EPA 0596
Health advisories for
other contaminants

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Other Contaminants Health Advisories
  CONTS - 15.25
-Dichloromethane Health Advisory
  D-284 - 1.50            .        .        •
-1,2-Dichloropropane Health Advisory

  D-255  -  1 . 50     '                       .
-Formaldehyde - Informal Guidance level  fo
  D-286  -  1.00        .  '
-Lead Health Advisory
  D-287  -  2.00
-p-Dioxane Health Advisory
  D-288  -  1.00
-Zinc Chloride Health Advisory
  D-289  -  8.25

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      EPA 0596                                             March  31,  1987
      RX000027824
                                  DICHLOROMETHANE

                                  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.

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    uicnioromethane                                         March  31, 1987

                                         -2-


         This Health Advisory  is  based upon information presented in the Office
    of Health and Environment  Assessment  Criteria Document  (CD) for Dichloromethan
    (U.S. EPA, 1985a).   Die  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 a fee from the  National Technical Information Service, U.S. Department of
    Commerce, 5285 Port Royal  Rd., Springfield,  VA 22161, PB85 191559.  The toll-
    free number is (800) 336-4700; in the Washington, D.C. area:   (703) 487-4650.


II. GENERAL INFORMATION AND  PROPERTIES

    CAS No.  75-09-2

    Structural Formula
                                      Cl
                                       I
                                    H-C-C1
                                       I
                                      H

    Synonyms

         0  Methylene chloride, methylene dichloride, methylene bichloride, DCM

    Uses

         0  Solvent for insecticides, paints, varnish and paint removers and in
            food processing; degreasing and cleaning fluids.

    Properties  (Verschueren,  1977;  Windholtz, 1983)

            Chemical Formula               CH2C12
            Molecular Weight               84.94
            Physical State                 Colorless liquid
            Boiling Point                  40°C (760 mm Hg)
            Melting Point                  -95  to -978C
            Density                        1.3255 (20/4°C)
            Vapor Pressure                 349  mm Hg  (20°C)
            Water Solubility               20 g/L (20°C)
            Log Octanol/Water  Partition
              Coefficient
            Odor Threshold
            Taste Threshold
            Conversion  Factor               —

    Occurrence

         *  Dichloromethane  (DCM) is a synthetic chemical with no known natural
            sources.

         0  Production  of DCM  was approximately  600  million Ibs in  1983  (U.S.
            ITC, 1984).            .

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     Dichloromethane                                               March  31,  1987

                                          -3-
          0  The major sources of DCM released to the environment are  from  its
             industrial uses where the majority of all DCM produced is released.
             Most of the releases occur to the atmosphere by  evaporation.   However,
             large amounts of DCM are disposed of by burial in landfills  or dumping
             on the ground or into sewers.  Because DCM is involved in industrial
             operations performed nationwide, releases occur in all urban areas.
             Releases of DCM during its production are relatively minor in  comparison
             to releases during its use.

          0  Dichloromethane released to the air is degraded in a matter  of a few
             days.  Dichloromethane released to surface waters migrates to  the
             atmosphere in a few days or weeks where it also degrades. Volatiliza-
             tion is the major transport process for its removal from  aquatic
             systems (U.S. EPA, 1979).  Dichloromethane which is released to the
             land does not sorb onto soil and migrates readily to ground  water
             where it is expected to remain for months to years.  Dichloromethane,
             unlike some other chlorinated compounds, does not bioaccumulate in
             individual animals or food chains.

          0  Because of the large and dispersed releases, DCM occurs widely in  "the
             environment.  It is ubiquitous in the air with levels in  the ppt
             range and is a common contaminant in ground and surface waters with
             higher levels found in ground water.

          0  Very limited information is available on the occurrence of dichloro-
             methane in food.  Dichloromethane has been reported to occur in fish.
             It is used as an extraction solvent for the decaffination of coffee
             and other food processing operations.  Low levels of DCM  have  been
             reported to occur in some foods from these operations.

          0  The major sources of exposure to DCM are from contaminated water.
             Air and food are only a minor sources (U.S. EPA, 1980c).


III. PHARMACOKINETICS

     Absorption
                     «*.
          0  Dichloromethane is expected to be absorbed completely when ingested.
             A single oral dose of 1 or 50 mgAg 14C-DCM administered  to  male rats
             (3/dose) was exhaled as unchanged DCM (12.3 or 72.1%, respectively)
             within 48 hours (McKenna and Zempel, 1981).

     Distribution

          c  Tissue distribution after administration of 1 or 50 mgAg of 14c-DCM
             in water by gavage to male rats (3/dose) was measured by  McKenna and
             Zempel (1981).  The highest concentration of radioactivity was present
             in liver and the lowest in fat, 48 hours after either dose.

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    Dichloromethane.                                              March 31, 1987

                                         -4-


    Metabolism

         0  The major metabolites of DCM are carbon  monoxide and carbon dioxide.
            McKenna and Zempel (1981) studied the  metabolism of V4C-DCM after
            gavage administration to groups of three male  Sprague-Dawley rats
            dosed at 1  or 50 mgAg-   They metabolized about 88 or 28% of the
            dose, respectively.  The major metabolites  exhaled after 48 hours
            were carbon monoxide  (30.9 and 11.9% of  the 1  or 50 mgAg doses,
            respectively) and carbon dioxide (35.0 and  6.3% of the  1 or 50 mgAg
            doses, respectively).
    Excretion
            Metabolites of DCM are excreted  in  urine.  McKenna and Zempel  (1981)
            reported that, in rats given 1 or 50 mgAg  14C-DCM, 4.52 +0.05% or
            1.96 ±0.05% of the dose,  respectively,  was  excreted in the urine
            within 48 hours.  The fecal elimination of DCM after oral or intra-
            peritoneal administration of DCM is low (<1.0%)  (DiVincenzo and
            Hamilton, 1975; McKenna and Zempel,  1981).
IV. HEALTH EFFECTS
    Humans
            Bonventre et al. (1977)  described a fatal  intoxication with DCM
            which was being used as  a paint remover.   Postmortem examination
            revealed the presence of DCM in the liver  (14.4 mg/100 g tissue),
            blood (51 mg/dL or 510 mg/L) and brain (24.8 mg/100 g tissue).
            The carboxyhemoglobin content was 3% saturated.
    Animals
    Short-term Exposure
            Oral LD50s for DCM were reported as  1,987 mgAg for mice and  2,121
            mgAg for rats (Kimura et al.  1971;  Aviado  et  al.  1977).

            Kimura e-t al. (1971) administered single oral  doses of DCM  to young
            adult Sprague-Dawley rats and  determined that  an approximate  dose
            of 1.3 gAg body weight was the lowest dose to induce the first
            observable signs of toxicity (dyspnea,  ataxia, cyanosis and/or coma)
    Long-term Exposure
            Bornmann and Loeser (1967)  administered DCM in drinking water at
            2.25 g/18L (or 125 mg/L)  to 30 male  and 30 female Wistar rats for 13
            weeks.   This is equivalent  to a dose of about 15 mgAg/day assuming
            that 10 mL of water is consumed daily.  The animals were examined
            for changes in behavior,  body weight, blood and urine chemistries,
            reproductive function, organ to body weight ratios and histology.
            No treatment-related effects were observed, even though some rats
            may have consumed as much as 250 mg  DCM (36.6 mg/kg/day) during this

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Dichloromethane                                               March 31,  1987

                                     -5-
        experiment.  The urine albumin test was frequently positive;  however,
        the authors did not attach any biological significance to this obser-
        vation.  Prom this study, a NOAEL of 125 mgAg/day was identified.

      0  Hazelton Labs (1982) reported on the toxicity and carcinogenicity of
        DCM in a chronic two-year drinking water study in Fischer 344 rats.
        Two control groups (85 and 50 rats/sex/group) received deionized
        drinking water.  Four groups of animals (85 rats/sex/group) were
        given DCM in drinking water at target doses of 5, 50, 125 and 250
        mgAg/day.  A high-dose recovery group (25 rats/sex) was given DCM
        in drinking water at a target dose of 250 mgAg/day for the initial
        78 weeks and deionized drinking water subsequently for the remainder
        of the study.  At 26, 52 and 78 weeks of treatment, there were incre-
        mental sacrifices of 5, 10 or 20 rats/sex/group, respectively.  At
        104 weeks of exposure, all survivors were sacrificed.  Survival,
        body weight gains, total food consumption, water consumption, clinical
        observations; ophthalmoscopie findings, clinical pathology,  absolute
        and relative organ weights and gross and microscopic pathology were
        examined to evaluate any compound-related effects.  The dose  of
        5 mgAg was identified as the no-effect level based on the absence  of
        effects on body weight, hematological parameters and histopathological
        changes in the liver (incidence of foci/areas of cellular alteration
        and/or fatty changes).

Developmental Effects

      0  No positive conclusion can be drawn regarding the potential  for
        developmental effects of DCM.

      0  Maternal exposure of rats and mice to DCM (4337 mg/m3) on days 6
        through 15 of gestation was associated with soft tissue abnormalities
        in the offspring of rats and skeletal changes in the offspring of
        both rats and mice (Schwetz et al., 1975).

      0  Other workers have found no increased incidence of gross external,
        skeletal or soft tissue anomalies in offspring after maternal exposure
        of rats to DCM at 15,615 mg/m3 (6 hours/day, 7 days/wk) before and
        during gestation.  (Hardin and Manson, 1980).

Mutagenicity

      0  DCM has been reported to be mutagenic in several bacterial and yeast
        test systems, as well as in mammalian test systems.  DCM was  also
        reported to be positive in a mammalian transformation test (U.S. EPA,
        1985a).

garcinogenicity

      0  In a pulmonary tumor response assay, DCM administered intraperitoneally
        did not produce an increased incidence of lung tumors in mice (Theiss
        et al. 1977).

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   uicnj.orometnane                                               March  31,  1987

                                        -6-
           An inhalation bioassay conducted in male and female F344/N rats  and
           B6C3Fi mice indicated clear evidence of carcinogenicity in male  and
           female mice as shown by increased incidences of lung (alveolar/
           bronchiolar adenoma and/or carcinoma) and liver (hepatocellular
           adenoma and carcinoma combined) tumors (NTP, 1985,  as cited in U.S.
           EPA, 1985c).  Some evidence of carcinogenicity in male rats and
           sufficient or clear evidence of carcinogenicity in  female rats was
           indicated by an increased incidence of benign neoplasms of the mammary
           gland.  These animals were exposed at concentrations of 0, 1,000,
           2,000 and 4,000 ppm for rats and 0, 2,000 and 4,000 ppm for mice,
           6 hours/day, 5 days/week for 102 weeks.

           Hazelton Laboratories (1982) studied the carcinogenicity of DCM  in a
           chronic two-year drinking water study in Fischer 344 rats, using the
           protocol as described under longer-term exposure.  Hepatic histological
           alteration detected in the 50 to 250 mgAg/day dose groups (both
           sexes) included an increased incidence of foci/areas of cellular
           alteration.  Fatty liver changes were detected in the 125 and 250
           mgAg/day groups after 78 and 104 weeks of treatment.  The authors
           stated that DCM did not induce carcinogenicity under the conditions
           of the study.

           The U.S. EPA (1985b) performed an independent assessment of the  data
           from the Hazelton Laboratories (1982) study and determined that
           incidences of hepatic neoplastic nodules and carcinomas (combined
           in females exposed to 50 mgAg/day (4.8%), 250 mgAg/day (7.1%)  and
           250 mgAg/day,  recovery group (8.0%) were significantly (P<0.05)
           higher than that in matched controls (0%).  No significant increase
           in liver tumors was evident in any of the male dose groups.  The U.S.
           EPA (1985b) considered data on historical control values and concluded
           that the 250 mgAg/day dose was borderline for carcinogenicity in
           Fischer 344 rats.
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)  s 	   /L (	   „)
                        (UF) x (    L/day)
   where:
           NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                            in mgAg bw/day.

                       BW = assumed body  weight of a child (10 kg)  or
                            an adult (70  kg).

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Dichloromethane                                               March  31,  1987

                                     -7-
                    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

     The study by Kiraura et al. (1971) has been selected to serve as the
basis for the One-day HA for the 10 kg child because no other acute oral
studies of appropriate duration or  design were located in the literature.
This study identified a LOAEL in young adult Sprague-Dawley rats on the basis
of the first observable gross signs of toxicity (i.e., dyspnea,  ataxia,
cyanosis and/or coma) following administration of a single oral  dose of DCM
by gavage.  The authors implied that multiple dose levels were administered
to define dose-response, although details were not reported.   The calculations
for a One-day HA for a 10-kg child  are given below:

       One-day HA = 1'326 mg/kg/day) (10 kg) = 13.3 mg/L ('13,300 ug/L)
                       (1,000) (1 L/day)

where:

        1,326 mg/ko/day = LOAEL, based on the first observable gross signs of
                          toxicity  in rats.

                  10 kg = assumed body weight of  a child.

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

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

Ten-day Health Advisory

     The study by Bornmann and Loeser (1967) in which DCM was administered
in drinking water at 125 mg/L to Wistar rats for  13 weeks, has  been selected
to serve as the basis for. the Ten-day HA for the  10-kg child  because it was
the most comprehensive short-term oral toxicity study located.

     The Ten-day HA for a 10 kg child is calculated as follows:

          Ten-day HA = (15 mg/kg/day) (10 kg) . K5 mg/L (1 500 u /L)
                          (100)  (1  L/day)                       *'
where:
        15 mgAg/day = KOAEL, based on absence of effects on body weight gain,
                       blood and urine chemistries, reproductive function,
                       organ/body weight ratios,  or histopathological changes
                       in Wistar rats.

               10 kg = assumed body weight of a child.

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Dichloromethane                                              March  31,  1987

                                     -8-
                 100 = uncertainty factor,  chosen in accordance with  ODW/NAS
                       guidelines for use with a NOAEL from an animal study.

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

Longer-term Exposure

     There were no suitable data available from which to calculate  Longer-Term
Health Advisories.

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
(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.

     Dichloromethane may be classified in Group B2:  Probable Human Carcinogen,
according  to EPA's guidelines for assessment of carcinogenic risk  (U.S. EPA,
1986).  Because of this, caution must be exercised in making a decision on
how to deal with possible lifetime exposure to this substance.  The risk
manager must balance this assessment of carcinogenic potential against the
likelihood of occurrence of health effects related to non-carcinogenic end-
points of  toxicity.  In order to assist the risk manager in this process,
drinking water concentrations associated with estimated excess lifetime cancer
risks over the range of one in ten thousand to one in a million for the 70-kg
adult, drinking 2 liters of water per day, are provided in the following
section.   In addition,  in this section, a Drinking Water Equivalent Level
 (DWEL) is  derived.  A DWEL is defined as the medium-specific  (in this case,
drinking water) exposure which is interpreted to be protective for non-.
carcinogenic end-points of toxicity over a lifetime of exposure.  The DWEL
is determined for the 70-kg adult, ingesting 2 liters of water per day.  Also
provided is an estimate of the excess cancer risk that would result if exposure
were to occur at the DWEL over a lifetime.

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Dichloromethane                                               March 31,  1987

                                     -9-


     Neither the risk estimates nor the DWEL take relative source contribution
into account.  The risk manager should do this on a case-by-case basis,
considering the circumstances of the specific contamination incident that has
occurred.

     The study by Hazelton Laboratories (1982) is most appropriate from  which
to derive the DWEL because it is an oral chronic (two year) study that admini-
stered DCM in drinking water in multiple dose levels to rats.  This is the
most comprehensive chronic oral study available.  There were sufficient
numbers of animals in the dose groups and a dose-response was demonstrated.
A NOAEL of 5 mgAg/day was identified in this study.

     The DWEL for a 70-kg adult is calculated as follows:

Step 1:  Determination of the Reference Dose (RfD)

                     RfD = (5 mg/kg/day) a 0.05 mgAg/day


where:

        5 mg/kg/day = NOAEL based on the absence of liver and blood effects
                      in rats.

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

Step 2:  Determination of the Drinking Water Equivalent Level (DWEL)

           DWEL = (0.05 mg/kg/day) (70 kg) = U75 mg/L (1,750 ug/L) "
                         (2 L/day)

where:

        0.05 mgAg/day = RfD.

                 70 kg = assumed body weight of an adult.

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

Step 3:  Determination of the Lifetime Health Advisory

     Dichloromethane is classified in Group B2:  Probable Human Carcinogen.
A Lifetime HA has not been calculated for DCM.

     The estimated excess cancer risk associated with lifetime exposure to
drinking water containing DCM at 1,750 ug/L is approximately 3.7 x 10~4.
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 consid-
erable uncertainty as tc the accuracy of risks calculated by this methodology.

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    Dichlororaethane                                               March 31,  1987

                                         -10-


    Evaluation of Carcinogenic Potential

         0  IARC (1982) has classified DCM in group 3:  Limited evidence of
            carcinogenicity in animals.

         0  Applying the criteria described in EPA's guidelines for assessment of
            carcinogenic risk (U.S. EPA, 1986), DCM 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  More recently, EPA's CAG (U.S. EPA, 1985c)  estimated that the upper-
            bound incremental unit carcinogenic risk for drinking water containing
            1 ug/L DCM for a lifetime was 2.1 x 10-7 (ug/L)-1,.  This risk estimate
            was the mean of the derived carcinogenic risk estimates based on the
            finding of liver tumors (not based on lung tumors) in the NTP (1985)
            draft inhalation study in female mice and the suggestively positive
            finding of liver tumors in the Hazelton (1982) unpublished ingestion
            study in male mice.  Since the extrapolation model is linear at low
            doses,  additional lifetime cancer risk is directly proportional to
            the water concentration of DCM.  Thus, levels of 10"4, 10"5 and 10-6
            are 0.48, 0.048 and 0.005 mg/L, respectively.

         0  The linear multistage model is only one method of estimating carcino-
            genic risk.  Using the 1O"6 risk level, the following comparisons in
            micrograms/L may be made:   Multistage, 4.8; Probit, 74,000; Logit,
            4,000;  Weibull, 10.  Each model is based on differing assumptions.     ,
            No current understanding of the biological  mechanism of carcinogenesis
            is able to predict which of these models is more, accurate than another.
            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
            selection of one model over another.  In the interest of consistency
            of approach and in providing an upper bound on the potential cancer
            risk, the Agency has recommended use of the linearized multistage
            approach.


VI. OTHER CRITERIA,  GUIDANCE AND STANDARDS

         0  ACGIH (1984) has recommended a time-weighted average threshold limit
            value (TWA-TLV) of 100 ppm (   360 mg/m3) in the absence of occupa-
            tional  exposure to carbon monoxide and is based upon experimental
            data obtained from nonsmoking males at rest.  A short-term exposure
            level (STEL) of 500 ppm is also recommended.

         0  The Occupational Health and Safety Administration (OSHA, 1979) has
            established occupational exposure standards as follows:  an eight-hour
            time-weighted-average (TWA) of 1,737 mg/m3; an acceptable ceiling
            concentration of 3,474 mg/m3;  and an acceptable maximum peak above
            the ceiling of 6,948 mg/m3 (five minutes in any two hours).

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     Dichloromethane                                               March 31,  1987

                                          -11-
          0  Due to the metabolic formation of carboxyhemoglobin and the additive
             toxicity with carbon monoxide, the National Institute of Occupational
             Safety and Health (NIOSH, 1976) has recommended a ten-hour TWA exposure
             limit of 261 mg/m3 and a 1737 mg/m3 peak (15 minute sampling), in the
             presence of carbon monoxide concentrations less than or equal to 9.9
             ng/m3 (TWA).  Proportionately lower levels of DCM are required in the
             workplace when carbon monoxide concentrations greater than 9.9 mg/m3
             are present.

          0  Based on noncarcinogenic risks, a water quality criterion of 12.4 mg/L
             is the acceptable concentration of DCM in drinking water (U.S. EPA,
             1980a).  This calculation was performed by the U.S. EPA as part of the
             overall process for developing a U.S. EPA Water Quality Criteria for
             halomethanes as a group and uses a limit of 200 ppm (694 mg/m3) for
             protection against excessive carboxy-hemaglobin formation.  In that
             calculation, the EPA assumed that the average person consumes approxi-
             mately two liters of water and eats 6.5 g of contaminants in fish and
             seafood per day, and that the estimated coefficient of absorption via
             inhalation versus ingestion is 0.5.

          0  The original U.S. EPA Suggested-No-Adverse-Response-Levels (SNARLs,
             now referred to as Health Advisories) for DCM were set at 13, 1.5
           .  and 0.150 mg/L in drinking water for One-day, Ten-day and Longer-term
             exposures, respectively  (U.S. EPA, 1980b).  The U.S. EPA-SNARLs were
             established for a 10 kg body weight child and did not consider the
             possible carcinogenic risk that may result from exposure to a chemical.

          0  The NAS (1980) calculated one-day and seven-day NAS-SNARLs for DCM
             in drinking water based on the minimal-effect acute oral dose in rats
             reported by Kimura et al. (1971).  The NAS concluded that data on the
             no-effect dose do not exist.  Using the 1 ml/kg (1.3'g/kg) minimal-
             effect acute oral dose in the rat, assuming two liters/day of drinking
             water as the only source (consumed by a 70 kg adult) and*employing a
             safety factor of 1,000, the NAS (1980) calculated the one-day SNARL.
             Since no appropriate data were available for the seven-day SNARL, the
             one-day SNARL was divided by a factor of seven (days).  However, the
             NAS (1980) erroneously reported a value of 35 mg/L for the one-day
             and 5 mg/L for the seven-day calculation.  Re-examination of calcula-
             tions indicated that the one-day and seven-day adult NAS-SNARLs
             should be 45.5 mg/L and 6.5 mg/L, respectively.


VII. ANALYTICAL METHODS

          0  Analysis of DCM.is by a purge-and-trap gas chromatographic procedure
             used for the determination of volatile organohalides in drinking water
             (U.S. EPA, 1985d).  This method calls for the bubbling of an inert
             gas through the sample and trapping DCM on an adsorbant material.
             The adsorbant material is heated to drive off the DCM onto a gas
             chromatographic column.  This method is applicable to the measurement
             of DCM over a concentration range of less than 1 to 1500 ug/L; however,
             measurement of DCM at low concentrations is difficult due to problems
             with contamination.  Dichloromethane vapors readily penetrate tubing

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      Dichloromethane                                              March  31,  1987

                                           -12-

              during the purge/trap procedure.  Confirmatory  analysis  for  DCM  is
              by mass spectrometry.  (U.S.  EPA 1985e).   The detection  limit for
              confirmation by mass spectrometry is  0.3  ug/L.


VIII. TREATMENT TECHNOLOGIES

           0  Limited information is available concerning  the removal  of dichloro-
              methane from drinking water.   However/  evaluation of physical and
              chemical properties and some  experimental data  suggest that  adsorp-
              tion by granular activated carbon  (GAC) and  aeration are feasible
              technologies to remove this contaminant in drinking  water supplies.

           0  Dobbs and Cohen (1980) developed adsorption  isotherms for several
              organic chemicals,  including  DCM.  This study reported that  Filtrasorb*
              300 exhibited adsorptive capacities of  1.3 mg and 0.09 mg DCM per gm
              carbon at equilibrium concentrations  of 1,000 mg/L and 100 mg/L,
              respectively.

           0  Another study reported activated carbon usage of 3.9 lb/1,000 gal of
              treated water to maintain an  effluent DCM concentration  below 1  ug/L
              from a raw water influent concentration above 20 mg/L (ESE,  1982).
              This particular treatment scheme employed two activated  carbon columns
              operating in series with extremely long empty bed contact time (262
              minutes).

           0  The calculated Henry's Law constant for DCM  is  2.5 x 10-3 atm-m3/mole
              (ESE, 1982).  In a  bench-scale study, distilled water which  was
              spiked with 225 ug/L of DCM was passed  through  a diffused air aerator.
              The results showed  82 percent reduction in DCM  at an air-to-water
              ratio of 15:1 (Love,  1983).  Dichloronethane will, therefore,  be
              amenable to air stripping treatment.  Actual field performance data,
              however, have not been reported for this  compound.

           0  Air stripping is ah effective,  simple and relatively inexpensive
              process for removing DCM and  other volatile  organics from water.
              However, use of this process  then transfers  the contaminant  directly
              to the air stream.   When considering  use  of  air stripping as a treatment
              process, it is suggested that careful consideration  be given to  the
              overall environmental occurrence, fate, route of exposure and various
              hazards associated  with the chemical.

           0  Treatment technologies for the removal  of DCM from water have not
              been extensively evaluated except on  an experimental level.   Selection
              of individual or combinations of technologies to attempt DCM reduction
              must be based on a  case-by-case technical evaluation, and an assessment
              of the economics involved.

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    Dichloromethane                                               March 31, 1987

                                        -13-


IX. REFERENCES

    ACGIH.  1984.  American Conference of Governmental Industrial Mygienists.
         Documentation of  the  threshold limit values.  4th ed.   1980-1984 supplement.
         pp. 275-276.

    Aviado,  D.M.,  S. Zakhari and T. Hatanabe.  1977.  Methylene  chloride.  In;
         Non-fluorinated propellants and solvents for aerosols,  L. Goldberg, ed.,
         CRC Press, Inc.,  Cleveland, Ohio, pp. 19-45.

    Bonventre, J., 0.  Brennan,  D.  Jason, A. Henderson and M.L. Bastos.  1977.
         Two deaths following  accidental inhalation of dichloromethane and 1,1,1-
         trichloroethane.  J.  Anal. Toxicol.  1:158-160.

    Bornmann,  G.,  and  A. Loeser.   1967.  Zur Frage einer chronisch-toxischen
         Wirkung von Dichloromethan.  Z. Lebensm.-Unters. Forsch.  136:14-18.

    DiVincenzo,  G.D.,  and  M.L.  Hamilton.  1975.  Fate and disposition of carbon-14
         labelled  methylene chloride in the rat.  Toxicol. Appl. Pharmacol.  .
         32:385-393.

    Dobbs, R.A.,  and J.M.  Cohen.   1980.  Carbon adsorption isotherms for toxic
         organics.  EPA 600-8-80-023.  Office of Research and Development/ MERL,
         Wastewater Treatment  Division, Cincinnati, Ohio.

    ESE. 1982.  Environmental  Science and Engineering.  Review of organic con-
         taminants in  ODW  data  base for summary of all available treatment tech-
         niques,  compound  dichloromethane.  Prepared for U.S. EPA, Office of
         Drinking  Water, EPA-68-01-6494.

    Hardin,  B.D.,  and  J.M. Manson. 1980.  Absence of dichloromethane teratogenicity
        . with inhalation exposure  in rats.  Toxicol. Appl. Pharmacol.   52:22-28.

    Hazelton Laboratories  America, Inc.   1982.  National Coffee  Association
          (prepared for the twenty-four month chronic toxicity and oncogenicity  study
         of methylene  chloride in  rats).  Final Report, Vols. I-IV.  Vienna, Va.:
         2112-101.. August 11,  1982.

    lARCi  1982.   IARC monographs  on the evaluation of the carcinogenic risk of
         chemicals to  humans.   Supplement 4, Lyon, France.

    Kimura,  E.T.,  D.M. Ebert and P.W. Dodge.  1971.  Acute toxicity and limits  of
         solvent residue for sixteen organic solvents.  Toxicol. Appl.  Pharmacol.
         19:699-704.

    Love, O.T.,  Jr.   1983. Treatment of volatile organic compounds in  drinking
         water.  NTIS, U.S. Department of Commerce.

    McKenna, M.J.,  and J.A. Zempel.  1981.  The dose-dependent metabolism of
          [14C]methylene chloride following oral administration to rats.  Fd.
         Ccsmet.  Toxicol.  19:73-78.

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Dichloromethane                                               March  31,  1987

                                     -14-
NAS.  1980.  National Academy of Sciences.   Drinking Water and Health.
     Vol. 3.  National Academy Press,  Washington,  D.C.

NTP.  1985.  National Toxicology Program.   NTP technical report on the  toxicology
     and carcinogenesis studies of dichloromethane (methylene  chloride)
     in F344/N rats and B6C3F1 mice (inhalation studies) NTP TR 306.  Draft.
     Research Triangle Park, N.C.  94 pp.   As  cited in  U.S. EPA, 1985c.

NIOSH.  1976.  National Institute for Occupational Safety and  Health.  Criteria
     for a recommended standard.. .occupational exposure to methylene  chloride.
     U.S. Department of Health, Education and  Welfare (NIOSH).  Washington,
     D.C., pp. 1-3, 76-138, 142.

OSHA.  1979.  Occupational Safety and Health Administration.  General industry
     standards.  (OSHA) 2206, Revised January, 1978. U.S. Dept. of Labor,
     Washington,  D.C.

Schwetz, B.A., B.J. Leong and P.J. Gehring.  1975.  The effect of maternally
     inhaled trichloroethylene, perchloroethylene, methyl chloroform, and
     methylene chloride on embryonal and fetal development in  mice and rats.
     Toxicol. Appl. Pharmacol.  32:84-96.

Theiss,  J.C., G.D.  Stoner, M.B. Shimkin and  E.K. Weisberger.  1977. Test  for
     carcinogenicity of organic contaminants of United  States  drinking waters
     by pulmonary tumor response in Strain A mice.  Cancer Res.  37:2717-2720.

U.S. EPA.  1979.   U.S. Environmental Protection Agency.  Water Related  Environ-
     mental Fate  of 129 Priority Pollutants.  Office of Water  Planning and
     Standards.  EPA-440/4-79-029.

U.S. EPA.  1980a.  U.S. Environmental Protection Agency.  Ambient water
     quality criteria for halomethanes.  Office of Water Regulations and
     Standards.  Criteria and Standards Division.   Washington,  IX. C.
     EPA 440/5-80-051.

U.S. EPA.  1980b.  U.S. Environmental Protection Agency.  Advisory opinion
     for dichloromethane (methylene chloride)  (Draft).   Office of Drinking
     Water.  Washington, D.C.

U.S. EPA.  1980c.  U.S. Environmental Protection Agency.  Dichloromethane
     occurrence in drinking water, food, and air.   Office of Drinking Water.

U.S. EPA.  1985a.  U.S. Environmental Protection Agency.  Health assessment
     document for dichloromethane (methylene chloride).  Office of Health  and
     Environmental Assessment.  EPA-600/8-82/004F.

U.S. EPA.  1985b.  U.S. Environmental Protection Agency.  Health assessment
     document for dichloromethane (methylene chloride)  (Final  report). Office
     of Health and Environmental Assessment.  Washington, D.C.

U.S. EPA.  1985c.  U.S. Environmental Protection Agency.  Addendum to health
     assessment document for dichloromethane (methylene chloride.) (Final
     report). Office of Health and Environmental Assessment.  Washington, D.C.
     EPA 600/8-82-004FA.

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Dichloromethane                                            March  31,  1987

                                     -15-
U.S. EPA.  1985d.  U.S. Environmental Protection Agency.  Method 502.1.
     Volatile Halogenated Organic Compounds  in Water by  Purge  and Trap Gas
     Chromatography.  Environmental Monitoring and Support Laboratory,
     Cincinnati,  Ohio 45268.

U.S. EPA.  1985e.  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.

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

U.S. ITC.  1984.   United States International  Trade Commission.  Synthetic
     Organic Chemicals United States Production.  USITC  Publication  1422,
     Washington,  D.C. 20436.

Verschueren,  K.  1977.  Handbook.of Environmental Data on Organic Chemicals.
     2nd ed.  Van Nostrand Reinhold Company, NY.  pp. 451-452.

Windholz, M.  1983.  The Merck Index.  10th  Edition.  Merck and Co., Inc.,
     Rahway, NJ.   p. 869.

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    EPA 0596                                                *«* 31'  1987
    PX000027824
                                1,2-DICHLOROPROPANE

                                  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.

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     1,2-Dichlorpropane                                        .   March 31,  1987

                                          -2-
          This Health Advisory is based on Information presented in the Office
     of DriSJ^^Wa^ter's Health Effects Criteria Document (CD) for 1,2-Dichloro-
     propane 4p#S. (kPA, 1985a).  The HA and CD formats are similar for easy
     referenceTff 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, 5285 Port Royal Rd., Springfield,  VA 22161,  PB #86-117850/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.   78-87-5

     Structural Formula
                                       H Cl Cl
                                       Ml
                                      HC—C--C-H
                                       I   I   I
                                       H  H  H

     Synonyms

          0  Propylene dichloride,  1,2-DCP

     Uses

          0  1,2-Dichloropropane has been used as a solvent for oils and fats,
             dry cleaning and degreasing operations, and as a component of soil
             fumigants.

     Properties (U.S. EPA, 1985a)

             Chemical Formula                  C3H6Cl2
             Molecular Weight                  112.99
             Physical State (room temp)        colorless liquid
             Boiling Point                     96.8° C
             Vapor Pressure                    50 (mm Hg at 20° C)
             Specific Gravity                  1.15
             Water Solubility                  2,700 mg/L
             Log Octanol/Water Partition       2.28
               Coefficient
             Odor Threshold (air)              420 mg/m3

     Occurrence

          0  1,2-Dichloropropane (1,2-DCP) is a volatile synthetic compound with
             no natural sources.  The majcr release of 1,2-DCP to the environment
             will be from its use as a soil fumigant (U.S. EPA, 1983).

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      1,2-Dichlorpropane                                           March 31,  1987

                                           -3-
           0  1,2-DCP is expected to be a persistent and mobile compound in soil.
              The major route of removal of 1,2-DCP from soil and surface waters is
              by volatilization (U.S. EPA, 1979).   1,2-DCP has been shown to be
              stable in some soil for years (Roberts, 1976).  1,2-DCP has been shown
              to migrate in soil and has been reported as a contaminant in ground
              water (Cohen, 1983).  1,2-DCP is expected to be removed from surface
              water by volatilization.  1,2-DCP also has been shown to biodegrade
              in water over a number of weeks.  There is no available information  on
              1,2-DCP's potential for bioaccumulation.

           0  1,2-DCP has been identified as a contaminant of both ground and surface
              water.  1,2-DCP has been surveyed for in the Ground Water Supply Survey
              and has been found in approximately  1-2% of rural wells at levels
              around 1  ug/L.  Local monitoring has found levels as high as 1,200
              ug/L in shallow wells njsar sites where 1,2-DCP has been used as a soil
              fumigant (Cohen, 1983).'  1,2-DCP also has been reported in the Delaware
              river at levels of 20-30 ug/L (U.S.  EPA, 1983).  1,2-DCP has been
              identified as a contaminant in fish.  1,2-DCP also has been reported
              in urban air at low levels, approximately 100 ppt.  The available
              data are insufficient to show whether drinking water is the major
              route of exposure for 1,2-DCP.


III.  PHARMACOKINETICS

      Absorption

           0  The results of various studies suggest that the absorption of 1,2-DCP
              is approximately 90 percent of the orally administered dose (Hutson
              et al., 1971).

