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.

-------