of rabbits. At necropsy, all organs from treated animals were
indistinguishable from the controls. No histopathological differences
between control and treated animals were observed.
Long-term Exposure
0 Masri et al. (1964) administered dimethrin to male (five/dose) and
female (six/dose) weanling albino rats for 16 weeks at dietary levels
of 0, 0.2, 0.6, 1.5 or 3.0%. Based on food consumption and body
weight data presented in the study, these dietary levels of dimethrin
were calculated to correspond to about 0, 120, 320, 1,000 or 2,300
mg/kg/day for males, and 0, 130, 400, 1,100 or 2,500 mg/kg/day for
females. Results indicated a significant reduction in body weight
in males receiving 0.6 or 3.0% and females receiving 1.5 or 3.0%.
Absolute liver weight and liver-to-body weight ratios were signifi-
cantly higher in both the male and female 1.5- and 3.0%-dose groups.
Kidney-to-body weight ratios were also significantly higher for these
groups. Scattered gross pathologic changes did not appear to bear a
-------
Dimethrin August, 1987
-5-
relationship to dose. Histopathological examination revealed dose-
related morphological changes in the liver that consisted of a round
eosinophilic ring in the cytoplasm, approximately the size of the
nucleus. Amorphous material within the ring stained less densely
than the rest of the cytoplasm. Also, many hepatic cells of rats
receiving 1.5 or 3.0% dimethrin appeared larger than those of controls
and had less distinct basophilic cytoplasmic particles. Hepatic
changes were less pronounced in the 0.6% group. No cell inclusions
were seen in rats receiving 0.2% dimethrin. The effects of increased
liver and kidney-to-body weight ratios as well as histopathological
changes in the liver were shown to be reversible after withdrawal of
dimethrin. The No-Observed-Adverse-Effect-Level (NOAEL) identified
in this study was 0.2% dimethrin (120 mg/kg/day for males; 130 mg/kg/day
for females).
0 Ambrose (1964) administered dimethrin to male and female albino
Wistar-CWL rats (10/sex/dose) for 52 weeks at dietary levels of 0,
0.05, 0.1, 0.5, 1.0 or 2.0%. These dietary levels correspond to 0,
30, 60, 300, 600 or 1200 mg/kg/day. The only statistically significant
effect reported in this study was an increase in the liver-to-body
weight ratios in both male and female animals receiving 1.0 or 2.0%
dimethrin. Withdrawal of dimethrin from the diet for 6 weeks resulted
in return of liver weights to levels indistinguishable from the
controls. No differences in hemoglobin parameters were noted between
the treated and control animals at any time during the 52-week period.
Histologically, no significant changes or lesions that could be attrib-
uted to dimethrin in the diet were observed in any of the test groups
of animals. A NOAEL of 300 mg/kg was identified from this study.
0 Dimethrin has been implicated as a hypolipidemic agent and causes an
increase in hepatic peroxisome proliferation (Cohen and Grasso,
1981). Dietary administration of hypolipidemic agents to rodents has
resulted in induced liver carcinomas.
Reproductive Effects
0 No information on the reproductive effects of dimethrin was found in
the available literature,
Developmental Effects
0 No information on the developmental effects of dimethrin was found in
the available literature.
Mutagenicity
0 No information on the mutagenicity of dimethrin was found in the
available literature.
Carcinogeni ci ty
0 No information on the carcinogenicity of dimethrin was found in the
available literature. However, the report by Cohen and Grasso (1981)
-------
Dimethrin August, 1987
-6-
implicating dimethrin as a hypolipidemic agent may indicate that
dimethrin has carcinogenic potential in rodents. (It should be noted
that the relationship between hypolipodemic agents and liver carcinomas
in rodents has not been observed in humans.)
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formulas
HA = (NOAEL or LOAEL) x (BW) = mg/L ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in ing/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day » assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No information was found in the available literature that was suitable
for determination of the One-day HA values for dimethrin. It is therefore
recommended that the Longer-term HA for a 10-kg child (12 mg/L, calculated
below) be used at this time as a conservative estimate of the One-day HA value.
Ten-day Health Advisory
No information was found in the available literature that was suitable
for determination of the Ten-day HA values for dimethrin. It is therefore
recommended that the Longer-term HA for a 10-kg child (12 mg/L, calculated
below) be used at this time as a conservative estimate of the Ten-day HA value.
Longer-term Health Advisory
The 16-week rat study by Masri et al. (1964) has been selected to serve
as the basis for determination of the Longer-term HA. In this study, male
and female rats were administered dimethrin at dietary levels of 0, 0.2, 0.6,
1.5 or 3.0% for 16 weeks. Results of this study indicated a statistically
significant reduction in body weights of males receiving 0.6 or 3.0%, and
in females receiving 1.5 or 3.0%. Absolute liver weight and liver-to-body
weight ratios were significantly higher in the 1.5- and 3.0%-dose groups.
-------
Dimethrin August, 1987
, «
-7-
Kidney-to-body weight ratios were also significantly higher in those groups.
