March 31, 1987
                                  EPICHLOROHYDRIN

                                  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 predict 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.

-------
    Epichlorohydrin                                            March 31,  1987

                                         -2-
         This Health Advisory (HA) is based on information presented in the Office
    of Drinking Water's Health Effects Criteria Document (CD) for Epichlorohydrin
    (U.S. EPA, 1985a).  The HA and CD formats are similar for easy reference.
    Individuals desiring further information on the toxicological data base or
    rationale for risk characterization should consult the CD.  The CD is available
    for review at each EPA Regional Office of Drinking Water counterpart (e.g.»
    Water Supply Branch or Drinking Water Branch),  or for a fee from the National
    Technical Information Service, U.S. Department of Commerce, 5235 Tort Royal
    Rd., Springfield, VA 22161,  PB #86-118023/AS.  The toll-free number is (800)
    336-4700; in the Washington, D.C. area: (703) 487-4650.


II. GENERAL INFORMATION AND PROPERTIES

    CAS No.   106-89-8

    Structural Formula

                                    H2C-CH-CH2C1

    Synonyms

         0  1-Chloro-2,3-epoxypropane, 3-chloro1-1,2-epoxypropane,  (chloromethyl)
            oxirane, 2-(chloromethyl) oxirane and chloropropylene oxide.

    Uses

         0  Used in the manufacture of: epoxide resins,  surface active agents,
            Pharmaceuticals, and agricultural chemicals (Verschueren,  1983).

    Properties (U.S. EPA, 1985a)

            Molecular Formula                 C3H5C1O
            Molecular Weight                  92.53
            Physical State                    Colorless liquid
            Boiling Point                     116.1°C
            Melting Point                     -57.2°C
            Density
            Vapor Pressure                    12 mm at 20°C
            Specific Gravity                  1.18 at 20°C
            Water Solubility                    66 g/L at 20°C
            Log Octanol/Water Partition       0.26
              Coefficient
            Taste Threshold                   ~
            Odor Threshold                    0.5 - 1.0 mg/L; 3 mg/L (Amoore and
                                                Hautala, 1983)
            Conversion Factor                 1 mg/m3 = 0.265 ppm
                                              1 ppm =3.78 mg/m3
            Irritation Threshold              0.1 mg/L

-------
     Epichlorohydrin                                            March 31,  1987

                                          -3-


     Occurrence

          0  Total epichlorohydrin production in 1982 was  approximately 350 mil-
             lion pounds.  Though epichlorohydrin reportedly hydrolyzes readily in
             aqueous solution (hydrolysis  half-life  of 8.2 days  at 20°C and pH 7)
             to water soluble alcohols,  its  use  in water treatment resins  and
             coatings make exposure possible (Mabey  and Mill,  1978).

          0  No information has  been located in  either State or  Federal surveys to
             indicate the presence or absence of epichlorohydrin in drinking water.


III. PHARMACOKINETICS

     Absorption

          0  Epichlorohydrin is  absorbed readily following either oral,  inhalation
             or dermal exposures (U.S. EPA,  1985a).

          0  Gingell at al.  (1985)  assessed  the  pharmacokinetics and  metabolism
             of epichlorohydrin  in male  Fischer  344  rats treated (6 mg/kg  once by
             gavage) with [2-14C] epichlorohydrin (98% pure) in  water and  sacrificed
             after 3 days.  Ready absorption was shown by  an initial  elimination
             half-life of 2 hours and total  excreta  recovery of  91.61% of  the
             radiolabel.

          0  Smith et al. (1979) have reported the extensive absorption of epichloro-
             hydrin in water by  male Fischer 344 rats (190 to 220 g)  following a
             single gavage exposure.  Based  on excretion data, the extent  of
             absorption, approximately 100%  within 72 hours after administration,
   	,.	——appeared to be similar following doses  of either 1  or iOO mgAg bw.
             Smith et al.  (1979)  indicated  that epichlorohydrin was  absorbed
             readily by male Fischer 344 rats  (190  to 220 g)  following  a  6-hour
             exposure to atmospheres containing 1 or  100 ppm  epichlorohydrin
             (approximately 3.78  or  378 mg/m3).  Uptake  rates of 15.48  and  1394
             ug/hr were calculated for  exposures to 1  and 100 ppm, respectively.
             The  investigators  stated that  these exposures correspond to  doses of
             0.37 and 33 mg/kg  bw«

             The  toxicity  study of Kremneva and Tolgskaya (1961 ) indicates  that
             epichlorohydrin also is absorbed  following  dermal exposure.  When the
             tails of mice were immersed in epichlorohydrin either for  a  single
             exposure of 1  hour or for  repeated exposures of  20 to 30 minutes/day
             on 2 to 3 successive days,  toxic  signs and  death were observed within
             3 days.
     Distribution
             In the  study by  Gingell  et  al.  (1985),  8-9% of  14C was  in  tissues,
             with the highest levels  (specific activity, dpm x 10~3/
-------
Epichlorohydrin                                            March 31, 1987

                                     -4-
     0  Smith et al.  (1979) compared the distribution of  [1,3-14C]-epichloro-
        hydrin in male Fischer 344 rats following oral  (100 mgAg bw) or
       -inhalation  (100 ppm for 6 hours) exposure.  At  3 hours post-exposure
        in the oral study and at the termination of inhalation exposure, the
        plasma levels of radioactivity were 36.1 and 18.3 mg/g, respectively.
        Concentrations in tissues were expressed as ug  equivalents of epi-
        chlorohydrin per g of tissue.  After oral treatment, the greatest
        concentrations were in stocach, followed by intestine, kidney, liver,
        pancreas and lung.  Following inhalation exposure, the highest
        levels were in nasal turbinates, followed by intestine, liver and
        kidney.

