CARBON  TETRACHLORIDE

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

        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.

    Carbon Tetrachloride                                       March 31, 1987


         This Health Advisory (HA)  is based on information presented in the
    Office of Drinking Water's Health Effects Criteria Document (CD) for carbon
    tetrachloride (U.S. EPA,  1985a).   The HA and CD formats are similar for easy
    reference.  Individuals desiring  further information on the toxicological
    data base or rationale for risk characterization should consult the CD.  The
    CD is available for review at each EPA Regional Office of Drinking Water
    counterpart (e.g., Water  Supply Branch or Drinking Water Branch),  or for a
    fee from the National Technical Information Service, U.S. Department of
    Commerce, 5285 Port Royav Rd.,  Springfield,  VA 22161,  PB #85-118155/AS.
    The toll-free number is 1800) 336-4700; in the Washington, D.C. area:
    (703) 487-4650.


    CAS No.   56-23-5

    Structural Formula


         0  Methane tetrachloride,  tetrachloromethane,  CC14,  perchloroethane.


         0  The major use of  CC14 is  in the production of  chlorofluorocarbons,
            which are used as refrigerants, foam-blowing agents and solvents.
            Carbon tetrachloride also is  used in fumigants, as a solvent in
            metal cleaning and in manufacture of paints and plastics (Rams,
            et al., 1979).  It is being replaced in grain fumigation by other
            registered pesticides (U.S. EPA,  1980a).

    Properties (U.S. EPA, 1985a)

            Chemical Formula                   CC14
            Molecular Weight                  153.8
            Physical State                    Colorless liquid
            Boiling Point                     76.5°C
            Melting Point                     -23°C
            Density                           d|°  1.594
            Vapor Pressure                    115.2 mm Hg at 25°C
            Water Solubility                   800 mg/L
            Taste Threshold                   not available
            Odor Threshold                    0.52 mg/L (Amoore and Hautala, 1983)
            Conversion Factor                 6.4 mg/m^ = 1 ppm

     Carbon Tetrachloride                                       March 31, 1987


             Carbon tetrachloride (CC14)  is a synthetic chemical with no natural
             sources (U.S. EPA,  1983).

             Production of CC14  was approximately 600 million Ibs in 1983 (U.S.ITC,
             1983).  Carbon tetrachloride also is produced as a by-product of the
             manufacture of a number of other chlorinated materials.

             Current major sources of CC14 released to the environment are from
             accidental releases from production and uses.  Previously,  large
             amounts of CC14 were released from its use as a solvent.  Most of the
             releases of CC14 occur to the atmosphere by evaporation because of
             its high volatility.  Some CC14 may be released to the environment
             during the disposal of wastes in landfills or surface waters.  The
             majority of releases will occur in the areas near its production and
             use (U.S. EPA, 1983).

             Carbon tetrachloride released to:  (1) the environment is fairly stable;
             (2) the air,  degrades slowly; (3) surface waters, migrates  to the
             atmosphere in a few days or weeks; and (4) the land, does not sorb
             onto soil and migrates readily to ground water.  Carbon tetrachloride
             is expected to remain in ground water for months to years.   Unlike
             more highly chlorinated compounds,  CC14 does not bioaccumulate in
             individual animals  or food chains (U.S. EPA, 1979).

             Carbon tetrachloride occurs  ubiquitously in the air but at concen-
             trations of less than 10 ppt.  Carbon tetrachloride is a fairly rare
             contaminant in ground and surface waters, with higher levels found in
             ground water.   The Agency estimates that less than 1% of all ground
             waters derived drinking water systems have levels of CC14 greater
             than 0.5 ug/L and less than  0.2 % greater than 5 mg/L (U.S. EPA, 1983).

             Very limited  information is  available on the occurrence of  carbon
             tetrachloride in food.  In the past,  CC14 has been used as  a grain
             fumigant and  low levels have been reported to occur in some foods from
             this use (U.S. EPA,  1983).