Histopathological examinations revealed dose-related morphological changes in
the liver occurring at dose levels as low as 0.6%. A NOAEL of 0.2% dimethrin
(120 mg/kg/day for males; 130 mg/kg/day for females) was identified in this
study. -
Using a NOAEL of 120 mg/kg/day, the Longer-term HA for a 10-kg child is
calculated as follows:
Longer-term HA = (120 mg/kg/day) (10 kg) . 12 mg/L (12,000 ug/L)
(100) (1 L/day)
where:
120 mg/kg/day = NOAEL, based on absence of hepatic effects in male
rats exposed to dimethrin via the diet for 16 weeks.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Using a NOAEL of 120 mg/kg/day, the Longer-term HA for a 70-kg adult is
calculated as follows:
Longer-term HA = (12° °«gAg/day) <70 k?> = 42 mg/L (42,000 ug/L)
* (100) (2 L/day)
where:
120 mg/kg/day = NOAEL, based oh absence of hepatic effects in rats
exposed to dimethrin via the diet for 16 weeks.
70 kg = assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three-step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
-------
Dimethrin August, 1987
i *
-8-
(DHEL) can be determined (Step 2). A DUEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The 52-week study in rats by Ambrose (1964) has been selected to serve
as the basis for determination of the Lifetime HA for dimethrin. In this
study, dimethrin was administered to albino Wistar-CWL rats for 52 weeks at
dietary levels of 0, 0.05, 0*1, 0.5, 1.0 or 2.0%. A statistically significant
increase in the liver-to-body weight ratio was observed in both male and
female rats receiving 1.0 or 2.0% dimethrin (600 and 1,200 mg/kg/day).
Histologically, no changes that could be attributed to dimethrin were observed
in any of the test groups. Mo adverse effects were reported in rats receiving
dimethrin at 0.5% (300 mg/kg/day for males) or lower.
Using a NOAEL of 300 mg/kg/day, the Lifetime HA is derived as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (300 mg/kg/day) = 0.3 mg/kg/day
(1,000)
where:
300 mg/kg/day = NOAEL, based on absence of increased liver-to-body
weight ratio in rats exposed to dimethrin in the diet
for 52 weeks.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL =» (0.3 mg/kg/day) (70 kg) = 10.5 mg/L (10,500 ug/L)
(2 L/day)
where:
0.3 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
-------
Dimethrin August, 1987
-9-
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (10.5 mg/L) (20%) = 2.1 mg/L (2,100 ug/L)
where:
10.5 mg/L = DWEL
20% = assumed percentage of daily exposure contributed by
ingestion of drinking water.
It should be noted that the Lifetime HA of 2.1 mg/L apparently exceeds the
water solubility of dimethrin (insoluble).
Evaluation of Carcinogenic Potential
0 No information on the carcinogenicity of dimethrin was found in the
available literature. However, the report by Cohen and Grasso (1981)
implicating dimethrin as a hypolipidemic agent may indicate that
dimethrin has carcinogenic potential in rodents. (It should be noted
that the relationship between hypolipidemic agents and liver carcinomas
in rodents has not been observed in humans.)
0 The International Agency for Research on Cancer has not evaluated the
carcinogenicity of dimethrin.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), dimethrin may be classified in
Group D: not classified. This category is for substances with
inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 No information on existing criteria, guidance, or standards pertaining
to dimethrin was found in the available literature. However, tolerances
for pyrethroids, of which dimethrin is a member, range from 0.05 ppm
in potatoes (post-harvest) to 3 ppm in wheat, barley, rice and oats
(CFR, 1985).
VII. ANALYTICAL METHODS
0 No information on the analytical methods for measuring dimethrin in
water was found in the available literature.
VIII. TREATMENT TECHNOLOGIES
0 The manufacture of this compound was discontinued (Meister, 1986). No
information was found in the available literature on treatment tech-
nologies capable of effectively removing dimethrin from contaminated
water.
-------
Dimethrin August, 1987
-10-
IX. REFERENCES
Ambrose, A.M. 1964. Toxicologic studies on pyrethrin-type esters of chrysan-
themumic acid II. Chrysanthemumic acid, 2,4-dimethylbenzyl ester.
Toxicol. Appl. Pharmacol. 6:112-120.
CFR. 1985. Code of Federal Regulations. 40 CFR 180.128.
Cohen, A.J., and P. Grasso. 1981. Review of hepatic response to hypolipidemic
drugs in rodents and assessment of its toxicological significance to
man. Food Cosmet. Toxicol. 4:585-605.
Gaines, T.B. 1969. Acute toxicity of pesticides. Toxicol. Appl. Pharmacol.
14:515-534.
Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs,
cosmetics. Assoc. Food Drug Off. U.S. Q. Bull.
Masri, M.S., A.P. Henderson, A.J. Cox and F. De, eds. 1964. Subacute toxicity
of two Chrysanthemumic acid esters: barthrin and dimethrin. Toxicol.
Appl. Pharmacol. 6:716-725.
Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister
Publishing Company, p. C81.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Fed. Reg;51(185):33992-34003. September 24.
------- |