Metabolism

     0  Gingell et al. (1985) concluded that the initial elimination half-
        life of 2 hours indicated rapid metabolism in their study.  Main
        urinary metabolites were N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-
        cysteine and X -chlorohydrin, representing 36 and 4% of the delivered
        dose, respectively.  One major metabolite and 4 minor metabolites
        were identified in urine.  These investigators stated that the presence
        of the two dominant urinary metabolites is.consistent with initial
        metabolic reactions being conjugation of the epoxide with glutathione
        and hydration of the epoxide.

     0  Smith et al. (1979) administered [1,3-14c]-epichlorohydrin to male
        Fischer 344 rats as single oral doses of 1 or 100 mg/kg bw or as
        6-hour inhalation exposures to 1 or 100 ppm (approximately 3.78 or
        378 mg/m-3).  Urinary metabolites were separated by ion-exclusion
        chromatography.  Seven radioactive peaks were found in the urine
        following oral dosing and six radioactive peaks following inhalation
        exposure, but none corresponded to epichlorohydrin.  The authors
        noted that the patterns of urinary metabolite excretion were similar
        following oral or inhalational dosing; metabolites were not identified.

     0  Epichlorohydrin has two electrophilic centers and may bind to cellular
        nucleophiles.  It is also a substrate for epoxide hydratase resulting
        in the formation of *-chlorohydrin which may be oxidized to oxalic
        acid, converted to glycidol or phosphorylated to 3-chloroglycero-
        phosphate (U.S. EPA,  1985a).  However, Gingell et al. (1985) did not
        find oxalic acid as a metabolite in their study.

     0  Rossi et al. (1983) found that epichlorohydrin rapidly disappeared
        from the blood of CD1 mice, with a half-life of approximately five
        minutes, with f< -chlorohydrin appearing as epichlorohydrin levels
        dropped. 2/ 50% was
        excreted as urinary metabolites, and 39% was eliminated in feces.

-------
    Epichlorohydrin                                            March 31,  1987

                                         -5-
            Smith et al. (1979)  administered [1,3-14c]-epichlorohydrin by
            single gavage doses  of 1  or 100 mgAg to groups of four male Fischer
            344 rats.  In parallel experiments,  four rats were exposed (head
            only) to atmospheres containing 100 ppm (378 mg/m^)  epichlorohydrin
            for six hours.  An additional three rats were exposed to atmospheres
            containing 1 ppm (3.78 rag/m^)  for six hours.  The rates or routes of
            excretion essentially were unaffected by either the  route of exposure
            or the dose administered.  Urine was  the major route of excretion,
            accounting for 46% to 54% of the dose.  An  additional 25% to 42% was
            recovered as -4C02 in the expired air.  Only 3% to 6% of the dose was
            recovered in the feces.  Excretion was biphasic,  with an initial
            rapid phase that dominated the first 24 hours post-exposure and a
            slower second phase  that  was dominant after 24 hours.  The calculated
            half-lives for elimination from the plasma  were 1 to 2 hours and 26
            to 27 hours for the  fast  and slow phases, respectively.
IV. HEALTH EFFECTS
    Humans
         0  In humans,  acute effects have been reported following both dermal and
            inhalation  exposures (U.S.  EPA,  1985a).   Dermal exposure produces
            predominantly local irritation effects,  but inhalation produces
            significant systemic effects, including  hepatic and renal toxicity.
            In one case report of a worker exposed to epichlorohydrin vapor,
            systemic effects were evident .for at, least 2 years  after the exposure.
            (U.S. EPA,  1985a)  Chronic  exposure to epichlorohydrin has been
            associated  with chromosome  and chromatid breaks, decreased hemoglobin
            concentration,  decreased erythrocyte counts and decreased leukocyte
            counts.  Increases (not statistically significant)  in the mortality
            due to lung cancer have been reported in workers sequentially exposed
            to isopropyl alcohol and epichlorohydrin (U.S.  EPA, 1985a). No
            effects on  reproductive function have been detected.
    Animals
    Short-term Exposure
            Epichlorohydrin is  acutely toxic following oral,  percutaneous,  subcu-
            taneous or respiratory exposure, producing similar symptoms in  each
            case.  At the site  of  application,  epichlorohydrin is  a strong
            irritant.  The major acute systemic effects occur in the central
            nervous system,  with death being due to depression of  the respiratory
            center.  The major  internal organs  affected are the lungs,  liver and
            kidneys (U.S. EPA,  1985a).