      Distribution

           0  Although no specific data were located which quantified the distribu-
              tion of 1,2-DCP in animals, approximately 0.5% of a radioactive dose
              was recovered from the gut of animals within 96 hours, 1 .6% was
              recovered from skin and 3.6% was detected in the carcass (Hutson
              et al., 1971).

      Metabolism

           0  The metabolic end products of 1,2-DCP are predominantly N-acetyl-S-
              (2-hydroxypropyl) cysteine and B-chloroacetate (Jones and Gibson,
              1980).
      Excretion
              1,2-DCP was eliminated rapidly by rats dosed orally with 4 mgAg (Hutson
              et al., 1971).  Approximately 80% to 90% of the radioactivity was
              excreted in thi. urine,  feces and expired air of rats following dosing.
              Urinary and fecal excretion accounted for 53% and 6%, respectively,
              of the radioactivity recovered in the expired air of rats as  carbon
              dioxide; 23% was recovered as other volatile radioactivity.

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                                              -4-
IV.  HEALTH EFFECTS
     Humans
             Data on the toxicity of this compound to humans are limited to a
             single case of acute poisoning, reported only as an abstract (Larcan
             et al., 1977).  Centro- and mediolobular hepatic necrosis were observed
             in a man who died 36 hours after ingesting approximately 50 ml of
             a cleansing substance.  The toxic material was found to contain 1,2-DCP,
             but it is unclear whether it contained other compounds as well.
     Animals

     Short-term Exposure
                                                   \
            . The acute LD5o values for 1,2-dichloropropane  are  given .below:

             Route          Species     LDe;n Value       Reference

             Inhalation     Rat         9224 mg/m3       Smyth  et al.  (1969)
             Oral           Rat         2200 mgAg       Smyth  et al.  (1969)
                            Rat         2200 mgAg       Ekshtat et al.  (1975)
             Dermal         Rabbit      10,200 mgAg     Smyth  et al.  (1969)

             The acute toxicity of 1,2-DCP was determined following single oral
             administration to fasted dogs of unspecified age and sex  (Wright and
             Schaffer,  1932).   Doses  of approximately  250 to 350 mgAg in  the dogs
             produced gastrointestinal irritation without any histologic changes
             in the kidney. A dose of 580 mgAg  produced swelling  of the  epithelial
             cells of the  kidney tubules  and fatty infiltration in  the convoluted
             tubules.  At  an approximate  dose of  5800  mgAg* there  was a lack
             of coordination and partial  narcosis followed  by death in one dog.
             Necropsy revealed congestion in the  lungs, kidney,  and bladder,
             hemorrhage in the stomach and respiratory tract, and fatty  degeneration
             of the liver  and  kidneys.

             Heppel et al.  (1946)  reported no apparent signs of toxicity following
             single 7-hour  inhalation exposures to 6900 mg/m^ in rats, rabbits  and
             guinea pigs.

             Inhalation exposure for  1  hour at 10,400  mg/m3 showed  evidence of
             slight visceral congestion,  fatty liver and  kidneys, liver  glycogen
             storage and marked necrosis  of the adrenals  (Heppel et al., 1946).

             Drew et al. (1978) measured  SCOT,  SGPT, glucose-6-phosphatase and
             ornithine carbamyl transferase enzymes  in the  serum of male rats
             following a single 4-hour inhalation exposure  to 1,2-DCP at a concen-
             tration of 4620 mg/m3.   A significant increase in  enzyme activities
             was observed for  SCOT, SGPT  and ornithine carbamyl transferase at
             24 and 48 hours.

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1 , 2-Dicloropropane                                           March' 31,  1967

                                     -5-


Longer-term Exposure

     8  Heppel et al.,  (1948) reported the results of multiple inhalation
        exposures to 1,2-DCP by rats, mice, guinea pigs and rabbits to daily
        7-hour exposure periods in the concentration range of 4400 mg/m3 to
        10,400 mg/m3.  The concentration of 10,400 mg/m3 produced lethality in
        over 50 percent of the animals.  Gross and histopathological findings
        included liver abnormalities such as visceral congestion, fatty
        degeneration, extensive coagulation and necrosis in multilobular
        areas.  Renal tubular necrosis and fibrosis, splenic hemosiderosis,
        pulmonary congestion, bronchitis,  pneumonia and fatty degeneration of
        the heart were observed among animals exposed to all concentrations.

     0  The effects, of  1 , 2-DCP on the functional state of the liver in rats
        has been studied by Kurysheva and Ekshtat (1975).  The groups of
        animals were given daily oral doses of 1,2-DCP at 14.5 mgAg or
        360 mgAg for 30 days. t Levels of serum cholesterol,  betalipoprotein
        and gamma globulin increased after the 10th day following the daily
        administration of both doses.  By the 20th day of dosing, serum
        cholinesterase activity was inhibited, whereas the fructose-1 -mono-
        phosphate aldolase,  SGPT and SCOT activities were increased; after
        30 days of dosing, only SGPT activity was inhibited.

     0  Ekshtat et al., (1975) orally administered 1,2-DCP to rats at daily
        doses of 8.8, 44 or 220 mgAg for 20 days.  The animals were reported
        to have had disturbances in protein formation and hepatic enzyme and
        lipid metabolism.

     0  NTP (1983) dosed groups of female F344 rats and B6C3F1  male and
        female mice with 1,2-DCP (0, 125 or 250 mg/kg/day) in corn oil by
        gavage (5 days/week) for about 2 years (103 -weeks).  Groups of male
        Fischer 344 rats were administered 1,2-DCP at 0, 62 or 125 mg/kg/day
        in the same manner.  Observations included survival, body weight,
        overt signs of  toxicity and gross and histological appearance of a
        wide range of organs and tissues.  In rats, survival was decreased
        only among the  females of the 250 mgAg group.  An increased incidence
        of liver lesions (focal and centrilobular necrosis ) and decreased
        mean body weight also were observed in this group.  At the 125 mgAg
        dose level, survival among rats was unaffected, but males had decreased
        mean body weights and females had increased incidences of mammary
        gland hyperplasia.  No effects were observed in male rats given
        62
        In mice (NTP,  1983),  there was a decrease in survival rates among
        females receiving both 125 and 250 mgAg 1,2-DCP.   This  was attributed,
        in part, to an increased incidence of severe infections  of the
        respiratory tract for both low- and high -dose groups. The only other
        non-neoplastic effects in mice were increased incidences of liver
        lesions (hepatomegaly and focal and centrilobular  necrosis) in males
        receiving 125  or 250  mgAg«

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                                                                iviarcn

                                        -6-
   Mutaqenicity
        0  A positive dose-related mutagenic response at concentrations of 10,
           20 or 50 mg/plate 1,2-DCP was observed in Salmonella typhimurium
           strains TA 1535 and TA 100 (DeLorenzo et al., 1977).  No increase
           in mutagenicity was seen following the addition of the S-9 liver
           microsomal fraction.

   Carcinogenicity

        0  The NTP (1983) chronic gavage study (discussed under longer-term
           exposure) is the only adequately designed carcinogenicity study
           available.  The results show that 1,2-DCP may be carcinogenic for
           mice as indicated by dose-related increased incidences of hepato-
           cellular adenomas in male and female mice.  The incidences of
         •  hepatocellular carcinomas were increased (not significantly) in males
           and in females.  Evidence of carcinogenicity in rats was equivocal.


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) = _   «  ( _   /L)
                        (OF) x ( _ L/day)           *'         y
   where:
           NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                            in mg/kg bw/day.

                       BW = assumed body weight of  a child  (10 kg)  or
                            an adult (70 kg).

                       UF as 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

        There are insufficient toxicological data  available  in  the published
   scientific literature to derive  a One-day HA.

   Ten-day Health Advisory

        Three studies in animals  have been considered  for use in  the calculation
   of a Ten-day HA;  these are Kurysheva and Ikshtat (1975);  Ekshtat et  al.  (1975);

-------
 1,2-Dichloropropane                                          March_31, 1987

                                     -7-
and NTP  (1983).  However, these studies lack some relevant toxicological data
necessary for use in this calculation.  Kurysheva and Ekshtat (1975) reported
the effect of 1,2-DCP on the functional state of the liver of rats.  The
groups of animals were given daily doses of 1,2-DCP at 14.5 mg or 360 mgAg
orally for 30 days.  Increases in the serum levels of cholesterol, lipoprotein,
and gamma-globulin were noted after the tenth day following the daily dosing.
By day 20 of dosing, serum cholinesterase was inhibited, whereas fructose-1-
monophosphate aldolase, SGPT and SCOT enzyme activities were increased; after
30 days  of dosing, only SGPT was inhibited.  Other information such as strain,
number of animals, weight and age, as well as which doses caused what effects
were not reported.

     The study by Ekshtat et al. (1975) is selected as the basis for the
Ten-day  HA.  TJie authors reported the results of orally administered 1,2-DCP
at dose  levels'of 8.8, 44 or 220 mgAg for 20 days.  The investigators observed
disturbances in the animals' protein formation, hepatic enzyme levels and
lipid metabolism.  The NAS (1979) in a request from the Office of Drinking
Water provided a 7-day Suggested-No-Adverse-Response-Level (SNARL) for 1,2-DCP
based on the Ekshtat et al. (1975) study in rats.  The following formula was
used to derive a 7-day level for a 70 kg adult consuming 2 liters water/day.
The NAS SNARL can be used as an interim Ten-day HA as well.  The HA is derived
as follows:

     For a 10 kg child, the level of 1,2-DCP would be:

        Ten-day HA = (8.8 mg/kg/day) (10 kg) = 0.088 mg/L = 0.090 mg/L
                        (1,000) (1 L/day)
                                                               or 90 ug/L
where:
        8.8 mg/kg/day = minimal effect level from the subacute ingestion
                        studies in rats.

                10 kg = assumed weight of a child.

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

              1 L/day = assumed water consumption by a child.
Longer-term Health Advisory

     There are no satisfactory toxicological data available from which to
calculate a Longer-term Health Advisory.
Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's cotal exposure
that is attributed to drinking water and is considered protective of

-------
                                     -8-
noncarcinogenic adverse health effects over a lifetime exposure.  The Life-
time 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
estimate 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 (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 classifica-
tion scheme of carcinogenic potential (U.S. EPA, 1986), then caution should
be exercised in assessing the risks associated with lifetime exposure to this
chemical.

     Only one chronic ingestion study (NTP,  1983) has been carried out for
1,2-DCP.  This study was designed primarily to. investigate carcinogenic
effects.  This study may provide some data on non-carcinogenic effects which
may be considered for a Lifetime HA in absence of other chronic animal studies.
However, it should be noted that the NTP (1983) study is recently audited and
there are some changes as a result of this audit.  These changes are being
evaluated before its consideration for a Lifetime HA for 1,2-DCP.

Evaluation of Carcinogenic Potential

     0  The dose-response data for hepatocellular adenoma and carcinoma in
        B6C2F1 mice (NTP, 1983) are used for a quantitative assessment of
        cancer risk from exposeure to 1,2-DCP.  Based on these data and using
        a linearized multistage model, a carcinogenic potency factor (q-|*) for
        humans of 6.33 x 10~2 (mg/kg/day)"1  was calculated from the data for
        male mice and a q.j* of 2.25 x 10~2 (mg/kg/day)~1 was calculated from
        the data for female mice.  The higher of the two values is the appropriate
        basis for the estimation of cancer risk levels.  The doses corresponding
        to increased lifetime excess cancer risks for a 70 kg human of 10~4,
        10-5 and 10-6 are 1.11 x 10-1, 1.11  x 10-2 and 1.11 x 10-3 mg/day,
        respectively.  Assuming a water consumption level of 2 liters per day,
        the corresponding concentrations of 1,2-DCP in drinking water at 5.6 x
        10-2, 5.6 x 10"3 and 5.6 x 10"4 mg/L,' respectively.  However,  it should
        be noted that these risk assessments for 1,2-DCP are based on the
        results of a carcinogenicity bioassay in animals reported in the NTP
        (1983) draft report.  An audit has been completed and minor changes
        noted in the audit will be incorporated in the near future.

     0  Cancer risk estimates (95% upper limit) with other models are presented
        for comparison with that derived with the multistage.  For example,
        one excess cancer per 1,000,000 (10-6) is associated with exposure to

-------
      1,2-DIchloropropane                                          March 31, 1987

                                           -9-


             . 1,2-DCP in drinking water at levels of 0.5 mg/L (Probit), 0.002 mg/L
              (Logit), and 0.0002 mg/L (Weibull).

           0  IARC has not assessed 1,2-DCP for its carcinogenic potential.

           °  Applying the criteria described in EPA's guidelines for assessment of
              carcinogenic risk (U.S. EPA, 1986), 1,2-DCP is classified in Group C:
              Possible human carcinogen.  This category is for agents with limited
              evidence of carcinogenicity in animals in the absence of human data.
              (However, the Carcinogen Assessment Group upgraded the classification
              of 1,2-DCP (to Group B2) on February 26, 1987.  The final decision
              be incorporated in the near future.


  VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

           0  The ACGIH (1983) has adopted a TLV of 75 ppm ( 350 mg/m^) and STEL of
              110 ppm { 500 mg/m3) for 1,2-DCP in workroom air.   The TLV
              represents A TWA concentration for an 8-hour day or 40-hour workweek.
              The TLV and STEL are based primarily on the data of Heppel et al.
              (1946, 1948).

           0  The U.S. EPA (1980)  concluded that data regarding the toxicity of
              1,2-DCP were insufficient for the derivation of an ambient water
              quality criterion for the protection of human health.


 VII. ANALYTICAL METHODS

           0  Analysis of 1,2-DCP  is by a purge-and-trap gas chromatographic procedure
              used' for the determination of volatile organohalides in drinking water
              (U.S. EPA,  1985b).  This method calls for the bubbling of an inert
              gas through the sample and trapping 1,2-DCP on an adsorbant material.
              The adsorbant ./material is heated to drive off the 1,2-DCP onto a gas
              chromatographic column.  The applicable concentration range for this
              method has not been  determined.  Confirmatory analysis for 1,2-DCP
              is by mass spectrometry (U.S. EPA, 1985).  The detection limit for
              confirmation by mass spectrometry is 0.2 ug/L.


VIII. TREATMENT TECHNOLOGIES

           0  Treatment technologies which have been shown to be effective in
              removing 1,2-DCP from drinking water are adsorption on granular
              activated carbon (GAG) and ion exchange.   Other methods which are
              expected to be effective for removal of 1,2-DCP from water are air
              stripping and boiling.

           0   Granular activated carbon (GAC)  and powdered activated carbon (PAC)
              have been tested for their effectiveness in removing 1,2-dichloropro-
              pane.  Dobbs  and Cohen (1980) developed adsorption isotherms for DCP.
              They reported that Filtrasorb® 300 carbon exhibited adsorption capa-
              cities of 5.9 mg of  DCP per gram of carbon at equilibrium concentration

-------
1,2-Dichloropropahe                                         March  31,  1987

                                     -10-
        of 1.0 mg/L and 1.5 mg of DCP per gram of carbon at equilibrium
        concentration of 0.1  mg/L.

        Isotherm studies using Filtrasorb* 400 carbon  reported  carbon loadings
        of 240 mg DCP/gm of carbon and 480 mg  DCP/gm of  carbon  at  equilibrium
        concentrations of 100 mg/L and 1,000 mg/L,  respectively.   No  usage  or
        loading rates were available (U.S. EPA, 1985d).

        Removal of DCP by air stripping is expected to be effective.   Several
        methods of air stripping have been tested.  Air  stripping  in  a column
        packed with 1/4" Ceramic Intalox Saddle,  proved  to  be effective in
        removing chloroform with a Henry's Law Constant  of  3.4  x 10~3 atm-m3/
        mole and 1,2-dichloroethane with a Henry's  Law Constant of 1.1  x 10-3
        atm-m3/mole.   Although no actual performance data have  been provided
        for removing DCP by this treatment system,  its Henry's  Law Constant of
        2 x 1*0~3 atm-m3/mole  is an indication  that  this  chemical is amenable  to
        air stripping (Love & Eilers,  1982;  Singley and  Bilello, 1981;  McCarty
        and Sutherland, 1979).

-------
    1,2-Dichloropropane                                         March-31,  1987

                                         -11-
IX. REFERENCES

    ACGIH.   1983.   American Conference  of Governmental  Industrial Hygienists.
         Threshold limit values  for chemical  substances and physical  agents in
         the work  environment with  intended changes  for 1983-1984.  Cincinnati,
         OH.  p. 30.

    Cohen,  D.B., D. Gilmore,  C.  Fischer and G.W.  Bowes.   1983.   1,2-Dichloropropane
         and 1,3-dichloropropane.   Prepared for State of California,  Water Resources
         Control Board,  Sacramento,  CA.

    DeLorenzo, F., S.  Degl'Innocenti, A. Ruocco,  L.  Silengo and  R. Cortese.
         1977.  Mutagenicity of  pesticides containing 1,3-dichloropropane.
         Cancer Res.   37:1915-1917.

    Dobbs,  R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms  for toxic
         organics. U.S. EPA,  Contract  No. EPA-600/8-80-023.

    Drew, R.T., J.M. Patel and F.N. Lin.  1978.  Changes in serum enzymes in rats
         after inhalation of organic solvents singly and in combination.  Toxicol.
         Appl. Pharmacol.  45:809-819.

    Ekshtat, B. Ya., N.G. Kurysheva,  V.N.  Fedyanina  and M.N. Pavlenko.  1975.
         Study of  the  cumulative properties of substances at different  levels of
         activity. Uch. Zap.-Mosk. Nauchno-Issled.  Inst. Gig..   22:46-48.

    Heppel, L.A.,  P.A. Neal,  B.  Highman and V.T.  Potterfield.  1946.  Toxicology
         of 1,2-dichloropropane. I.  Studies on  effects of daily inhalations.
         J. Ind. Hyg.  Toxicol.  28:1-8.

    Heppel, L.A.,  B. Highman and E.Y. Peake.   1948.  Toxicology  of 1,2-dichloro-
         propane.   IV.  Effects  of  repeated exposures to a low concentration of
         the vapor. J. Ind. Hyg. Toxicol.  30:189-191.

    Hutson, D.H.,  J.A. Moss and  B.A. Pickering.  1971.   Excretion and retention
         of components of the soil  fumigant D-D and  their metabolites in the rat.
         Food Cosmet.  Toxicol,  9(5):677-680.

    Hwang,  S.T., and P. Fahrenthold.  1980.   Treatability of the organic priority
         pollutants by steam stripping. The  American Institute  of Chemical
         Engineers.

    Jones,  A.R., and J.  Gibson.  1980.   1,2-Dichloropropane:  Metabolism and fate
         in the rat.   Xenobiotica.   10:835-846.

    Kurysheva, N.G., and B.Y.  Ekshtat.   1975.  Effect of 1,3-dichloropropylene
         and 1,2-dichloropropane on the functional state of the  liver in animal
         experiments.   Uch. Zap.-Mosk.  Nauchno-Issled.  Inst. Gig.  22:89-92.
         (CA 86:115725).

    Larcan, A., H. Lambert, M.C. Kaprevok  and B.  Gustin. 1977.  Acute  poisoning
         induced by dichloropropane.  Acta. Pharmacol.  Toxicol.  . 41:330.   (Abstr.)

-------
 i,^-uichloropropane                                      •    March 31,  1987

                                     -12-
Love, O.T., Jr., and R.G. Eilers.  1982.  Treatment of drinking water containirJ
     trichloroethylene and related industrial solvents.  AWWA.                ™

McCarty, P.L., and K.H. Sutherland.  1979.  Volatile organic contaminants
     removal by air stripping.  Paper presented at the Seminar on Controlling
     Organics in Drinking Water,  American Water Works Annual Conference,  San
     Francisco, CA.

NAS.  1979.  National Academy of  Sciences.  Emergency Response Report on  1,2-
     Dichloropropane.

NTP.  1983.  National Toxicology  Program.  NTP technical report on the carcino-
     genicity bioassay of 1,2-dichloropropane (CAS No. 78-87-5) in F344/N
     rats and B6C3Ft mice (gavage study).  May.  NIH Publ. No. 83-2519.  Draft.
     Final Technical Report in Preparation (Management Status Report,  6/10/86).

Perry, R.H., and C.H. Chilton.  1973.  Chemical Engineers Handbook, 5th
     edition, McGraw Hill Book Company,  New York.

Roberts, T.R., and G. Stoydin.  Degradation of (Z) and (E) 1,3-Dichloropropane
    and 1,2-dichloropropane in soil.   Pestic. Sci.  7:325-335.

Singley, J.E., and L.J. Bilello.   1981.   Advances in the development of design
     criteria for packed column aeration.  Environmental Science and Engi-
     neering, Inc.

Smyth, H.F., Jr., C.P. Carpenter,  C.S. Weil,  U.C. Pozzani,  J.A. Striegel  and
     J.S. Nycum.  1969.  Ranges-finding toxicity data, VII.  Am. Ind. Hyg.
     Assoc. J.  30(5):470-476.

U.S. EPA.  1979.  U.S. Environmental  Protection Agency.   Water related environ-
     mental fate of 129 Office of Water  Planning and Standards.  EPA-440/4-79-
     -029.

U.S. EPA.  1980.  U.S. Environmental  Protection Agency.   Ambient water quality
     criteria for dichloropropanes/ propenes.  Environmental  Criteria  and
     Assessment Office, Cincinnati, OH.   EPA 440/5-80-043.  NTIS PB81-117541.

U.S. EPA.  1983.  U.S. Environmental  Protection Agency.   Philadelphia  Geographic
     Area Multimedia Pollutant Survey, Integrated Environmental Management
     Division.  Washington,  DC.

U.S. EPA.  1985a.  U.S. Environmental Protection Agency.   Draft drinking
     water  criteria document  for  1,2-dichloropropane.  Office of Drinking
     Water.

U.S. EPA.  1985b.  U.S. Environmental Protection Agency.   Method 502.1,
     Volatile halogenated organic compounds in water by  purge and trap gas
     chromatography.  Environmental Monitoring and Support Laboratory,  Cin-
     cinnati, OH. 45268.

-------
1,2-Dichloropropane                                         _March 31,  1987

                                     -13-
U.S. EPA.  1985c.  U.S. Environmental Protection Agency.  Method 524.1,
     Volatile organic compounds in water by purge and trap gas chromato-
     graphy/mass spectrometry.  Environmental Monitoring and Support Labora-
     tory, Cincinnati, OH. 45268.

U.S. EPA.  1985d.  U.S. Environmental Protection Agency.  Treatment techniques
     available for removal of 1,2-dichloropropane. (Draft) Science and
     Technology Branch, Criteria and Standards Division, Office of Drinking
     Water.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.   Guidelines for
     carcinogenic risk assessment.  Federal Register.  51(185):33992-34Q03.
     September 24.

Wright, W.H., and J.M. Schaffer.  1932.  Critical antihelminthic tests of
     chlorinated alkyl hydrocarbons and a correlation between the antihel-
     minthic chemical structure and physical properties.  Am. J. Hyg.
     16:325-428.

-------
                                                          September 30,  1985
     EPA 0596
     RX000027824
                                     LEAD

                               Health Advisory
                           Office of Drinking Water
                     U.S. Environmental Protection Agency


     The Office of Drinking Water's non-regulatory Health Advisory Program

provides information on health effects, analytical methodology and treatment

technology that would be useful in dealing with contamination of drinking

water.  Health Advisories also describe concentrations of contaminants in

drinking water at which adverse effects would not be anticipated to occur.

A margin of safety is included to protect sensitive members of the population.

     Health Advisories are not legally enforceable Federal standards.  They

are subject to change as new and better information becomes available.  The

Advisories are offered as technical guidance to assist Federal, State and >
-------
    Lead                                                          September 30, 1985

                                         -2-

                                                                     e,l~;*i  A  ..-»<•"/«
                                                                     id.o.n|',^he' i

    Office of HM*arch and Development's Air Quality Criteria for Lead  (U.S.  EPA

    1984a) and^^e. Office of Drinking Water's Quantification of Toxicological

    Effects (QTE) (U.S. EPA, 1985).  Individuals desiring further information on

    the toxicological data base or rationale for risk characterization  should

    consult the QTE.  The QTE 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, 5285 Port Royal Rd., Springfield, VA 22161,

    PB #_, $	.  The toll free number is (800) 336-4700; in  Washington,

    D.C.  area:  (703) 437-4650.


II. GENERAL INFORMATION AND PROPERTIES


    Synonyms

            Plumbum


    Uses

            Lead is used in the production of storage batteries , gasoline antiknock

            additives, pigments and ceramics, ammunition, solder, cable coverings,

            caulking lead, pipe and sheet lead, type metal, brass and bronze, and

            bearing metals.


    Properties

            CAS #                             7439-92-1
            Molecular Weight                  82
            Oxidation States                  +2, +4
            Density                           11.35 g/cm3 at 20 C
            Melting Point           .          327.5°C
            Boiling Point                     1740°C

-------
     Lead                                                          September 30,  1985




                                          -3-






     Occurrence




                  Ls a relatively rare metal which occurs in the earth's crust
             at§j» average concentration of 15 ppm.  Lead is ubiquitous in the




             environment and occurs at low levels in most ground and surface




             waters.  While lead and its compounds are used in a number of




             industrial processes, contamination of drinking water supplies is the




             result of naturally-occurring mineral deposits.  Lead also can enter




             drinking water supplies as a result of the corrosion of lead pipe




             and lead-containing solder.




          0  Available data on the occurrence of lead in water supplies are




             limited.  Based upon EPA surveys, most water supplies are believed




             to contain less than 20 ug/L.  Currently, 59 ground water supplies-J




             and 7 surface water supplies exceed the maximum contaminant level •




             (MCL) of 50 ug/L.  The  major sources of lead exposure are from




             food, where it occurs at low levels, and drinking water.  Where




             drinking water exceeds 20-30 ug/L, it is the major source of lead




             exposure.







III. PHARMACOKINETICS




     Absorption




          0  Based on long-term metabolic studies with adult human volunteers,




             Kahoe (1961a,b,c) estimated that approximately 10% of dietary lead is




             absorbed from the human gut.




          0  Heard and Chamberlain (1982) calculated a rate of 63.3% absorption by




             humans after a fasting period.  Isotope studies such as this support




             the observations of Garber and Wei (1974) and Baltrop and Khoo (1975)




             that lead in beverages consumed between meals is absorbed to a greater




             extent than is lead from food.

-------
Lead                                                          September 30,  1985


                                     -4-
Distribution                                                	    	
                                                                     i a

            "rthan 99% of blood lead in humans is associated, with the_ erythro-^

           •'>•'•
        cif£jiaT under typical conditions, but it is the very small fraction of


        lead transported in plasma and extracellular fluid that provides


        lead to various body organs (Baloh, 1974; DeSilva, 1981).


     0  Whole blood lead in daily equilibrium with other compartments was


        found to have a mean life of 35 days (25-day half-life)  and an approxi-


        mate total content of 1.9 mg in humans (Rabinowitz et al., 1976).


        Chamberlain et al. (1978) established a similar half-life for 203Pb


        in blood when volunteers were given the labeled lead by ingestion,


        inhalation or injection.


     0  Alterations in blood lead levels in response to abrupt changes in J


        exposure apparently occur over somewhat different periods, depending


        on whether the direction of change is greater or smaller. With


        increased lead intake, the blood lead level achieves a new value in


        approximately 60 days (Tola et al., 1973; Griffin et al., 1975).  A


        decrease may involve a'longer period of time depending on the magnitude


        of the past higher exposure (Rabinowitz et al., 1977; Gross, 1981,


        0'Flaherty et al., 1982).


     0  There is an equilibrium between blood content in red blood cells and


        plasma, such that the levels in the plasma rise with levels in whole


        blood.


     0  The relative percentage of blood lead in plasma versus red blood


        cells is constant up to a blood lead level of about 50 to 60 ug/dL,


        but becomes increasingly greater above this level.

-------
    Lead                                                          September 30,  1985


                                         -5-
    Metabolism


                 Cen, particularly infants, retain a significantly higher amount


                 id than do adults [35 vs. 3.5 fold] (Barry, 1981).


         0  Lead crosses the placenta beginning in the twelfth week of life and


            continues until birth (Baltrop and Khoo, 1975).


    Excretion



         0  In adults, approximately 90 percent of ingested lead is eliminated in


            the feces without prior gastrointestinal absorption (Kehoe 1961 a;


            Wetherill et al., 1973).


         0  The primary elimination route for lead is urine, representing about 95


            percent of the total output of absorbed lead (Rabinowitz et al., 1973),
                                                                              .1

         0  Lead is excreted by the kidneys into the urine, by both glomerular-


            filtration and transtubular flow (Goyer and Mahaffey 1972).


         0  Renal effects of lead may compound lead toxicity by interfering with


            urinary lead excretion.



IV. HEALTH EFFECTS


    Humans
    Short-term Exposure


         0  Short-term or acute exposures to lead through drinking water of ten


            days or less do not have any adverse effects (U.S. EPA, 1984a).


         0  The health effects resulting from lead exposure become manifest only


            after the blood lead level exceeds 15 ug/dL.  It takes a minimum of


            35 days to achieve that blood lead level and some unspecified time


            after that to express the effect.

-------
Lead                                                          September 30,  1985




                                     -6-
                                                               "
Longer-TerafegBd Chronic Effects




     0  Ca^lgSjlJation of health advisory values for lead requires several




        changes in the normal approach used for other Health Advisories or




        RMCLs/MCLs.  This is because most studies in humans evaluate the




        degree of lead exposure by measuring the concentration of lead in the




        blood (PbB) rather than by measuring ingestion.  This requires that




        the NOAEL be described first in terms of a PbB, and then an oral




        exposure which produces that PbB must be calculated.




     0  Lead interacts adversely with several key enzymes involved in heme




        biosynthesis , i.e., delta-aminolevulinic acid dehydratase (ALA-D),




        ferrochetalase and delta-aminolevulinic acid synthetase.  The PbB  ;




        that will inhibit ALA-D is as low as 12 ug/deciliter in adults (Secchi




        et al., 1974).  Ferrochetalase inhibition produces measurable zinc




        protoporphyrin (ZPP) after a lag of several weeks; ZPP will persist




        long after the termination of exposure to lead.  In children, the




        threshold for ZPP accumulation is between 15.5 and 1.5 ug/dL




        (Roels et al., 1976;   Piomelli et al., 1976).




     0  Lead also causes decreased red blood cell survival.  Inhibition of




        pyrimidine-5-nucleotidase (Py-5-N) occurs as a result of lead exposure




        and decreases RBC survival by increasing membrane fragility (Angle




        and Mclntire, 1978).  Py-5-N inhibition occurs in children; no




        threshold level has been determined.




     0  Renal 1-hydroxylase mediates the final step in the synthesis of the




        biologically active form of Vitamin D.  Lead inhibits this enzyme at




        a PbB level of 12 ug/dL (Mahaffey, 1982).  Active Vitamin D is required

-------
Lead                                                         .September 30,  1985




                                     -7-                     ff°*< .T~
        f jg;-j|jMnnal intestinal calcium absorption.   Vitamin D promotes differ-




                  of myeloid stem cells into macrophages;  receptors for




        Vitamin D have been found in monocytes and lymphocytes.   Thus,  active




        Vitamin D appears to have functions involving cell differentiation




        and immunoregulatory capacity.




     0   Harlan et al. (1985) and Pirkle et al. (1985) examined the relation-




        ship between PbB levels and blood pressure by statistical analysis




        of the data base obtained during the National Health and Nutrition




        Examination Survey (NHANES-II).  They showed that PbB levels in




        normotensive persons were significantly lower than in hypertensives.




     0   Pirkle et al.  (1985),  using segmented regression analyses, indicaJ^ed




        that there was no threshold below which blood pressure was not related




        to PbB.  In addition, the authors calculated that the 37% decrease in




        average PbB in the white adult population  from 16.7 to 10.5 ug/dL




        which occurred in the United States between 1976 and 1980 will result




        in 77,300 fewer myocardial infarctions and 27,500 fewer strokes over




        a ten year period.




     0   Considerable evidence exists that peripheral nerve dysfunction occurs




        in adults at PbB levels as low as 30 to 50 ug/dL (Seppalainen and




        Hernberg, 1980,1982).




     0   Children's nervous systems appear to be more sensitive to lead than




        those of adults.  There is a significant linear relationship between




        PbB and slow wave (SW)  voltage beginning with a PbB of 7 ug/dL (Otto




        et al., 1981).  EEC gain, is altered in children whose PbB levels are




        15 ug/dL or higher (Benignus et al., 1981).  Two years later, there




        were still measurable changes in central nervous systems of these




        children (Otto et al.,  1982).

-------
 Lead                                                          September 30, 1985

                                     -8-                        " ~    -  -

                                                             .'• •< ,r.'i j\ r* •
                                                             ^•j\^\r |
     0  Prenatal exposure of the fetus to PbB levels below those causing

        f«fS|iiniicity results in damage to the brain.  PbB levels of mental

        retairdates, measured during the second week of life, were found to be

        significantly higher than those of control subjects (25.5 * 8.9 vs.

        20.9 * 7.9 ug/dL) (Moore et al. 1977).

Teratogenicity/Reproductive Effects

     0  Premature fetal membrane rupture occurs in term and preterm infants

        in mothers whose PbB levels were 26 ug/dL (Fahim et al., 1976).

        Normal deliveries occurred in mothers whose PbB levels were 14 ug/dL

        and below.

Mutagenicity

     0  Lead is a specific cellular poison.  The short term tests that are

        used to predict mutagenicity result in cellular toxicity before

        mutagenicity can be expressed.

     0  Fifteen studies of cytogenetic abnormalities in persons exposed to

        lead have been reported (IARC, 1980).  Positive results were reported

        in nine of these studies.  The incidence of abnormal metaphases

        doubled in workers whose PbBs increased from an initial mean of 35 to

        45 micrograms/dL (Forni et al., 1976).

Carcinogenicity

     0  There are at least 12 positive carcinogenicity studies, eleven in

        rat* and one in the mouse, using different lead salts.

     0  The most useful study in establishing a quantitative relationship

        between lead ingestion and frequency of renal tumors is reported by

        Azar et al. (1973).   A dose-dependent increase in renal tumor frequency

        in rats was observed over the range of 500 to 2000 ppm Pb (as lead

        acetate) in the diet.  It should be noted that these effects also are

-------
   Lead                                                          September 30,  1985

                                        -9-                        "  '
                                                                   •'   • V  A  r*r
                                                                   .-^ ,  ,  f--.t  *» I
                                                                        "  a J  J
           associated with moderate to severe non-carcinogenic effects in rats.