             The major source of exposure to CC14 is from contaminated air.   Water
             and food are  only a minor sources.
             Carbon tetrachloride  is  absorbed readily  from the gastrointestinal
             tract,  the respiratory  tract and the  skin.   About 60% of  an oral dose
             (1600 mg/kg)  was  absorbed  by rats within  six hours (Reddrop et al.,
             1981),  and 65 to  86%  of  oral doses of 2,000-4,000 mg/kg were absorbed
             by rats within 24 hours  (Paul and Rubinstein, 1963;  Seawright and
             McLean, 1967;  Marchand  et  al.,  1970).

Carbon Tetrachloride                                       March 31, 1987

        Absorption from the lung has been reported as about 30% in monkeys
        exposed to 290 mg CCl4/m3 for 139, 344 or 300 minutes (McCollister
        et al., 1952).

     °  Bruckner et al. (1986a) assessed potential effects of different vehicles
        on the pharmacokinetics of CC14.  Fasted 200 g male Sprague-Dawley
        rats with indwelling arterial cannulas received 25 mg/kg 0014 by
        gavage:  in corn oil; as an aqueous emulsion; in water; and as pure
        undiluted chemical.  A 25 mg/kg dose was given intravenously for
        calculation of bioavailability.  Serial blood samples were taken and
        analyzed for 0014.  Peak concentrations of CC14 in the blood were
        reached within 8 minutes after dosing in the emulsion and saturated
        water groups.  These peak levels were slightly higher than in the
        pure CC14 group and substantially higher than in the corn oil group.
        There was evidence of later secondary peaks of lesser magnitude in
        the corn oil group.  The absolute bioavailability for the emulsion
        and saturated water groups was higher than for the corn oil and pure
        chemical groups, and comparable to the intravenous group.


     0  Carbon tetrachloride appears to be distributed to all major organs
        following absorption (U.S. EPA, 1985a).  Carbon tetrachloride has been
        found in fat, liver, blood, brain, kidney and muscle,  with particularly
        high concentrations in fat.  Carbon tetrachloride reaches maximal
        concentrations in most tissues at approximately two to four hours
        following intragastric administration (Marchand et al., 1970).


     0  Carbon tetrachloride metabolism occurs primarily in the liver.  The
        first step is thought to be formation of a trichloromethyl radical in
        the cytochrome heme moiety.  This trichloromethyl radical undergoes a
        variety of reactions, including hydrogen abstraction to form chloro-
        form, dimerization to form hexachloroethane and addition to cellular
        molecules.  Further metabolism of the heme-bound trichloromethyl
        radical is postulated to result in the eventual formation of carbonyl
        chloride (phosgene) (Shah et al., 1979 with an in vitro study with
        rat liver).

     0  After a single oral dose of CC14 in Wistar rats, Bini et al. (1975)
        proposed that the trichloromethyl free radical was the main metabolite
        of CC14 after they found chloroform and hexachloroethane as metabolites
        in the rats.  Fowler (1969) found these metabolites in rabbits given
        CC14 orally.  McCollister et al. (1951) detected labeled carbon
        dioxide exhaled by monkeys exposed to 14C-CC14 by inhalation.
        Carbon tetrachloride and its volatile metabolites are excreted pri-
        marily in exhaled air and also in the urine and feces (U.S. EPA,
        1985a).  Elimination of orally ingested CC14 occurs with an estimated
        half-time of four to six hours,  and most of an oral dose is excreted

    Carbon Tetrachloride                                              March 31,  1987

            within one to two days.   No reports were located regarding the tissue
            accumulation and retention of CC14 during chronic exposure.



         0  The effects  of  CC14  exposure in  humans  are similar to effects  seen
            in animals,  with the liver,  kidney and  lungs  being most sensitive.

         0  Single oral  doses of 2.5  to 15 mL (57 to 343  mg/kg)  are usually
            without effect,  although  changes may occur in liver and kidney
            (U.S.  EPA,  1985a).  Some  individual adults suffer adverse effects
            (including death) from ingestion of as  little as 1.5 mL (34 mg/kg),
            and 0.18 to  0.92 mL  may be fatal in children  (29 to 150 mg/kg)
            (U.S.  EPA,  1985a).