            Oral doses as low as 10 mgAg for 5 days/week for 2 weeks resulted
            in decreased (p <0.05) erythrocyte  counts in male rats and decreased
            (p <0.01) kidney/body  weight ratios in females (Van Esch, 1981).
            Similar exposures to 40 or 80 mgAg resulted in degenerative changes
            in the kidneys of both male and female rats.

-------
 Epichlorohydrin                                           March  31,  1987
Long-term Exposure

      0  Epichlorohydrin given in drinking water  at  levels  of  375,  750 and
        1,500 ppm (18,  39 and 89 nig/kg/day)  to male Wistar rats  for  81 weeks
        induced  forestomach  hyperplasia  and  decreased body weights at all
        doses (Konishi  et al.,  1980).

      0  with  gavage  administration of epichlorohydrin in water at doses of 2
        and 10 mgAg* 5 days /week for 104 weeks, stomach hyperplasia and a
        dose-related decrease in white blood cells  were observed in  male and
        female Wistar rats (Van Esch, 1982).

      0  Inhalation exposure  of  Fischer 344 rats, Sprague-Dawley rats,
        B6C3P1 mice  and New  Zealand rabbits  to epichlorohydrin at 19 mg/m3
        for 90 days  was without observable effect.  Higher  exposure levels
        induced  nasal irritation, eye irritation, kidney lesions and respiratory
        tract lesions (Quast et al., 1979; John et  al., 1983).

      0  Lifetime inhalation  exposure of  male Sprague-Dawley rats to  38 and
        114 mg/m3 epichlorohydrin elicited kidney lesions  (Laskin et al., 1980).

Reproductive  Effects

      0  Male  and female Wistar  rats were given epichlorohydrin in water start-
        ing 10 days before mating and continuing for three months (Van Esch,
        1981).   A dose  of 2  mgAg was ineffective.  A 10 mgAg dose reduced
      .  fertility and crossmating with untreated rats attributed the antifer-
        tility effect to males.   Sterility of male rats given epichlorohydrin
        orally also was  observed  by Hahn (1970) and Cooper et al.  (1974)
        with  gavage doses of '15 mgAg and higher for 15 and 5 days, respectively?
        however,  these  investigators showed the effect to be reversible.

      0  Exposure  of male rats to  epichlorohydrin by inhalation at levels above
        19 mg/m3  for 10 weeks resulted in reversible sterility,  and the
        fertility of male rabbits was unaffected by inhalation exposure
        levels of  epichlorohydrin as high as 189 mg/m3 (John et al.,  1983).

Developmental Effects

      0  Epichlorohydrin  was not teratogenic when given by gavage in cotton-
        seed  oil  to pregnant CD rats and CD-1 mice on days 6 through 1 5' of
        gestation (Marks et al.,  1982).   Doses above 40 mgAg were maternally
        toxic  (reduced body weight,  increased liver weight, death) in rats.
        Doses above 80 mgAg were maternally toxic (increased liver weight,
        death) and fe to toxic  (reduced body weight) to mice.

        Inhalation exposures of pregnant Sprague-Dawley rats and New Zealand
        rabbits to 9.5 and 95 mg/m3  of  epichlorohydrin during gestation days
        6 through  15 (rats) and 6 through 18 (rabbits) were neither teratogenic
        nor fetotoxic.   Pregnant rats exposed to 95 mg/m3 weighed less  than
        controls  (Pilny et al., 1979).

-------
Epichlorohydrin                                            March 31, 1987

                                     -7-


Mutagenicity

     0  Epichlorohydrin is a rautagen in several systems (U.S. EPA,  1985a).
        It is a potent inducer of base-pair substitution-type mutations in
        prokaryotic systems.  Incubation with mammalian liver homogenates
        results in a marked reduction in mutation frequency.  Epichlorohydrin
        also induces gene mutations and very likely chromosomal aberrations
        in mouse lymphoma cell cultures (Moore-Brown and Clive, 1979) and
        clastogenesis in human lymphocytes in vitro (Norppa et al., 1981)
        but not in rat liver cell cultures (Dean and Hodson-Walker, 1979).
        Epichlorohydrin was found to induce sister chromatid exchange in
        cultured human lymphocytes (Norppa et al., 1981; Carbone et al.,
        1981; White, 1980).  Examination of occupationally exposed workers
        indicates that chromosomal aberrations also occur in vivo (Picciano,
        1979a,b; Kucerova et al., 1977; Sram et al., 1976).

     0  In in vivo studies, epichlorohydrin treatment results in an increased
        incidence of sex-linked recessive lethals in Drosophila when admini-
        stered by injection, but not when incorporated in the food (Knapp
        et al., 1982; Wurgler and Graf, 1981).  In other in vivo studies,
        epichlorohydrin has produced negative results in the mouse dominant
        lethal assay (Epstein et al., 1972; Sram et al., 1976) and the mouse
        micronucleus assay (Kirkhart, 1981; Tsuchimoto and Matter,  1981).
        Clastogenic effects of epichlorohydrin in bone marrow cells in vivo
        were found in mice (Sram et al., 1976) but not in rats (Dabney
        et al., 1979).