V. QUANTIFI<^jRlljl OF TOXICOLOGICAL EFFECTS

        HealOT*»avi series are based upon the identification of adverse health

   effects associated with the most sensitive and meaningful non-carcinogenic

   end-point of toxicity.  The induction of this effect is related to a particular

   exposure dose over a specified period of time, most often determined from the

   results of an experimental animal study.  Traditional risk characterization

   methodology for threshold toxicants is applied in HA development.   The general

   formula is as follows:

                          (NOAEL or LOAEL) (BW) _ 	 ug/L
                           (UF(s)) (	 L/day)

   Where:

           NOAEL or LOAEL = No-Observed-Adverse-Effeet-Level
                                       or
                            Lowest-Observed-Adverse-Effect-Level
                            (the exposure dose in mg/kg bw)

           BW             = Assumed body weight of protected individual
                            in kg (10 or 70)

           UF(s)          = uncertainty factors, based upon
                            quality and nature of data

           	 L/day       = Assumed daily water consumption (1 or 2)  in liters


   One-day and Ten-day Health Advisories

        The adverse'health effects resulting from lead exposure become manifest

   only after the blood lead level exceeds 15 ug/dL. It takes a minimum of 35

   days to achieve that blood lead level and some unspecified time after that

   to express an effect.  It is, therefore, inappropriate to determine One- or

   Ten-day Health Advisories for lead.

   Longer-term and Life-time Health Advisories

        Because so many body systems are affected by chronic exposure to lead, and

   and because so many studies provide data regarding the relationship between PbB

-------
 Lead                                                          September 30, 1985

                                     -10-                           "	- - ...
levels and toxic effects, it does not seem appropriate to select a singlMstibdy

as the baag^^Rjr calculation of the long term or chronic level.  RatherTit-   	

appears mofS*^ippropriate to identify a "consensus" PbB value that represents the

collective indication of the NOAEL based on all the relevant studies in children.

     Although a number of the studies mentioned above suggest that there may

be no threshold for certain lead-induced effects, it does not seem appropriate

at present to conclude that a PbB value of zero must be achieved to avoid

adverse effects.  Rather, it is judged that the effects at PbB values between

15 and 20 ug/dL do not constitute biologically significant adverse effects in

their own right, although they may be preclinical indicators of adverse

effects which could develop with increased exposure.
                                                                           V*
     In order to protect the fetus, however, it is advisable to limit the I&B

level in women of child-bearing age to between 15 and 20 ug/dL since

certain studies (Harris and Holley, 1972; Hubermont et al., 1978) indicate

that the ratio of fetal/maternal PbB values is close to 1:1.  Thus, a NOAEL for

both children and adults is 15 ug/dL.

     Since blood lead levels above 15 ug/dL will cause measurable adverse

health effects in children who are less than two years old, it seems

appropriate to set a single health advisory for all extended periods of


exposure.

     Using-the relationship derived from the data of Ryu et al., (1983)

(PbB = 0.16 PbD), HA is calculated as follows:


                     Lifetime HA = (15 ug/dL) = 20 ug/day
                                   (0.16H5)

-------
     Lead                                                          September 30, 1985

                                         -11-                                  ••-•
                      • .blood lead level (PbB) at which no adverse effects are"
                       observed

            0.16     = Proportionality constant between lead intake in the diet
                       (PbD) and blood lead level (PbB) in infants (Ryu et al.
                       1983).  The units of this constant are (ug/dL)(ug/day).

               5     = Uncertainty factor selected to account for intra-human
                       variability.  The end-points measured are extremely subtle
                       and sensitive and do not require a full order-of magnitude
                       safety factor.


    Evaluation of Carcinogenic Potential

         0  Although some lead salts are associated clearly with increased renal

            tumor frequency, no quantitative estimate of excess cancer risk has been

            performed by the Carcinogen Assessment Group of the U.S. EPA.

         0  IARC put lead in category 3 which means that there is sufficient

            animal data to conclude that lead is a carcinogen in animals but

            insufficient evidence of carcinogenicity in humans (IARC, 1980).

         0  Applying the criteria described in EPA's proposed guidelines for

            assessment of carcinogenic risk (U.S. EPA, 1984b), lead may be

            classified in Group B2: Probabalt Human Carcinogen.  This category

            is for agents for which there is inadequate evidence from human studies

            and sufficient evidence from animal studies.

VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

         0  The WHO European standard for lead is 100 ug/dl in blood.

         0  The National Academy of Sciences (NAS 1977) concluded that the "no-

            observed-adverse-health-effect level cannot be set with assurance at

            any given value greater than 0.025 mg/L" (25 ug/L).

-------
      Lead                                                          September 30, 1985




                                           -12-                          - .  _
 VII. ANALYSIS




                     Lnation of lead is accomplished by atomic absorption. (AA) using




                     direct aspiration into a flame (Method 239.1.  Atomic Absorption,




              direct aspiration.  U.S. EPA, 1979a) or a furnace technique (Method




              239.2.  Atomic Absorption, furnace technique.  U.S. EPA, 1979b).




           0  The direct aspiration AA procedure is a physical method based on the




              absorption of radiation at 283.3 run by lead.  The sample is aspirated




              into an air-acetylene flame and atomized.  A light beam is directed




              through the flame into a monochromator and onto a detector that




              measures the amount of light absorbed.  Absorbance is proportional




              to the concentration of lead in the sample.  The detection limit is




              100 ug/L using this procedure.




           0  The furnace AA procedure is similar to direct aspiration AA except.




              that a furnace, rather than a flame, is used to atomize the s'ample




              The detection limit is 1 ug/L using this procedure.







VIII. TREATMENT




           0  Experience indicates that direct filtration, coagulation/filtration,




              lime softening, ion exchange and reverse osmosis can effectively




              remove lead from source drinking waters.




           0  Laboratory filtration tests, without coagulation, have been effective




              on river water having a turbidity of 40 Jtu and a concentration of 0.15




              mg/L lead.  Lead removals of 85 to 90 percent were obtained through




              removal of turbidity (EPA, 1977; Sorg, 1978).




           0  Laboratory studies performed by Naylor, et al. (1975) on the removal




              of lead by coagulation indicated that ferric sulfate and alum




              coagulation can achieve better than 97% removal from river water




              containing 0.15 mg/L of lead in the pH range of 6 to 10.  Experiments

-------
Lead                                                          September  30,  1985




                                     -1 3-
                                                                          r
   on well water under similar test conditions showed ferric sulfe




       phieve the same high removal rate,  greater than 97%,  while altmt  —"




   obtained slightly lower removals, 80 to 90%.




0  Laboratory and pilot plant studies by Sorg (1978)  indicate that lime




   softening can be more effective for lead removal than coagulation




   with alum or ferric sulfate.  Over 98%  removal was obtained throughout




   the pH range 8.5 to 11.3 for well water containing 0.15 mg/L of




   lead.  Results of tests for conventional lime softening showed lead




   removal below 0.05 mg/L in the pH range 9.2 to 10.4.  Pilot-plant




   work has achieved lead removal of 99% by lime softening for well




   water at pH 9.5 and an initial lead concentration of 0.41 mg/L




   (Sorg, 1978).




0  Patterson (1975) reported that ion exchange can be a successful




   treatment in the removal of lead from industrial wastewaters.  Highly




   effective removal of lead has been reported for the cation exchange




   resin clinopilolite (natural zeolite) (NAS, 1977).




0  In tests of home softeners with tap water spiked with 1.0 mg/L of




   lead nitrate, the lead content was reduced to less than 0.05 mg/L




   for 330 cycles before leakage (Personal communications, Ciccone




   Engineers with Culligan Co., 1982).  Pakalns, et al. (1978) reported




   that lead removal may also be achieved by some chelating resins




   which have been used increasingly in recent years to remove trace




   metals from natural waters.




0  Bench scale reverse osmosis tests by Mixon (1973)  showed excellent




   removal of lead from spiked tap water by three types of cellulose




   acetate membranes at a rejection pressure of 400 psi.  Greater than




   99% removal was observed for initial lead concentrations of 0.95

-------
Lead                                                          September  30,  1985
            £.- while reductions of more than 94%  were found for initial lead




               of 9.3 mg/L.   Rejections of 85.5  and 97.6%  were observed for




        two types of cellulose acetate membranes for distilled water spiked




        with 10 mg/L of lead (Johnston, et al.,  1978).




     0   Protection against lead contamination from water distribution systems,




        in general, may be achieved by a number  of methods including pH




        adjustment, addition of lime,  increasing alkalinity or addition of




        corrosion inhibitors.   The city of Boston has successfully reduced




        and maintained lead  levels below 0.05 mg/L by increasing the pH




        level of the water over 8.3 by the addition of  sodium hydroxide.




        Simultaneous elevation of pH and alkalinity achieved successful




        control of lead contamination  from the corrosion of lead pipes in




        the Bennington,  Vermont,  water distribution system.




     0   In Framingham,  Mass.,  which uses the same water as Boston,  adjustment




        of pH levels above 7 by the addition of  caustic compounds resulted




        in low lead concentration levels (Karalekas,  1977).   Lead concentration




        levels  below 0.05  mg/L are maintained at Providence,  Rhode Island,




        where lime is added  to raise the water pH to 10.1,  with the subsequent




        increase of hardness to 40 mg/L and alkalinity  to  20 mg/L (Karalekas,




        et al.,  1977).




     0   In three Schuylkill/Carbon County water  supply  systems in Pennsylvania,




        where lead contamination from  corrosion  of lead pipe was a problem,




        addition of phosphate  inhibitors successfully reduced lead levels to




        below 0.05 mg/L.




     0   Another method to  prevent lead contamination of the drinking water  is




        to replace existing  materials  containing lead in the water supply




        distribution system  and to use lead-free materials such as lead-free

-------
    Lead                                                          September 30,  1985

                                         -15-                           '   "-•  --_
                    in newly constructed plumbing.  The feasibility of replacing

            l
-------
 Lead                                      .                    September 30, 1985

                                     -16-                          -- .
Goyer R.A., K.R. Mahaffey. 1972.  Susceptibility to lead toxicit
     Health Pcrspect.  5:73-80.
Griffin, IPlr F« Coulston, H. Willis, J.C. Russel and J.H. Knelson.  1975"." ""
             ?:studies on men continuously exposed to airborne particulate
     lead. In: Griffin TB, Knelson, JH., eds. Lead. New York, NY. Academic
     Press, pp. 221-240. (Coulston, F.; Korte, F., eds. Environmental
     quality and safety: supplement v. 2).

Gross, S.B.  1981.  Human oral and inhalation exposures to lead: Summary of
     Kehoe balance experiments.  J. Toxicol. Environ. Health.  8:333-377.

Harlan, W.R., R. Landis, R.L. Schmouder, N.G. Goldstein and L.C. Harlan.
     1985.  Blood lead and blood pressure.  Relationship in the adolescent
     and adult population.  J. Am. Med. Assoc.  253:530-534.

Harris, P., and M.R. Holley.  1972.  Lead levels in cord blood.  Pediatrics.
     49:606-608.

Heard, M.J., and A.C. Chamberlain.  1982.  Effect of minerals and food on
     uptake of lead from the gastrointestinal tract in humans.  Hum. Toxicol.
     1:411-445.
                                                                           'i
Herrera, C.E., G.J. Kermeyer and B.P. Hoyt.  Seattle Distribution System   :
     corrosion control study. Volume III:  Potential for drinking water
     contamination from tin/antimony solder. Environmental Protection Agency
     Contract No. R806686-010.

Hubermont, G., J.P. Buchet, H. Roels and R. Lauwerys.  1978.  Placental
     transfer of lead, mercury and cadmium in woman living in a rural area:
     importance of drinking water in lead exposure.  Int. Occup. Environ.
     Health.  41:117-124.

I ARC.  1980.  International Agency for Research on Cancer. Lead and lead
     compounds. In: IARC monographs on evaluation of the carcinogenic risk
     of chemicals to humans: some metals and metallic compounds. October,
     1979. Lyon, France.  Geneva, Switzerland.  World Health Organization/
     IARC; pp. 325-416.

Johnston, H.K., and H.S. Lim. 1978.  Removal of Persistent Contaminants from
     Municipal Effluents by Reverse Osmosis.  Volume III.  Environment Canada,
     Wastewater Technology Centre, Project No. 73-3-14.

Karalekas, P.C., Jr.  1977.  Lead Corrosion Controls, Internal memorandum.
     U.S. Environmental Protection Agency, Region I.  March 28.

Karalekas, P.C., Jr., C.R. Ryan, C. Larson and F. Taylor.  1977.  Alternative
     methods for controlling the corrosion of lead pipe. Paper presented at
     the Annual Conference of the New England Water Works Association, Boston,
     Mass., September 13.

Kehoe, R.A.  1961 a.  The metabolism of lead in man in health and disease.
     Lecture I. The normal metabolism of lead.  (The Harben Lectures, 1960).
     J.R. Inst. Public Health Hyg.  24:81-97.

-------
Lead                                                          September 30,  1985

                                     -17-
Kehoe, R.A.  1961b.  The metabolism of lead in man in health and disease"."   •
            ^^1.  The metabolism of lead under abnormal conditions. .. (The
               tures, 1960).  J.R. Inst. Public Health Hyg.  24:129-143.
          j?HV*~
Kehoe, R.A.  1961c.  The metabolism of lead in man in health and disease.
     Lecture III.  Present Hygienic problems relating to the absorption of
     lead.  (The Harben Lectures, 1960).  J.R. Inst. Public Health Hyg.
     24:177-203.

Mahaffey, K.R., J.P. Rosen, R.W. Chesney, J.T. Peeler, C.M. Smith and
     H.F. Deluca.  1982.  Association between age, blood lead concentration,
     and serum 1, 25-dihydrocalciferol levels in children.  Am. J. Clin.
     Nutr.  35:1327-1331.

Mixon, F.O.  1973.  The removal of toxic metals from water by reverse osmosis.
     U.S. Department of the Interior, Office of Saline Water. Research and
     Development Progress Report No. 889.

Moore, M.R., P.A. Meredith and A. Goldberg.  1977.  A retrospective analysis
     of blood-lead in mentally retarded children.  Lancet.  1(8014):717-719.

Murrel, N.E., Holzmacher, and McClendon.  1982.  Lead in drinking water du^j
     to lead-tin solder joints utilized in interior residential and other
     plumbing. H2M Corp., Melville, NY.

NAS.  1977.  National Academy of Sciences.  Drinking Water and Health, Volumes
     1 and 2.  U.S. National Academy of Science.

Naylor, L.M., and R.R. Dague.  1975.  Simulation of lead removal by chemical
     treatment.  J. AWWA.  67(10):560-565.

0'Flaherty, E.J., P.B. Hammond and S.I. Lerner.  1982.  Dependence of apparent
     blood lead half-life on the length of previous lead exposure in humans.
     Fund. Appl. Toxicol.  2:49-54.

Otto, D.A., V.A. Benignus, K.E. Muller and C.N. Barton.  1981.  Effects of
     age and body lead burden on CNS function in young children.  I:  Slow
     cortical potentials.  Electroencephal. Clin. Neurophysiol.  52:229-239.

Otto, D.A., V.A. Benignus, C. Barton, K. Seiple, J. Prah and S. Schroeder.
     1982.  Effects of low to moderate lead exposure on slow cortical poten-
     tials in young children: Two year follow-up study.  Neurobehav. Toxicol.
     Teratol.  4:733-737.

Pakalns, P., G.E. Batley, et al.  1978.  The effect of surfactants on the
     concentration of heavy metals from natural waters on Chelex-100 resin.
     Analytica Chimica Acta.  99:333-342.

Patterson, J.W.  1975.  Wastewater Treatment Technology.  Ann Arbor Science
     Publishers, Inc.

Personal Communication between V.J. Ciccone Engineers and Culligan Corporation,
     August 4, 1982.

-------
Lead                                                     September  30,  1985

                                     -18-                         ......
                                                                    RAFT
Piomelli/ §», C. Seaman, D. Zullow, A. Curran and B.  Davidow.   1982.
     Thredjfijpi" for lead damage to heme synthesis in urban children* . .Prqc.
     NatL||||pid. Sci. U.S.A.  79:3335-3339. '

Pirkle, J.L., J. Schwartz, J.R. Landis and W.R.  Harlan.   1985.   The relation-
     ship between blood lead levels and blood pressure and its  cardiovascular
     risk implications.  Am. J. Epidem. 121:246-258.

Rabinowitz, M.B., G. Wetherill, J.D. Kopple,  1973.   Lead metabolism in  normal
     the human:  Stable isotope studies.  Science 182:725-727.

Rabinowitz, M.B., G.W. Wetherill and J.D. Kopple.  1976.  Kinetic  analysis of
     lead metabolites in healthy humans.  J.  Clin.  Invst.   58:260-270.
     risk implications.  Am J. Epidem.  121:246-258.

Rabinowitz, M.B., G.W. Wetherill and J.D. Kopple.  1977.  Magnitude of  lead
     intake from respiration by normal men.   J.  Lab.  Clin.  Med.  90:238-  248.

Roels,  H.A., J.P. Buchet,  R. Lauwerys, G. Hubermont,  p.  Bruaux,  F. Claeys-
     Thoreau, A. LaPontaine and J. Van Overrschelde.   1976.   Impact of  air
     pollution by lead on the heme biosynthetic  pathway in school-age children.
     Arch. Environ. Health.  31:310-316.                                  1
                                                                          •\

Ryu, J.E., E.E.  Ziegler, F.E. Nelson and S.J. Fomon.   1983.   Dietary intake of
     lead and blood lead concentration in early  infancy.  Am. J. Dis. Child.
     137:886-891.

Secchi, G.C., L. Erba and G. Cambiaghi.  1974.  Delta-aminolevulinic acid
     dehydratase activity of erythrocytes and liver tissue in man: relation-
     ship to lead exposure.  Arch. Environ.  Health.   28:130-132.

Seppalainen, A.M.,  and S.  Hernberg.  1980.  Subclinical lead  neuropathy.
     Am. J. Ind. Med.  1:413-420.

Seppalainen, A.M.,  and S.  Hernberg.  1982.  A follow-up study of nerve  conduc-
     tion velocities in lead exposed workers. Neurobehav.  Toxicol. Teratol.
     4:721-723.

Sorg, T.J., M. Csanady, et al.  1978.  Treatment technology to  meet the int.
     primary drinking water regulations for  inorganics:   Part 3.   J. AWWA.
     70(12):680-691.

Tola, S., Si" Hernberg, S.  Asp and J. Nikkanen.  1973.   Parameters  indicative
     of absorption and biological effect in  new  lead  exposure:   a  prospective
     study.  Br. J. Ind. Med.  30:134-141.

U.S. EPA.  1977.  U.S. Environmental Protection  Agency.   Manual of treatment
     techniques  for meeting the interim primary  drinking water  regulations,
     revised.  EPA-600/8-77-005.

U.S. EPA.  1979a.  U.S. Environmental Protection Agency.  Method 239.1.
     Atomic Absorption, direct aspiration.  Methods for Chemical analysis of
     water and wastes.  EPA 600/4-79-020.

-------
                                                        O C £..-_:. ,1^,1= L  J ^ ,  , 'JOJ


                                     -19-                              '•••
U.S. EPA.  1979b. U.S. Environmental Protection Agency.  Method  239.2." Atomic   -'
     Abso^jfejtton, furnace technique.  Methods  for chemical  analysis  of  water
     and «3lktB8.  EPA 600/4-79-020.
U.S. EPA.  1979c.  U.S. Environmental Protection Agency.  Water  related
     environmental fate of  129 priority pollutants. Office  of Water  Planning
     and Standards.  EPA-440/4-79-029.

U.S. EPA.  1983.  U.S. Environmental Protection Agency.   Lead occurrence  in
     drinking water, food,  and air.   Office of Drinking  Water.

U.S. EPA.  1984a. U.S. Environmental Protection Agency.   Air quality criteria
     for lead. Office of Health and Environmental  Assessment for the Office of
     Air and Radiation.

U.S. EPA. 1984b.  U.S. Environmental Protection Agency. Proposed guidelines
     for carcinogen risk assessment; Request for comments.  Federal  Register.
     49(227):46294-46301.   November 23.

U.S. EPA. 1985.  U.S. Environmental Protection Agency.  Quantification of
     toxicological effects  for lead (Draft).  Office  of Drinking Water.    -T
                                                                           ••!
Wetherill, G.W., M. Rabinowitz, J.D. Kopple.  1974.   Sources and metabolic5
     pathways of lead in normal humans.  Proc. Int. Symp. June  1974. Comnu'
     Eur. Commun. U.S. EPA,  World Health Organization, pp. 847-860.

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                                                           March  31,  193?
    EPA 0596
    RX000027824
                                     p-DIOXANE

                                  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 aodel is based on differing assumptions, the estimates that are
   derived can differ by several orders of magnitude.
                                                              OFC29 1093

-------
                                         -2-
         This Health Advisory  is  based  upon  information  presented  in  the  Office
    of Drinking Water's Health Advisory Document for p-Dioxane (U.S.  EPA,  1981).
    The 1981  Health Advisory  is available  for  review at  each  EPA  Regional Office
    of Drinking Water counterpart (e.g., Water Supply Branch  or Drinking  Water
    Branch) .
II. GENERAL INFORMATION AND PROPERTIES
    CAS No.   123-91-1
    Structural Formula
    Synonyms

         0  1,4-Dioxane;  1", 4-Diethylene dioxide

    Uses^

         0  Solvent for cellulose acetate,  resins,  oils and waxes.

    Properties  (Windholtz,  1983, Verschueren,  1977)
            Chemical formula
            Molecular weight                88.10
            Physical state                  Colorless liquid
            Boiling point                   101.1°C            ;
            Melting point                   11.8°C
            Vapor pressure                  30 mm (20°C)
            Density                         1.033 g/ml (20°C)
            Solubility                      miscible in water at all concentrations
            Taste/ odor threshold            ~
    Oceurrence
            1,4-Dioxane is a synthetic organic compound with no known natural
            sources.  Production of dioxane in 1979 was 6 million Ibs.

            Based upon dioxane's physical properties,  it is expected to volatilize
            from soil and surface waters.  Dioxane also is expected to be mobile
            in soil.  No information on the bi ©degradation of dioxane has been
            identified.

            Dioxane has not been included in Federal and State surveys of drinking
            water supplies.  However, it has been reported to occur in both surface
            and ground water (U.S. EPA, 1979).  No information on the occurrence
            of dioxane in food or air has been identified.

-------
     p-Dioxane                                              March  31,  1937

                                          -3-


III. PHARMACOKINETICS

     Absorption

          •  Dioxane has  been  reported  to  be absorbed  readily  through  the lungs,
             skin and gastrointestinal  tracts  of  mammals.

          8  There is evidence that dioxane is absorbed  after  ingestion.   Several
             investigators  administered dioxane in water to rats  and observed
             systemic adverse  health effects (Argus *et al.,  1965;  Hoch-Ligeti
             et al., 1970;  Kociba  et al.,  1974).   However,  the quantities absorbed
             following ingestion are not known.   Based on  the  physico-chemical
             properties of  this compound,  and  for the  purpose  of  HA estimation,
             100% absorption will  be assumed after ingestion.

     Distribution

          8  Woo et al. (1977b) studied the binding of H3-dioxane  to tissue
             macromolecules of animals. Male  Sprague-Dawley rats,  weighing  95 to
             130 g,  were  administered a single intraperitoneal dose of H^-dioxane
             at 500 uCi/100 g  body  weight, and sacrificed  after 1,  2,  6 or 16
             hours.  Cystolic, microsomal, mitochondrial and nuclear fractions
             were examined. The percent covalent binding, was  highest in  the
             nuclear fraction  followed  by  mitochondrial  and microsomal fractions
             and the whole  homogenate.   The binding of dioxane to  the macromolecules
             in the cytosol was mainly  noncovalent. Pretreatraent  of rats with
             inducers of  microsomal enzymes had no significant effect on  the
             covalent binding  of dioxane to the various  subcellular fractions of
             the liver.

     Metabolism/Excretion

          8  Oioxane has  been  reported  to  be metabolized in animals to 2-hydroxy-
             ethoxyacetic acid and 1,4-dioxan-2-one.   After a  single oral dose of
             1,000 mgAg  bw of 1,4-(14c)dioxane to rats, Braun and Young  (1977)
             recovered from the urine 85%  of the  dose  as   -hydroxyethoxyacetic
             acid (HEAA)  and most  of the remainder as  unchanged dioxane.   Woo et  al.
             (1977a) isolated  and  identified p-dioxane-2-one from the urine  of
             rats given intraperitoneal doses  of  100 to  400 mg dioxane/kg body
             weight; the amount of p-dioxane-2-one excreted increased with the
             dose level administered.

          8  Humans exposed to 50  ppm dioxane  for six  hours eliminated it from the
             body primarily by metabolism  to  HEAA, which was subsequently eliminated
             rapidly in the urine  (Young et al.,  1977).


 IV. HEALTH EFFECTS
     Humans
             The lowest oral lethal dose for humans has been recorded as 500
             (NIOSH, 1978).

-------
p-Oioxar.e                                               March  3',  19-5'

                                     -4-
        Johnstone (1959)  described a  fatal  case of  dioxane  poisoning.   The  i
        estimated exposure by  inhalation in this case was  470 ppm (1,690 mg/ms
        for one week; the extent of dermal  exposure was not known.   Postmortem
        examination revealed hepatic  and renal  lesions as  well as demyelination
        and edema of the brain.
Animals
Short-term Exposure

     0  Oral LD50 values for experimental animals are 4200 mgAg (rat),  5700
        mgAg (mouse),  2000 mgAg (cat),  2000 mgAg (rabbit)  and 3150 mgAg
        (guinea pig) (NIOSH, 1978).

     0  Pairley et al.  (1934) intravenously  injected four rabbits with a
        single dose of  either 1, 2, 3 or 5 mL of 80% dioxane  diluted with
        saline to a total volume of 10 mL.  Three other rabbits each were
        given two 5 mL intravenous injections of dioxane mixed with 5 mL of
        saline with an  interval of 48 hours  between injections.  One rabbit,
        used as a control, received 10 mL of saline.  The immediate effect of
        dioxane injection in all of the rabbits was violent struggling,  which
        began as soon as the first few drops were injected..  With doses of
        4 or 5 mL dioxane, the struggling was followed by convulsions and
        collapse; the rabbits then rapidly returned to normal.  The four
        rabbits given the single doses of 80% dioxane were killed 1 month
        later.  Degeneration of the renal cortices with hemorrhages was
        observed by microscopic examination.  In the rabbit administered the
        3 mL dioxane dose, the degenerative changes extended into the medulla
        and the liver showed extensive cellular degeneration starting at the
        periphery of the lobules.  No abnormality was found in other organs.
        The livers of the rabbits given the 1- and 5 mL doses showed no
        microscopic abnormalities; areas of cloudy swelling were seen in the
        liver of the rabbit given 2 mL of dioxane.

Longer-term Exposure

     0  Kociba et al. (1974) reported liver and kidney damage in male and
        female Sherman strain rats.  The animals were given drinking water
        containing 0, 1.0, 0.1 or 0.01% dioxane for up to 716 days.  Toxico-
        logical analysis included changes in body weights, survival rates,
        blood chemistry (packed cell volume, total erythrocyte count, hemo-
        globin, total and differential white blood cell counts) and complete
        histopathological examination.  There was no evidence of toxicity with
        regard to the tested parameters in animals receiving 0.01% dioxane  in
        drinking water; however, liver and kidney damage was observed at 0.1%
        dosage level.  Decrease in body weight gains, survival rates, water
        consumption and an increase in the incidence of tumors (hepatocellular
        and nasal carcinomas) was observed at  1% dosage level.

Reproductive Effects

      0  No reports were available on the reproductive effects of 1
        in humans or other mammalian species.

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?-Dioxane                   .                            March  31,  1937

                                     -5-


Developmental Effects

     0  No reports were available on the developmental effects of  1,4-dioxane
        in humans or other mammalian species.

Mutagenicity
                    •
     *  No reports were available on the mutagenic potential of 1,4-dioxane.

Carcinogenicity

     0  Hoch-Ligeti et al. (1970) and Argus  et al. (1973)  observed a linear "
        relationship between the total dose  of 1,4-dioxane in drinking  water
        and the incidence of liver neoplasms in rats.   The levels  of 1,4-
        dioxane in the drinking water were 0.75, 1.0,  1.4  and 1.8% for  13
        months.  A minimum effective tumor dose (105),  50% tumor dose (TDso),
        and maximum effective dose (TDgs) were calculated  for 1,4-dioxane.
        These were 72, 149 and 260 g, respectively.

     0  In a two-year study in Sherman strain  rats (60/sex/level)  given .
        1,4-dioxane in drinking water, Kociba  et al. (1974) reported that the
        group receiving 1% 1,4-dioxane (calculated to  be equivalent to  approxi-
        mately 1015 mg/kg/day  and 1599 mgAg/day foe male  and female rats,
        respectively ) showed a significant increase compared to controls in
        the incidence of hepatocellular carcinomas and squamous cell carcinomas
        of the nasal cavity.  At 0.01% (9.6  and 19.0 mgAg/day, respectively
        for males and females) and 0.1% (94.0  and 148.0 mgAg/day, respec-
        tively), there was no significant difference in the incidence of
        neoplasms between the control and the  experimental groups.

     0  In a 90-week study in B6C3Fi mice (50/sex/level) on the oncogenic
        effects of reagent-grade 1,4-dioxane in drinking water, a  significant
        increase in hepatocellular carcinomas  over controls was reported in
        both the 0.5 and 1% groups of both sexes (NCI,  1978).  The average
        daily low dose (0.5% v/v) was 720 (530 to 990)  mgAg/day for males
        and 380 (180 to 620) mgAg/day for females; at the 1% level, the
        doses were 830 (680 to 1150) and 860 (450 to 1560) mgAg/day,
        respectively.

     0  In the NCI (1978) study, Osborne-Mendel rats (35/sex/level) exposed
        to 1,4-dioxane in drinking water exhibited a dose-related, statisti-
        cally significant incidence of squamous cell carcinomas of the  nasal
        turbinates in both sexes.  Hepatocellular adenomas were observed in
        female Osborne-Mendel rats at both dose levels*  Average doses  for
        110 weeks for males were 240 (130 to 380) and  530 (290 to  780)  mgAg
        body weight; for females, the doses  were 350 (200 to 580)  and 640
        (500 to 940) mgAg body weight.

Effects on Immunologic Status and Competence

     *  Thurman et al. (1978)  reported on the  in vitro effects of  1,4-dioxane
        on the mitogenic stimulation of murine lymphocytes.  At 2.5 and 5
        g/L, 1,4-dioxane greatly enhanced lipopolysaccharide stimulation of

-------
p-Qioxane                                              .March 31, 1967

                                     -6-
        lymphocytes as well as depressing phytohemagglutinin stimulation of
        lymphocytes.  These results were interpreted to indicate stimulation
        of B-cell proliferation and suppression of T-cell responses.  The
        authors did not discuss the implications of the results in human
        lymphocytes which appeared to be opposite to the findings with murine
        lymphocytes.  In vitro, at 25 g/L of 1,4-dioxane, a slight enhancement
        of»phytohemagglutinin stimulation of human lymphocytes was seen, indi-
        cating a stimulation of T-cell responses and an enhancement of the
        immune response; little or no effect was seen at lower concentrations.
        More data confirming this initial finding in murine lymphocytes are
        necessary before any valid conclusions can be made on the immuno-
        suppressive effects of 1,4-dioxane.
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) , _ mg/L ( _ u /L)
                     (UF) x ( _ _ L/day)

where:                                  •

        NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                         in mg/kg bw/day .

                    BW = assumed body weight of a child (10 kg) or
                         an adult (70 kg).

                    UF » uncertainty factor (10, 1 00 or 1,000), in
                         accordance with NAS/OCW guidelines.

             _ L/day * assumed daily water consumption of a child
                         (1 L/day) or an adult (2 L/day).

One-day Health Advisory

     A study by Fairley et al. (1934) has been selected for calculating a One-
day HA.  In this study, a single dose of 1, 2, 3 or 5 mL of 1,4-dioxane was
given intravenously to rabbits.  Even though one rabbit was used per dose
level, the dose-response data  generated by this study provide more useful
information concerning the toxic effects of dioxane than the other available
studies.  Rabbits sacrificed one month later had degeneration of the renal
cortices with hemorrhages as observed by microscopic examination,  with the
increasing dose levels, the degenerative change extended into the medulla
and the liver also showed extensive and gross cellular degeneration.

-------
                                     -7-
     A One-day HA for a 1 0 Jcg child is calculated as follows:
LOA£L (mgAg/day) = (1 "I/day ) (1.03 g/ml ) (0.80) (1000 mg/g) = 412 mg/kg/day
                                     ( 2 kg)

Where:

        1 ml/day  = Administered dose of p-dioxane (LOA£L)

        1 .03 g/ml • Density of dioxane

       *0.80      » Percent composition of dioxane solution

        1000 mg/g « Conversion factor for grams to milligrams

        2 kg      - Assumed body weight of rabbit

         One-day HA - (412 mg/kg/day ) (10 kg) « 4.12 mg/L (4,120 ug/L)
                         (1 L/day)  (1,000)

Where:

        412 mg/lcg/day » LOA£L for liver and kidney effects in the rabbit

              10 kg   » Assumed weight of a child

              1 L/day » Assumed volume of water consumed daily by a child

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

Ten-day Health Advisory

     In the absence of an acceptable study for the calculation of a Ten-day
HA, the One-day HA value is divided by ten; therefore, the Ten-day HA is
estimated as 0.412 mg/L (412 ug/L).

Longer-term Health Advisory^

     No suitable data are available to determine a Longer-term HA.  Kociba
et al. (1974) observed a no effect  level of 9.6 mgAg/day based on a two-year
drinking water study in rats.  This study, although scientifically sound,
should not be used for estimating a Longer-term HA because of the carcinogenic
potential of p-dioxane.  p-Dioxane  has been reported to be carcinogenic  in
both sexes of rats and mice by several independent investigators.  This  may
be compared with trichloroethylene  where only one species responded to  the
carcinogenic effects of the chemical.  Another reason for not calculating a
Longer-term HA for dioxane is its potential of being chlorinated in water,
thus producing a highly toxic chemical.  Woo et al. (1980) showed that
chlorination of dioxane increased the toxicity by as much as  1,000 fold.

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  p-Dioxane                          '                     March  31,  1937

                                       -8-


  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
  (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.

      Because of its suspected carcinogenicity, a Lifetime Health Advisory for
 p-dioxane is not recommended.

  Evaluation of Carcinogenic .Potential

      0  A number of studies show that p-dioxane is carcinogenic  in more than
         one animal species.

      0  IARC has classified 1,4-dioxane in Group 2B, indicating  sufficient
         evidence of its carcinogenicity in animals (IARC, 1982).

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

      0  Drinking water concentrations estimated by EPA to increase the risk
         by one excess cancer per million (10-6) would be 7 micrograms per
         liter, assuming consumption of 2 liters of water per day by a 70-kg
         adult over a 70-year lifetime and using the linearized multistage
         model.  The drinking water concentrations associated with  a risk of
         10-4 and 10-5 would be 700 and 70 ug/L, respectively.