         0  Inhalation exposure  also  results in central nervous system depression
            and renal and hepatic damage (U.S. EPA,  1985a).   No ill effects
            result from  three hours of exposure to  63 mg/rn3,  but 70 minutes  of
            exposure to  2,309 mg/m3 may produce liver effects.  High levels
            (1,500 mg/m3) may produce severe poisoning and death.


    Short-term Exposure

         0  Carbon tetrachloride is toxic to animals,  with oral LDso values  ranging
            from 1,000 to 12,800 mgAg (U.S. EPA, 1985a).

         0  The tissue most affected  by CC14 is the liver.  Using release  of
            liver  enzymes into serum  and histological examination as end-points,
            single oral  doses (in corn oil)  of 40 mg CCl4/kg did not produce
            adverse effects,  while doses of  80 mgAg °r higher did in male Sprague-
            Dawley rats  (Bruckner et  al.,  1986b).   Numerous  studies have found
            that oral doses  ranging from about 100  to 4,000  mg/kg produce  fatty
            infiltration, loss of cytochrome P-450  and other enzymes,  inhibition
            of protein synthesis and  histological alterations in the liver.  When
            damage is severe, hepatocellular necrosis may result, but the  effects
            observed following lower  doses are largely reversible (U.S.  EPA, 1985a).

         0  Kidney and lung also are  affected following oral exposure to CC14
            (U.S.  EPA,  1985a).  Single doses of about 4,000  mg/kg result in  lesions
            of the renal proximal tubule in  rats and pulmonary Clara cells and
            endothelial  cells in rats and/or mice.   These changes also appear to
            be reversible when damage is not too severe.

         0  Bruckner et  al.  (1986b) found  hepatotoxic effects (increased serum
            enzymes,  pathology)  in rats  given CC14  in corn oil at daily doses of
            20 mg/kg and higher  by gavage  for 9 days in an 11-day study.

Carbon Tetrachloride                                       March 31, 1987

     0  Hayes et al. (1986) observed hepatotoxicity (increased serum enzymes,
        increased organ weight) in male and female CD-1 mice given 0014 in
        corn oil by gavage at doses of 625, 1,250 or 2,500 mg/kg for 14
        consecutive days.

     0  The objective of a study by Kim et al. (1986)  was to assess the
        influence of dosing vehicles on the acute hepatotoxicity of 0014.
        Fasted 200 g male Sprague-Dawley rats were given 0, 10, 25, 50,
        100, 250, 500,  1,000 or 2,000 mg CCl^/kg by gavage in:  corn oil;
        as an aqueous emulsion; as the undiluted chemical; and in the 10 and
        25 mg/kg doses  only in water.  Blood and liver samples were taken
        24 hrs after dosing for measurement of serum and microsomal enzymes.
        Pathological examination of liver samples was  also conducted.  Dose-
        dependent increases in serum enzyme levels and pathological changes,
        and dose-dependent decreases in microsomal P-450 and glucose-6-
        phosphatase activity were observed in each vehicle group.  CC14 was
        less hepatotoxic at each dosage level when given in corn oil than
        when given as an emulsion or as the pure chemical.  CC14 in corn oil
        was also less toxic than CC14 in water at the  10 and 25 mg/kg doses.

Long-term Exposure

     0  The effects of  longer-term exposure to CC14 are similar to the effects
        of short-term exposure:  the liver is the most sensitive tissue,
        showing fatty infiltration, release of liver enzymes,  inhibition of
        cellular enzyme activities, inflammation and,  ultimately, cellular
        necrosis (U.S.  EPA, 1985a).

     0  Rats exposed by gavage to 0014 in corn oil at doses of 1 mg/kg
        5 days/week for 12 weeks did not show measurable adverse effects,
        while doses of  10 or 33 mg/kg resulted in enzyme release, centri-
        lobular vacuolization and necrosis in liver (Bruckner et al., 1986b).