Carcinogenicity

     0  Epichlorohydrin is carcinogenic at the site of administration.

     0  Administration of 375, 750 and 1,500 ppm epichlorohydrin in drinking
        water [equivalent to 18, 39 and 89 mg/kg/day based on data by the
        authors (total doses of 5.0, 8.9 and 15.1 g/rat during 81  weeks of
        treatment divided by body weight)] to male Wistar rats for 81 weeks
        resulted in forestomach hyperplasia at all doses and papillomas and
        carcinomas of the forestomach at the two highest doses (Kbnishi
        et al., 1981).

     0  Lifetime gavage treatment of male and female Wistar rats with aqueous
        epichlorohydrin solution at doses of 2 and 10 mg/kg induced papillomas
        and carcinomas of the forestomach (Wester et al.,  1985; Van Esch,
        1982).

     0  Laskin et al. (1980) found nasal carcinomas in male Sprague-Dawley
        rats exposed to 378 mg/m^ of epichlorohydrin by inhalation 6 hours/day,
        5 days/week for six weeks followed by lifetime observation.
        Subcutaneous injection of epichlorohydrin in ICR/Ha Swiss mice induced
        local sarcomas; epichlorohydrin was effective as an initiator but not
        as a complete carcinogen on the. skin of ICR/Ha Swiss mice (Van Duuren
        et al., 1972; 1974).

-------
   Epichlorohydrin                                            March 31, 1987

                                        -8-


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 formula:

                 HA = (NOAEL or LOAEL) x (BW) = 	 m /L (	   *}
                        (UF) x (	 L/day)

   where:

           NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                            in rag/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).

   Organoleptic Properties

        A reported threshold for odor perception of epichlorohydrin is 0.5 to
   1.0 mg/L,  and 0.1 mg/L was cited as the threshold for its irritant action by
   the MAS (1980).  Amoore and Hautala (1983) reported an odor threshold of 3
   mg/L.

   One-day Health Advisory

        Because appropriate data for calculation of a One-day HA are not avail-
   able, the Ten-day HA (0.14 mg/L) is recommended for use as the One-day HA.

   Ten-day Health Advisory

        The reproductive toxicity study by Van Esch (1981) can be used to derive
   the Ten-day HA.  In this study, male and female rats were given epichloro-
   hydrin by gavage 5 days/week at doses of 0, 2 or 10 mg/kg-  Exposure was
   started 10 days prior to mating and continued until the Fjjrj generation was
   produced.  The fertility index at the first mating was reduced in the high-
   dose group but not in the low-dose group.  The study of Hahn (1970) which
   reported infertility in male rats exposed by gavage to epichlorohydrin at
   15 mg/kg/day for 12 days supports an assumption that at least a portion of
   the reduced fertility index observed by Van Esch (1981) was the result of
   infertility in the males associated with the ten-day exposure prior to mating.
   In this study, 2 mg/kg was a NOAEL for reproductive effects and is appropriate
   for use in deriving the Ten-day HA.

        Using the NOAEL of 2 mgAg/day, the Ten-day HA for a 10-kg child is
   calculated as follows:

-------
Epitihlorohydrin                                            March 31, 1987

                                     -9-


         Ten-day HA = 2 mg/kg/day) (10 kg) (5) = 0>14 mg/L (140 ug/L)
               y        (1005 (1 L/day)fTT

where:

        2 mg/kg/day = NOAEL based on absence of reproductive toxicity in rats.

              10 kg = assumed body weight of a child.

                5/7 = conversion of dose to represent continuous exposure
                      (7 days per week).

            1 L/day = assumed daily water consumption of a child.

     Although the antifertility effect in male rats in the Van Esch (1981)
study relates to men as a specific sensitive subpqpulation for this effect,
this study is preferred for the calculation of a Ten-day HA for the general
population because of its design with oral short-term exposure and its
demonstration of no-effect and effect levels.  Additionally, the 2 mgAg
NOEL in the Van Esch (1981) study appears consistent with the dose responses
in the overall Van Esch (1981) work where both systemic and reproductive .
effects were found with 10-day oral exposures to 10 rag/kg of epichlorohydrin.

Longer-term Health Advisory

     There are insufficient data for calculation of a Longer-term HA.  The
DWEL (0.07 mg/L), is recommended as a conservative estimate of the Longer-term
HA.

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 NQAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s).  From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL 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.