      0  The linearized multistage model is  only one method of estimating car-
         cinogenic risk.  Using the 10~6 risk level, the following  comparisons
         in micrograms/L can be made:   Multistage,  7; Logit, 10"7; and Weibull,

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      ?-Oioxane                                               March 31, 1987

                                           -9-


               10-?.  Each model is based on differing assumptions.  No current
              understanding of the biological mechanisms of carcinogenesis is able
              to predict which of these models is more accurate than another.

           0  While recognized as statistically alternative approaches, the range
              of risks described by using any of these modelling approaches has
              little biological significance unless data can be used to support
              the selection of one model over another.  In the interest of consistency
              of approach and in providing an upper bound on the potential cancer
              risk, the Agency has recommended use of the linearized multistage
              approach.
                                            •^

  VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

           8  NIOSH has recommended an exposure standard of 1 ppm/30 M in air
               (NIOSH, 1977).

           0  TLV - 25 ppm; STEL » 100 ppm (ACGIH,  1980).


 VII. ANALYTICAL METHODS

           0  There is no standardized method for tKe determination of p-dioxane
              in drinking water.  However, p-dioxane can be determined by the purge
              and trap gas chromatographic-mass spectrometric (GC-MS) procedure
              used for determination of volatile organic compounds in industrial
              and municipal discharges (U.S. EPA, 1984).  In this method, a 5 mL
              water sample is spiked with an internal standard of an isotopically
              stable analog of p-dioxane and purged with an inert gas.  The volat:.2
              compounds are transferred from the aqueous phase into the gaseous
              phase where they are passed into a sorbent column and trapped.  After
              purging is completed, the trap is backflushed and heated to desorb
              the compounds on to a gas chromatograph (GC).  The compounds are
              separated by the GC and detected by a mass spectrometer (MS).  The
              labeled compound serves to correct the variability of the analytical
              technique.  The method detection limit is dependent upon the nature
              of interferences*
VIII. TREATMENT TECHMOLOGIES

           0  Treatment technologies which are capable of removing p-dioxane from
              drinking water include adsorption by granular activated carbon (GAC) or
              powdered activated carbon (PAC).  The only data available demonstrating
              removal of p-dioxane are for carbon adsorption.  Further studies are
              required to determine the effectiveness of 03 or 03-UV oxidation.
              The available adsorption data are from laboratory bench-scale studies.
              Field pilot studies or plant-scale data on p-dioxane are not.available.

           0  McGuire et al. (1978) developed isotherms for a number of organic
              chemicals, including dioxane.  Based on the isotherm data, they
              reported that the activated carbon Filtrasorb® 400 exhibited adsorptive

-------
xane                                               March  31,  "93"

                                -10-
   capacities of 0.6 mg dioxane/g  carbon and 3.5 mg dioxane/g carbon at
   equilibrium concentrations  of  1  mg/L and 10 mg/L.   They also tested
   the effectiveness of PAC treatment at 50 mg/L with 5-hour contact
   time.  The results showed poor  removal efficiency.  However, it was
   concluded  that greater  removal  of  1/4-dioxane could be achieved using
   PAC at higher dosages.

   Suffet et  al.  (1978)  used a pilot-scale test column packed with an
   experimental polymeric  resin and compared its performance to granular
   activated  carbon.  The  resins showed poor performance with respect
   to p-dioxane removal.

   A batch laboratory study to demonstrate oxidation of p-dioxane by 100
   mg/L chlorine and 100 mg/L  permanganate showed no reductions after
   12-hour and 3-hour contact times,  respectively (McGuire et al.,
   1978).   A  batch laboratory  study showed diffused aeration to be
   ineffective, achieving  less than 3% removal at an 80:1 air-to-water
   ratio over a 2.4-hour period (McGuire et al., 1978).

   Treatment  technologies  for the  removal of 1,4-dioxane from drinking
   water have 'not been extensively  evaluated (except on an experimental
   level). An evaluation  of some  of  the physical and/or chemical
   properties of 1,4-dioxane indicates that the following techniques
   would be candidates for further  investigation:  adsorbtion by activated
   carbon and oxidation by ozone or ozone/ultraviolet light.  Individual
   or combinations of technologies  selected to attempt 1,4-dioxane
   reduction  must be based on  a case-by-case technical evaluation, and
   an assessment of the economics  involved.

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    ?-Dioxane  '                                      .       March 31, 1337

                                         -1 1-


IX.  REFERENCES

    ACGIH.   1980*  American Conference of Governmental Industrial Hygienists.
         Documentation of the threshold limit values.  4th ed.  Cincinnati, OH.
         pp.  154-155.

    Argus,  M.P.,  J.C.  Arcos and C.  Hoch-Ligeti.   1965.  Studies on the carcino-
         genic activity of protein-denaturing agents:  Hepatocarcinogenicity of
         dioxane.  J.  Nat. Cancer Inst.  35:949-958.

    Argus,  M.F.,  R.S.  Sohal, G.M. Bryant, C.  Hoch-Ligesti and J.C. Arcos.  1973.
         Dose-response and ultrastructural alterations in dioxane carcinogenesis.
         Influence of  methylcholanthrene on acute toxicity.  Eur. J. Cancer.
         9(4):237-243.

    Braun,  W.H. and J.D.  Young.  1977.  Identification of   -hydroxyethoxyacetic
         acid as the major urinary metabolite of 1,4-dioxane in the rat.  Toxicol.
         Appl.  Pharmacol.  39:33-38.

    Fairley,  A.,  B.C.  Linton and A.H.  Ford-Moore.  1934.   The toxicity to animals
         of 1,4-dioxane.   J. Hyg.  34:486-501.

    Hoch-Ligeti,  C., M.F. Argus and J.C. Arcos.   1970.  Induction of carcinomas
         in the nasal  cavity of rats by dioxane.  Brit. J* Cancer.  24(1):164-167.

    IARC.   1982.   International Agency for Research on Cancer.  IARC monographs
         on the evaluation of the carcinogenic risk of chemicals to humans.
         Supplement 4.  IARC, Lyon, France.

    Johnstone, R.T.  1959.  Death due  to dioxane?  AMA Arch. Ind. Health.
         20:445-447.

    Kociba, R.J., S.B. McCollister, C. Park,  T.R. Torkelson and P.J. Gehring.
         1974.* 1,4-Dioxane.  I.  Results of  a 2-year ingestion study in rats.
         Toxicol. Appl. Pharmacol.   30(2):275-286.

    McGuire,  M.J., I.H. Suffet and J.V. Radziul.  1978.  Assessment of unit
         processes for the removal of  trace organic compounds from drinking water.
         JAWWA.  10:565-572.

    NCI.   1978*  National Cancer Institute.   Bioassay of 1,4-dioxane for possible
         carcinogenicity.  Washington, D.C.:   U.S. Department of Health, Education
         and Welfare,  National Institute of  Health.  DHEW Pub. No. (NIH) 78-1330.

    NIOSH.   1977.  National Institute  of Occupational Safety and Health.  Criteria
         for a recommended standard — occupational exposure to dioxane.  Washing-
         ton, D.C.:  U.S. Department of Health,  Education and Welfare.  DHEW
         (NIOSH)  Pub.  77-226.

    NIOSH.   1978.  National Institute  of Occupational Safety and Health.  Registry
         of toxic effects of chemical  substances.  U.S. Department of Health,
         Education and Welfare.  Washington,  D.C.

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 o-Dioxane                      '                          March  31,  1937

                                      -12-
Suffet,  I.H., L.  Brenner, J.T.  Coyle and  P.R.  Cairo.   1978.   Evaluation of
     the capability  of  granular activated carbon  and  XAD-2 resin to remove
     trace organics  from  treated drinking water.   Environmental Science and
     Technology.   1(12):1315-1322.

Thurman, G.B., B.C.  Sinuns,  A.L. Goldstein and  D.J.  Kilian.   1978.   The
     effects of organic compounds used  in the  manufacture  of plastics on the  c,,,,
     responsivity of murine and human lymphocytes.  Toxicol.  Appl.  Pharmacol.
     44:617-641.

U.S. EPA.  1979.  U.S. Environmental Protection Agency.  Chemical  Hazard
     Information  Profile: Dioxane, Office of Toxic  Substances.

U.S. EPA.  1981.  U.S. Environmental Protection Agency.  Health advisory
     document for p-dioxane.   Draft.  Office of Drinking Water.

U.S. EPA.  1984.  U.S. Environmental Protection Agency.  Method 1624 Revision
     B, Volatile Organic Compounds by Isotope  Dilution GC/MS.   Federal Register.
     49(209):433407-433415.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogenic risk assessment.  Fed.  Reg*  51{185):33992-34003.
     September 24.

Verschueren, K.   1977.  Handbook of environmental data on  organic  chemicals.
     1st ed.  Van Nostrand  Reinhold Company, N.Y.   p.  377.

Windholz, M., ed.  1983.  Merck Index,  10th ed.  Merck and Company, Inc.
     Rahway, NJ.  pp. 481-482.

Woo, Y-T, J.C. Arcos and M.F. Argus.  1977a.   Metabolism in  vivo of dioxane:
     Identification  of p-dioxane-2-one  as the  major urinary  metabolite.
     Biochem. Pharmacol.  26:1535-1538.

Woo, Y-T, M.F. Argus and J.C. Arcos.  1977b.   Tissue and subcellular distri-
     bution of 3H-dioxane in the rat and  apparent lack of  microsome-catalyzed
     covalent binding in the target tissue.  Life Sci.  21(10):1447-1456.

Woo, Y-T, B.J. Neuburger, J.C. Arcos, M.F. Argus, K. Nishiyama  and G.w.  Griffin.
     1980.  Enhancement of  toxicity and enzyme-repressing  activity of p-dioxane
     by chlorination:  Stereo-selective effects.  Toxicol.  Letts.   5:69-75.

Young, J.D., W.H. Braun, L.W. Rampy, M.B.  Chenoweth and G.E.  Blau.   1977.
     Pharmacokinetics of  1,4-dioxane in humans.   J. Toxicol.  Environ. Health.
     3(3):507-520.

-------
EPA 0596
KX000027824
              Zinc Chloride Health Advisory
                     Health Advisory
                     Office of Water
          U.S.  Environmental  Protection Agency
                  Washington, DC  20460
                      September 1992

-------
           Zinc Chloride
              Authors:

      Joyce M. Donohue, Ph.D.
         Lori Gordon, M.S.
         Chris Kinnan,  M.S.
     Welford C. Roberts, Ph.D.
          Project Officer:
       Krishan Khanna, Ph.D.

          Office  of Water
U.S. Environmental Protection Agency
       Washington, DC  20460
           September 1992

-------
                                    PREFACE

This report was prepared in accordance with the Memorandum of Understanding
between the Department of the Army, Deputy for Environmental Safety and
Occupational Health (OASA(IL&E)),  and the U.S. Environmental Protection Agency
(EPA), Office of Water (OU),  Office of Science and Technology, for the purpose
of developing drinking water Health Advisories (HAs) for selected
environmental contaminants, as requested by the Army.

Health Advisories provide specific advice on the levels of contaminants in
drinking water at which adverse health effects would not be anticipated and
which include a margin of safety to protect the most sensitive members of the
population.  A Health Advisory provides health effects guidelines and
analytical methods and recommends treatment techniques on a case-by-case
basis.  These advisories are normally prepared for one-day, ten-day, longer-
term, and lifetime exposure periods where available toxicological data permit.
These advisories do not condone the presence of contaminants in drinking
water, nor are they legally enforceable standards.  They are not issued as
official regulations and they may or may not lead to the issuance of national
standards or Maximum Contaminant Levels (MCLs).

This report is the product of the Health Advisory Development process.
Available toxicological data (as provided by the Army and as found in open
literature sources) on the munitions chemical zinc chloride have been
reviewed, and relevant findings are presented in this report in a manner that
allows for evaluation of the data without continual reference to the primary
documents.  Additional data on the properties of other soluble zinc compounds
are also presented.  This report has been submitted for critical internal and
external review by the EPA.

I would like to thank the authors, who provided the extensive technical
knowledge required for the preparation of this report.  I am grateful to the
members of the EPA Toxicology Review Panel who took time to review this report
and to provide their invaluable input, and I would like to thank Dr. Edward
Ohanian, Chief, Human Risk Assessment Branch, and Ms. Margaret Stasikowski,
Director, Health and Ecological Criteria Division, for providing me with the
opportunity and encouragement to be a part of this project.

The preparation of this Health Advisory was funded, in part, by Interagency
Agreement  (IAG) 85-PP5869 between the U.S. EPA and the U.S. Army Medical
Research and Development Command (USAMRDC).  This IAG was conducted with the
technical  support of the U.S. Army Biomedical Research and Development
Laboratory (USABRDL), Dr. Howard T. Bausum, Project Manager.

                                    Krishan Khanna, Project Officer
                                    Officer of Water

-------
                            TABLE OF CONTENTS

                                                                       PAGE

LIST OF TABLES	ii

LIST OF APPENDICES	ii

EXECUTIVE SUMMARY  	 ES-1

I.     INTRODUCTION	1-1

II.    GENERAL INFORMATION AND PROPERTIES   	 II-l

III.   OCCURRENCE	III-l
       A.  Zinc Chloride	III-l
       B.  Other  Zinc Compounds.  .     	III-l

IV.    ENVIRONMENTAL  FATE	IV-1
       A.  Zinc Chloride	IV-1
       B.  Elemental  and Ionic Zinc   	IV-1

V.     TOXICOKINETICS	V-l
       A.  Absorption   	V-l
           1.  Zinc Chloride	V-l
           2.  Other Zinc  Compounds    	V-2
       B.  Distribution   	V-3
           1.  Zinc Chloride	V-3
           2.  Other Zinc  Compounds    	V-5
       C.  Metabolism   	V-6
       D.  Excretion	V-6
           1.  Zinc Chloride	V-6
           2.  Other Zinc  Compounds    	V-7

VI.    HEALTH EFFECTS	VI-1
       A.  Health Effects in Humans   	VI-1
           1.  Short-Term  Exposure   	 VI-1
              a.  Zinc Chloride   	VI-1
              b.  Other Zinc Compounds	VI-2
           2.  Dermal/Ocular  Effects	VI-7
              a.  Zinc Chloride   	VI-7
              b.  Other Zinc Compounds	VI-8
           3.  Long-term Exposure   	VI-8
              a.  Zinc Chloride   	VI-8
              b.  Other Zinc Compounds	VI-8
       B.  Health Effects in Animals	VI-9
           1.  Short-Term  Exposure   	 VI-9
              a.  Zinc Chloride   	VI-9
              b.  Other Zinc Compounds	VI-11
           2.  Skin and Eye  Irritation,  Dermal  Sensitization   ....  VI-12
              a.  Zinc Chloride   	VI-12
              b.  Other Zinc Compounds	VI-12
           3.  Longer-Term Exposure    	VI-13
              a.  Zinc Chloride	VI-13
              b.  Other Zinc Compounds	VI-13

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Table of Contents -  continued
                                                                          PAGE

             4.  Reproductive Effects   	VI-14
                 a.   Zinc Chloride   	VI-14
                 b.   Other Zinc Compounds	VI-14
             5.  Developmental Effects  	   VI-15
                 a.   Zinc Chloride   	VI-15
                 b.   Other Zinc Compounds	VI-16
             6.  Genotoxicity   	VI-16
                 a.   Zinc Chloride   	VI-16
                 b.   Other Zinc Compounds	VI-18
             7.  Carcinogenicity	VI-19
                 a.   Zinc Chloride   	VI-19

   VII.    HEALTH ADVISORY DEVELOPMENT	VII-1
          A. Quantification  of Toxicological Effects  	   VII-2
             1.  One-Day Health Advisory	VII-3
             2.  Ten-Day Health Advisory  	   VII-3
             3.  Longer-Term Health Advisory	VII-4
             4.  Lifetime Health Advisory	   VII-5
          B. Quantification  of Carcinogenic Potential   	   VII-7

   VIII.  OTHER CRITERIA,  GUIDANCE AND STANDARDS  	  VIII-1
          A. Zinc Chloride	VIII-1
          B. Other  Zinc Compounds   	  VIII-1

  IX.     ANALYTICAL METHODS	IX-1

   X.     TREATMENT TECHNOLOGIES	X-l

   XI.    CONCLUSIONS	XI-1

   XII.    REFERENCES	XII-1
                                LIST OF TABLES

TABLE                                                                     PAGE

II-1   Chemical  and Physical Properties of Zinc Compounds	II-3
VI-1   Categories  of Effects   	VI-3
VI-2   Acute  Oral  Studies of Zinc Chloride and Other Zinc Compounds  .  .   VI-10


                              LIST OF APPENDICES

       Data Deficiencies/Problem Areas and Recommendations for Additional
       Data Base Development for Zinc Chloride and other Zinc Compounds  .  Al-1
                                      11

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                              EXECUTIVE  SUMMARY
Zinc is a naturally occurring element commonly found in the earth's crust.
Zinc is a bluish-white metal in its pure form, but also can exist as a number
of divalent inorganic compounds such as zinc chloride,  zinc sulfate, and zinc
oxide.   Although zinc occurs naturally in the environment, zinc may be
released to the environment from a number of industrial processes including
galvanization,  wood preservation, soldering, -dry-battery cell production and
organic synthesis.   In addition, zinc chloride may be introduced into the
environment through its use as a military screening smoke.  In the
environment, zinc hydrolyzes when dissolved in water.  Adsorption of zinc to
sediments and soils and the bioaccumulation of zinc have been reported to
occur.

The pharmacokinetics of zinc have been well studied in animals and humans.
Zinc is absorbed moderately well following oral intake.  Absorption through
the skin is minimal while data on absorption following inhalation of
particulate zinc is limited.  Radiolabeled zinc (administered as zinc
chloride) mainly distributes to the intestines, prostate, liver and kidney
with kidney levels remaining highest after intravenous administration.
Metallothionein plays an important role in regulating zinc homeostasis.
Excretion is mainly through the feces.

Following acute oral exposures of humans to high doses, up to 1,000 mg/kg,  of
zinc, symptoms including vomiting, diarrhea, lethargy,  and irritation of the
mouth,  throat and stomach may occur.  Acute symptoms of zinc toxicity from
exposure via inhalation include dyspnea, chest constriction, retrosternal and
epigastric pain, hoarseness, stridor, cough, lacrimation, expectoration and an
occasional hemoptysis.  Pale grey cyanosis usually develops, pulse is
elevated, fever is present and bronchopneumonia can develop.  Edema is
widespread.  Death is usually due to respiratory insufficiency.  Effects are
related to the hygroscopic nature of the inhaled zinc particles which combine
with moisture in the lungs to form caustic substances.

Oral exposures to zinc (as the gluconate) for longer periods of time
(6-12 weeks) were shown to reduce serum erythrocyte superoxide dismutase [E-
SOD] and ceruloplasmin (biomarkers of copper stakes) as well as HDL levels.

In animal studies, oral LDjgS  as  well  as  average lethal  oral  doses have been
reported for zinc compounds in several species.  Zinc chloride causes both
skin and eye irritation, and percutaneous toxicity has been demonstrated.
Oral exposure to approximately 100 mg/kg/day of zinc chloride for up to
six weeks has been shown to precipitate a deficiency syndrome when combined
with a synthetic diet low in pantothenic acid.  Renal damage was observed in
rats exposed orally to 190.6 mg/kg/day zinc acetate for 90 days.  Several
studies indicate that high doses of various forms of zinc can interfere with
reproductive function at doses as low as 25 mg/kg/day and is fetotoxic.

Mutagenicity and carcinogenicity studies have largely yielded equivocal or
negative results.  Zinc chloride was not mutagenic in a variety of bacterial
(Salmonella typhimumum. Escherichia coli. Saccharomyces cerevesiae) and rn
vitro mammalian (Chinese hamster ovary and embryo cells, human lymphocytes and
white blood cells) cell systems.  Zinc chloride also did not cause chromosomal
                                     ES-1

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aberrations in mouse bone marrow cells when administered to the animals in an
in vivo assay.


Health advisory values for zinc chloride are based upon measuring zinc (Zn**)
in water.  Based on the available animal toxicity data, the HA for One-day and
Ten-days is 5 mg/L for the 10 kg child.  The Longer-term HA for the 10 kg
child is 3 mg/L and for the 70 kg adult is 10 mg/L.  The Lifetime HA is
2 mg/L.  These values are considered protective against toxic effects for the
most sensitive members of the population.  The essentiality of zinc was
considered in the derivation of these HA values.  Currently, adequate
available data to assess the carcinogenic risk of zinc are inadequate.  Using
the EPA criteria for classification of carcinogenic risk, zinc chloride and
other zinc compounds currently meet the criteria for category D, not
classifiable as to human carcinogenicity.  This category is for agents with
inadequate human and animal evidence of carcinogenicity or for which no data
are available.
                                     ES-2

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                       ZINC CHLORIDE AND OTHER ZINC COMPOUNDS

I.  INTRODUCTION

   The Health Advisory (HA) Program, sponsored by the Office of Water (OW),
   provides information on the health effects, analytical methodology 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 Advisories 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 percent of an individual's lifetime) and
   lifetime exposures based on data describing noncarcinogenic end points of
   toxicity.  For those substances that are known or probable  human carcinogens,
   according to the Agency's 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 linearized multistage model with 95% upper confidence
   limits on risk.   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 and Probit models.  Current understanding of the
   biological mechanisms involved in cancer do not suggest that any one of these
   models is able to predict risk more accurately than another.  Because each
   model is based upon differing assumptions, the estimates that are derived can
   differ by several orders of magnitude.

   The major emphasis of this Health Advisory is on zinc chloride.   However,
   because in water zinc chloride and other zinc compounds hydrolyze to form
   ionic zinc (Zn**),  a review of  zinc  chloride health effects must  include
   observations and data associated with all forms of ionizable zinc compounds.
   Throughout this document when the term "zinc" is used without identifying it
   as a salt (e.g., chloride, acetate, sulfate, etc.) or other compound (e.g.,
   zinc oxide), it refers to the ion.
                                         1-1

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II.  GENERAL INFORMATION AND PROPERTIES

    Cas No.

         Zn:         7440-66-6
         ZnCl2:       7646-85-7
         ZnS04-7H20:  7446-20-0
         ZnO:         1314-13-2

    Synonyms
         Zn:  Zinc
         ZnCl2:   Zinc  chloride, butter  of  zinc;
         ZnS04-7H20:   Zinc sulfate heptahydrate, Op-Thal-Zin, Verazinc;
         ZnO:   Zinc oxide,  flowers of zinc, philosopher's wool,  zincite
    Worldwide yearly production of zinc averages several million metric tons.
    Annual industrial demand in the United States is 1.5 metric tons.   Zinc metal
    is used extensively in the United States in the machine,  building and
    automotive industries as a component of galvanized steel  (NRC,  1979).  Zinc
    oxide, the most important inorganic zinc compound, is used in the rubber
    vulcanizing process,  pigments, paints, ceramics and Pharmaceuticals.   Zinc
    sulfate is used in plastics production; zinc chloride is  used in batteries;
    zinc sulfide and zinc silicate are used as phosphors in cathode ray tubes; and
    zinc chromate is used as a wood preservative.  Zinc chloride,  zinc gluconate,
    zinc oxide, zinc stearate, and zinc sulfate are used as additive nutrients in
    foods and dietary supplements; zinc carbonate is used as  a dietary supplement
    for farm animals.  Zinc borate is used as a fire retardant.  Zinc sulfate and
    zinc chloride are added to potable water to reduce corrosion.

    Zinc chloride is a highly deliquescent, white, granular or crystalline
    substance that is used commercially in textiles, adhesives, wood preservation,
    embalming fluids, deodorants and numerous other commercial processes.  It has
    been used medicinally as a dentifrice, astringent and antiseptic and is used
    by the military as a screening smoke.  Zinc chloride is highly soluble in
    water and several organic solvents.  It fluoresces in solution, and the
    hydrated form evaporates to produce a white, semi-solid mass similar in
    consistency to butter, hence its synonym, butter of zinc.   Its chemical and
    physical properties are listed in Table II-l.

    Zinc chloride is produced by the action of hydrochloric acid on zinc, zinc
    oxide or zinc sulfide ore (Cumpston, 1983) and may be purified by
    recrystallization.  The commercial product is 95% pure with the remainder
    being water and some oxychloride (ZnCl2-ZnO) (Hill et al.,  1978).   It is
    trimorphic in nature with «-,  £- and y-forms.  The commercial product is
    either «-, y-, °r «- plus -y-zinc chloride (Farnsworth and Kline, 1973 as cited
    in Hill et al., 1978).

    In its solid form, zinc chloride is odorless but corrosive; as an aqueous
    solution it is highly acidic and may cause chemical burns.  Its fumes act as
    an irritant to the eyes and mucous membranes.  Zinc chloride smoke, (the
    military screening agent), is produced when mixtures of zinc oxide,
    hexachloroethane (HCE) and 10% calcium silicide or, more  recently, 9% grained

                                         II-l

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aluminum is ignited.   The resulting chemical reaction produces mostly
particulate zinc chloride along with free carbon, calcium carbonate and silica
(Macaulay and Mant,  1963).  The highly hygroscopic zinc chloride combines with
the moisture in the  air to produce hydrochloric acid and zinc oxychloride.  In
an enclosed space,  the particulate zinc chloride can be inhaled and hydrolyzed
in the lungs,  resulting in widespread mucosal damage.
                                     II-2

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                                                                              Table 11-1
                                                         Chemical and Physical Properties of Zinc Compounds'
u>
Properties.
Chemical Formula
Atomic/Molecular Weight
Physical State (25'C)
Boiling Point
Melting Point
Density
Vapor Pressure
Water Solubility
Specific gravity (25'C)
Log Octanol/Water
Partition Coefficient
Taste Threshold (Water)
Odor Threshold (Water)
Zinc
Zn
65.38
Solid; bluish-white.
lustrous metal
908' C
419.5'C
7.U (25'C)
1 mm Hg (487* C)
Insoluble
7.U
Not applicable
None found
None found
Zinc chloride
ZnCl2
136.29
Solid, white hexagonal
crystals or powder,
deliquescent
732'C
290'C
2.91
None found
432 g/100 ml <25'C)
2.91
None found
None found
None found
Zinc sulfate
heptahydrate
ZnS04 -7H20
287.54
Solid, rhombic crystals
efflorescent
2BO'Cb
100'C
1.96
1 mm Hg (428*C)
96.5 g/100 mt (20'C)
1.96
None found
None found
None found
Zinc oxide
ZrO
81.4
Solid, white hexagonal
crystals
None found
1,975'C
5.67
None found
Insoluble
5.67
None found
None found
None found
        "deferences: Budavarl, 1989; Weast, 1987; Sax, 1975)
          Temperature at which the water of hydratlon is lost.  No boiling point was available for ZnSo,.

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III. OCCURRENCE

     A.  Zinc Chloride

Zinc is  ubiquitous in nature, found in most foodstuffs,  water and air, and an
essential trace nutrient.  Zinc in the soil is taken up by plants.  The
average  daily consumption is estimated at 12-15 mg, mostly from food (Klaassen
et al.,  1986).   Zinc chloride, an inorganic salt of zinc, is produced by the
action of hydrochloric acid (HC1) on zinc or zinc oxide.  Its introduction
into the environment may result from industrial effluent from such processes
as galvanizing, wood preservation, soldering, dry-battery cell production, and
organic  synthesis.  It also may enter the environment via military screening
smokes,  primarily hexachloroethane/zinc oxide smokes, where the principle end
product  of combustion is zinc chloride.

When hexachloroethane (HCE) smoke, containing approximately 47.5% zinc oxide,
is detonated, the principle component of the reaction product is zinc
chloride.  Cullumbine (1957), as cited in Hill et al. (1978), estimated that
for every 100 g of HCE smoke mixture used, approximately 40 g of zinc chloride
is released.  Complete combustion of a typical HCE smoke pot, with an HCE
charge capacity of 13.6 kg would generate approximately 545 g of zinc
chloride.  Helm et al. (1971), as described by Heimburger (1977), reported a
concentration in air of 4 g zinc chloride/m3 and 0.1 g ZnO/m3 following
detonation of a smoke flair.

Under conditions of high humidity, the highly deliquescent zinc chloride, with
a particle size of approximately 0.1 microns, reacts with water droplets to
form highly acidic, highly caustic zinc compounds with a particle size of up
to 3 microns.  The reaction products are known as zinc oxychlorides.   Further
hydrolysis can result in the formation of zinc hydroxide and hydrochloric acid
(Heimburger, 1977).

When smoke is generated in a closed environment, under conditions of low
humidity, the zinc chloride particles remain and may be inhaled, passing deep
into the respiratory passages.  It is here that they react with the moisture
in the lungs to produce the highly corrosive products responsible for the
severe damage seen after inhalation exposure (Heimberger, 1977).

As a part of a risk analysis for exposure to high concentrations of zinc
chloride, air samples were collected following the burning of M5, HCE smoke
pots under controlled conditions Stocum and Hamilton (1976).  Analysis of the
particles collected on membrane filters indicated a geonetrie mean
concentration of 1.1 g/m3.   A maximum concentration of 8.5 g/m3  was calculated
for a 12 minute emission time.

When zinc chloride comes into contact with water, it dissociates to its ionic
form and combines with substances in the water to form various hydroxides as
well as insoluble precipitates with other ions (Hill et al., 1978).

     B.  Other Zinc Compounds

Zinc is a naturally occurring element found in the earth's crust at an average
concentration of 123 ppm (mg/kg)  (Weast, 1987).  The zinc concentration
averages about 70 ppm (mg/kg) in most rock-forming minerals.  The zinc content

                                     III-l

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in soil is highly variable, averaging about 54 ppm (mg/kg); it is generally
higher near industrial locations or highways owing to emissions and tire wear.

Zinc concentration in sea water averages about 8 ng/L; fresh water has varying
amounts of zinc but averages about 64 ng/L (NRC, 1979).  The highest mean
value for dissolved zinc was found in the Lake Erie basin at a level of
205 ng/L while the lowest mean of 16 Mg/L was recorded in the California
basin.  While it is present at only trace levels in most surface and ground
waters, it has been detected at levels as high as 50 mg/L in mining areas
(Hill et al., 1978).In natural waters, zinc can be found in several chemical
forms (e.g., as simple hydrated ions, as inorganic complexes or as
organometallic complexes) (Cotton and Wilkinson, 1972).

Zinc occurs chiefly as the minerals sphalerite (ZnS), smithsonite (ZnC03),
willemite (ZrijCrC^)  and  zincite  (ZnO);  it also  replaces magnesium  in silicate
minerals to some extent and is found in most igneous rock (Cotton and
Wilkinson, 1972).

Zinc is ubiquitous in all living cells, is a constituent of over 200
metalloenzymes and is involved in most major metabolic pathways (NAS, 1989;
McClain et al., 1985; Prasad, 1985).

Meats, fish and poultry are the richest sources of zinc in foods, and they
contribute 40-50% of the total daily intake of zinc to the diets of older
children and adults.  Dairy products and grains are also good sources of zinc.
They each contribute 10-13% of the zinc in the  adult diet.  Dairy products
play a more important role as sources of zinc in the diets of young children
(Pennington and Young, 1991).

The National Research Council (1989) estimates that, in the United States,
typical mixed diets furnish between 10 and 15 mg zinc/day.  A comprehensive
analysis, based on 3-day intake records of 150 individuals showed that the
average daily zinc intake from food was 12 ± 5.5 mg/day for men and 9.5 ±
0.8 mg/day for women (Bowerman and Harrill, 1983).  Women in the 19- to
50-year-old groups had the lowest average zinc intake with only 8.7 ±
4.5 mg/day.  Spencer and Gatza (1980) found an average daily intake of
12.5 mg/day from the analysis of institutional metabolic diets over a 10-year
period.  In another analysis of dietary food composites from 22 subjects,
average zinc intake was 8.6 ± 0.5 mg/day  (Holden and Wolf, 1979).

During the period from 1982 to 1989, the average zinc intake for United States
adults (as determined by the Food and Drug Administration Total Diet Study)
was 9-16 mg/day (Pennington and Young, 1991).  The zinc in the diet was not
sufficient to meet the Recommended Dietary Allowance (RDA) for young children,
adolescent females or adult females.  In addition, the zinc intake from the
diet was below the RDA for elderly males and females (Pennington and Young,
1991) .  Recent surveys of the American population indicate that there is no
widespread occurrence of zinc deficiency in individuals consuming a balanced
diet selected from the available food supply, although zinc intakes are lower
than recommended, particularly in women  (Pilch, 1989).

The average zinc concentration in tap water across the United States is
0.245 mg/L  (Greathouse and Craun, 1978).  The highest mean value reported for
tap water zinc concentrations from standing water in galvanized pipes is
1.979 mg/L  (Sharrett et al., 1982).

                                     III-2

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IV.  ENVIRONMENTAL FATE

         A.  Zinc Chloride

    Ignition of zinc-containing smokes results in the dispersion of additional
    zinc chloride into the environment.   Hydrolysis is the main transformation
    process  for zinc chloride in both air and water.   In air,  zinc  chloride
    hydrolyses with the available moisture to form hydrochloric acid and zinc
    oxychlorides (ZnClj-ZnO).   In high-temperature  hydrolysis  studies,  zinc
    chloride had a half-life of 17,000 minutes in the aerosol  state.   Similar
    studies  were not available for environmental temperatures  at various relative
    humidities (Spanggord et al., 1985).

    Once introduced into the water,  zinc  chloride is  rapidly transformed by
    hydrolysis to zinc ions (Zn**) and chloride  ions  (Cl"*.   The ionic zinc may
    then react to form such chemical species as Zn(OH)*,  Zn(OH)*3 and Zn(OH)2.  In
    very basic solutions, zincates may form.  The zinc ion also forms insoluble
    precipitates with carbonates, sulfides,  phosphates and silicates present,
    resulting in the immobilization of zinc in the water (Hill et al.,  1978).

    In soil, adsorption plays a major role.   The fate of zinc  in soil is highly
    dependent upon pH and oxygen availability as well as various physical
    characteristics of soil.  Zinc chloride is not likely to be affected by
    photolysis, vaporization, or biotransformation processes.

         B.  Elemental and Ionic Zinc

    Zinc, as a trace element, is carried by prevailing winds from natural and
    anthropogenic sources to remote marine environments.  The  transport of zinc in
    the aquatic environment is controlled by the speciation of the  ion.  In most
    unpolluted waters, zinc exists mainly as a divalent cation and  is easily
    absorbed by hydrous metal oxides and clay minerals.  In polluted areas,
    organic  material has a significant effect on the  chemical  form  of zinc.
    Precipitation of zinc compounds appears to be important only in reducing
    environments or highly polluted waters.   Photolysis and volatilization of zinc
    are not  likely in an aquatic environment (Callahan et al., 1979).