     0  Condie et al. (1985) investigated the effects  of a corn oil vehicle
        as well as Tween-60 on the subchronic hepatotoxicity of carbon
        tetrachloride (0014).  Male and female CD-1 mice were given 0,  1.2,
        12 and 120 mg/kg CC14 by gavage in either corn oil as a solution or
        1 % Tween-60 as  a suspension once daily for five consecutive days per
        week for 90 days.  Hepatotoxicity was greater  in the corn oil vehicle
        groups of mice  than in the Tween-60 groups.  Significant increases in
        serum enzyme activities were detected in the 12 mg/kg CC14 corn oil
        male and female groups but not in the corresponding Tween-60 groups.
        When comparing  the serum enzyme activities in the high dose groups,
        there were dramatic increases in both the male and female corn oil
        groups as compared to the corresponding Tween—60 groups.  Liver and
        liver/body weights were significantly greater in each high dose
        group.  Histopathological findings indicated that hepatocellular
        changes occurring during the administration of CC14 at the 12 mg/kg
        (hepatocellular cytomegaly, fat and necrosis)  and 120 mg/kg (necrosis
        and fat) dose levels were more frequently observed when CC14 was
        given in corn oil than when it was administered in Tween-60.  The
        experimental findings indicate that the corn oil vehicle lowered the
        no-observed-adverse-effect level (NOAEL) from CC14 exposure by an

Carbon Tetrachloride                                       March 31,  1987


        order of magnitude (from 12 mgA<3 to 1-2 n»g/kg) compared to the
        Tween-60 vehicle and also enhanced the hepatotoxicity of CC14 in the
        high dose treatment groups.

     0  Hayes et al. (1986) reported hepatotoxic effects (increased serum
        enzymes, increased organ weight, pathological lesions) in male and
        female CD-1  mice given CC14 in corn oil by gavage at doses of 12,
        120, 540 or 1,200 mgA9 f°r 90 consecutive days.

     0  Alumot et al. (1976) fed 18 male and 18 female rats (strain not
        given) 0, 80 or 200 ppm CC14 in the diet until final sacrifice at two
        years.  The authors equated 200 ppm to 10-18 mg/kg body weight/day.
        No adverse effects from exposure to CC14 were observed.  However,
        tissues were not examined microscopically, liver weights were not
        taken, and survival was below 50% at 21 months.  In an earlier 6-week
        study, Alumot et al. (1976) found no effect with 22 mg/kg and
        increased lipid and triglyceride in liver with 40 and 76 mg/kg.  Only
        body weight was additionally measured.

     0  Prendergast et al. (1967) found hepatotoxicity in guinea pigs, rats,
        monkeys, rabbits and dogs exposed to 515 mg CCl4/m3 air eight hours/day,
        five days/week for six weeks.  Liver effects were also found in these
        species after continuous exposure to 61 mg/m3 for 90 days but not to
        6.1 mg/m3.  After inhalation exposure of Wistar rats to CC14 eight
        hours/day, five days/week for ten months, Smyth et al. (1936) found
        liver toxicity with levels above 315 mg/m3 and kidney changes with at
        least 315 mg/m3 (lowest level tested).  Adams et al. (1952) noted
        liver damage in Wistar rats, guinea pigs, and rabbits at some inhalation
        exposures ranging from 32.5 to 2,600 mg/m3, seven hours/day, five
        days/week for 258 days and no observable effect in a Rhesus monkey
        similarly exposed to 25 mg/m3 for 212 days, but the study cannot be
        adequately assessed from the limited details reported.

Reproductive Effects

     0  No reproductive evvects were noted in rats fed diets containing CC14
        at 80 and 200 ppm for up to two years  (Alumot et al., 1976)

Developmental Effects

     0  No evidence was located to demonstrate that CC14 is teratogenic  (U.S.
        EPA, 1985a).  Newborn rats appear to be less sensitive to liver damage
        by CC14 than 7-day-old rats (Dawkins, 1963).  An intraperitoneal dose
        of 2,400 mg/kg has resulted in adverse effects on testicular function
        in rats  (Chatterjee, 1966).