-------
Epichlorohydrin
    March 31, 1987
                                     -10-
     Of the reviewed studies in which the effects of long-term exposure to
epichlorohydrin were investigated  (Laskin et al., 1980; Konishi et al., 1980,
also reported by Kawabata, 1981; Wester et al., 1985, also reported by Van Esch,
1982), the Laskin et al.  (1980) study was selected as the most appropriate
from which to derive the DWEL.  Forestomach hyperplasia in all three treatment
groups and papillomas and carcinomas of the forestomach in the two highest
dose groups were found in the study by Konishi et al. (1980).  Since the
hyperplasia could be considered a pre-neoplastic effect and the progression
of forestomach lesions beyond the 81-week duration of this btudy is uncertain,
it would be questionable to use this effect in the low-dose group (18 mg/kg/day)
for calculating a DWEL for drinking water exposure.  Dose-response for
toxicity/carcinogenicity in the Konishi et al.  (1980) drinking water study
is given preference over that in the bolus gavage dosing study by Wester, et
al. (1985), and use of the estimated 2.16 mg/kg/day dose in the Laskin, et
al. (1980) study is concluded to be consistent with the dose-response indicated
by the Konishi et al. (1980) study.  The LOAEL based on renal damage of 2.16
mg/kg/day estimated from the data in the Laskin et al.  (1980) study was,
therefore, used to derive a DWEL.  Additionally, carcinogenic effects were
not apparent at the LOAEL in the Laskin et al. (1980) study.  Using this
LOAEL, the DWEL is derived as follows:

Step 1:  Conversion of Inhalation Exposure to Oral Exposure

     Applying the 38 mg/m3 inhalation LOAEL in the Laskin et al. (1980)
study and the assumptions in U.S. EPA (1985a) for converting inhalation
exposure to oral exposure for the rat, the estimated oral dose would be:
        (38 mg/m3)(0.0093 m3/hr)(6 hr/day) (5)(0.5)
                        (0.35 kg)          (7)
2.16 mg/kg/day
where:
        38 mg/m3  = LOAEL based on kidney toxicity in rats.

        0.0093 m3 = amount of air breathed by a rat/hour.

         6 hr/day = a 6-hour exposure each day.

              5/7 = adjust from a 5 days/week exposure to 7 days/week,

              0.5 = the assumed inhalation absorption factor.

          0.35 kg = the assumed weight of a rat.

Step 2:  Determination of the Reference Dose (RfD)

            RfD = (2.16 mg/kg/day) = Q.002 mg/kg/day (2 ug/kg/day)
where:
        2.16 mg/kg/day = LOAEL based on kidney toxicity in rats.

                 1,000 = uncertainty factor, chosen in accordance with NAS/ODW
                         guidelines for use with a LOAEL from an animal study.

-------
Epichlorohydrin                                            March 31 , 1 987

                                     -11-


Step 3:  Determination of the Drinking Water Equivalent Level  (DWEL)
           DWEL = (0«002 mg/kg/day) (70 kg) = 0>07   /L (70
                         (2 L/day)

        0.002 mg/kg/day = RfD.

                  70 kg = assumed body weight of an adult.

                2 L/day = assumed daily water consumption of an adult.

     Epichlorohydrin may be classified in Group B:  Probable human carcinogen.
The estimated excess cancer risk associated with lifetime exposure to drinking
water containing epichlorohydrin at 70 ug/L is approximately 2 x 10-5.  This
estimate represents  the upper 95% confidence limit from extrapolations prepared
by EPA's Carcinogen Assessment Group using the linearized/ multistage model.
The actual risk is unlikely to exceed this value, but there is considerable
uncertainty as to the accuracy of risks calculated by this methodology.

Evaluation of Carcinogenic Potential

     0  Applying the criteria described in EPA's guidelines for assessment of
        carcinogenic risk (U.S. EPA, 1986), epichlorohydrin may be classified
        in Group B2:  Probable human carcinogen.  This category is for agents
        for which there is inadequate evidence from human studies and
        sufficient evidence from animal studies.

     0  The study of Konishi et al. (1980) -provides appropriate data for a
        quantitative risk assessment based on the relevant route of exposure
        and the observed dose-response pattern.  Using the calculated q-|* of
        9.9 x 10-3  (mg/kg/day ) -1 , the 95% upper-limit lifetime dose associated
        with a 10-5 risk level may be calculated to equal 70.7 ug/day.
        Assuming an average water consumption of 2 L/day, this risk level
        corresponds to a water concentration of 35.4 ug/L.  Corresponding
        levels for 10-6 and 10-4 are 3.54 and 354 ug/L, respectively.

     0  Maximum likelihood estimates as well as 95% upper limits of cancer
        risks by the multistage model have been calculated (U.S. EPA, 1984).
        For example, at 1 0 ug/L cancer risk estimates are 1 .4 x 10-17 (MLE)
        and 2.8 x 10-6 (UL)»and at 100 ug/L cancer risk estimates are 2.6 x
        10-14 (MLE)  and 2.8 x 10-5 (UL) .

     0  The EPA's Carcinogen Assessment Group has estimated cancer risks with
        other models besides the multistage (U.S. EPA, 1984).  As an example,
        10 ug/L lifetime exposure was associated with additional risks (95%
        upper confidence limit) of 2.8 x 10-5 by the multistage, 3.4 x 10-5
        by the one-hit, 0 by the Weibull, and 0 by the log-probit.  While
        recognized as statistically alternative approaches, the range of
        risks described by using any of these modeling approaches has little
        biological significance unless data can be used to support the selec-
        tion of one model over another.  In the interest of consistency of
        approach and in providing an upper bound on the potential cancer risk,
        the EPA has recommended use of the linearized multistage approach.