    Concentrations of zinc in suspended and bed sediments always exceed
    concentrations in ambient waters (Angino et al.,  1976), and an  inverse
    correlation exists between zinc concentration in the sediment and sediment
    grain size (Perhac, 1974b; Pita and Hyne, 1975),  which implies  that sorption,
    rather than precipitation, is responsible for this phenomenon.

    The composition of the dissolved and suspended solids load has  an important
    effect on the mode of transport of zinc in ambient water.   In cases where the
    solids are primarily dissolved, most of the zinc  in ambient water is
    transported in solution as the hydrated cation or complex  species (Perhac,
    1972, 1974a; DeGrott and Allersma, 1975).  In cases where  suspended solids
    make up a high proportion of the total solids load, most of the zinc
    transported will be sorbed to the suspended and colloidal  particles (Kubota
    et al.,  1974; Steele and Wagner, 1975).   Residence in impoundments reduces the
    concentration of dissolved zinc, apparently due to scavenging by suspended
    solids and subsequent deposition (Pita and Hyne,  1975; Perhac,  1974b).
                                         IV-1

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The tendency of zinc to be adsorbed is also affected by pH,  salinity, and the
concentration of complexing ligands.   In a study of heavy metal adsorption by
two oxides and two soils,  zinc was completely removed from solution when the
pH exceeded 7; below pH 6, little or no zinc was adsorbed (Huang et al.,
1977).  Helz et al.  (1975) found that zinc was desorbed from sediments as
salinity increased;  this,  apparently, was due to displacement of the adsorbed
zinc ions by alkali  and alkaline earth cations which are abundant in brackish
and saline waters.  Addition of inorganic complexing ligands enhanced the
affinity adsorption  of zinc (Huang et al., 1977).

Colloidal and suspended organic matter also adsorb zinc.  Rashid (1974)
reported that about  26.1 mg of zinc were adsorbed per gram of sedimentary
organic matter added to a solution of zinc.

Holmes (1977) concluded that formation of zinc sulfide controls the mobility
of zinc in Corpus Christi Harbor (an estuarine system).  Seasonal fluctuations
in dissolved zinc levels were attributed to variations in reduction-oxidation
potential.  In studying an impoundment polluted with zinc (400 ng/L)
introduced by the dumping of mine wastes, Weatherley and Dawson (1973) found
that zinc was precipitated as an amorphous colloidal deposit of basic
carbonates and sulfates.  Under oxidizing conditions, precipitation of these
zinc compounds is probably important only where high concentrations of zinc
exist.

Zinc is ubiquitous in soil with levels ranging from 10-300 mg/kg (Hill et al.,
1978).  In general,  Zn** is retained  in  the  top  few  centimeters  (5-10  cm).
Its movement through soil is affected by various factors,  with movement
facilitated by anaerobic conditions and in acidic soil.

Adsorption of zinc ions in the soil is facilitated by the presence of hydrous
oxides of iron, aluminum and manganese, giving rise to hydrous -oxide zinc
compounds.  Adsorption is also facilitated in finely divided soils such as
silt, clays and colloids.   Zinc has been shown to precipitate near the surface
in soils containing calcium carbonate or lime or in soils high in organic
content.  Zinc-soil  complexes also are formed.  At pH 7.7 and below, Zn**  is
found in equilibrium with soil zinc while above that pH, Zn(OH)2 predominates
(Hill et al., 1978).  Addition of a digested sewage sludge containing
4,300 mg/kg of zinc  to soil during eight growing seasons showed that 46% of
the applied zinc was retained in the soil (Hinesly et al., 1977).

From its natural presence in water and soil, zinc has been shown to accumulate
in biological species.  Application of a fertilizer containing 129 mg/kg of
zinc resulted in accumulation of the zinc in grains, leaves and legumes but
not in roots, squashes and tomatoes (Schroeder et al., 1967).

Hill et al. (1978) reported that marine species accumulate zinc, with tissue
levels measured at 6-1,500 mg/kg (EPA, 1976).  Application of 10 millicurie of
65zinc by spraying a pond  surface resulted in a  rapid movement  of the  zinc
from water to sediments to organisms with 36% in sediment, 5% in biota and the
remaining 59%, mainly as suspended material, in water after the first 24 hours
(Duke, 1967).  Maximum levels were reached in organisms after 2 days, while
0.6% was found in biota and 99.4% in sediment after 100 days.

Wildlife and domestic animals also accumulate zinc, mainly in muscle.  Over a
45-year period, the human body accumulates zinc to levels of 30-60 mg

                                     IV-2

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(Schroeder et al.,  1967).   As the infant body contains little or no zinc, an
accumulation rate  of 0.67-1.3 mg/year has been calculated.
                                     IV-3

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V. TOXICOKINETICS

    The toxicokinetics of zinc have been well studied in animals and humans.  Zinc
    is absorbed moderately well following oral intake.  Absorption through the
    skin is minimal while data on absorption following inhalation of particulate
    zinc is limited.  Radiolabeled zinc was mainly distributed to the intestines,
    prostate,  liver and kidney with kidney levels remaining highest after
    intravenous administration.  Metallothionein plays an important role in
    regulating zinc homeostasis.   Excretion is mainly through the ^eces.

         A. Absorption

         1. Zinc Chloride

    Payton et al. (1982) reported on a method for determining human zinc
    absorption following oral administration.  Intestinal absorption was
    determined from the ratio of 65[Zn]-zinc  chloride  and a non-absorbed
    radioactive marker, 51 [Cr] -chromic  chloride.  The  marker had no effect on zinc
    absorption and had a intestinal transit time similar to that of zinc.
    Absorption was measured by both whole body and stool counting.  Retention was
    determined from the proportion of the dose remaining in the body 7-10 days
    after administration.  Doses were administered to 17 healthy adult volunteers
    (sex not specified) ranging in age from 18-46 years.  The individuals were
    fasted overnight prior to dosing.  An initial dose-response study indicated
    that approximately 55% of the administered 65zinc  chloride was absorbed  at
    doses of 18, 45 and 90 nmol of zinc.  Absorption was reduced with increasing
    dose, indicating that zinc absorption is saturable.  At a test dose of
    900 nmol,  only 25% of 65Zn was  absorbed.
    Further studies were conducted by Payton et al .  (1982) using a dose of 92
    of 65zinc with the  chromium marker.  Results of  zinc absorption, as measured
    by dual isotope stool counting or whole body counting, and zinc body
    retention,  as measured by whole body counting 7-10 days after dosing, were
    comparable.  Among 16 healthy individuals, average initial absorption as
    measured by body counting was 48% and by stool counting 50% ,  with a close
    correlation between individual results by the two methods.  No significant
    differences were found between sexes .   Absorption values corresponded closely
    with the predicted mean absorption of 48%, corrected for endogenous excretion.
    Similar studies were conducted in ostomy patients, patients with celiac
    disease in relapse and in one patient with radiation injury of both small and
    large intestine.  There was no difference in absorption among the ostomy
    patients but those with intestinal malabsorption showed a significant decrease
    in absorption  (average 30%).   This finding indicated the importance of the
    proximal intestinal mucosa in the absorption of inorganic zinc.

    Hill et al. (1978) reviewed the absorption studies of zinc chloride in animal
    species and concluded that there were conflicting results.  In a study by
    Feaster et al . (1955), only 5% of a single .tracer dose was absorbed in adult
    female rats over 24 hours.  In contrast, Methfessel and Spencer (1973)
    reported that  25% of a dose of labeled 65zinc  chloride was  absorbed within 30
    minutes of oral intubation.  There was little increase in zinc uptake from the
    gastrointestinal tract over the next 6 hours.

    Four healthy men were given three different oral doses of tracer TOzinc
    (expressed as  mg 70zinc  chloride)  at weekly intervals  against  a background of

                                          V-l

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15 mg/day dietary zinc.  Absorption was 81% from a 4.52-mg tracer dose, 77%
from a 6.47-nig tracer dose, and 61% from a 24.52-mg tracer dose.  For a 70 kg
man the doses were approximately 0.06 mgAg. 0.09 mg/kg and 0.35 mg/kg
respectively.  A linear increase in absorption of dietary zinc within the
range 4.52 to 24.52 mg zinc and a decrease in fractional absorption with
larger zinc doses were observed.  A reduction in dietary zinc from 15 to about
1.6 mg resulted in a significant (p<0.005) increase in fractional zinc
absorption of the fixed tracer dose (1.19 mg) from 81 to 92%. Thus, the dose
of zinc has a significant effect on its fractional absorption, and dietary
restriction of zinc results in prompt increase of zinc absorption (Istfan
et al., 1983).

In a study by Methfessel and Spencer (1973), 65zinc  as  the  chloride  salt was
instilled in vivo into ligated sacs formed from the duodenal portion of the
small intestines of rats.  The absorption of 65zinc  was  significantly  greater
from the duodenum than from the more distal portions of the small intestine.
The mid jejunum and ileum exhibited similar absorption; only minimal amounts
were absorbed from the stomach, cecum and colon.

Uptake of 65zinc  from  labeled  zinc  chloride  was  measured in four 10-cm
consecutive intestinal segments of weanling pigs starting 1 cm distal to the
pylorus.  Data from a continuous-flow in vitro perfusion system for noneverted
sacs, revealed no significant differences attributable to gut segment position
(Hill et al., 1987).

Skog and Wahlberg (1964), indicated that absorption following percutaneous
application was minimal when solutions of 0.08-4.87 M aqueous "zinc chloride
were applied to the skin of guinea pigs.  In these studies less than 1% of the
administered dose was absorbed over 5 hours.

Absorption following inhalation of particulate zinc chloride by five soldiers
from a smoke ammunition bomb was indicated by a slow (rate not reported)
increase in plasma zinc levels following exposure for two minutes or less
(Hjortso et al., 1988).  Treatment with acetylcysteine, a heavy metal
chelating agent, by either intravenous infusion or nebulization resulted in
increased urinary zinc excretion.

     2. Other Zinc Compounds

The absorption of zinc is similar in humans and other mammalian species and is
affected by the amount of zinc ingested, physiological need, the fiber content
of the diet, and the ratio of dietary zinc to other divalent cations  (Davies
and Nightingale, 1975; Greger, 1992; NRC, 1989; Seal and Heaton, 1983;
Solomons and Jacob, 1981; Turnlund et al., 1984; U.S. EPA, 1987).

Numerous studies indicate that zinc absorption is regulated, in part,  by the
zinc content in the intestinal mucosa, which, in turn, is regulated by the
zinc content of plasma (Evans et al., 1973; Ansari et al., 1976; Weigand and
Kirchgessner, 1978; Cousins, 1985). The zinc absorption process includes both
passive diffusion and a carrier-mediated process (Tacnet et al., 1990).  A
cysteine-rich low molecular weight protein has been identified in the
intestinal mucosa which may be responsible for the carrier-mediated process
(Hempe and Cousins, 1991).  This protein bound nearly 50% the radiolabeled
zinc entering the intestinal cells from the lumen in ligated loops of the
small intestine of anesthetized rats when the zinc concentration was 5 iiM, but

                                      V-2

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only 25% of the label when the concentration was 300 ^M.  This suggests that
the cysteine-rich protein has a limited binding capacity for zinc and is
saturated when the intestinal concentration of zinc is high.

The zinc in animal products has a higher coefficient of absorption than that
from vegetable products.  Phytates (inositol hexaphosphate) present in whole
grains adversely affect the bioavailability of zinc by reducing its absorption
(Mason et al., 1990; Sandstead et al., 1990).  The concentrations of iron and
calcium in the diet can also decrease zinc absorption (Dawson et al., 1989;
Sandstead et al., 1990; Solomons, 1982).

The typical American diet favors zinc absorption since it includes a high
consumption of meat and dairy products.  Zinc absorption from different diets
(e.g., vegetarian, high fiber) can be considerably lower.  Many studies report
zinc absorption of only 20-30% (Sanstead, 1973).  Recent guidelines use an
absorption coefficient of 20% to account for the lower absorption of zinc from
fiber-rich diets (NRC, 1989).

Studies using everted sacs of rat duodenum and ileum revealed that zinc uptake
was greater in the duodenum than the ileum and was influenced by the pH of the
medium.  Reducing the pH of the incubation medium from 7.3 to 6.4
significantly decreased zinc uptake (p<0.001) by the duodenal sacs from
23.4 ± 0.9 to 15.2 ± 1.5 ng/g dry tissue (mean ± SE) after 30 minutes of
incubation. Increasing the pH from 7.3 to 8.3 also significantly decreased the
uptake of zinc (p<0.001) by the ileal sacs from 13.0 ± 0.5 to 8.6 ± 1.1 ng/g
dry tissue (mean ± SE) per 30 minutes of incubation.  Zinc uptake from salts
varied in the following order: zinc acetate>zinc sulfate>zinc chloride>zinc
phosphate> zinc citrate.  Addition of aspartic acid and/or histidine to zinc
chloride increased the uptake, and addition of galactose and lactose decreased
it (Seal and Heaton, 1983).

     B. Distribution

     1. Zinc Chloride

Upon post-mortem examination of two victims (death from respiratory
complications) of inhalation exposure to a zinc chloride smoke bomb, Hjortso
et al. (1988) reported that the striated muscle showed elevated zinc levels
when compared to tissue of non-zinc chloride exposed trauma victims.  Only one
of the victims showed elevated levels of zinc in lung tissue.  All other
tissue zinc levels were within normal limits.

Average total body retention of 65zinc  administered  orally  as  zinc chloride
was measured after an overnight fast in 50 patients with taste and smell
dysfunction (Aamodt et al., 1986).  There were no significant differences
(pX).25) in zinc retention between the first phase of the experiment (days
1-21) and the second "placebo" phase of the experiment (days 22-336).  During
the third phase of the experiment (112-440 days, mean 307 days), 14 patients
were continued on the placebo and 36 patients received zinc sulfate (100 mg
Zn^/day).   The  latter group  demonstrated an accelerated loss  of total body
zinc  (shortened biological half-time of 235 ± 8 days; mean ± SEM), which was
significantly different (p<0.001) from the placebo-treated group (biological
half-time of 384 ± 8 days; mean ± SEM).  Accelerated loss of 65zinc  from the
thigh muscle was apparent immediately; however, loss from the liver began


                                      V-3

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after a mean delay of 107 days.  There was no apparent effect on loss of
65zinc  activity  from  red blood cells.

Feaster et al.  (1955) reported that the highest concentrations of radio-
activity, were recovered in the kidney, liver and pancreas, 4 days following
the oral administration of a single tracer dose of 65zinc  chloride  to female
rats.  Relatively little radioactivity was recovered from the muscle, hide  and
hair, and bones.

Six hours after oral administration of 0.1 jiCi of 65zinc as  zinc  chloride  to
30 Wistar rats (sex not reported), highest levels of radioactivity were found
in the small intestine followed by the kidney, liver and large intestine.
Smaller amounts were found in the lungs and spleen.  At 14 days after
administration, highest levels of radioactivity could be found in the hair,
testicles, liver and large intestines (Kossakowski and Grosicki, 1983).

Following oral intubation of 65zinc  (1 i»Ci of  *5zinc chloride, specific
activity 0.81 jiCi/mg zinc) in the intact  rat  ingesting a diet containing
40 ppm zinc, maximum radioactivity (0.09% of  the administered dose) was
attained in the whole blood at 30 minutes (Methfessel and Spencer, 1973).   The
activity decreased to about 0.045% at 1 hour  and to 0.01% at 24 hours.  Liver
and pancreas both had a 6*zinc concentration of  0.1%  (percent of  dose/g wet
tissue) at 15 minutes which increased to  0.6% at 8 hours and decreased to 0.3
and 0.2%, respectively, at 24 hours.  The uptake of 65zinc in femur and muscle
was generally low (0.01-0.17% over 24 hours).

Following intravenous administration of a single dose of 65zinc  (as zinc
chloride) in mice, the  liver contained 25%, and the pancreas, kidneys, and
small  intestines contained about 1.7-2.4% of  the administered label at
2-3 hours post-dosing (Sheline et al., 1943a).  Levels in bone tissue
increased from approximately 4-10% of the 65zinc dose/g  tissue during the
first week post-dosing.

In two dogs (sex not reported) administered a single IV dose of 65zinc (as
zinc chloride), radiolabeled-zinc levels  in erythrocytes during the first
24 hours post-dosing ranged from 1.9  to 3.2%  of recovered radioactivity and
were about 4% at the end of 1 week (Sheline et al., 1943a).  Approximately
9.5% of the radiolabeled-zinc appeared in skeletal muscles 3-8 hours post-
dosing.  The total radioactivity recovered 1  day after dosing was 13%; at
4 days, 35%; and at  7 days, 26%.

The  tissue uptake of radiolabeled 15  yCi  65zinc  (as the  chloride  salt)  was
determined in adult male Vistar rats  following a bolus intraperitoneal
injection (Pullen et al., 1990).  For each of the 12 organs evaluated there
was  a  straight line  relationship of uptake with time.  The regression
coefficients for the uptake plots were calculated; the liver displayed the
greatest uptake of zinc  (2.14 E-2 mL/min/g),  followed by the kidney  (1.30),
pancreas  (1.25), spleen (1.03), ileum  (0.91), lung (0.52), heart (0.43), bone
(0.42), testis  (0.15).  blood cells (0.12), muscle  (0.06) and brain (0.05),  all
in units of E-2 mL/min/g.  Additional data on zinc uptake by the brain
indicate that the blood-brain barrier is  minimally permeable to zinc.

Eight  hours following intravenous administration of 65zinc chloride to
rabbits, tissue levels  were highest in the liver, intestine and kidney with
levels reported as being 2 10%/g in tissue  (Lorber et al., 1970).  Sheline  et

                                      V-4

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al.  (1943b)  injected a total of 31 mice and 5 days (sex and strain not
reported for either species) with an unspecified dose of 65zinc  chloride.   In
mice,  at 8 hours post-dosing, 17% of the dose was recovered from the liver,
while  levels in the small intestine, colon, kidney, spleen and stomach were
between 10%  and 1%.  Percentage recovery from the liver remained high (3.3%)
up to  170 hours after injection.  In dogs, levels in the liver (34%), small
intestine (10%) and skeletal muscle (9.6%) were highest followed by kidneys,
pancreas, stomach,  colon and heart (i3.9%) at 8 hours after treatment.  As in
mice,  the liver levels of radioactivity remained elevated (il%) in the
170 hour assay.

     2.  Other Zinc Compounds

The body of  a normal human male weighing 70 kg contains approximately 1.4 to
2.3 g  of zinc.  About 20% of this total is thought to be present in the skin.
The highest  concentrations of zinc are found in the prostate (100 pg/g wet
tissue)  and  semen (100-350 ng/L).  Typical zinc concentrations (expressed as
Hg/g fresh tissue)  in other human tissues are: kidney, 55; liver, 55; muscle,
54;  heart, 33; pancreas, 29; spleen, 21; testes, 17; lung, 15; brain, 14; and
adrenal gland, 12 (U.S. EPA, 1987).

About  98% of serum zinc is bound to proteins (85% to albumin; most of the
remainder to a-2-macroglobulin).  Diffusible zinc in blood is associated with
albumin and  amino acids and not with a-2 macroglobulin (U.S. EPA, 1987).
Normal human serum zinc values are 75-120 ng/dL (Monsen, 1987) and are not
particularly valuable as indicators of zinc status (Grider et al., 1990; King,
1986).

Zinc is present in erythrocytes (92.4% as cofactor for carbonic anhydrase
isoenzymes and superoxide dismutase), leukocytes (mostly as zinc
metalloprotein), and platelets  (U.S. EPA, 1987).

Dietary supplementation of 600 ppm zinc as zinc oxide (a high, but not toxic,
level) in young Cherokee S-D albino male rats (9/treatment group), for periods
of 7-42 days, produced no change in the zinc levels of the tibia, liver,
kidneys, small intestines (first 15 cm), heart, muscle (semi-tendinous) and
whole  blood  (Ansari et al., 1975).  However, when a single gavage dose of
labeled 65zinc chloride in acetate  buffer (4 |*Ci) was  administered along with
the supplement 7 days prior to sacrifice, label retention of the tissues
declined sharply in direct proportion to the duration of exposure in rats that
had received the supplement for periods of from 7 to 21 days. The decrease in
the level of label in the tissues of the zinc-supplemented animals indicates
that the turnover of body zinc stores increases when the zinc load increases.
There  was no significant difference in the label retention in the animals
given the supplement for 21 or 42 days, suggesting that there are limits to
the body's ability to homeostatically adapt to continued exposure to excess
zinc.

In a different study, varying dietary levels of zinc were fed to rats for
21 days  (Ansari et al., 1976).  Zinc (as zinc oxide) was added to the diet at
levels of 1,200-8,400 ppm (in 1,200 ppm increments) for 21 days.  There was an
increase  (p<0.05) in the levels of zinc in the liver, kidney and tibia with
additions of 1,200 and 2,400 ppm to the diet.  The tissue levels of zinc
remained relatively constant for the 3,660, 4,800, 6,000 and 7,200 ppm


                                     V-5

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supplements but increased again with the 8,400 ppn supplement.  Zinc levels in
the muscle and heart were unaffected by any dietary level of zinc.

After 14 days, the rats were administered a single dose of labeled *5zinc  as
the chloride salt (29.8 i*Ci) 7 days before sacrifice (Ansari et al., 1976).
The label retention in all tissues was dramatically reduced by one to two
orders of magnitude in the animals receiving 1,200 ppm supplement as compared
to the controls,  indicating that the animals increased the metabolic turnover
of zinc in response to the increased zinc intake.  However, the presence of
additional zinc in the diet (up to 8,400 ppm) did not cause any additional
change in label retention.  In contrast to the soft tissues, the zinc label in
bone increased when supplemental zinc was increased from 3,600 to 6,000 ppm
and remained fairly constant with still higher intakes.  These results
indicate homeostatic adaptations in zinc turnover and absorption accompany
increases in dietary zinc to prevent the accumulation of zinc in the tissues.
Decreased absorption and increased turnover appear to regulate the body load
with dietary zinc concentrations of up to 1,200 ppm; decreased absorption is
more important than changes in turnover at dietary intakes higher than
1,200 ppm.

     C. Metabolism

Zinc is an essential trace nutrient and is a cofactor for the function of as
many as 200 enzymes including DNA and RNA polymerase,  carbonic anhydrase,
carboxypeptidase, aminopeptidase and superoxide dismutase (NAS, 1989).  The
essentiality of zinc in the human diet was recognized as the result of a
series of studies in which inadequate dietary zinc was determined to be the
cause of retarded growth and development of children in Iran, Egypt and
Australia (Holt et al., 1980; Prasad, 1991).  Inhuman and animal research,
adverse effects associated with inadequate dietary zinc include lethargy,
impaired taste acuity, impaired wound healing, delayed gonadal development,
abnormal dark adaptation, impaired immune response and dermatitis (Abernathy
et al., 1991; Prasad, 1991).

The protein metallothionein plays an important role in regulating zinc
homeostasis.  This low molecular weight protein is found in the liver,
kidneys, intestines, erythrocytes and other tissues.  It has binding sites for
cadmium, copper, mercury and zinc.  Nearly one third of the 61 to 62 amino
acids  in metallothionein are cysteines.  Metallothionein synthesis is induced
by zinc exposure, stress, endotoxins, steroid hormones and interleukin-1
(Nutrition Reviews, 1989).  Metallothionein is believed to act as a storage
protein for zinc and thereby help to maintain homeostasis.

     D. Excretion

     1. Zinc  Chloride

Richmond et al. (1962) reported an average biological half life of 154 days in
four human subjects following a single oral dose of 0.6-1.0 yCi of 65zinc
chloride.  The range was 149-161 days.

Sheline et al. (1943a) reported that mice intravenously injected with
radiolabeled  zinc chloride  (dose not specified) excreted over 50% of the dose
via the gastrointestinal  (GI) tract.  Approximately 20% of the dose was found
in the feces within the first 10 hours.  In contrast,  urinary excretion

                                      V-6

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 amounted to 2%  of  the  dose  over  170  hours  of recovery.   In  dogs  which also
 were  administered  65zinc chloride (dose not specified),  excretion in the feces
 was less,  with  only  25%  of  the dose  recovered over a 15  day period.   Less  than
 5% of the  dose  was excreted in the urine.

 After intravenous  administration of  65zinc chloride  (dose not specified) to
 male  Wistar rats,  Barrowman et al.  (1973)  reported that  the feces was the  main
 route of excretion with  the bile involved  in this process.   Over a  period  of
 48 hours,  4% of the  administered dose  was  recovered in the  bile, largely
 associated with a  low  molecular  weight protein and with  bile pigment.

 Rats  receiving  a single  intravenous  injection of 65zinc chloride (0.012 or
 0.020 mM zincAg)  excreted  31-42% of the radioactivity in the feces within
 75-92 hours of  injection (Bruner, 1950).   In mice, after a  single IV injection
 (0.33-1.6  |ig 65zinc chloride), more than 50% of the *5zinc dose was  present in
 the feces  and 20%  was  present in the urine at the end of a  170-hour
 observation period.  Dogs administered a single IV injection of  65zinc (5.7 or
 6.5 jig 65zinc chloride) excreted 25% of the radioactivity in the feces and
 less  than 5% in the  urine over a 15-day observation period  (Sheline et al.,
,1943b).

      2.  Other Zinc Compounds

 In humans  and other  mammalian laboratory species, fecal  excretion is the
 predominant route  of zinc loss  (as much as 70-80% of the ingested amount),  and
 urinary excretion  is a relatively insignificant route (1-2% of the  ingested
 amount)  (U.S. EPA, 1987).   A portion of the zinc excreted with the  fecal
 matter represents  absorbed  zinc  that is lost from the body  with  the bile
 (Wastney et al., 1991).

 In one study of six  healthy adult human males fed conventional foods,  five
 were  able to maintain  zinc  balance  in  the  tissue (equivalence between dietary
 zinc  and total  excretory zinc) at an intake of as little as 5.5  mg/day (King,
 1986).  Balance apparently  was achieved by a decrease in the fecal  excretion
 of zinc which may  have resulted  from either an increase  in  zinc  absorption
 and/or a decrease  in the zinc lost  in  the  gastrointestinal  secretions.

 Following dietary  supplementation of rats  with zinc (as  zinc oxide)  at 600 ppm
 for 7-42 days (Ansari  et al., 1975)  or at  1,200-8,400 ppm for 21 days (Ansari
 et al.,  1976) and  intubation with an oral  tracer dose of 65zinc (4 pCi 65zinc
 chloride,  specific activity 2.1  |iCi/mg zinc),  there was  a linear increase  in
 fecal excretion of stable zinc  in proportion to the dietary intake.   The fecal
 excretion of the labeled zinc increased as concentrations increased to
 1,200 ppm and then remained relatively constant with the higher  supplemental
 doses.

 Rats  receiving  the same  amounts  of  different zinc salts  in  their diets
 (53.2 ppm of either  zinc chloride,  zinc sulfate,  zinc phosphate  or  zinc
 citrate) over a 4-day  period, excreted similar amounts of fecal  zinc
 (87.0-98.1% of  intake) and  urinary  zinc (1.43-2.04% of intake)  (Seal and
 Heaton,  1983).   Balance  studies  showed no  differences in fecal excretion,
 total excretion or retention of  zinc among rats receiving diets  containing
 different forms of zinc.
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VI. HEALTH EFFECTS

         A.   Health Effects in Humans

    Following acute oral exposures of humans to high doses of zinc, symptoms
    including vomiting, diarrhea,  lethargy, and irritation of the mouth, throat
    and stomach may occur.  Acute  symptoms of zinc toxicity from exposure via
    inhalation include dyspnea, chest constriction,  retrosternal and epigastric
    pain, hoarseness, stridor,  cough, lacrimation, expectoration and an occasional
    hemoptysis.  Pale grey cyanosis usually develops, pulse is elevated, fever is
    present and bronchopneumonia can develop.  Edema is widespread.  Death is
    usually due to respiratory insufficiency.  Effects are related to the
    hygroscopic nature of the inhaled zinc particles which combine with moisture
    in the lungs to form caustic substances.  Zinc chloride is corrosive to skin
    and mucous membranes.   Oral exposures to zinc acetate for longer periods of
    time (6-12 weeks) were shown to reduce serum erythrocyte superoxide dismutuse
    (E-SOD) and ceruloplasmin (biomarkers of copper status) as well as HDL levels.

    All of the reports of health effects in humans are based upon studies with
    small numbers of subjects.   Therefore, they may not reflect the responses of
    the general population because of variabilities due to factors such as sex,
    age, race, etc.

         1.   Short-Term Exposure

         a.   Zinc Chloride

    Data concerning the effects of zinc chloride in humans after short-term oral
    exposure are limited to a few case reports.  These are described below.

    In 1981, Potter reported on a single case of ingestion of 4 oz of an acid
    soldering flux containing zinc chloride (11% as measured by atomic absorption
    spectrophotometry) by a 28-month old child weighing 13.1 kg (approximately
    1,000 mg/kg)•  The child vomited twice within 5-10 minutes, before admission
    to a hospital for emergency treatment.  Subsequent vomitus contained Hematest-
    positive material.  Although the child was lethargic, no adverse effects were
    noted upon physical examination except for an increase in serum zinc levels at
    a high of 1,944 jig/dl approximately one hour after ingestion.  Twelve hours
    after the administration of a single dose of 150 mg of calcium disodium
    ethylenediamine-tetra acetic acid (EDTA) in 75 mL of 1:5 normal saline, the
    serum zinc level was 134 |ig/dl (normal values are 77-137 ng/dl).
    Esophagoscopy was generally normal except for some minor bleeding from mucosal
    abrasions.  Radiologic examination of the skeleton, electrocardiographic
    examination of the heart and detailed neurological evaluations were all within
    normal limits.  Two years after the incident, the condition of the child
    remained unremarkable.  It was felt that the powerful emetic properties of the
    zinc chloride prevented absorption of the ingested dose thereby limiting
    systemic effects.

    In a similar incident reported by Chobanian (1981), a 24-year old male
    ingested 3 oz of a solder flux containing zinc chloride (concentration not
    specified).  Symptoms were manifested as an immediate burning of the mouth and
    throat and were accompanied by severe abdominal pain, nausea and vomiting.
    While vital signs were normal, the patient developed indications of lethargy.
    Abnormal laboratory findings included elevated white cell counts, blood sugar,

                                         VI-1

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amylase and zinc while the serum calcium was mildly decreased.   Urinalysis
disclosed a microhematuria without casts or other cellular elements.  Physical
examination revealed erythema,  edema and erosion of the pharynx and esophagus
without ulceration.   A mild diffuse erythema of the stomach was evident.
Within 24 hours of chelation therapy serum zinc levels were normal,
50-90 ng/dl, while the microhematuria persisted over the next 72 hours with no
signs of renal dysfunction.  Clinical signs, in this case, were suggestive of
acute pancreatitis.   This is consistent with zinc in the pancreatic
secretions.  Pancreatic damage  might account for the increased serum glucose
levels encountered in this individual.  The amount of zinc chloride ingested,
in mg/kg, could not be determined from the available information.

Markwith (1940) reported on a single case of industrial intoxication occurring
in a closed environment due to  exposure to solders that contained copper and
zinc chloride.  Clinical symptoms included malaise, headache, chills and pain
on swallowing.  Physical examination revealed a reddening and loosening of the
mucous membranes of the mouth and throat, followed by the membranes becoming
dry and leathery until swallowing became impossible.  On the 10th day
following exposure,  a carbuncle formed on the chin.  The patient died on the
13th day with clinical signs of sepsis.

A number of studies reported toxic effects in humans following the inhalation
of particulate zinc chloride smoke in military and industrial environments.
Toxic symptoms mainly involved the mucous membranes of the nasopharynx and
respiratory tract.  Damage to the lungs was minimal, with little or no venous
congestion. Symptoms associated with inhalation exposures to zinc chloride
include inflammation of the respiratory tract, respiratory difficulty,
bronchopneumonia, sore throat,  metallic taste, cough, chest pain, fever,
headache, fatigue, nausea, vomiting, edema, and necrosis and hemorrhage of
mucous membranes (Evans, 1945;  Milliken et al., 1963; Macauley and Mant, 1963;
Hjortso et al., 1988; Matarese  and Hatthews, 1986; Schenker et al., 1981).
Death may occur following serious exposures (Evans, 1945; Milliken et al.,
1963; Macauley and Mant, 1963;  Hjortso et al., 1988).  Following less serious
exposures, full recovery may occur within 1-6 weeks (Evans, 1945; Schenker
et al., 1981).  Although these  studies generally did not provide quantitative
information on exposure, Stocum and Hamilton (1976) analyzed the dose-response
effects from several reports of inhalation injuries due to exposure to zinc
chloride smoke.  Based on the concentration and exposure duration, these
authors categorized inhalation effects as indicated in Table VI-1.

     b.   Other Zinc Compounds

Data on adverse health effects  in humans exposed to excessive amounts of zinc
are limited.  Since zinc is an essential element for human growth and
nutrition, most of the available studies on humans relate to functional
consequences of zinc deficiency, pharmacologic use of zinc supplements,
accidental exposure (mostly to  zinc fumes) in occupational settings, or cases
involving suicide (Cousins, 1986; McClain et al., 1985; Prasad, 1985; Prasad
et al., 1978; U.S. EPA, 1987).

King (1986) conducted a study in which dietary zinc was reduced from 16.5 to
5.5 mg/day in the diets of 6 men over an 8-week period.  Several metabolic and
physiological changes were observed: serum albumin, prealbumin and retinal-
binding protein concentrations  decreased.  Also, the levels of thyroid-
stimulating hormone (TSH), T4 (thyroxine),  free T4,  and the basal metabolism

                                     VI-2

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                                 Table VI-1

      Categories  of Effects Due  to  the  Inhalation of  Zinc Chloride  Smoke"
    Dosageb
   g-min/m3                            Effect                         Grade
     NAe                Essentially no effect, some awareness
                       of presence

0.16 to 0.24           Noticeable irritation of nose, throat
                       and chest

1.7 to 2.0             Marked irritation,  hospitalization
                       and treatment required

    20                 Severe irritation,  chemical pneumonia,
                       hospitalization and treatment
                       required

    50                 Massive injury, may be fatal
8 Reference:   Stocum and Hamilton,  1976.
b Concentration x exposure time
e NA - not applicable
                                     VI-3

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rate decreased.   Fasting plasma glucose levels increased.   While none of the
changes were  large and may not be clinically significant,  the author surmised
that 5.5 ing/day is probably below the amount required for  good tissue status.

Short-term, high-level intake, resulting in acute gastroenteritis, can result
from consuming foods improperly stored in zinc-containing  vessels (NRC, 1989).
It has been reported that the emetic dose of zinc is 225-450 mg in humans
(Brown, 1964).   Approximately 300-350 persons developed intestinal symptoms
such as severe diarrhea with abdominal cramping (about 50% developed gross
blood in the  feces) within 24-48 hours after ingesting food which became
contaminated  with zinc during preparation and storage in galvanized containers
(Brown, 1964).   The concentration of zinc in the fecal matter collected from
several subjects during the investigation of the food poisoning episode ranged
from 59 to 1,200 mg/kg as compared to a normal value of 90-100 mg/kg.  The
available data do not present enough information for an exposure calculation.