     0  No evidence of mutagenic activity for CC14 has been found in bacterial
        test systems or in cultured liver cells  (U.S. EPA, 1985a), except that
        Sina et al.  (1983) found CC14 weakly positive at cytotoxic levels in
        an alkaline elution/rat hepatocyte assay to measure DNA single-strand
        breaks.  Increased gene crossover and mitotic recombination were

   Carbon Tetrachloride                                       March 31,  1987

           observed in yeast cells  exposed to CC14 at 3,300 to 5,400 mg/L buffer
           (Callen at al.,  1980).   Amacher and Zelljadt (1983) concluded CC14 as
           positive for cell transformation in Syrian hamster embryo cells.

        0  In an in vivo-in vitro hepatocyte DNA repair assay by Mirsalis,
           et al. (1985), CC14 failed to induce unscheduled DNA synthesis in
           male and female  BgC3F'| mice but did significantly elevate hepatic
           cell proliferation.  The latter effect was also induced by CC14 in
           male Fischer 344 rats but at higher doses.


        0  Carbon tetrachloride is  carcinogenic in animals,  producing mainly
           hepatic neoplasms.  Doses of about 30 mg/kg/day or higher for six
           months or longer have been found to produce an increased frequency of
           hepatocellular tumors in mice,  rats and hamsters (U.S. EPA,  1985a).

        0  In an exploratory study  of a large number of solvents and cancers in
           rubber industry  workers,  Wilcosky et al. (1984) associated exposure
           to carbon tetrachloride  with lymphosarcoma and lymphatic leukemia,
           but they stressed cautious interpretation because of the modest number
           of cases and biases.


        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/Ij (	 Ug/Il)
                        (UF) x (	 L/day)


           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, 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 acute animal study by  Bruckner et al. (1986b) has been selected to
   serve as the basis for the One-day Health Advisory in the 10-kg child because
  ' this study clearly defined a one-day NOAEL (40 mgAg) and LOAEL (80 mg/kg)

Carbon Tetrachloride                                       March 31, 1987

for CC14 based on changes in BUN, GPT, SDH and OCT and histopathological
changes in the liver and kidneys of rats sacrificed 24 hours after dosing.
The abstract report of the study by Kim et al. (1986) does not provide
sufficient details for assessment as a basis for the One-day HA.

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

         One-day HA = (40 mg/kg/day) (10 kg) = 4>0   /L (4 000 ug/L)
                         (100) (1 L/day)


        40 mg/kg day = NOAEL based on absence of liver toxicity following
                       one-day exposure in rats.

               1 0 kg = assumed body weight of a child.

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

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

Ten-day Health Advisory

     The short-term study by Bruckner et al. (1986b) has been selected to
serve as the basis for the Ten-day HA for the 10-kg child.  This study identi-
fied a LOAEL of 20 mgAg/day in rats given 9 doses over 11 days, based on
significant increases in serum enzyme levels and hepatic midzonal vacuolization
by 11 days.  Higher doses of CC14 caused even more extensive liver damage.
The 14-day study by Hayes et al. (1986) is not selected because all doses
used were effect levels above those in the Bruckner et al. (1986b) study.

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

        Ten-day HA = (20 mg/kg/day) (10 kg) (9) = 0.16 mg/L (160 ug/L)
                       (1,000) (1 L/day) (11)


        20 ing/kg/day = LOAEL based on liver toxicity in rats.

                9/11  = factor accounting for 9 doses given over 11 days.

               10 kg = assumed body 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 of a child.