-------
      Epichlorohydrin                                            March 31,  1987

                                           -12-


           0  Epichlorohydrin is classified as a 2B carcinogen by IARC (1982)  with
              sufficient animal evidence and inadequate human evidence.


  VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

           0  The NAS (1980) SNARLs (Suggested-Nq-Adverse-Response-Levels)  for
              1- or 7-day exposures to apichlorohydrin are 0.84 and 0.53 mg/L,
              respectively.  An ADI (Acceptable Daily Intake) or a cancer risk was
              not calculated by the NAS (1980).

           0  The ACGIH has recommended a TLV (Threshold Limit Value) of 2 ppm
              (10 mg/m3) (ACGIH, 1982).  Current OSHA standards allow a TWA occupa-
              tional exposure of 19 mg/m3 (29 CFR 1910.1000); however,  they are
              currently considering lowering this value to 0.5 ppm (2 mg/m3) with
              a ceiling value of 15 ppm (60 mg/m3) for 15 minutes.  Occupational
              standards in other countries range from 0.26 ppm in Russia and
              Czechoslovakia to 3.6 ppm in the Federal Republic of Germany  (Sram,
              et al., 1980).

           0  Epichlorohydrin has not been regulated under the Safe Drinking Water
              Act; however, discharge of >1,000 pounds (454 kg) into navigable
              waters is prohibited under the Clean Water Act (40 CFR 116).

           0  Epichlorohydrin is also classified as a "hazardous waste" by the U.S.
              EPA and quantities exceeding 100 kg must be disposed of in a special
              landfill (40 CFR 261; 40 CFR 122).

           0  The proposed RMCL by the U.S. EPA Office of Drinking Water is zero
              (U.S. EPA, 1985b).


 VII. ANALYTICAL METHODS

           0  There is no standardized method for the determination of epichloro-
              hydrin in drinking water samples.  However, epichlorohydrin may  be
              determined by a purge-and-trap gas chromatographic/mass spectrometric
              procedure used for the determination of volatile organic compounds
              in water (U.S. EPA, 1985c).  This method calls for the bubbling  of
              an inert gas through the sample and trapping epichlorohydrin on  an
              adsorbent material.  The adsorbant material is heated to drive off
              epichlorohydrin onto a gas chromatographic column.  The gas chromato-
              graph is temperature programmed to separate the method analytes  which
              are then detected by the mass spectrometer.


VIII. TREATMENT TECHNOLOGIES
           0  No data are available on the removal of epichlorohydrin from potable
              water by any treatment technique (ESE, 1984; U.S. EPA, 1985d).

           0  The amenability of epichlorohydrin to removal by conventional treat-
              ment or by adsorption is not known.  The Henry's Law Constant for

-------
Epichlorohydrin
                                     -13-
March 31, 1987
        eptchlorohydrin has been estimated to be 2.44 x 10~5 atm x m3/mole
        (ESE, 1984).  This value suggests that aeration is unlikely to be a
        successful removal technique for epichlorohydrin.-  It also has been
        concluded that epichlorohydrin would not be removed from water by
        ozone oxidation (U.S. EPA,  1985d).

-------
    Epichlorohydrin                                            March 31,  1987

                                         -14-


IX. REFERENCES

    ACGIH,  1982.  American Conference of Governmental Industrial Hygienists.
         Threshold limit values for chemical substances  and physical agents  in
         the workroom environment.   Cincinnati,  Ohio.

    Amoore, J.E.,  and E. Hautala.  1983.  Odor as  an aid to chemical safety:
         Oder threshold compounds with threshold unit values and volatilities for
         214 industrial chemicals in air and water dilution.  J. Appl.  Toxicol.
         3:272-290.

    Carbone, P., G. Barbata,  G. Margiotta,  A. Tomasino and G.  Granata.   1981.
         Low epichlorohydrin  concentrations induce sister chromatid  exchanges in
         human lymphocytes in vitro.  Caryologia.   34(3):261-266.

    40 CFR  116.   Code of Federal Regulations.

    40 CFR  122.   Code of Federal Regulations.

    40 CFR  261.   Code of Federal Regulations.

    Cooper, E.R.,  A.R. Jones  and H. Jackson.   1974.   Effects of  alpha-chlorohydrin
         and related compounds on the reproductive organs and  fertility of the
         male rat.  J. Reprod. Fert.  39(2): 379-386.

    Dabney, B.J.,  R.V. Johnston, J;F. Quast and C.N.  Park.  1979.  Epichlorohydrin
         ~ Subchronic studies.  III.  Cytogenetic evaluation  of bone marrow
         cells from rats exposed by inhalation to  epichlorohydrin  for four weeks.
         ICPEM (International Commission for Protection  Against Environmental
         Mutagens  and Carcinogens)  Document No.  128.   15 pp.

    Dean, B.J.,  and G. Hodson-Walker.  1979.   An in vitro chromosome assay using
         cultured rat-liver cells.   Mutat.  Res.  64:329-337.

    ESE.   1984.   Environmental Science and  Engineering.   Review of treatability
         data for removal of  twenty-five synthetic organic chemicals from drinking
         water.   U.S. EPA. Office  of Drinking Water.