In another episode, individuals consuming a zinc-contaminated alcoholic fruit
punch developed a hot taste and dryness in the mouth, nausea, vomiting and
diarrhea from 20 to 90 minutes after ingestion (Brown, 1964).  In the post-
acute phase,  the individuals reported general discomfort and muscular pain.
All of the victims recovered from the acute adverse effects within 24 hours of
exposure.  The zinc concentration of a 5 oz serving of the punch was 325 mg or
a dose of 4.6 mg zinc/kg for a 70-kg person.  The dose increased with the  .
number of glasses of punch consumed.

Gastrointestinal distress has also been reported in individuals receiving zinc
supplements (as the acetate or sulfate) of 50-150 mg/day over a period of
6 weeks to 2  years (Freeland-Graves et al., 1982; Prasad et al., 1978; Samman
and Roberts,  1988).

An accidental parenteral administration of 7.4 g zinc sulfate over a 60-hour
period (approximate dose 2.96 g/day or 289 mg zinc/kg/day  in a 60-kg female)
to a Crohn's  disease patient produced hypotension, pulmonary edema,  diarrhea,
vomiting, jaundice, oliguria, high serum zinc (4.184 mg/100 mL; normal serum
zinc is 0.075-0.124 mg/100 mL) and death (Brocks et al., 1977).

Chandra (1984) reported on the effects of administering 150 mg of dietary zinc
(as the sulfate salt) twice daily (300 mg zinc/day) to 11  adult males for
6 weeks.  Average dietary zinc during the supplementation period was
10.1 mg/day,  based on 24-hour recall data and 11.2 mg/day in the pretest
period.  Thus, the daily zinc intake was 311 mg/day (or 4.4 mg/kg/day for a
70-kg male) during the supplementation period.  Fasting serum cholesterol,
high density  lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-
cholesterol and triglycerides were measured on a biweekly  basis for 6 weeks;
follow-up measurement of these parameters was conducted at 2 and 10 weeks
after the supplement use ended.  Total lymphocytes, T-lymphocytes and
B-lymphocytes also were measured.  Lymphocyte activity was monitored through
polymorphonuclear migration response to chemotactic phytohemagglutinin (PHA)
stimulation and phagocytosis of opsonized bacteria.

Plasma zinc values increased during the supplement administration period.
There was a significant decrease in serum HDL values during weeks 4 (p<0.1)
and 6  (p<0.01) with a return to baseline levels at week 16 (Chandra, 1984).
LDL-cholesterol levels were significantly increased (p<0.05) at week 6, but
there were no significant changes in serum cholesterol and triglycerides.

                                     VI-4

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There were no significant changes in lymphocyte counts during the period of
zinc supplementation, but polymorphonuclear response to PHA stimulation
(chemotactic migration) and phagocytosis were diminished (Chandra, 1984),
suggesting that there was some functional impairment in immunological response
which accompanied the zinc supplementation.  This study indicates a Lowest-
Observed-Adverse-Effect-Level (LOAEL) for zinc of 4.4 mg/kg/day.

Supplementation with 160 mg zinc (as zinc sulfate) was found to lower HDL-
cholesterol values in 11 healthy males when administered over a 5-week period
(Hooper et al., 1980).  A control group of eight subjects received a placebo.
Fasting cholesterol, HDL-cholesterol and triglycerides were determined on a
weekly basis for 7 weeks and again 11 weeks after the end of supplementation.
Dietary zinc levels were not measured.  The total zinc intake was 176 mg/day
(or 2.5 mg/kg/day f°r an individual with a 70-kg body mass and a dietary
intake of 16 mg zinc/day).  After an initial HDL increase during the first
2 weeks of supplementation, HDL levels became significantly lower than those
for the controls during weeks 4 through 7 (p-0.002 to 0.0001) (Hooper et al.,
1980).  HDL levels returned to normal 11 weeks after supplementation ended.
Serum cholesterol, LDL-cholesterol and triglycerides did not change
significantly during the study; serum zinc levels increased during the
supplementation period.  Serum cholesterol values were normal.  This study
suggests a LOAEL of 2.5 mg/kg/day for zinc.

Groups of 15 healthy white males were administered 0, 50 or 75 mg/day zinc (as
zinc gluconate) for a 12-week period (Black et al., 1988). The subjects were
given instructions to avoid foods high in calcium, fiber and phytic acid,
dietary constituents which have a negative impact on zinc absorption.
Subjects also were told to restrict their intake of zinc- and copper-rich
foods.  Three-day dietary records were collected on a biweekly basis.  These
records indicated that the zinc intakes of the three treatment groups were
12.5, 14.0 and 9.5 mg/day, respectively.  Based on the average body weights
for each treatment group, the doses for diet plus supplement correspond to
zinc intakes of 0.16, 0.85 and 1.10 mg/kg/day.

Biweekly fasting blood samples were collected from all subjects and analyzed
for total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, zinc
and copper.  Urinary zinc and copper values were also determined.  There was a
general decline in the mean serum HDL-cholesterol for the 75 mg supplement
group between weeks 6 and 12.  HDL values for this group were significantly
lower than those for the placebo group at weeks 6 and 12 (p>0.05).  There was
also a decline in the HDL values for the 50 mg group from weeks 8 through 12.
However, this decline was not significantly different from that for the
controls until the 12th week of treatment (p<0.05).  Serum zinc, copper, total
cholesterol, LDL-cholesterol, and triglycerides did not appear to be affected
by treatment.

Samman and Roberts  (1988) administered 150 mg zinc (as the sulfate salt) to a
group of 21 healthy young male and 20 female volunteers in a 12-week double
blind cross-over trial.  The subjects were instructed not to change their
lifestyle, including their diet, alcohol consumption and exercise patterns
during the study.  No other dietary directions were given.  The subjects were
seen at 3-week intervals.  The duration of the zinc exposure period was
6 weeks; subjects were given a placebo for the other 6 weeks.  Non-fasting
blood samples were collected for determination of plasma lipoproteins (LDL,
HDL, HDLj, HDLj)  and indicators of copper status  (hematocrit,  ceruloplasmin,

                                     VI-5

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E-SOD, Cu-Zn-SOD).  There was a slight, but nonsignificant, decline in the HDL
values for both males and females.  There also appeared to be a shift in HDL
distribution from HDLj to HDLj.  There  was  a  slight nonsignificant  increase in
LDL levels in males after 6 weeks of supplemental zinc, but there was a
significant decrease in the LDL values for females.  Accordingly, the exposure
to zinc appeared to have no influence on the cardiovascular risk for the male
subjects and a benefit for the females.  There was considerable variability in
the LDL response of the females since only about 50% of the study population
exhibited a decrease in LDL values; the remainder of the subjects had LDL
values that remained constant or increased.

A study of HDL response to zinc in premenopausal females suggests that
supplemental zinc does not appear to have the sane effect on females that  it
has on males.  Healthy adult females were given supplemental zinc doses of 0,
15, 50 and 100 mg/day zinc as zinc acetate for 60 days (Freeland-Graves,
1982).  Three-day dietary records kept at weekly intervals were used to
evaluate the nutrient content of the diet including values for dietary lipids,
zinc  (8.1-8.5 mg/day) and copper (2.6-2.7 mg/day).  Fasting plasma
cholesterol, HDL-cholesterol and zinc were monitored at biweekly intervals.
Cholesterol values were not reported and there was no measurement of LDL
values.  A transitory decrease in HDL values was noted at 4 weeks only in the
group receiving the 100 mg/day supplement and 8.1 mg/day zinc in the diet
(diet records) (or 1.8 mg/kg/day based on a 60-kg body weight).  This decrease
in HDL values was not apparent at 6 and 8 weeks.  Serum zinc levels were also
highest in these subjects at 4 weeks.

A very slight but statistically significant  (p-0.04) 2 mg/dL increase in HDL
cholesterol was seen in a group of 22 elderly male and postmenopausal female
subjects (sex ratio unknown) 8 weeks after they ceased using zinc supplements
(Goodwin et al., 1985).  Serum zinc values fell from 92 to 86 |ig/dL during the
same period.  The average supplement intake was 29.1 mg/day (with a range of
17.5-52.2 mg/day).  The increase in HDL values seemed to be greatest for the
subjects with the highest ratings for physical activity.  Although the data in
this  study are far from conclusive with regard to the relationship between
zinc  and HDL values, they do add to the weight-of-evidence which suggests that
supplemental zinc can impact HDL levels.

Healthy adult males given 25 mg of zinc (as  the gluconate) twice daily for a
6-week period, displayed a significant decrease (p<0.05) in E-SOD activity at
the end of 6 weeks of exposure (Fischer et al., 1984).  The decreased
concentration of E-SOD is indicative, not only of a copper deficiency, but
also  of a diminished capacity of the cells to respond to oxidative stress.
There were no differences in serum copper levels or ceruloplasmin activity in
the 13 members of the supplement group as compared to the controls.  Serum
zinc  levels were significantly increased in  the supplement group after
2 weeks.  Dietary zinc was not measured.  The diet plus supplement intake was
66 mg/day or a LOAEL of 0.96 mg/kg/day for a 70-kg male with a dietary intake
of 16 mg/day.

Almost identical results were obtained from  a 10-week study of zinc
supplementation in 18 healthy adult females  given  supplements of 50 mg
zinc/day (as zinc gluconate) (Yadrick et al., 1989).  E-SOD concentrations
declined over the 10-week supplementation period and, at 10 weeks, were
significantly different  (p<0.05) from values during the pre-treatment period.
Ceruloplasmin concentrations were not  altered, but serum zinc was

                                     VI-6

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significantly increased.  There was also a significant decline in serum
ferritin and hematocrit values at 10 weeks.  However, neither ferritin nor
hematocrit values were altered when iron (50 ing/day) was added to the zinc
supplement which corrected the iron-zinc imbalance but not the copper-zinc
imbalance.  The zinc plus supplement intake for the females was 59.7 ag/day or
a LOAZL of 1.0 mg/kg/day for a 60-kg female with a dietary copper intake of
9.7 mg/day.

Several indicators of a copper deficiency were noted in the 20 females
administered 150 mg zinc/day for 6 weeks during a double blind placebo study
(Samman and Roberts, 1988).  Ceruloplasmin, E-SOD and Cu-Zn-SOD concentrations
were all significantly decreased during the zinc supplement period when
compared to the values during placebo administration.  There was a 20%
decrease in E-SOD and a 23% decrease in Cu-Zn-SOD at the end of 6 weeks.  The
same parameters were very slightly decreased in the males, changes were not
significant.

Nine healthy men (21-27 years of age) were given daily diets containing
2.63 mg copper/day (0.13 mg from the diet and 2.5 mg from copper sulfate) and
1.8, 4.0, 6.0, 8.0, 18.5 or 20.7 mg zinc (1.8 mg from the diet and the
remainder as zinc carbonate) for 1- or 2-week periods randomized over 9 weeks
(Festa et al., 1985).  The purpose of this protocol was to examine the effect
of zinc on copper excretion and retention.  The weekly mean (± SEM) plasma
copper concentrations (81 ± 3.3 to 100 ±5.8 jig/dL) remained within the normal
range with all zinc doses.  On two occasions, the 18.5 mg zinc/day dose was
administered for 2 consecutive weeks after 1 week on a lower zinc dose
(1.8-8 mg/day).  In each instance, the mean fecal copper excretion was
increased during the second week as compared to the first (from 1.92 mg/day to
approximately 2.62 mg/day), and copper balance became more negative.  This
study demonstrated that feeding 18.5 mg zinc/day (an amount only 3.5 mg above
the recommended dietary allowance (RDA) which is 15 mg zinc/day for adult
males) resulted in elevated fecal copper excretion and reduced copper
retention during a 2-week period.

Some data suggest that supplemental zinc impacts iron absorption.  Crofton
et al. (1989) administered solutions of 23.5 mg of ferrous iron (as the
hydrated sulfate salt) either alone or combined with zinc (as the sulfate
salt) (27.5 or 68.5 mg zinc) to a group of seven subjects and measured the
area under the plasma time curves.  The minerals were administered after an
overnight fast and testing episodes were separated by 35 days.  There was an
incremental decrease in the area under the curve (AUC) for iron at 3 and
6 hours when the combination of zinc and iron was used.   The lower zinc
concentration decreased the AUC for iron by 66% at 3 hours and 72% at 6 hours;
the higher dose decreased the value by 80% at 3 hours and by 90% at 6 hours.

     2.   Dermal/Ocular Effects

     a.   Zinc Chloride

Contamination of the eye with concentrated solutions of zinc chloride causes
severe damage to both the cornea and the lens.  In 1973, Houle and Grant
reported on a case of splash injury with concentrated zinc chloride
galvanizing solution (pH 3.53) to both eyes and the nasal passages of a
38-year old male.  Despite extensive irrigation with water, the initial
ophthalmic examination revealed a reduced visual acuity, puffy swelling of the

                                     VI-7

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eyelids, pale and markedly chemotic conjunctiva and epithelial edema of the
cornea.  The cornea remained permanently scarred with persistent gray spots
present beneath the anterior lens capsule.  Prior to this injury, uncorrected
visual acuity was 20/20.  Two years later, visual acuity in the more severely
damaged right eye was 20/200 correctable by refraction to 20/60 while the left
eye was correctable to 20/30.

Examination of the nasal passages revealed whitish speckled eschar-like
lesions on the anterior mucosa with complete bilateral nasal obstruction.  The
patient permanently lost all sense of smell from the zinc chloride injury
(Houle and Grant, 1973).

Du Bray (1937) described symptoms of fatigue, anorexia, weight loss and pain
in the long bones of a man exposed to aqueous zinc chloride solution by
frequent and long-term immersion of the hands.  Concentration of the aqueous
solution was not reported.

     b.   Other Zinc Compounds

No information was found in the available literature regarding dermal/ocular
effects in humans of other zinc compounds.

     3.   Long-term Exposure

     a.   Zinc Chloride

No information was found in the available literature regarding long-term
health effects in humans of zinc chloride.

     b.   Other Zinc Compounds

Anemia and neutropenia developed in a 44-year-old male patient who had taken
43 mg zinc/day (as zinc gluconate) for a 2-year period (Simon et al., 1988).
Serum zinc was elevated (262 jig/dL) while serum copper (15 ng/dL) and
ceruloplasmin (2 ng/dL) values were low; hemoglobin (9 g/dL),  hematocrit
(25.7%) and white cell count (2,000/(»L; 6% neutrophils) were also depressed.
At 7 weeks after discontinuing the supplement, all physiological measurements
of copper and zinc status returned to normal and the patient's anemia was
resolved.

A 35-year-old woman with a history of gastrointestinal problems (gastric
ulcers, reflux gastritis, intestinal obstruction and ulceration) was
prescribed a zinc supplement for ulcers of the mouth and tongue (Hoffman
et al., 1988).  For a 10-month period she ingested 142-197 mg zinc/day as the
sulfate salt.  Although the oral ulcers responded to the zinc treatment, the
patient developed a microcytic hypochromic anemia which did not respond to
6 months of iron therapy.  After 10 months of the zinc therapy combined with
iron for 6 months to resolve the anemia, the patient's serum copper and
ceruloplasmin values were extremely low (0.15 yg/dL for copper and 0 for
ceruloplasmin).  (Normal is 0.75-1.45 jig/dL for copper and 22.9-43.1 mg/dL for
ceruloplasmin.)  The use of the zinc supplement was then discontinued and the
patient was given 2 mg/day copper for 2 months.  Although there was some
initial increase in serum copper and ceruloplasmin, the patient's
hematological parameters did not improve, and zinc excretion continued to be
high.  Over a 5-day period, a total dose of 10 mg copper (as the chloride

                                     VI-8

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 salt)  was  given  intravenously.  Within  2  weeks, ceruloplasmin  increased to
 19.5 mg/dL.  Oral  copper  therapy  (2  mg/day) was continued.   The  patient's
 anemia was resolved,  serum copper and ceruloplasmin,  and white cell  count
 returned to normal after  5 months.

 Prasad et  al.  (1978)  reported  the occurrence  of a microcytic anemia  and
 neutropenia in a sickle-cell anemia  patient who had  received 75-200  mg/day
 zinc  (as either  the acetate or sulfate  salt)  as an antisickling  agent for a
 period of  2 years.  The patient's condition was discovered when  he enrolled in
 a study involving  the use of zinc to control  pain in sickle-cell patients.
 Based  on plasma  zinc  and  copper data which had been  collected  over the 2-year
 period, the zinc supplement caused an initial increase  in plasma zinc values
 which  gradually  decreased with time;  plasma copper values continuously
 decreased  during the  zinc supplementation period but increased when  1 g of
 copper (as copper  sulfate) was added to the therapy.    As a  result of these
 findings,  13 other individuals who were taking part  in  a study of pain in
 sickle-cell patients  were surveyed.   Ceruloplasmin levels were below normal
 for seven  patients.  The  addition of copper to the therapeutic program for
'these  individuals  resulted in  normalization of the ceruloplasmin values.

      B.    Health Effects  in Animals

 In animal  studies,  oral LD50s as well as average lethal oral doses have been
 reported for zinc  compounds in several  species.  Zinc chloride causes both
 skin and eye irritation,  and percutaneous toxicity has  been  demonstrated.
 Oral  administration of zinc chloride to rats  for up  to  6 weeks precipitated a
 deficiency syndrome when  combined with  a synthetic diet low  in pantothenic
 acid.   Renal damage was observed  in  rats  exposed orally to zinc  for  90 days.
 Several studies  indicate  that  high doses  of zinc can interfere with
 reproductive function and can  be  fetotoxic.   Mutagenicity and  carcinogenicity
 studies have yielded  equivocal or negative results.

      1.    Short-Term  Exposure

      a.    Zinc Chloride

 Limited data are available on  the toxic effects of zinc chloride following
 acute  oral exposures  in animals (Table  VI-2). In 1941, Voodard  and  Calvery,
 as cited in Calvery (1942), reported acute median oral  lethal  doses  of
 350 mg/kg  for  rats, 350 mg/kg  for mice  and 200 mg/kg for guinea  pigs.   These
 data suggest that  the guinea pig  may be slightly more sensitive  to the acute
 toxicity of zinc chloride than other laboratory animals.  In 1974, Yakuri
 indicated  an oral  LD50 of  502 mg/kg in male dd-K mice.  Hahn and Schunk (1955)
 reported an average oral  lethal dose of 750 mg/kg in rats and  1,000  mg/kg in
 rabbits (cited in  Hill et al., 1978).  Rats were given  a single  oral dose by
 gavage of  zinc chloride  in solution  at  500, 750 or 1,000 mg/kg.   Approximately
 40% of the dosed rats died within 24 hours.   Upon necropsy,  perforations of
 the stomach or penetration into the  liver tissue, as well as pyloric stenosis,
 were evident.  Mucosal damage  was less  prevalent among  animals dying early,
 but ataxia, tremor, dyspnea and a drop  in body temperature were  evident.   A
 dose response  was  not indicated.   Doses in rabbits were reported to  be 250,
 500 or 1,000 mg/kg.  Similar effects were reported upon necropsy.  Mortality
 rate was not specified.   Domingo  et  al. (1988) reported oral LD50 values  for
 zinc chloride  of 528  mg/kg in  rats and  605 mg/kg in  mice.
                                      VI-9

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                         Table VI-2



Acute Oral Studies of Zinc Chloride and Other Zinc  Compounds

Chemical
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc sulfate
Zinc sulfate
Zinc sulfate
Zinc acetate
Zinc acetate
Zinc nitrate
Zinc nitrate
Species
Rat
Rat
Rat
Mouse
Mouse
Mouse
Guinea pig
Rabbit
Rat
Rat
Mouse
Rat
Mouse
Rat
Mouse
Effect
Median lethal dose
LD50
Average lethal dose
LD50
Median lethal dose
LD50
Median lethal dose
Average lethal dose
L050
LD50
LD50
LD50
L050
LD50
LD50
Dose
(ing/kg)
350
528
750
1,000
350
502
200
1,000
623
920
337
237
86
293
204
Reference
Woodward and Calvery, 1941
Domingo et at., 1988
Hahn and Schunk, 1955
Domingo et al., 1988
Woodward and Calvery, 1941
Yekurl, 1974
Woodward and Calvery, 1941
Hahn and Schunk, 1955
Domingo et al., 1988
Fabrlclo, 1974
Domingo et al., 1988
Domingo et al., 1988
Domingo et al., 1988
Domingo et al., 1988
Domingo et al., 1988

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Gross et al.  (1941) studied the effects of orally administered zinc chloride
in young female rats (40 g average weight) fed a synthetic diet.  The animals
were orally intubated with a vitamin-supplemented filtrate fraction low in
pantothenic acid.  Oral intubation with zinc chloride in cod liver oil at
4 mg/day (approximately 100 mg/kg/day for a 40-g rat) occurred at 4 hours
after the vitamin supplement, 6 days/week for up to 6 weeks.  Deficiency
symptoms characterized by growth retardation, severe alopecia, rusting and
ruffling of the fur, and crusting of the nose, chin and eyelids, were reported
in i50% of the rats after 5 weeks of treatment.  Control animals grew at a
slightly suboptimal rate and had some rusting of the fur which cleared
spontaneously, but developed no other symptoms.  Black rats similarly treated
with 5-6 mg/day of zinc chloride in olive oil developed alopecia and a severe
graying of the coat as well as crusting of the nose, chin, tail and eyelids.
Oral supplementation of the daily regimen with 150 pg of synthetic calcium
pantothenate reversed the progress of the deficiency symptoms, even with
continued intubation of the zinc chloride.  Neither a No-Observed-Adverse-
Effect-Level (NOAEL) nor a LOAEL could be determined.

     b.   Other Zinc Compounds

The acute oral LD50 value  for  zinc  sulfate  in rats was  920 mg/kg (Fabrizio,
1974) .  LDeo values were calculated in  rats  and mice  (10/dose  group)  for  four
zinc salts using the Litchfield-Wilcoxon method after intragastric
administration of a single dose of the salt in solution (Domingo et al.,
1988) .  The LD50  for zinc  (as  zinc  acetate  dihydrate)  in rats  was  237 mg/kg
and in mice,  86 mg/kg.  The LD50 value  for  zinc nitrate  hexahydrate  in rats
was 293 mg/kg and  in mice it was 204 mg/kg.  Zinc sulfate dihydrate had an
LD50  of  623 mg/kg in rats  and  337 mg/kg in  mice.

Two studies on the homeostasis and tissue distribution of zinc in male
Cherokee Sprague-Dawley rats weighing 100-120 g have been described (Ansari
et al., 1975, 1976).  In the 1975 study, one control group (seven rats)  and
four experimental  groups (nine rats/group) were fed zinc oxide in the diet at
0 or 600 ppm for 7, 14, 21 or 42 days  (Ansari et al., 1975).  In the 1976
study, zinc oxide was fed to groups of 6-8 rats at 1,200,  2,400, 3,600,  4,800,
6,000, 7,200 or 8,400 ppm for 21 days  (Ansari et al., 1976).  There was
increased excretion when zinc added to the diet was elevated above the
1,200 ppm level.  This finding, as well as the observed sharp increases in
stable zinc in the  liver, kidney, and tibia at the highest dietary zinc intake
(8,400 ppm), suggested some breakdown in zinc homeostasis.  However, body
weight gain and food consumption were similar  in controls and zinc-treated
groups, and gross  clinical signs of toxicity such as skin lesions, diarrhea
and muscular incoordination were not observed  in any of the treated groups.

Several case studies of dogs which have swallowed zinc-containing coins or
metal objects report hemolytic anemia in the affected animals (Latimer et al.,
1989; Luttgen et al., 1990; Torrance and Fulton, 1987).  In these cases,  it  is
impossible to determine the dose of zinc received by the animal in order to
unequivocally attribute the symptoms to zinc since zinc was not the only metal
present in the objects swallowed.
                                     VI-11

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     2.    Skin and Eve Irritation. Dermal Sensitization

     a.    Zinc Chloride

In a test for dermal irritation, 0.5 ml of a 10% solution of zinc chloride was
applied to the skin of six male albino rabbits (Williams, 1984). The
application area was prepared for testing by clipping the area free of hair.
The area was covered and occluded for 24 hours prior to scoring for erythema
and edema.  The authors reported that zinc chloride caused severe edema and a
necrotic erythema in the test area.  When 0.1 ml of the 10% zinc chloride
solution was instilled into the lower conjunctival sac of one eye,
conjunctivitis and a moderate, penetrating corneal opacity were observed.
Recovery from these effects occurred after 7-14 days.

Percutaneous administration of 2 ml of 0.239 moles of aqueous zinc chloride to
a 3.1 cm2 area of the skin of guinea pigs (mean weight 375 g)  resulted in a
cessation of weight gain after 1 week.  Mortality was unaffected over the
four-week observation period.  A low absorption rate of less than 1.0 % per
5 hour exposure period was indicated (Wahlberg, 1965).

Experiments were conducted in albino rabbits (Johnstone et al., 1973) to
evaluate the effects of zinc chloride on the eye with the possibility of
developing more specific treatment techniques for use in human injuries.
Corneal injuries were obtained by exposure for one minute to a 50% solution of
zinc chloride followed by a ten second irrigation with water to remove excess
test solution.  One group of rabbits received no further treatment, while a
second group received a 15 minute eye irrigation with either 0.9% sodium
chloride or 0.05 M neutral sodium ethylenediamine-tetra acetic acid (EDTA) at
one minute post-exposure.  A third group received the same two treatments
starting at 15 minutes after exposure to the 50% zinc chloride.  Zinc content
of the cornea was measured at various time intervals following injury.
Neither treatment was effective in its rate of removal of zinc when compared
to the untreated cornea injured by exposure.  While treatment with 0.05 M EDTA
did not prevent the corneal opacification seen following injury with zinc
chloride, treatment within one minute following injury did result in a
progressive improvement.  By 2 weeks after injury the corneal opacity in the
EDTA treated eyes was 1+, a marked improvement over those treated with normal
saline.   If treatment was delayed for 15 minutes, neither procedure resulted
in improvement.

Johnstone et al. (1973) also conducted experiments with excised bovine corneal
buttons.  They found that zinc chloride acts as a fixative or denaturant of
the cornea and that EDTA acts to some degree to reverse this denaturation when
the exposure is relatively mild.

     b.    Other Zinc Compounds

No reports were found on the toxic effects of zinc following dermal exposure,
although zinc may be absorbed across the broken and unbroken epithelial
membrane (NRC, 1979).
                                     VI-12

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     3 .    Longer-Term Exposure

     a.    Zinc Chloride

All data on the longer-term administration of zinc chloride are associated
with reproductive,  developmental or carcinogenic screening studies.  Details
are presented in the related sections.

     b.    Other Zinc Compounds

Weanling COX-SP rats of both sexes (180 control rats and 40 rats/experimental
group) were administered zinc phenolsulfonate (a cosmetic product) for 91 days
at dietary levels of 62.5, 250 or 1,000 mg/kg/day (corresponding to calculated
doses of 1, 4 and 16 mg zinc/kg/day, respectively, based on 200-g weight and
20 -g/ day food consumption).  There was no unusual variation in food
consumption, body weight gain or hematological parameters between the control
and treated groups.  One mg zinc/kg/day produced minor, randomly distributed
variations in organ-to-body weight ratios and increased testicular fluid at
the 4-week necropsy.  The 4-week necropsy also revealed hydropic changes at
the intermediate dose and increased vacuolar changes at the high dose in the
seminiferous tubules.  These effects were absent at the 8 -week necropsy and at
the end of the study, suggesting a temporary failure of zinc homeostasis and a
subsequent endogenous repair (Elder, 1986).  The influence of the organic
cation on toxicity, if any, cannot be determined from the results presented in
this study.  Usefulness of this study for the calculation of an HA value is
questionable, given the type of compound used.

Doses of 0, 47.6, 95.3 or 190.6 mg zinc/kg/day (as the acetate salt) were
administered to groups of 10 female Sprague-Dawley rats in drinking water for
90 days (Llobet et al., 1988).  The animals were observed daily for clinical
signs, food and water consumption, and urine and fecal excretion; body weights
were determined weekly.  Prior to sacrifice, blood samples were collected and
analyzed for biochemical indices and hematological parameters.  After
sacrifice, the major organs were weighed and examined histologically.  There
were no differences for food consumption, body weight or fecal matter
production between the dose groups.  The animals in the highest dose group
exhibited apathy, decreased water consumption and urine production, increased
serum urea and creatinine.  There were no differences in hematocrit,
hemoglobin or serum enzymes between groups.  At the two highest dose levels
there were significant increases in the zinc concentration in the liver,
kidneys, heart, bone and blood but no significant differences in organ weights
for the liver, kidney and heart.  Lesions were seen in the kidneys of the
animals exposed to the highest dose.  Bowman's capsule epithelial cells were
flattened and there was loss of some of the surface epithelial cells in the
proximal tubules along with pyknotic nuclei in the tubular epithelial cells.
There were no adverse effects associated with the 95.3 mg/kg/day dose (NOAEL) ,
but there were some indications of renal damage at the LOAEL of
190.6
Male  and female C3H mice were provided with zinc sulfate (0.5 g/L) in
distilled drinking water ad libitum  for up to 12 months.  The outward
appearance, appetite and activity were similar to controls (Aughey et al . ,
1977).  A total of 150 mice, including an unspecified number of controls, was
used.  Plasma zinc levels in the zinc -supplemented mice rose to a peak of
2.1 jig/mL at day 3 of ingestion while the control level was 1.02 |ig/mL;

                                     VI-13

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thereafter, a plateau with minor fluctuations was evident over the 34-day
observation period.  (On day 34, plasma zinc was about 1.5 ng/mL.)  No
significant difference in zinc content between the control and zinc-
supplemented groups was observed for the liver, spleen, or skin over a 6-month
observation period; no sex difference was observed with respect to zinc
content of these tissues.  Plasma insulin and glucose levels were unaffected
by dietary zinc supplementation.  However, some histological and
ultrastruetural changes were noticed in tissues of zinc-supplemented groups as
compared to tissues of controls.  Individual beta cells of the pancreas were
larger than in controls.  The zona fasciculata of the adrenal cortex was
hypertrophied and highly positive to lipid staining at 3 months of zinc
ingestion; at 6 months or more, the glomerulose and reticularis zones also
gave strongly positive reactions for lipid staining.  Cells of the anterior
lobe of the pituitary showed morphological changes consistent with
hyperactivity.  It was not possible to derive a LOAEL or a NOAEL from this
study for the following reasons: only one dose was used, the amount of
ingested zinc could not be estimated because water spilled during drinking,
intestinal absorption was uncertain, and data on body weights were
unavailable.   However, assuming an approximate water consumption of 10 mL/day
and a mean body weight of 25 g, the daily dose in this study corresponds to
about 200 mg zinc sulfate/kg/day.

     4.    Reproductive Effects

     a.    Zinc Chloride

In general, results of oral administration indicate maternal toxicity
evidenced by a decrease in weight gain when zinc chloride administered by
gavage at a dose of 150 mgAg/day.   In contrast, administration in the diet
during reproduction revealed no toxic effects at levels up to 250 mg/kg/day.

Heller and Burke (1927) reported no toxic effects on growth,  reproduction or
offspring of rats following the ingestion of zinc chloride in the diet.   Diets
containing 0.25 or 0.5% of zinc as zinc chloride were administered during
breeding and continued for one generation after the parental FQ animals.   This
is equivalent to approximately 12.5 or 25.0 mg/kg/day, assuming normal dietary
intake of 20 g/day for a 0.4 kg rat (Lehman, 1959).  The 0.25% group consisted
of 2 rats/sex; the 0.5% group had two males and 7 females.  A control group of
3 males and 1 female were fed a diet that did not have added zinc.   It appears
that growth,  mating and number of offspring were not affected by zinc
chloride.  The offspring, continued on the same treatment, also produced
normal,  vigorous offspring.  No lesions or pathological conditions  were  seen.
Tissue zinc levels (which were reported as average zinc concentration and
included tissues from animals fed zinc carbonate, zinc oxide,  and zinc dust)
were comparable to controls.  Results from this study are difficult to
interpret due to its design and lack of experimental detail;  therefore,  a
LOAEL and NOAEL are not identified.  No other data were found in the available
literature on the reproductive effects of exposure to zinc chloride in
animals.

     b.    Other Zinc Compounds

Kumar (1976)  orally administered 150 mg/kg/day zinc (as 2% zinc sulfate)  in
drinking water to 13 pregnant rats.  Zinc content of the diet was 30 ppm.   All
animals were sacrificed on day 18 of pregnancy and examined.   Eight

                                    VI-14

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experimental animals showed 11 resorptions out of 116 implantations.  Two
control animals revealed a total of 2 resorptions out of 101 implantations.
Data suggest that moderately high levels of zinc may have harmful effects on
pregnancy.

In a study in which groups of 10 female Sprague-Dawley rats were maintained on
diets containing 2,000 and 5,000 ppm zinc oxide for 35-38 days (from day 1 of
gestation to day 14 of lactation), no malformations were observed; however,
fetal mortality was noted (Ketcheson et al.,  1968).  A dietary level of
2,000 ppm corresponds to a calculated dose of 200 mg zinc/kg/day, assuming a
body weight of 200 g and a dietary intake of 20 g/day while the 5,000 ppm dose
is equivalent to 500 mg zinc/kg/day.  Among the 10 litters given 2,000 ppm, 4
dead pups were observed; in the 8 litters given 5,000 ppm, 2 litters consisted
entirely of dead pups (the number of dead pups in these 2 litters was not
mentioned).

Dietary supplementation with zinc carbonate at 1,000, 5,000 or 10,000 ppm
(corresponding to calculated doses of 100, 500 and 1,000 mg/kg/day) for
10-16 weeks resulted in an increase in stillbirths at 5,000 ppm and no
reproduction at 10,000 ppm in groups of five young rats (three females and two
males; strain not reported) (Sutton and Nelson, 1937).  Three females on the
5,000-ppm diet had 6/11 dead pups from their first pregnancies; during their
second pregnancies, all 23 pups died.  No effects were observed at 1,000 ppm.

The effect of zinc on the male reproductive organs was evaluated in male
Sprague-Dawley rats (number not specified) over a 3- to 6-week period (Saxena
et al., 1989).  The experimental animals received a diet containing 500 ppm
zinc.   The control animals were fed a diet with adequate zinc to support
nutritional needs.  The water used for both groups of animals contained 2 mg/L
zinc.  The total zinc intake of the experimental animals was 25 mg/kg/day.
Animals were sacrificed at 3 and 6 weeks for examination of their reproductive
organs.  Spermatogenesis was found to be impaired in the exposed animals at 3
and 6 weeks.