Carbon Tetrachloride                                       March 31, 1987


Longer-term Health Advisory

     The 12-week study by Bruckner et al. (1986b) has been selected to serve
as the basis for calculation of the Longer-term HA.  Bruckner and co-workers
dosed rats with CC14 ^n corn oil by gavage five times weekly for 12 weeks
with doses of 1 , 10 or 33 rngAg*  This study identified a NOAEL of 1 mg/kg/day
and a LOAEL of 10 mg/kg day for hepatotoxicity.  Condie et al. (1985) obtained
similar results with a NOAEL of 1.2 mg/kg/day and a LOAEL of 12 mg/kg/day in
CD-mice given CC14 in corn oil by gavage five times weekly for 90 days.  In
the same study,  Condie et al. (1985) found a NOAEL of 12 mgAg/day with CC14
suspended in Tween-60, but these data are not selected for the Longer-Term HA
calculation because of use of a rather insoluble form of CC14 (suspension) as
the method of dosing.  The 90-day study by Hayes et al. (1986) is not selected
because a NOAEL was not found, although the LOAEL of 12 mg/kg/day approximates
the 10 mgAg/day LOAEL in the Bruckner et al. (1985) study.

     The Longer-term HA for a 10-kg child is calculated as follows:

      Longer-term HA = (1 mg/kg/day) (10 kg) (5) = 0.071 mg/L (71 ug/L)
                          (100) (1 L/day)    (7)


        1 mg/kg/day = NOAEL based on absence of liver toxicity in rats.

              1 0 kg = assumed body weight of a child.

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

                5/7 = factor to account for dosing five days per week.

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

     The Longer-term HA for a 70-kg adult is calculated as follows:

      Longer-term HA =   (1 mg/kg/day) (70 kg) (5) = 0.25 mg/L (250 ug/L)
                           (100)  (2 L/day)    (7)


        1 mgAg/day = NOAEL based on absence of liver toxicity in rats.

              70 kg = assumed body weight of an adult.

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

                5/7 = factor to account for dosing five days per week.

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

Carbon Tetrachloride                                       March 31, 1987


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.

     The 12-week study by Bruckner et al. (1986b)  described under Longer-term
Health Advisory is the most appropriate from which to derive the DWEL in that
the available animal toxicity studies with chronic exposure to CC14 are
concluded to be insufficient for use in the DWEL calculation.  From these
results,  a NOAEL of 1 mg/kg was identified.

     The two-year study in rats by Alumot et al. (1976) was not chosen
because the assessment of CCl^ toxicity was deficient with respect to tissue
examination.  The inhalation studies by Prendergast et al. (1967),  Smyth
et al. (1936), and Adams et al. (1952) were not used since inhalation data
are less desirable for HA development.

     Using the NOAEL of 1  mgAg/  the DWEL is derived  as follows:

Step 1:  Determination of the Reference Dose (RfD)

                  RfD = (1  mgAg/day) (5) = 0.0007 mgAg/day
                           (1,000)    (7)

                    = NOAEL based on absence of liver toxicity in rats orally
                      given CC14 for 90 days.

              1,000 = uncertainty factor,  chosen in accordance with NAS/ODW
                      guidelines for use with a NOAEL from an animal study
                      of less-than-lifetime duration.

                5/7 = factor to account for dosing 5 days per week.

Carbon Tetrachloride                                       March 31, 1987


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

           DWEL = (0.0007 ug/kg/day) (70 kg) = 0.025 mg/L (25 ug/L)
                          (2 L/day)


        0.0007 ug/kg/day = RfD.

                   70 kg = assumed body weight of an adult.

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

     Carbon tetrachloride may be classified in Group B:  Probable human
carcinogen.  The estimated excess cancer risk associated with lifetime exposure
to drinking water containing carbon tetrachloride at 25 ug/L is approximately
8 x 10~5.  This estimate represents the upper 95% confidence limit  from extrap-
olations prepared by EPA's Carcinogen Assessment Group using the linearized,
multistage model.  The actual risk is unlikely to exceed this value, but
there is considerable uncertainty as to the accuracy of risks calculated by
this methodology.

Evaluation of Carcinogenic Potential

     0  The IARC (1979) classified carbon tetrachloride as a 2B carcinogen with
        sufficient animal evidence and inadequate human evidence.

     0  Applying the criteria described in EPA's guidelines for assessment
        of carcinogenic risk (U.S. EPA, 1986a), carbon tetrachloride maybe
        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  U.S. EPA calculated a unit risk estimate (the 95% upper limit by the
        linearized multistage model) of 0.37 x 10~^ for a human continuously
        exposed to 1 ug CC14 per liter of water (U.S. EPA, 1984).   The
        corresponding 10"^, 10~^ and 10~4 risks are associated with 0.3, 2.7
        and 27 ug/L, respectively.