    Epstein, S.S., E. Arnold, J. Andrea, W. Bass and  Y.  Bishop.   1972.   Detection
         of chemical mutagens by the dominant lethal  assay in  the  mouse.  Toxicol.
         Appl. Pharmacol.  23:288-325.

    Gingell, R., H.R. Mitschke, I.  Dzidic,  P.W.  Beatty,  V.L. Sarvin  and A.C.  Page.
         1985.  Disposition and metabolism  of [2-14c] epichlorohydrin after oral
         administration to rats. Drug Metab. Dispos. 13:333-341.

    Hahn, J.D.  1970.  Post-testicular antifertility  effects of  epichlorohydrin
         and 2,3-epoxypropanol.  Nature (London).   226:87.

    IARC  1982.  International Agency for Research  on  Cancer.  IARC monographs
         on the  evaluation of the carcinogenic rice of chemicals to  humans.
         Chemical Industrial  Processes and  Industries Associated with Cancer  in
         Humans.  Suppl. 4, pp. 122-123.

-------
Epichlorohydrin                                            March 31, 1987

                                     -15-
John, J.A., J.F. Quast, F.J. Murray, L.S. Calhoun and R.E. Staples.  1983.
     Inhalation toxicity of eplchlorohydrin:  Effects on fertility in rats
     and rabbits.  Toxicol. Appl. Pharmacol.  68:415-423.

Kawabata, A.  1981.  Studies on the carcinogenic activity of epichlorohydrin
     by oral administration in male Wistar rats.  J. Nara Med. Assoc.
     32:270-280.

Kirkhart, B.  1981.  Micronucleus test on 21 compounds.  In;  Evaluation of
     Short-Term Tests for Carcinogens, F.J. deSerres and J. Ashby, eds.
     Elsevier/North Holland, Amsterdam,  pp. 698-704.

Knapp, A.G.A.C., C.E. Voodg and P.G.N. Kramers.  1982.  Comparison of the
     mutagenic potency of 2-chloroethanol, 2-bromoethanol, 1,2-epoxybutane
     epichlorohydrin and glycidaldehyde in Klebsiella pneumoniae, Drosophilla
     melanogaster and L5178Y mouse lymphoma cells.  Mutat. Res.  101:199-208.

Konishi, T., A. Kawabata, A. Denda et al.  1980.  Forestomach tumors induced
     by orally administered epichlorohydrin in male Wistar rats.  Gann.
     71:922-923.                       '

Kremneva, S.N., and M.S. Tolgskaya.  1961.  Toxicology of epichlorohydrin.
     Toksikol. Nov. Prom. Khim. Veschestv.  2:28-41.

Kucerova, M., V.S. Zhurkov, Z. Polwkova and J.E. Ivanova.  1977.  Mutagenic
     effect of epichlorohydrin.  II.  Analysis of chromosomal aberrations in
     lymphocytes of persons occupationally expo'sed to epichlorohydrin.
     Mutat. Res.  48:355-360.

Laskin, S., A.R. Sellakumar, M. Kuschner et al.  1980.  Inhalation carcino-
     genic! ty of epichlorohydrin in non-inbred Sprague-Dawley rats.  J. Natl.
     Cancer Inst.  65(4):751-758.

Mabey, W., and T. Mill.  1978.  Critical review of hydrolysis of organic com-
     pounds in water under environmental conditions.  J. Phys. Chem. Ref. Data.
     7:385-415.

Marks, T.A., F.S. Gerling and R.E. Staples.  1982.  Teratogenic evaluation
     of epichlorohydrin in the mouse and rat and glycidol in the mouse.
     J. Toxicol. Environ. Health.  9:87-96.

Moore-Brown, M.M., and D. Clive.  1979.  The L5178Y/TK+/~ mutagen assay
     system: In situ results.  Banbury Report.  2:71-88.

NAS.  1980.  National Academy of Sciences.  Drinking Water and Health.
     Volume 3.  National Academy Press.  Washington, D.C.  pp. 111-124.

Norppa, H., K. Hemminki, M. Sorsa and H. Vainio.  1981.  Effect of mono-
     substituted epoxides on chromosome aberrations and SCE in cultured human
     lymphocytes.  Mutat. Res.  91:423-250.

Picciano, D.  1979a.  Cytogenic investigation of occupational exposure  to
     epichlorohydrin.  Mutat. Res.  66:169-173.

-------
Epichlorohydrin                                            March 31, 1987

                                     -16-
Picciano, D.  1979b.  Faulty experimental design and underutilization of
     cytogenetic data.  Benzene and epichlorohydrin.  Ann. NY Acad. Sci.
     329:321-327.

Pilny, M.K., T.S. Lederer, J.S. Murray, et al.  1979.  Epichlorohydrin sub-
     chronic studies.  IV.  The effects of maternally inhaled epichlorohydrin
     on rat and rabbit embryonal and fetal development.  Unpublished report.
     Toxicol. Has. Lab., Health Environ. Sci., Dow Chemical U.S.A., Midland, MI.