No effect on embryonic mortality, male fertility, or pregnancies/ effective
mating was produced by zinc chloride in the dominant lethal mutation assay
using mice [Fl hybrids (CBA/X/C57BL)] and a single intraperitoneal dose
(15 mgAg) in males (Vilkina et al., 1978).

     5.   Developmental Effects

     a.   Zinc Chloride

No effects were found on reproductive parameters, but zinc chloride may be a
teratogen.

Seidenberg et al.  (1986) screened 55 chemicals, including zinc chloride, for
possible teratogenicity, utilizing the Chernoff/Kavlock developmental toxicity
screen.  This method identifies developmental toxicity, including potential
teratogenicity, based on growth and viability of embryonic, fetal, and
postnatal mice.  The screen was designed to prioritize chemicals for
subsequent, more detailed, conventional study and may not be appropriate to
classify chemicals as developmental toxicants.
                                     VI-15

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In the zinc chloride screen, 28 timed-pregnant mice received by gavage an oral
dose of 150 mg/kg/day in water on Day 8 through Day 12 of gestation.  The mice
were weighed on Days 7 and 13 of gestation and at one day postpartum.  Dams
were allowed to deliver, litters were counted and weighed on day of birth and
on Day 3.  Dead pups were examined for external abnormalities.  Dams not
delivering by Day 2.1 or 22 were necropsied and uteri were examined.  One of
the maternal animals died at this dose, and average weight gain was
significantly reduced as compared to controls (p<0.01).  Eleven litters were
produced with no resorptions.  No significant differences were found in the
average number of neonates/litter,  % survival Days 1-3, or average neonatal
weight on Days 1 and 3 (Seidenberg et al., 1986).

Based on the Chernoff/Kavlok method, Seidenberg and Becker (1987) reported
that zinc chloride caused a significant reduction in litter size and thus
classified it as a teratogen.  This parameter was not significantly different
when only the litters that came to term by Day 22 of gestation were counted.
Given the limitations of the method zinc chloride should be considered a
potential developmental toxin.  A NOAEL or LOAEL could not be determined
because only one dose was tested.

One intraperitoneal study suggests that zinc chloride is teratogenic.  Chang
et al. (1977) injected zinc chloride intraperitoneally in mice (number not
clearly specified for each dose group) in single doses of 0, 12.5, 20.5 and
25 mg/kg on days 8, 9, 10 or 11 of gestation.  Dams were sacrificed on
gestation day 18 (1 day prior to expected delivery).  Thereafter, the number
of fetuses and resorption sites was determined.  Fetuses were weighed, sexed
and examined for skeletal and visceral anomalies.  Quantitative data on
maternal toxicity and fetotoxic effects were not provided by the author for
evaluation.  Skeletal anomalies, including delayed ossification, were seen at
dose levels of 20.5 mg/kg/day or greater beginning on gestation day 8.  Ripple
ribs, an unusual skeletal anomaly,  first appeared when zinc chloride was given
on day 9 of gestation.  For the most part, the severity of the skeletal
lesions was dose and time dependent.  There were no significant differences in
soft tissue anomalies at any dose level.  Skeletal anomalies were observed at
doses of 20.5 mg/kg and above but not at 12.5 mg/kg.

     b.   Other Zinc Compounds

Dietary zinc deficiency (0.3-100 ppm zinc carbonate) in Sprague-Dawley rats
(10-20/group) and Long-Evans hooded rats (10-17/group) produced reproductive
and developmental effects including testicular lesions, abnormal estrous
cycles, embryotoxicity and malformed fetuses (most organ systems and the
skeleton were involved) (Hurley, 1969; Hurley and Swenerton, 1966; Rogers
et al., 1985; Hurley et al., 1971).

     6.   Genotoxicitv

     a.   Zinc Chloride

Mutagenicity studies produced mixed results in which some cytotoxicity was
indicated.

In an in vitro assay for detection of potential carcinogens and mutagens,
Casto et al. (1979) used hamster embryo cells (HEC) to detect the ability of
zinc chloride to enhance the transformation of Simian adenovirus SA7.

                                     VI-16

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Enhancement occurred in only 50% of the six assays.  The lowest concentration
producing a positive response was 0.18 mM with a transformation ratio of 8.7
(transformation frequency  (TF) of treated cells/TF of controls).  Because of
.the 50% response, the authors reported that the results of this study were
inconclusive.

Results of in vitro studies in normal stimulated human lymphocyte cultures did
not demonstrate the mutagenic potential of zinc chloride.  At a concentration
of 3xlO~5  M,  severe  chromosome  aberrations  were manifested as dicentric
chromosomes but the incidence was not significant against controls using the
chi-square analysis.  At a level of 3x10"^  M,  zinc  chloride was  cytotoxic  to
human lymphocytes (DeKnudt and Deminatti, 1978).

No evidence of DNA damage  was observed in human white blood  cells at the zinc
chloride concentration of  5xlO"5  M (McLean  et  al.,  1982).

Mutagenicity tests conducted with SL typhimurium strains TA1535, TA1537,
TA1538, TA98 and TA100 indicated that zinc chloride was not  mutagenic in any
strain either with or without S-9 mix, although zinc chloride was toxic at the
higher exposure levels (McGregor, 1980).  Sokolowska and Jongen (1984)
indicated that zinc chloride was not mutagenic in any strain at doses up to
5 mg/plate.  In contrast,  Kalinina and Polukhina (1977) indicated that zinc
chloride produced frame shift mutations in the indicator strains (not
specified) of S. tvphimurium in the Ames test.  The effect was measured by the
ability of the chemical to induce reversions  from histidine  auxotrophy to
prototrophy and was described as species-specific with respect to liver
homogenates, with the highest mutagenic activity evident in  the mouse liver.

In the E. coli DNA repair  test, zinc chloride did not show preferential
toxicity  for the polymerase-deficient strain  at 10 mg/plate, with or without
S-9 mix (McGregor, 1980).  In the S. cerevisiae mitotic recombinogenic
activity  test, zinc chloride did not show a reliable indication of toxicity to
the yeast cells during the 150 minute incubation.  An 18 hour incubation did
result in a reduced viability at 0.75 mg/ml.   In the presence of S-9 mix
toxicity was severe at kl  mg/ml.  At lower concentrations  in which moderate
toxicity was observed, there was no sign of an increase in recombinant
frequency.  In the absence of S-9 mix, results were not clear.

In an in vivo system using male and female F1 hybrid mice, Vilkina et al.
(1979) studied the effects of a single intraperitoneal dose  of 15 mg/kg of
zinc chloride in aqueous  solution on chromosome aberrations  in bone marrow
cells.  While single fragment rearrangements  were most commonly encountered in
this system, no statistically significant differences in frequency were seen
in treated animals compared to controls.  The authors also tested the ability
of zinc chloride to induce dominant lethal mutation in the germ cells of male
mice.  Three intact females were mated to zinc chloride injected mice for one
week at time periods corresponding to the  influence of the zinc chloride on
mature sperm, late and early spermatids, late and early spermatocytes and
spermatogonia.  There were no zinc chloride-related effects  on mortality
before or after  implantation.  Also the percentage of effective matings, and
numbers of corpora lutea,  implantation sites,  and live embryo were not
affected.
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Zinc chloride was studied for its ability to cause DNA strand breaks using the
fluorescence analysis of DNA unwinding (FADU) technique with freshly isolated
human white blood cells.  McLean et al. (1982) reported that zinc chloride
gave no firm evidence of DNA damage at a concentration of 5xlO"5 M.   In a
similar study using the average molecular weight of DNA to determine strand
breaks in Chinese Hamster Ovary (CHO) cells, Robison et al.  (1982) also
reported that zinc chloride caused no significant changes.

Rivedal and Sanner (1981) reported that zinc chloride was not an inducer of
transformations in hamster embryo cells, and it had no effect on the frequency
of transformation when tested in combination with benzo(a)pyrene.

When tested for induction of Y prophage in L coli WP2s(y),  Rossman et al.
(1984) reported that zinc chloride produced a two-fold increase (+/-)
in Y prophage at a concentration of 3.2xlO"3.   In  this  system,  positive
inducers produced increases ranging from 3 to 75 times that of controls.

Zinc chloride did not produce preferential inhibition of DNA repair-deficient
Bacillus subtilis M45 as compared to the DNA repair-competent parental strain,
H17 (Nishioka, 1975).

     b.   Other Zinc Compounds

Zinc compounds were generally negative in in vitro reverse bacterial mutation
assays with Salmonella tvphimurium (Marzin and Vo Phi, 1985; Thompson et al.,
1989); in mouse-mediated assays (Fabrizio, 1974); in the Escherichia coli
assay (Nishioka, 1975); the mouse lymphoma forward mutation assay (Amacher and
Paillet, 1980); and in in vivo rodent somatic and germinal cell cytogenetic
assays (Fabrizio, 1974).

Zinc acetate (10-1,000 ng/mL) did not cause unscheduled DNA synthesis in
cultured rat hepatocytes (Thompson et al., 1989).

Dose-related positive responses to concentrations of 1.3-13 jig/mL zinc acetate
were seen in the TK*'" mouse lymphoma assay and in the in vitro Chinese
Hamster Ovary (CHO) cell cytogenic assay both in the presence and absence of
microsomal activation (Thompson et al., 1989).

Acceptable evidence of zinc sulfate-induced genotoxicity in yeast has been
presented (Fabrizio, 1974).  Oral administration of 2.75, 27.5, and
275.0 mg/kg zinc sulfate in both acute (one exposure) and subacute (five
consecutive daily exposures) mouse host-mediated assays induced dose-related
recombinogenic effects in Saccharomvces cerevisiae D3.  For the acute study,
recombinant frequencies (RF) ranged from 8.22xlO"5 at  the  low dose  to
13.22xlO"5  at  the high  dose  (RF for negative  control,  4.06xlO"5).   For the
subacute study, more pronounced effects were observed.  The highest dose was
both cytotoxic (30% reduction in total survivors) and recombinogenic (four-
fold increase in the RF) .  The remaining doses were not cytotoxic, but the RF
was increased 2-fold at the low dose and 2.8-fold at the intermediate dose.
                                     VI-18

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     7.   CarcinoE.eni.citv

     a.   Zinc Chloride

Administration of zinc chloride  in  drinking water did not promote kidney  or
liver  lesions when administered  in  drinking water for 25 weeks.

Kurokawa et al.  (1985) treated a group of  7-week old male F344 rats  (15/group)
with zinc chloride (96% pure) at 450 ppm in drinking water  (equivalent  to «
28 mg/kg/day based on body weight and intake data provided) for  25 weeks.
Prior  to zinc chloride exposure,  another treatment group received 500 ppm of
N-ethyl-N-hydroxy-ethylnitrosamine  (EHEN)  in drinking water for  2 weeks.   Two
additional groups either received drinking water (DW) alone or DW following
initiation with  EHEN.  Mean final body weight  for the EHEN-zinc  chloride  group
were significantly lower (p<0.01) than the group receiving drinking  water
alone, but were  not significantly different from the EHEN-DW controls.  Mean
final  body weight for the DW-zinc chloride group were comparable to  both
control groups.  There were no significant differences in absolute kidney or
.liver  weights in either of the zinc chloride groups.  The relative kidney
weights of both  the initiated and uninitiated  zi'nc chloride groups were
significantly increased as compared to the DW  only controls (p<0.05).
However, these differences were  minor (0.61 versus 0.60).  Mean  intake  of
drinking water (mL/rat/day) were slightly  lower in both groups receiving  zinc
chloride as compared to either control group.

The EHEN-DW controls exhibited the  same significant increase in  relative
kidney weight when compared to the  DW controls.  Renal tissue was examined for
preneoplastic and neoplastic lesions.  The lesions were classified as
dysplastic foci  (DF) or renal cell  tumor (RCT).  Dysplastic foci were defined
as proliferation of lining epithelium of solitary tubules ranging from  a  focal
increase in cell numbers to complete obliteration of the tubules and included
dilated tubules  with multilayered epithelium or the projection of lining  cells
into the lumen (Kurokawa et al.,  1985).  While there was no significant
difference in the incidence of DF between  the  EHEN-zinc chloride and EHEN-DW
rats,  the mean number of DF/cm2  was significantly increased (p<0.01) in the
EHEN-zinc chloride group as compared to the control group.  There were  no
significant differences in either the incidence or the mean number of RCTs of
the EHEN-zinc chloride or EHEN-DW groups.  Renal cell tumors were single  or
multiple nodules usually with a  solid growth pattern but occasionally
presenting as cystic formations  with papillary-like ingrowth or  tumors  with
trabecular morphology.  All RCTs were benign.  Neoplastic nodules and
hepatocellular carcinomas were observed in the livers of both the zinc
chloride and DW  rats initiated with EHEN but no significant differences were
found  between these two treatment groups.  No  lesions were observed  in  the
rats receiving only DW or zinc chloride without prior initiation.  Based  on
the results of this study, the authors concluded that zinc chloride  could not
be considered a  promoter of kidney  lesions.

Testicular tumors (embryonal carcinomas) were  observed in 2 of 49 Syrian
hamsters administered 2 mg zinc  chloride by a  single intratesticular injection
at 8-14 weeks  (during rapid gonadal growth) (Guthrie and Guthrie, 1974).   All
but six animals  exhibited testicular pathology, such as fibrous-walled
cavities near the epididymis and areas of  coagulative necrosis in testes
surrounded by a  zone of pigmented and foamy macrophages.  The two tumors  arose
adjacent to the  area of necrosis (Guthrie  and  Guthrie, 1974).

                                     VI-19

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VII. HEALTH ADVISORY DEVELOPMENT

     Zinc is an essential trace element which is a constituent of a number of
     enzymes involved in key biological processes.  Zinc deficiency is associated
     with loss of appetite, growth retardation,  skin changes, inmiunological
     abnormalities, wound healing retardation, and developmental effects (HAS
     1989).  The development of a health advisory is complicated by the fact that
     there appears to be a narrow range of doses between the amount of zinc needed
     to fulfill physiological needs (5.5 mg/day) and the amount that will produce
     minimally adverse effects (depressed E-SOD at 60 mg/day) (King, 1989; Fischer
     et al., 1986; Yadrich et al., 1989).  The Recommended Dietary Allowance for
     zinc ranges from 5 mg/day for infants to 19 mg/day for lactating women (NAS,
     1989).  These values were used as a guide for Health Advisory derivation.

     Available data on the oral exposure of humans and animals to various forms of
     zinc compounds have been reviewed.  In animals (rats, mice, and guinea pigs),
     oral LD50's  and  average  lethal doses  range between  200  and  1,000 mg/kg.
     Results of exposure to zinc chloride while being fed a synthetic diet
     deficient in pantothenic acid, as well as those following exposure via
     drinking water for 25 weeks are reported.  Both reproductive and teratogenic
     effects have been evaluated.  No bioassay for carcinogenicity has been located
     in the literature, but a study of the tumor-promoting potential of zinc
     chloride is discussed.  Human exposure to zinc chloride, both by ingestion and
     inhalation, are reported.  Tissue damage has been indicated upon both ocular
     and dermal exposure, and a low dermal absorption rate has been indicated.

     Oral intake of an estimated zinc chloride dose of 1,000 mg/kg in humans
     resulted in gastrointestinal (GI) symptoms which included burns of the mouth
     and throat, abdominal pain and vomiting with blood in the vomitus and urine
     (Markwith, 1940; Chobanian, 1981; Potter, 1981).  Vomiting and diarrhea
     occurred in people who ingested approximately 225 mg (3.2 mg/kg) or greater of
     zinc leached from galvanized containers. (Brown, 1964).  Gastrointestinal
     distress is associated with doses of 50-150 mg/day (0.7-2.1 mg/kg/day of zinc
     acetate or sulfate) (Freeland-Graves et al., 1982;  Prasad et al.,  1978; Saoman
     and Roberts, 1988).  A number of human studies have reported that zinc
     (sulfate or gluconate) doses ranging from 29-311 mg/kg (0.4-4.4 mg/kg/day) for
     longer-term exposures decrease serum HDL, erythrocyte superoxide dismutase,
     copper, and ceruloplasmin levels (Black et al., 1988; Chandra 1984; Fischer
     et al., 1984; Goodwin et al., 1955; Hooper et al.,  1980; Samman and Roberts,
     1988).  In addition anemia and neutropenia have been reported in some people
     following doses of 43-200 mg/day zinc (sulfate or acetate) (0.6-2.8 mg/kg/day)
     for longer-term exposures (Hoffman et al.,  1988; Prasad et al., 1978; Simon
     et al., 1988).

     Mucosal damage is the most consistent effect reported after exposure to high
     doses of zinc chloride by both the oral and inhalation route.  Rats and
     rabbits receiving single oral doses of zinc chloride solution at doses between
     250 and 1,000 mg/kg developed perforations of the stomach, penetration into
     the liver and pyebric stenosis (Hahn and Schunk, 1955).  The only notable
     effect reported following short-term exposure of animals to zinc chloride were
     symptoms of  pantothenic acid deficiency.  This effect was evidenced mainly by
     severe alopecia and weight loss in rats maintained on a synthetic diet and
     orally administered approximately 100 mg/kg/day zinc chloride and a
     pantothenic acid-deficient vitamin supplement (Gross et al., 1941).  A slight
     decrease in the intake of drinking water was reported in rats exposed to

                                          VII-1

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28 mg/kg/day zinc chloride in that medium for 25 weeks (Kurokawa et al . ,
1985).  Histological changes were reported in the kidneys of rats exposed to
190.6 mgAg/day zinc chloride for 90 days (Llobet et al., 1988).
No effects on reproductive parameters were seen in rats exposed to 125 or
250 mg/kg/day zinc chloride as the acetate salt in the diet during breeding
and through production of one generation (Heller and Burke, 1927).  Offspring
were also treated and bred without notable effects.  Zinc chloride
(150 mg/kg/day) was considered an equivocal teratogen based on a slight but
significant reduction in live litter size, but only when the live litters
found in utero were included in the determination of litter size (Seidenberg
et al., 1986).  Treatment of parental females on days 8-12 of gestation
resulted in a significant decrease in average weight gain, as well as death of
one of the maternal animals.  Increases in resorption and fetal mortality have
been reported in animals orally exposed to 150-1,000 mg/kg/day of zinc oxide,
sulfate, or carbonate (Ketcheson et al. ,  1968; Kumar, 1976; Sutton and Nelson,
1937).  Zinc deficiency also adversely affects reproductive function, and
fetal development (Hurley, 1969; Hurley and Swenerton, 1966; Hurley et al .
1971; Rogers et al. 1985).

Dermal irritation studies resulted in the development of severe edema and
necrotic erythema following application of a 10% solution of zinc chloride to
the shaved skin of rabbits.  Mild conjunctivitis with moderate corneal opacity
developed after instillation of this solution into the eye (William, 1984).
Johnstone et al. (1973) indicated that zinc chloride solution acted as a
denaturant or fixative when applied to the cornea.  Evidence of dermal
absorption was indicated by a reduced weight gain in guinea pigs after
percutaneous administration of an aqueous solution (Wahlberg, 1965). An
absorption rate of <1% over a five hour period was indicated.

No evidence of tumor promotion was reported in male F344 rats given 28
mg/kg/day zinc chloride in drinking water for 25 weeks (Kurokawa et al. ,
1985) .  Equivocal evidence of testicular tumors was reported in hamsters
intratesticularly injected with 2 mg zinc chloride (Guthrie and Guthrie,
1974) .  Mutagenicity studies were inconclusive although most test results were
negative.  Some evidence of cytotoxicity was seen during mutagenic assays
(DeKnudt and Deminatti, 1978; McGregor, 1980).

     A.   Quantification of lexicological Effects

Health Advisories 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 noncarcino genie end point of toxicity.  The HAs for
noncarcino genie toxicants are derived using the following formula:

                      (NOAEL or LOAEL) (BW)
                       (UF(s)) (	 L/day)

where:

   NOAEL or LOAEL - No- or Lowest-Observed-Adverse-Effect Level
                    in mg/kg bw/day.

               BW - assumed body weight of a child (10 kg) or
                    an adult (70 kg).

                                    VII-2

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               UF - uncertainty factor (10, 100 or 1,000), in
                    accordance with NAS/EPA guidelines.

            L/day - assumed daily water consumption of a child
                    (1 L/day) or an adult (2 L/day).

The health advisory levels which follow were derived with both the
essentiality and toxicity of zinc in mind.  In doing so, the most recent set
of Recommended Daily Allowances (RDAs) for zinc, derived by NRC  (1989), were
used as a guide in the overall risk assessment analysis.  If traditional
procedures for developing RfDs are applied to the available data (uncertainty
factors of 100-1,000 applied to less-than-lifetime human study end points),
the resulting RfDs for zinc would be considerably lower than the RDAs.  With
these parameters in mind, the following numbers were derived.

     1.  One-Day Health Advisory

The oral LD50  for  zinc  sulfate  in  rats was  920 mg/kg,  and  the  oral  LD50 for
zinc chloride in rats, mice and guinea pigs ranged from 200 to 502 mg/kg
(Fabrizio, 1974; Calvery, 1942; Yakuri,  1974).  One-time ingestion of zinc in
beverages at 4.6 mg/kg produced severe abdominal and gastric symptoms in adult
humans (Brown et al., 1964).  However, since this value was derived from a
case study of zinc-induced food illness in adults, the accuracy of the dose
information is questionable.  Thus, the LD50 values  and food poisoning doses
are not appropriate for the calculation of the One-day Health Advisory for
zinc.  Therefore,  the RDA for a 1-year-old, 9-kg infant (5 mg/day) is used as
the basis of the One-Day HA value calculated below.


                        (0.56 mgAg/day) (10 kg)
          One-day HA -  	  - 5.6 mg/L (rounded to 5 mg/L
                             (1) (1 L/day)        to correspond to infant RDA)


where:

       0.56 mgAg/day  -  RDA for a 9-kg infant.

                10 kg  -  assumed weight of child.

                    1  -  uncertainty factor,  chosen in accordance with
                          NAS/EPA guidelines for use with an RDA which
                          provides adequate zinc for human growth and
                          nutrition (NAS,  1989).

              1 L/day  -  assumed daily water consumption by a 10-kg child.

This value is expected to be without any adverse effect even when the diet
contains zinc.  The RDA for the slightly heavier 13-kg child is 10 mg/day.

     2.  Ten-Day Health Advisory

No suitable information was found in the available literature for determining
the Ten-day HA for zinc for a 10-kg child.  The One-day Health Advisory of


                                    VII-3

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5 mg/L, based on the RDA for a 9-kg infant is suitable for use as the Ten-day
HA.

     3.   Longer-Term Health Advisory

Studies by Fischer et al.  (1984) and Yadrick et al. (1989) concerning the
effects of zinc on copper homeostasis were used as the basis of the Longer-
tern Health Advisory.  In these studies, healthy adults were given 25 mg of
zinc as the gluconate twice daily for 6 or 10 weeks.  There was a significant
decrease in erythrocyte-superoxide dismutase (E-SOD) activity or concentration
at both 6 and 10 weeks of exposure (Fischer et al., 1984; Yadrick et al.,
1989).   The decreased concentration of E-SOD is indicative of a copper
deficiency and a diminished capacity of the cells to respond to oxidative
stress.  There were no differences in serum copper levels or ceruloplasmin
activity as compared to the controls.  Serum zinc levels were significantly
increased; dietary zinc was not measured.  The total zinc intake of 66 mg/day
(dietary intake of 16 mg zinc/day plus a zinc supplement of 50 mg/day)
resulted in a LOAEL of 0.94 mg/kg/day for a 70 kg male  (Fischer et al.,
1984).    For females, the total zinc intake was 59.7 mg/day or a LOAEL of
1.0 mg/kg/day for a 60-kg female with a dietary intake of 9.7 mg/day (Yadrick
et al., 1989).

Similar findings were seen in females, but not males, administered 150 mg
zinc/day for 6 weeks during a double blind placebo study (Samman and Roberts,
(1988)  .  Ceruloplasmin, E-SOD and Cu-Zn-SOD concentrations were all
significantly decreased during the zinc supplement period when compared to the
values during placebo administration.  There was a 20% decrease in E-SOD and a
23% decrease in Cu-Zn-SOD at the end of 6 weeks.  The same parameters were
very slightly (but not significantly) decreased in the males.

The results from several case studies, in which zinc supplementation for
periods of 10 months to 2 years resulted in symptoms of a copper deficiency,
support the data by Fischer et al. (1984); Samman and Roberts, (1988); and
Yadrick et al. (1989).  Male and female patients experienced anemia and
neutropenia with ingestion of 43-200 mg zinc per day for 10 months to 2 years.
(Hoffman et al., 1988; Prasad et al., 1978; Simon et al., 1988).  Serum zinc
levels were high and ceruloplasmin values were low.  Both the anemia and
neutropenia were resolved after zinc supplementation ceased.

The LOAEL from the study by Yadrick et al. (1989) in adult females was used to
calculate the Longer-term HA for a 10-kg child as follows:

                       (1.0 mgAg/day) (10 kg)
   Longer-term HA -   	  -  3.33 mg/L (rounded to 3 mg/L)
                           (3)  (1 L/day)
where:
    1.0 mg/kg/day  -  LOAEL, based on a depression of E-SOD concentrations
                      in human  subjects following exposure to zinc for
                      10 weeks  (Yadrick et al. , 1989).

            10 kg  -  assumed weight of child.
                                     V1I-4

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                3  -  uncertainty factor, chosen in accordance with
                      NAS/EPA guidelines for use with a LOAEL from a
                      human study.  This factor also takes into account that
                      zinc is essential for human growth and nutrition.
                      [The RDA for a child ranges from 5 to 10 mg zinc/day
                      (NRC, 1989).]

          1 L/day  -  assumed daily water consumption by a 10-kg child.

Using the Yadrick et al. (1989) LOAEL, the Longer-term HA for a 70-kg adult is
calculated as follows:

                      (1.0 mgAg/day) (70 kg)
    Longer-term HA -  	  -  11.6 mg/L
                           (3) (2 L/day)          (rounded to 12 mg/L
                                                   or 12,000 (tg/L)
where:

     1.0 mg/kg/day  -  LOAEL, based on a depression of E-SOD concentrations
                       in human subjects following exposure to zinc for
                       10 weeks (Yadrick et al., 1989).

             70 kg  -  assumed weight of adult.

                 3  -  uncertainty factor, chosen in accordance with
                       NAS/EPA guidelines for use with a LOAEL from a
                       human study   This factor also takes into account that
                       zinc is essential for human growth and nutrition.   [The
                       RDA for an adult ranges from 12 to 19 mg zinc/day (NRC,
                       1989).]

           2 L/day  -  assumed daily water consumption by a 70-kg adult.

     4.   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 noncarcino-
genic 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 estimate 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
(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
                                     VII-5

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from drinking water is based on actual exposure data or, if data are not
available, a value of 20% is assumed.

If the contaminant is classified as a known, probable or possible carcinogen,
according to the Agency's classification scheme of carcinogenic potential
(U.S. EPA, 1986), then caution must be exercised in making a decision on how
to deal with possible lifetime exposure to this substance. For human (A) or
probable human (B) carcinogens, a Lifetime HA is not recommended.  For
possible human carcinogens (C), an additional 10-fold safety factor is used to
calculate the Lifetime HA.  The risk manager must balance this assessment of
carcinogenic potential and the quality of the data against the likelihood of
occurrence and significance of health effects related to noncarcinogenic end
points of toxicity.  To assist the risk manager in this process, drinking
water concentrations associated with estimated excess lifetime cancer risks
over the range of 1 in 10,000 to 1 in 1,000,000 for the 70-kg adult drinking
2 L of water/day are provided in the Evaluation of Carcinogenic Potential
section.

In establishing an RfD for zinc, the data on essential needs were combined
with the human data on toxic responses in studies of limited duration in order
to define a transition level which would meet the physiological requirements
of nearly all healthy persons without causing a toxic response in the most
sensitive population subgroup when consumed daily for a lifetime.

There appears to be only an order of magnitude between the amount of zinc that
will satisfy physiological need (5.5 mg/day; King, 1989) and the amount that
is associated with the appearance of minimally adverse effects (depress E-SOD
at 60 mg/day) with 6- to 10-week daily exposures (Fischer et al., 1986;
Yadrich et al., 1989).  Since an appropriate lifetime duration study was not
available and the animal data from the 12-month duration study by Aughey
et al.  (1977) did not evaluate the sensitive end points of zinc toxicity
identified in the human studies, the LOAEL of 1.0 mg/kg/day which was used for
the Longer-term HA is also used for determination of the .RfD and DWEL as
follows:

     Step 1.  Determination of the Reference Dose (RfD)

                (1.0 mgAg/day)
        RfD  -  	T-=T	  -  0.33 mg/kg/day (rounded to 0.3 mg/kg/day)

where:

     1.0 mg/kg/day  -  LOAEL, based on a depression of E-SOD concentrations in
                       human subjects following 10-week exposure (Yadrick et
                       al., 1989)

                 3  -  uncertainty factor, chosen in accordance with
                       NAS/EPA guidelines for use of a LOAEL from a human
                       exposure study (of an essential nutrient) in which
                       minimally adverse effects were observed.

This RfD was compared to the RDA expressed on a mg/kg/day basis for each age
and sex group.  For 79% of a 70-year lifetime, the RDA corresponds to a daily
zinc intake of 0.23 mg/kg/day or less, a value which provides the functional
and metabolic zinc requirements for over 99% of the population (NAS, 1989).

                                     VII-6

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The RfD of 0.3 mg/kg/day supplies adequate zinc to meet these requirements
over a lifetime without any concurrent physiologic impairment.  It does not
supply the RDA for infants, preadolescent children and pregnant women and,
therefore, does not apply to these groups.  The RfD dose is expected to be
without adverse effect when consumed on a daily basis over an extended period
of time.  It neither induces a nutritional deficiency in healthy nonpregnant
adult humans consuming the average American diet nor causes undesirable
inhibition of copper absorption. ,

     Step 2.  Determination of the Drinking Water Equivalent Level (DWEL)

                (0.3 mgAg/day) (70 kg)
        DWEL -  -  -  10.5 mg/L (rounded to 10 mg/L)
                     (2) (1 L/day)

where :
            0.3 mA/day  -  RfD.
                    70 kg  -  assumed weight of adult.

                  2 L/day  -  assumed water consumption by 70-kg adult.


     Step 3.  Determination of the Lifetime HA

                 Lifetime HA  -   (10  mg/L)  (0.2)   -  2.0  mg/L

where :

                10.0 mg/L  -  DWEL.

                      0.2  -  assumed percentage of the daily exposure (20%)
                              contributed by the ingestion  of drinking water.

According to NAS (1989), approximately 70% of the zinc consumed in human diets
comes from animal products.  Drinking water in the U.S. generally contains
less than 0.1 mg zinc/liter.

     B.   Quantification of Carcinogenic Potential

Due to the absence of toxicological evidence for classifying zinc as a
potential carcinogen, a quantification of carcinogenic risks for zinc is
inappropriate .

Groups of male F344 rats (15/group) were given 450 ppm (approximately 28
mg/kg/day) of zinc chloride in drinking water for 25 weeks to evaluate the
promoting effect on renal tumor igen'e sis (Kurokova et al.  , 1985).  Some animals
were pretreated with N-ethyl-N-hydroxyethylnitrosamine (EHEN) (500 ppm) as an
initiator.  Four groups were compared:  controls (no EHEN or zinc chloride),
EHEN-DW, EHEN-zinc chloride and DW-zinc chloride.  There were no significant
differences in the incidence of dysplastic foci (DF) between the EHEN-zinc
chloride and EHEN-DW groups.  The mean number of DF/CM* was increased
significantly (p<0. 01) in the EHEN-zinc chloride group compared to controls.
There were no significant differences between groups for the occurrence of
renal cell tumors and hepatocellular carcinoma.  Even though this study is

                                     VII-7

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limited by duration and use of one sex, it did not demonstrate that zinc
chloride is a promoter of kidney lesions.

Other limited available information on the carcinogenic potential of zinc
(testicular tumors in 2/49 hamsters from intratesticular injection) is
particularly relevant to zinc exposure via drinking water.

Applying the criteria described in EFA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), zinc *nd zinc salts are assigned to Group
D: not classifiable as to human carcinogenicity.  This category is for agents
with inadequate animal evidence of carcinogenicity.
                                     VII-8

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VIII. OTHER CRITERIA.  GUIDANCE AND STANDARDS

           A.    Zinc Chloride

      The ACGIH (1986) 8-hour time weighted average threshold limit value (TWA-TLV)
      for exposure to zinc chloride is 1 mg/n3.   This  limit  is  protective against
      the irritative effects that result from exposure to zinc chloride fume.  A
      short-term exposure limit (STEL) of 2 ag/nr also has been recommended.   The
      Occupational Safety and Health Administration (OSHA)  permissible exposure
      limit (PEL) for zinc chloride fume also has been set  at 1 mg/m3 averaged over
      an 8-hour work shift (Mackison et al., 1981).  An initial or pre-employment
      medical  examination is recommended to detect pre-existing conditions with
      examination of the respiratory system stressed.   In 1978, the exposure limit
      in Sweden was also 1 mg/m3 (ACGIH,  1986).

      Cullumbine (1957) calculated "safety distances"  for exposure to zinc chloride
      screening smoke for set time periods under the differing meteorological
      conditions of day and night exposure.  For daytime exposure, a distance of
      91 meters from the source for 43 minutes is considered safe while at
      914 meters exposure could last up to 37 hours.  Estimated zinc chloride
      concentrations at these distances are 47 and 0.9 mg/m3,  respectively.   Under
      night time conditions, a distance of 183 meters  from  the source would be
      considered safe for up to 24 minutes and 914 meters would be a safe distance
      for exposures up to 2.5 hours.  Zinc chloride levels  at these two distances
      are estimated at 85 and 13 mg/m3,  respectively (cited  in Hill et al. ,  1978).

           B.    Other Zinc Compounds

      The current EPA-recommended secondary standard based  on taste and odor for
      zinc in drinking water is 5 mg/L (NRC, 1979).

      Although standards for public exposure are not reported (NRC, 1979), air
      quality standards for zinc and its compounds have been established for
      occupational exposures in many countries,  including the United States.   For
      example, the American Conference of Governmental Industrial. Hygienists
      recommends a Threshold Limit Value-Time Weighted Average (TWA) of 1 mg/m3 for
      zinc chloride fumes and a Threshold Limit Value-Short-Term Exposure Limit
      (STEL) of 2 mg/m3 (ACGIH,  1990).   The corresponding values for zinc oxide
      fumes are 5 mg/m3 and 10 mg/m3 and  there is  a TWA  of 10 mg/m3 for zinc oxide.

      The Recommended Daily Allowance for zinc is 5 mg for  infants under 1 year of
      age; 10 mg for children under 10 years; 15 mg for adult males; 12 mg for adult
      females; 15 mg for pregnant women; and 16-19 mg for lactating women (NRC,
      1989).