Quast, J.F., J.W. Henck, B.J. Pastma, D.J. Scheutz and M.J. McKenna.  1979.
     Epichlorohydrin subchronic studies.  I.  A 90-day inhalation study in
     laboratory rodents (Fischer 344 rats, Sprague-Dawley rats,  and B6C3F-|
     mice).  Dow Chemical U.S.A., Midland, MI.  166 pp.

Rossi, A.M., D. Migliore,  D. Lascialfari,  I. Sbrana and N. Loprieno.  1983.
     Genotoxicity, metabolism, and blood kinetics of epichlorohydrin in mice.
     Mutat. Res.  118:213-226.

Smith, F.A., P.W. Langvardt and J.D. Young.  1979.  Pharmacokinetics of
     epichlorohydrin (EPI) administered to rats by gavage or inhalation.
     Dow Chemical U.S.A.,  Toxicology Research Laboratory, Midland,  MI.  52 pp.

Sram, R.J., M. Cerna and M. Kucerova.  1976.  The genetic risk of epichloro-
     hydrin as related to the occupational exposure.  Biol. Zbl.  95:451-462.

Sram, R.J., Z. Zudova and N.P. Kuleshov.  1980.  Cytogenic analysis of peri-
     pheral lymphocytes in workers occupationally exposed to epichlorohydrin.
     Mut. Res.  70:115-120.

Tsuchimoto, T., and B.E. Matter.  1981.  Activity of coded compounds in the
     micronucleus test.  In;  Evaluation of Short-Term Tests for Carcinogens,
     F.J. Seeres and J. Ashby, eds.  Elsevier/North Holland, Amsterdam.
     pp. 705-711.

U.S. EPA.  1984.  U.S. Environmental Protection Agency.  Health  assessment
     document for epichlorohydrin.  Final report.  Office of Health and
     Environmental Assessment.  Washington, D.C.  EPA-600/8-83-032F.

U.S. EPA.  1985a.  U.S. Environmental Protection Agency.  Drinking water
     criteria document for epichlorohydrin.  Final Draft.  Office of Drinking
     Water.  Washington, D.C.  ECAD-CFN-413.

U.S. EPA.  1985b.  U.S. Environmental Protection Agency.  National primary
     drinking water regulations; Synthetic organic chemicals, inorganic
     chemicals and microorganisms; Proposed rule.  Federal Register.
     50(219):4693-47002.  November 13.

U.S. EPA.  1985c.  U.S. Environmental Protection Agency.  Method 524.1.
     Volatile organic compounds in water by purge and trap gas chromatography/
     mass spectrometry.  Environmental Monitoring and Support Laboratory,
     Cincinnati, Ohio 45268.

-------
Epichlorohydrin                                            March 31, 1987

                                     -18-
U.S. EPA.  1985d.  U.S. Environmental Protection Agency.  Technologies and
     costs for removal of organic chemicals from potable water supplies.
     Draft.  Science and Technology Branch, CSD, ODW, Washington, D.C.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogenic risk assessment.  Federal Register 51(185):33992-34003.
     September 24.

Van Duuren, B.L., C. Katz and B.M. Goldschmidt.  1972.  Direct-acting alkyl-
     ating carcinogens — Chloro ethers and related compounds.  Toxicol.
     Appl. Pharmacol.  22:279-280.

Van Duuren, B.L., B.M. Goldschmidt, C. Katz, I. Seidman and J.S. Paul.  1974.
     Carcinogenic activity of alkylating agents.  J. Natl. Cancer 'Inst.
     53:695-700.

Van Esch, G.J.  1981.  Induction of preneoplastic lesions in the forestomach
     •of rats after oral administration of 1-chloro-2,3-epoxyproparie.  I.
     Range finding studies.  Prepared by Ryksinstitute Voor De Volksgezondheld
     Bilthoven Rapport nr.  627805 005.

Van Esch, G.J.  1982.  Induction of preneoplastic lesions in the forestomach
     of rats after oral administration of 1-chloro-2,3-epoxypropane.  II.
     Carcinogenicity study.  Prepared by Ryksinstitute Voor De Volksgezondheld
     Biltho.ven Rapport nr.  627805 005.

Verschueren, K.  1983.  Handbook of Environmental Data on Organic Chemicals.
     2nd ed.  Van Nostrand Reinhold" Co., NY.  pp. 611-613.

Wester, P.W., C.A. Van Der Heiden, A. Bisschop, and G.J. Van Esch.  1985.
     Carcinogenicity study with epichlorohydrin (CEP) by gavage in rats.
     Toxicol. 36:325-329.

White, A.D.  1980.  In vitro induction of sister chromatid exchange in human
     lymph'ocytes by epichlorohydrin with and without metabolic activation.
     Mutat. Res.  78:171-176.

Wurgler, F.E., and U. Graf.  1981.  Mutagenic activity of ten coded compounds
     in the Drosophila sex-linked recessive lethal assay.  In;  Evaluation of
     Short-Term Tests for Carcinogens, F.J. de Serres, ed.  Elsevier/North
     Holland, Amsterdam,  pp. 666-672.

-------