      No other criteria, guidelines or standards pertaining to zinc exposure via
      drinking water were found.
                                          VIII-1

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 ANALYTICAL METHODS

 The concentrations  of zinc  in  environmental media can  be  determined by several
 methods based on either emission or absorption spectroscopy.   Each of these
 methods can be used for the  determination of a number  of  metals  and is not
 specific for zinc or zinc chloride.   In each of the  methods  the  metal is
 dissolved using acid digestion and is then thermally excited.  All elements,
 when excited, emit  or absorb light frequencies characteristic  of that element
 and those frequencies can be used to identify the element.   Most metal
 analysis is done in the ultraviolet and x-ray regions  of  the spectrum.

 EPA Method Number 289.1 uses atomic absorption (AA)  spectroscopy to determine
 the zinc concentration in water and wastewater.  In  this  method  the dissolved
 metals are aspirated into a  flame source and excited to the  point that the
 metals are dispersed to a mono-atomic state.  A light  source,  whose cathode is
 the metal of interest,  passes  through the flame;  the resulting absorption of
 light by the element of interest is directly proportional to concentration.
 The disadvantage of this technique,  when multiple metal ions are present in
 the solution, is the fact that only one metal can be detected  during an
 analysis.  The detection limit of this technique  is  5.0 ng/L for zinc (EPA,
 1979).

 EPA Method Number 289.2, Graphite Furnace Atomic  Absorption  (GFAA), is an
 alternate atomic absorption technique for use with water  and wastewater.  In
 this approach, a specific amount of liquid is dried  on a  thermal source to
 concentrate the sample. The sample is then electrothermally excited for
 analysis and identification.  The detection limit for  zinc is  0.05 ng/L (EPA,
 1979).

 Inductively-Coupled Plasma  Atomic Emission Spectroscopy (EPA Method Number
 200.7) is a method  which is  applicable for the analysis of dissolved and/or
 suspended metals in water or wastewater.  In this technique  the  liquid sample
 is aspirated into the flace  source which is a plasma torch of  argon excited to
 super hot levels by radio-frequency (RF) radiation.  The  metals  are excited to
 the level where they emit radiation.  By using classical  dispersion grating
 optics, the intensities of  the spectral lines are monitored  by a
 photomultiplier tube.  The  spectral lines and their  intensities  are used to
, identify the metal  and its  concentration in the sample.   One advantage of this
 techniques is that  a large  number of metals can be determined  simultaneously;
 however, in samples with multiple analytes, interferences between analytes can
 sometimes limit the accuracy of the results.  The detection  limit for zinc in
 this method is 2.0  ng/L (EPA,  1982).

 In EPA Method Number 6020,  Inductively-Coupled Plasma  Mass Spectroscopy
 (ICP/MS), the excitation of the metal is again by a  radio-frequency plasma,
 but the excited atoms are then interfaced into a mass  spectrometer (MS) where
 they are sorted according to their mass/charge ratios  for identification and
 quantification.  The use of the mass spectrometer makes the  method applicable
 for determination of a large number of elements in water  and wastewater at low
 concentrations.  The detection limit for zinc is  0.08  (ig/L.  Quantification is
 achieved by computerized software programs similar to  those  used in EPA-MS
 methods for analysis of organic compounds.  By using appropriate filtration
 and digestion steps, this method can be used to measure both dissolved and
 particulate metals  in water  samples (EPA, 1990).


                                      IX-1

-------
Neutron activation is used to determine the concentration of zinc in
biological samples (Greenberg et al.,  1979; Jurgensen and Behne,  1977;  Lievens
et al., 1977).  The samples are irradiated by exposure to a high  neutron flux
to form radioactive **Zn and  then wet-ashed with concentrated sulfuric acid
and extracted with a diphenylthiocarbazone solution.  The zinc  concentration
is determined by a measurement of gamma ray emissions with a scintillation
counter used in conjunction with a pulse height analyzer and then quantified
by comparison with a standard containing a known amount of wZn (Lieberman and
Kramer, 1970).  The detection limit of this method for zinc varies with the
medium analyzed.  A detection level of 5E-5 jig/100 mL has been  reported for
blood samples (Jurgensen and Behne, 1977).
                                     IX-2

-------
TREATMENT TECHNOLOGIES

Zinc chloride in water is rapidly hydrolyzed to zinc ions (Zn~)  and chloride
ions (Cl"5; no specific  treatment  of water for  removal  of zinc  chloride  is
necessary.  The ionic zinc reacts to form various hydroxides and zincates.
Removal of zinc from water can be accomplished by standard water treatment
techniques, such as coagulation and filtration.

Available data indicate that reverse osmosis (RO),  chemical coagulation and
possibly ion exchange (IX) will significantly reduce zinc levels in drinking
water.

Foster et al. (1980) applied RO treatment to saline water with a zinc
concentration of 0.26 mg/L in Alamogordo, New Mexico.  The RO system consisted
of hollow fiber (HF) and spiral wound (SW) elements.  The HF was operated at
515 psi with a water recovery rate of 78%, while the SW was operated at
430 psi with a water recovery rate of 79%.  The HF element removed 73% of zinc
while the SW removed 92%.

Fox and Sorg (1987) tested the effectiveness of home-use reverse osmosis
devices in removing zinc.  RO systems typically consist of prefilters,
dechlorinators,  a RO module and an activated carbon filter.  The RO module, a
spiral-wound polyamide filter, was operated at a pressure of 42 ± 2 psig.
Zinc was reduced by 99% from an influent concentration of 5.42 mg/L.

Harries (1985) described the performance of a seeded RO pilot plant used to
desalinate gold mine water nearly saturated with CaSO^.  The pilot plant was
operated for 5,000 hours at a water recovery rate of 92-96%. Tubular cellulose
acetate membranes were operated at 400 psi.   Zinc was reduced by 81.8% from an
influent concentration of 2.2 mg/L.

Terril and Neufeld (1983) reported data from a RO unit used to treat blast
furnace scrubber effluent which,  in this case, had a zinc concentration of
27 mg/L.  The RO unit contained cellulose acetate (CA) membranes and was
operated at pressures of 350-450 psi and a water recovery rate of 70-80%.  The
system achieved 99% reduction in zinc levels.

Hrubec et al., (1979) reported the results of wastewater treatment by RO for
water reuse.  The RO system contained CA membranes in tubular configuration
and was operated at 580 psi and a water recovery rate of 60-80%.  Zinc was
reduced by 75% from an influent concentration of 40 mg/L.

Hrubec et al., (1979) reported that wastewater treatment by lime softening
reduced zinc by 92% from an influent concentration of 119 mg/L.  Lime [at
250-600 mg Ca(OH)2/L]  and polyelectrolyte (at 0.5 mg/L) were added to  the
rapid mix and flocculator influent at a pH of 11.2.  Retention time for the
clarifier was 1.5 hours.  Recarbonation was carried out in columns designed
for an optimum hydraulic time.  Filtration was accomplished on a double-layer
filter bed.

Adams et al. (1975), demonstrated that when dissolved zinc was added to the
influent of a wastewater treatment plant at levels of 2.5 to 20 mg/L,  primary
treatment removed only about 8 to 14% of the zinc.  After activated sludge
treatment, however, 74 to 96% of  the zinc was removed.  It is uncertain
whether the zinc was bioaccumulated by the microorganisms, or if further

                                      X-l

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removal of solids by sludge formation was responsible for the dramatic
reduction in zinc concentration.  Nevertheless, it is clear that in the
biodensity ranges found in sewage treatment plants, zinc is effectively
removed from solution, and bioaccumulation probably plays an important role in
such removal.

Laboratory jar tests were conducted to develop data on the removal of metal
ions, including zinc, from aqueous solutions (Uestbrook and Grohse, 1979).
Sodium sulfide was added at stoichiometric ratios of 1.1 and 1.5.  From an
initial concentration of 5 mg/L, zinc was reduced to below 1 mg/L by
precipitation with sodium sulfide.

The performance of natural zeolite clinoptilolite, used as an ion exchange
resin, was studied in a pilot plant by Blanchard et al. (1984).  Two columns,
each approximately 8 inches in diameter and packed with 40 inches of zeolite,
were operated in series.  The breakthrough concentration was set at 50 pg/L
for zinc, after which the zeolite was regenerated with NaCl solution at a flow
rate of 10 bed volumes (BV) per hour.  Zinc breakthrough occurred after 220 BV
with a leakage rate of 8 pg/L at an influent concentration of 0.235 mg/L.
                                      X-2

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I.   CONCLUSIONS

    Based  on  the  available  animal toxicity data,  the  HA for One-day and Ten-days
    is  5 mg/L for the  10 kg child.   The Longer-term HA for the  10 kg child is
    3 ag/L and for the 70 kg adult is 10 mg/L.  The Lifetime HA is 2 mg/L.   These
    values are considered protective against toxic  effects for  the most sensitive
    members of the population.   The essentiality  of zinc was considered in the
    derivation of these HA  values.   Currently,  adequate available data to assess
    the carcinogenic risk of zinc are inadequate  but  in view of its physical and
    chemical  properties,  and considering that zinc  is an essential element, it
    seems  unlikely that zinc chloride will present  a  carcinogenic risk to humans
    at  the levels considered safe for consumption.  Using the EPA criteria for
    classification of  carcinogenic risk, zinc chloride and other zinc compounds
    currently meet the criteria for category D, not classifiable as to human
    carcinogenicity,   This  category is for agents with inadequate human and animal
    evidence  of carcinogenicity or for which no data  are available.

    A companion report, "Data Deficiencies/Problem  Areas and Recommendations for
    Additional Data Base Development for Zinc Chloride" (Appendix 1), summarizes
    the scope of  existing data reviewed for this  HA.   Recommendations are made for
    additional studies to assess the short term effects of zinc chloride in
    drinking  water as  well  as developmental toxicity  studies to clarify the issue
    of  the teratogenicity of zinc chloride.
                                         XI-1

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XII. REFERENCES

     Aamodt, R.L.,  W.F.  Rumble,  A.K.  Babcock,  D.M.  Foster and R.I.  Henkin.   1982.
     Metabolism 31:326-334.

     Abernathy, C.O.,  R. Cantilli,  J.T.  Du and O.A.  Levander.   1991.   Essentiality
     versus toxicity:  considerations  in the risk assessment of essential trace
     elements.  U.S.  EPA,  Office of Science and Technology,  Human Risk Assessment
     Branch and U.S.D.A.,  Human Nutrition Research Center.

     ACGIH.  1986.   American Conference of Governmental Industrial Hygienists, Inc.
     Documentation of the  threshold limit values and biological exposure indices.
     Cincinnati, OH:  p.  643.

     Adams, C.E. Jr.,  W.W. Eckenfelder and B.L. Goodman.   1975.  The  effects and
     removal of heavy metals in biological treatment.  In:  Krenkel, P.A.,  ed.
     Heavy metals in the aquatic environment.   Oxford,  England: Pergamon Press,
     pp. 277-292.

     Amacher, D.E.  and S.C.  Paillet.   1980.  Induction of trifluorothymidine
     resistant mutants by metal ions  in L5178Y1 TK +/-  cells.   Mutat.  Res.
     78:279-298.

     Angino, E.E.,  L.M.  Magnuson and T.C. Waugh.  1976.  Mineralogy of suspended
     sediment and concentration of Fe, Mn, Ni, Zn,  Cu,  and Pb in water and Fe, Mn,
     and Pb in suspended load of selected Kansas streams.  Water Res.  10:1187-1191.

     Anonymous.  1989.  Interleukin-1 regulates zinc metabolism and metallothionein
     gene expression.   Nutr. Rev. 47(9):285-287.

     Ansari, M.S.,  W.J.  Miller,  J.W.  Lassiter, M.W.  Neathery and R.P.  Gentry.
     1975.  Effects of high but nontoxic dietary zinc on zinc metabolism and
     adaptations in rats.   Proc. Soc. Exp. Biol. Med. 150:534-536.

     Ansari, M.S.,  W.J.  Miller,  M.W.  Neathery, J.W.  Lassiter,  R.P.  Gentry and
     R.L. Kincaid.   1976.   Zinc metabolism and homeostasis in rats fed a wide range
     of high dietary zinc levels.  Proc.  Soc.  Exp.  Biol.  Med.  152:192-194.

     Aughey, E., L. Grant, B.L.  Furman and W.F. Dryden.  1977.   The effects of
     oral zinc supplementation in the mouse.   Pathology 87:14.

     Barrowman, J.A.,  R. Bonnet and P.J.  Bray.  1973.  Biliary excretion of zinc in
     rats.  Biochem.  Soc.  Transactions,  539th Meeting,  Uxbridge, 1:988-989.

     Black, M.R., D.M. Medeiros, E. Brunett and R.  Welke.  1988.  Zinc supplements
     and serum lipids in young adult white males.  Am.  J. Clin. Nutr.  47:970-975.

     Blanchard, G., M. Maunaye and G. Martin.   1984.  Removal of heavy metals from
     waters by means of natural zeolites.  Water Resources 18(12):1501-1507.

     Bowermen, S.J. and I. Harrill.  1983.  Nutrient consumption of individuals
     taking or not taking supplements.  Am. J. Diet. Assoc.  83:298-305.
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Carcinog. Mutagen. 7:17-28.

Seidenberg, J.M., D.G. Anderson and R.A. Becker.  1986.  Validation of an
in vivo developmental toxicity screen in the mouse.  Teratogenesis Carcinog.
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Sharrett, A.R., A.P. Cater, R.M. Orheim and M. Feinleib.  1982.  Daily
intake of lead, cadmium, copper and zinc from dietary water:  the 1982 Seattle
study of trace metal exposure.  Environ. Res. 28(2):465-475.

Sheline, G.E.,  I.L. Chaikoff, H.B. Jones and M.L. Montgomery.  1943a.  Studies
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Sheline, G.E.,  I.L. Chaikoff, H.B. Jones and M.L. Montgomery.  1943b.  Studies
on the metabolism of zinc with the aid of its radioactive isotope.  II. The
distribution of administered radioactive zinc in the tissues of mice and dogs.
J. Biol. Chem.  149:139-151.
                                    XII-10

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Simko, M.D.,  C.  Cowell and J.A. Gilbride.  1984.   Nutritional assessment.
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Simon, S.R.,  R.F.  Branda,  B.H. Tindle and S.L. Burns.  1988.  Copper
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Hematol. 28:181-183.

Skog, E. and J.E.  Wahlberg.  1964.  A comparative investigation of the
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Dermatol. 43:187-192 as cited in Hill et al. (1978).

Sokolowska, D.M. and W.M.F. Jongen.  1984.  Heavy metals and Salmonella
tvphimurium:  mutagenicity and interaction with model compounds.  Mutat. Res.
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Solomons, N.W. and R.A. Jacob.  1981.  Studies on the bioavailability of
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Spanggord, R.J., T.-W. Chou, T. Mill, R.T. Podoll, J.C. Harper and D.S. Tse.
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Steele, K,F.  and A.H.  Wagner.   1975.  Trace metal relationships in bottom
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                                              t

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Sutton, W.R.  and V.E.  Nelson.   1937.  Studies on zinc.  Pro. Soc. Exp. Biol.
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Tacnet, F., D.W. Watkins and P. Ripoche.  1990.  Studies of zinc transport
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Tacnet, F. , D.W. Watkins and P. Ripoche.  1991.  Zinc binding in intestinal
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Tanner, J.T.  and M.H.  Friedman.  1977.  Neutron activation analysis for trace
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Terril, M.E.  and R.D.  Neufeld.  1983.  Reverse osmosis of blast-furnace
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Thompson, E.D.,  J.A. McDermott, T.B. Zerkle, J.A. Skare, B.L.B. Evans and
D.B. Cody.  1989.   Genotoxicity of zinc in 4 short-term mutagenicity assays.
Mutat. Res. 223:267-272.

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Torrance, A.G. and R.B.  Fulton.   1987.   Zinc-induced henolytic anemia in a
dog.  J. Am. Vet. Med.  Assoc.   191(4):443-444.

Turnlund, J.R., J.C. King,  W.R.  Keyes,  B.  Gong and M.C.  Michel.   1984.   A
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Westbrook,  C.W.  and P.M. Grohse.  1979.  Coagulation and precipitation of
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Yakuri, 0.   1974.  [Japanese title]  Pharmacometries 8:1067-1072.
                                    X1I-13

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                       APPENDIX 1
Data Deficiencies/Problem Areas and Recommendations for
Additional  Data  Base  Development  for  Zinc  Chloride  and
                  other Zinc  Compounds
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INTRODUCTION

The Office of Water (OW),  Environmental Protection Agency (EPA),  in
conjunction with the Department of the Army, has reviewed the available data
on zinc and zinc chloride for the purpose of developing a Health Advisory (HA)
useful in dealing with contamination of drinking water, to include "state-of-
the-art" information on environmental fate, health effects and analytical
methodology.

OBJECTIVES

The objective of this appendix is to provide an evaluation of the data
deficiencies and/or problem areas encountered in the review process for zinc
and to make recommendations,  as appropriate, for additional data base
development.  This document is presented as an independent analysis of the
current status of zinc technology, as related to its possible presence in
drinking water, and includes a summary of the background information used in
the development of the HA.  For greater detail on the toxicology of zinc, the
Health Advisory on Zinc Chloride should be consulted.

BACKGROUND

Zinc is an essential trace element which is a constituent of a number of
enzymes involved in key biological processes.  Zinc deficiency is associated
with loss of appetite, growth retardation, skin changes, immunological
abnormalities, wound healing retardation, and developmental effects (HAS,
1989).  The development of a health advisory is complicated by the fact that
there appears to be a narrow range of doses between the amount of zinc needed
to fulfill physiological needs (5.5 mg/day) and the amount that will produce
minimally adverse effects ( depression of erythrocyte superoxide dismutase, E-
SOD, at 60 mg/day) (King,  1989; Fischer et al., 1986; Yadrich et al.,  1989).
The Recommended Dietary Allowance for zinc ranges from 5 mg/day for infants to
19 mg/day for lactating women (NAS, 1989).  These values were used as a guide
for Health Advisory derivation.

In water, zinc compounds readily dissociate to its ionic form, combining with
substances in the water to form hydroxides and insoluble precipitates.  It has
been detected only as trace amounts in most ground and surface waters (Hill
et al., 1978).  Hydrolysis is its main transformation process in the
environment.

Few data are available on the pharmacokinetic properties of zinc in animals.
Measurement of zinc chloride absorption in humans following jimol doses of zinc
indicates that approximately 50-55% of the dose was absorbed (Payton et al.,
1982).  Minimal absorption was indicated following percutaneous application in
guinea pigs (Skog and Wahlberg, 1964).  Absorption following inhalation by
five soldiers was indicated by an increase in plasma zinc levels (Hjortso
et al., 1988).  Distribution of zinc chloride to the tissues has been reported
in both human (Hjortso et al., 1988) and animal studies (Feaster et al., 1955;
Lorber et al., 1970; cited in Hill et al., 1978; Kossakowski and Grosicki,
1983) with levels highest in liver, kidney and intestines.  Distribution to
striated muscle also has been indicated (Sheline et al., 1943b).   No data on
the excretion of zinc following oral administration of zinc chloride was
located in the literature but intravenous studies in aice, rats and dogs


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indicated that most excretion takes place in the feces (Sheline et al.,
1943a).

Data on the exposure of humans to zinc chloride, both orally and by
inhalation, indicate that it is highly irritating to the mucous membranes
(Potter, 1981; Chobanian, 1981).  Death has been reported following inhalation
of zinc chloride in a closed environment (Markwith, 1940; Evans, 1945;
Milliken et al., 1963; Macaulay and Mant, 1963; HJortso, 1988), usually as a
result of toxicity to the respiratory tract.  Toxic signs include inflammation
with edema, bronchopneumonia with engorgement and necrosis (Evans, 1945).
Sloughing of the epithelium also has been reported (Milliken et al., 1963;
Macaulay and Mant, 1963).  Exposure by inhalation in open spaces results in
milder respiratory symptoms such as cough, hoarseness and sore throat,  and
also may include nausea, vomiting, fatigue and headache  (Schenker et al.,
1981).   Reduced visual acuity and loss of the sense of smell has resulted from
splash injuries from zinc galvanizing solutions (Houle and Grant, 1973).

In humans oral doses of zinc, approximately 225 mg (3.2 mg/kg) or greater
leached from galvanized containers produce vomiting and diarrhea (Brown,
1964).   Gastrointestinal distress is associated with doses of 50-150 mg/day
(0.7-2.1 mg/kg/day as zinc acetate or sulfate) (Freeland-Graves et al.,  1982;
Prasad et al., 1978; Samman and Roberts, 1988).  A number of human studies
have reported that zinc sulfate or gluconate doses ranging from 29-311 mg/kg
(0.4-4.4 mg/kg/day) for longer-term exposures decrease serum HDL, erythrocyte
superoxide dismutase, copper, and ceruloplasmin levels (Black et al., 1988;
Chandra 1984; Fischer et al., 1984; Goodwin et al., 1955; Hooper et al., 1980;
Samman and Roberts, 1988).  In addition anemia and neutropenia have been
reported in some people following doses of 43-200 mg/day (0.6-2.8 mg/kg/day as
zinc gluconate, -sulfate, or -acetate) for longer-term exposures (Hoffman
et al., 1988; Prasad et al., 1978; Simon et al., 1988).

An oral LD50 and average lethal  doses  for zinc  chloride were  reported in
animals.  Yakuri  (1974) reported an LD50 of 502 mg/kg in male mice while
Woodard and Calvery (1941) as cited in Calvery (1942) reported acute oral
median lethal doses of  350, 350 and 200 mg/kg in rats, mice and guinea pigs,
respectively.  Oral average lethal doses of 750 and 1,000 mg/kg were reported
in rats and rabbits, respectively (Hahn and Schunk, 1955).

Dermal application of a 10% solution of zinc chloride to the skin of albino
rabbits produced severe edema and necrotic erythema while mild conjunctivitis
and moderate penetrating corneal opacity was evident after application to the
conjunctival sac  (Williams, 1984).  Percutaneous administration of an aqueous
solution of zinc chloride to guinea pigs resulted in a cessation of weight
gain (Wahlberg, 1965).  Johnstone et al. (1973) indicated that zinc chloride
acted  as a  fixative and denaturant on excised bovine corneas.

Perforation of the stomach, penetration to the liver and pyloric stenosis
occurred in rats and rabbits following a single oral dose in the
250-1,000 mg/kg zinc chloride range (Hahn and Schunk, 1955).  Signs of vitamin
deficiency evidenced by severe alopecia, growth retardation and rusting of the
coat were precipitated  after five weeks by the oral administration of zinc
chloriac to female rats at a dose equivalent to approximately 100 mg/kg/day
for a  40 kg rat (Gross  et al., 1941).  During this study, rats were maintained
on a synthetic diet and orally administered a vitamin-supplemented filtrate
fraction low in pantothenic acid.

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 No  effects were  seen  in rats on reproductive  parameters,  offspring and the
 subsequent reproductive cycle of the offspring while  exposed to 2.5-5% of zinc
 in  the  diet.  A  NOAEL of approximately 250 mg/kg/day  was  indicated (Heller and
 Burke,  1927).  Seidenberg et al.  (1986) reported that zinc  chloride could be
 considered a  teratogen based on a slight but  significant  reduction in live
 litter  size,  but only when live litters found in utero were included in the
 calculations.  The  oral dose in this study was 150  mg/kg/day in the drinking
 water and was administered on Days 8-12 of gestation.   Average  weight gain of
 the maternal  rats was also significantly decreased  at this  dose level when
 compared to the  controls.   However,  the study method  was  designed to screen
 chemicals for additional,  more detailed, conventional evaluation;  therefore,
 zinc chloride should  be considered a potential teratogen.

 In  a study conducted  to measure the tumor-promoting potential of zinc
 chloride, Kurokawa  et al.  (1985)  treated young male rats  at 450 ppm
 (approximately 28 mg/kg/day) in drinking water for  25 weeks,  both with and
 without a prior  two week initiation period with N-ethyl-N-
 hydroxyethylnitrosamine (EHEN).  While the mean number of dysplastic foci were
 significantly increased at this dose level in the EHEN-initiated rats
 receiving zinc,  there were no significant differences in  the incidence of
 these lesions nor in  the incidence or mean number of  renal  cell tumors.   No
 effects were  seen on  final body weight and liver and  kidney weight, nor were
 any lesions seen in the zinc-treated rats not initiated with EHEN.

 Genotoxicity  studies  were somewhat inconclusive with  most studies indicating
 no  mutagenic  effects  with zinc chloride.  Kalinina  and Polukhina (1977)
 reported the  occurrence of frame shift mutations.   DeKnudt  and  Deminatti
 (1978)  reported  cytotoxicity in human lymphocytes and McGregor  (1980) reported
 toxicity at high levels in S. typhimurium strains and in  S^. cerivisea.
 Dominant lethal  mutation studies were negative (Vilkina et  al.,  1979).

 Analysis for  zinc can be accomplished by atomic absorption  spectrophotometry
.(AAS),  flameless AAS  and neutron activation analysis.   Calorimetric methods
 are also available.   A detection limit of 10  ng/L in  body fluids has been
 reported using AAS  (Hill et al.,  1978).

 Based on the  available animal toxicity data,  the HA for One-day and Ten-days
 is  5 mg/L for the 10  kg child.  The Longer-term HA  for the  10 kg child is
 3 mg/L  and for the  70 kg adult is 10 mg/L. The Drinking  Water  Equivalent
 Level  (DWEL)  is  10  mg/L.  The Lifetime HA is  2 mg/L.   These values are
 considered protective against toxic effects for the most  sensitive members of
 the population.   The  essentiality of zinc was considered  in the derivation of
 these HA values. Currently, adequate available data  to assess  the
 carcinogenic  risk of  zinc are inadequate but  in view  of its physical and
 chemical properties,  and considering that zinc is an  essential  element,  it
 seems unlikely that zinc chloride will present a carcinogenic risk to humans
 at  the  levels considered safe for consumption.  Using the EPA criteria for
 classification of carcinogenic risk, zinc chloride  and other zinc compounds
 currently meets  the criteria for category D,  not classifiable as to human
 carcinogenicity. This category is for agents with  inadequate human and animal
 evidence of carcinogenicity or for which no data are  available.
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DISCUSSION

Available data on the toxicokinetics,  health effects, analysis and treatment
of zinc have been reviewed.

While the toxicokinetic properties of zinc have not been extensively studied,
available data indicate that humans absorb between 50-55% of an oral dose in
the pool range.  Measurable zinc is distributed to the tissues with the
largest amounts in the liver, kidney and intestines and lesser amounts in
other tissues, including striated muscle.  Excretion is primarily via the
feces.  Since zinc is an essential trace nutrient, its presence in the body is
expected.  Removal of excess quantities of zinc has been accomplished with the
use of chelating agents.  Further studies are not required for development of
a HA.

Available studies on the toxicity of zinc include LD50  and average  lethal
doses.  However, little data is available on the short-term exposure of
animals to zinc by the oral route.  Inadvertent ingestion of zinc soldering
solutions has resulted in toxicity in humans.  It is, therefore, recommended
that studies be carried out in animals over periods ranging from several days
to several weeks to determine a short-term NOAEL or LOAEL for zinc.

Oral exposure to zinc (various compounds) for longer periods of time indicate
that doses of 29-311 mg/day (0.4-4.4 mg/kg/day) can produce marginally adverse
effects on several blood chemistry parameters including decreased levels of
HDL, erythrocyte superoxide dismutase, copper, and ceruloplasmin.  Anemia and
neutropenia may develop in more severe cases.  Weight loss and vitamin
deficiency have been demonstrated under conditions not routinely encountered,
i.e. special synthetic diets.   Available data is considered sufficient for
development of a Longer-term and Lifetime HA.

While no bioassay for carcinogenicity of zinc has been conducted, preliminary
studies to evaluate the tumor-promoting properties indicate that zinc chloride
is not a promoter of tumors in the two organs in which zinc is readily
distributed.  Most genotoxic studies indicate that zinc is negative for
mutagenicity.

Zinc chloride had no effect on the reproductive parameters nor on the
offspring in a reproduction study.  Mating of the litters of this study were
also negative for reproductive effects.  No further reproductive studies are
recommended for HA development.  Because zinc is a potential teratogen, based
on a reduction of litter size when in utero live litters were counted, further
studies on possible developmental effects should be undertaken.

Zinc is an essential trace element, and as a constituent of a number of
enzymes, a participator in numerous biological processes.  The National
Academy of Sciences (HAS, 1989) has developed Recommended Dietary Allowances
(RDAs) of 5-19 mg/day (0.3-0.6 mg/kg/day) for various populations.

Several methods for analysis of zinc in various matrices appear adequate for
use  in the detection of zinc in drinking water.  No further studies are
recommended.  Similarly, development of techniques for the removal of zinc
from water are not considered necessary at this time.
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RECOMMENDATIONS

Based on the above discussion, the following recommendations are made:

      1.  The available studies on the short-tern toxicity of zinc are
          limited.  It is recommended that short-term exposure studies in one
          or more animals species be conducted to confirm safe exposure levels
          to zinc in water for development of One-day and Ten-day HAS.

      2.  Available data on the developmental effects of zinc in animals
          indicate that it is an equivocal teratogen.  It is recommended that
          further studies be conducted to clarify its developmental effects.

     3.   A lifetime bioassay in male and female rodents, at least five
          species, should be conducted to determine the carcinogenic potential
          of zinc.

      4.  Aside from the aforementioned data gaps, no further studies on zinc,
          as related to its possible presence in drinking water, are deemed
          necessary at this time.
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REFERENCES

Calvery, H.O.  1942.   Trace elements in foods.   Food Res.  7:313-331.

Chobanlan, S.K.  1981.  Accidental ingestion of liquid zinc chloride: local
and systemic effects.   Ann. Emerg. Med. 10(2):91-93.

DeKnudt, G.H. and M.  Deminatti.   1978.   Chromosome studies in human
lymphocytes after in vitro exposure to metal salts.  Toxicol. 10:67-75. ..

Evans, E.H.  1945.  Casualties following exposure to zinc  chloride smoke.
Lancet 2:368-370.

Feaster, J.P., S.L. Hansard, J.T.  McCall and G.K. Davis.   1955.   Absorption,
deposition and placental transfer of zinc*5  in  the  rat.  Am. J. Physiol.
181:287-290 as cited in Hill et al. (1978).

Gross, P., Z. Harvalik and E. Runne.  1941.   Vitamin deficiency syndrome in
the albino rat precipitate by chronic zinc chloride poisoning.  J. Invest.
Dennatol. 4:385-398.

Hahn, F. and R. Schunk.  1955.  [Acute zinc poisoning.] Arch. Exp. Pathol.
Pharmakol. 226:424-434 (German) as cited in Hill et al. (1978).

Heller, V.G. and A.D.  Burke.  1927.  Toxicity of zinc.  J. Biol.  Chem.
74:85-93.

Hill, H.G., K. Wasti and J.E. Villaume.  1978.   A literature review - problem
definition studies on selected toxic chemicals.  Volume 5.  Occupational
health and safety and environmental aspects of zinc chloride.  Final Report.
Philadelphia, PA: The Franklin Institute Research Laboratories.   Contract No.
DAMD-17-77-C-7020, AD-A056 020.

Hjortso, E. , J. Qvist, M.I. Bud, J.L. Thomsen,  J.B. Andersen,
F. Wiberg-Jorgensen,  N.K. Jensen, R. Jones,  L.M. Reid and  W.M. Zapol.  1988.
ARDS after accidental inhalation of zinc chloride.  Intensive Care Med.
14:17-24.

Houle, R.E. and W.M.  Grant.  1973.  Zinc chloride keratopathy and cataracts.
Am. J. Ophthalmol. 75:992-996.

Johnstone, M.A., W.R. Sullivan and W.M. Grant.   1973.  Experimental zinc
chloride ocular injury and treatment with disodium edetate.  Am.  J.
Ophthalmol. 76(1):137-142.

Kalinina, L.M. and G.H. Polukhina.  1977.  Mutagenic effect of heavy metal
salts on Salmonella in activation systems in vivo and in vitro.   Mutat. Res.
46:223-224.

Kossakowski, S. and A. Grosicki.  1983.  Effect of mercuric chloride upon zinc
distribution in the rat.  Bull. Vet. Inst. Pulawy. 26(1-4):67-76.

Kurokawa, Y., M. Matsushima, T. Imazawa, N.  Takamura, M. Takahashi and
Y. Hayashi.  1985.  Promoting effect of metal compounds on rat renal
tumorigenesis.  J. Am. Coll. Toxicol. 4(6):321-330.

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Lorber, S.A., F.M. Gold, A.A. Maglione and S. Rubenfeld.  1970.  69m Zn-
chloride - a new scanning agent: a study of Its dosimetry and biological fate.
J. Nucl. Med.  11(12) :699-703 as cited in Hill et al.  (1978).

Hacaulay, M.B. and A.K. Mant.  1963.  Smoke-bomb poisoning.  A fatal case
following the inhalation of zinc chloride smoke.  J. Royal Array Med. Corps.
109:27-32.

Markwith, R.H.  1940.  Zinc and its. compounds --.(zinc)., .(brass) (zinc oxide).
Adult Hygiene Division, Ohio Department of Health, Columbus, OH.  Project No.
665-42-3-413.

McGregor, D.B.  1980.  Mutagenicity and DNA repair potential of 15 chemicals.
Final Report.  Inveresk Research International Limited, Edinburgh, Scotland.
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Milliken, J.A., D. Waugh and M.E. Kadish.  1963.  Acute interstitial pulmonary
fibrosis caused by a  smoke bomb.  Can. Med. Assoc. J.  88:36-39.

Payton, K.B., P.R. Flanagan, E.A. Stinson, D.P. Chodirker, M.J. Chamberlain
and L.S. Valberg.  1982.  Technique for determination of human zinc absorption
from measurement of radioactivity in a fecal sample or the body.
Gastroenterology  83:1264-1270.

Potter, J.L.  1981.   Acute zinc chloride ingestion in a young child.  Ann.
Emerg. Med. 10(5):267-269.

Schenker, M.B., F.E.  Speizer and J.O. Taylor.  1981.  Acute upper respiratory
symptoms resulting from exposure to zinc chloride smoke.  Environ. Res.
25:317-324.

Seidenberg, J.M., D.G. Anderson and R.A. Becker.  1986.  Validation of an
in vivo developmental toxicity screen in the mouse.  Teratogenesis Carcinog.
Mutagen. 6:361-374.

Sheline, G.E., I.L. Chaikoff, H.B. Jones and M.L. Montgomery.  1943a.  Studies
on the metabolism of  zinc with the aid of its radioactive isotope.  I.  The
excretion of administered zinc in urine and feces.  J. Biol. Chem.
147:409-414.

Sheline, G.E., I.L. Chaikoff, H.B. Jones, M.L. Montgomery.  1943b.  Studies on
the metabolism of zinc with the aid of its radioactive isotope.  II. The
distribution of administered radioactive zinc in the tissues of mice and dogs.
J. Biol. Chem. 149:139-151.

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