     0  It should be noted that this approach, which involved using the
        geometric mean of risk estimates based on four studies, for calculating
        unit risk estimates for CC14 is from U.S. EPA  (1984) which  was reviewed
        by the U.S. EPA's Science Advisory Board.

     0  There was an attempt to compare risk estimates derived with the
        multistage model with other models in U.S. EPA, 1984.  Of the studies
        used (Delia Porta et al., 1961; Edwards et al., 1942; NCI rat and
        mouse, 1976), risk estimates could not be calculated with the Weibull
        and log probit models, and a time-to-tumor model was successful only
        with the NCI  (1976) data which gave 95% upper confidence limits similar
        to those obtained with the multistage model.  Unit (ingestion of 1 ug
        CC14/L water/lifetime) risk estimates (95% upper confidence limits)
        with individual studies and the multistage model were 3.4 x 10~^

    Carbon Tetrachloride                                       March 31,  1987

                                         -1 3-

            (Della Porta et al.,  1961),  9.4  x 10~6 (Edwards et al.,  1942),
            1.8 x 10~6 (NCI mouse,  1976) and 3.1  x 10~7 (NCI rat,  1976).   Unit
            risk estimates (maximum likelihood estimates)  with individual studies
            and the multistage model were 2.1  x 10~5  (Delia Porta  et al., 1961),
            7.1 x 10~6 (Edwards et  al.,  1942), 1.4 x  10~&  (NCI mouse, 1976)  and
            1.9 x 10~7 (NCI rat,  1976).   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 EPA has recommended use  of
            the linearized multistage approach.


         0  Data from the animal  studies have  been used by NAS (1977) and U.S. EPA
            (1980b, 1984) to calculate the upper  95%  bound on the  number  of
            additional cancer cases  that may occur when CC14 is  consumed  in
            drinking water over a 70-year lifetime.  By these methods,  a  10-6
            lifetime excess cancer  risk  was  associated  with CC14 in  drinking
            water at levels of 4.5 ug/L  by the NAS (1977),  0.4 ug/L  by  the U.S.
            EPA (1980a)  and 0.3 ug/L by  the  U.S.  EPA  (1984).

         0  The criteria for the  U.S.  EPA, OHEA and NAS risk calculations differ
            in two respects:   (1) NAS  used the multistage  model, while  U.S.  EPA
            used an "improved" multistage model;  and  (2) NAS used  the data set
            from the National Cancer Institute (NCI)  study  in male rats while
            U.S. EPA initially used  the  data set  from the  NCI study  in  male  mice
            (U.S.  EPA,  1980b)  and subsequently used a geometric  mean of four
            studies (NCI, 1976 -  mice; NCI,  1976  - rats; Edwards et  al.,  1942 -
            mice;  and Delia Porta et al.,  1961  - hamsters)  (U.S. EPA,  1984).

         0  Ambient water quality criteria for CC14 calculated by  the EPA (U.S.
            EPA 1980b)  were based on increased lifetime cancer risk  estimates of
            10-5 (4.0 ug/L),  10-6 (0.40  ug/L),  and 10~7 (0.04 ug/L).   It  is  note-
            worthy that these estimates  were derived  by assuming a lifetime  con-
            sumption of  both drinking  water  (2 L/day) and  aquatic  species (6.5 g
            fish and shellfish/day)  taken from waters containing the corresponding
            CC14 levels.  Specifically,  daily  CC14 exposure  assumptions were as
            follows:   94% from ingesting drinking  water and  6% from  consuming
            seafood "fish factor."   The  corresponding "drinking  water only"
            concentrations  were 4.41,  0.44,  and 0.04  ug/L,  respectively.

         0  Using the carcinogenicity  data set and a  linear  multistage  model,
            WHO (1984)  derived a  recommended tentative  limit for CC14 of  3 ug/L
            as a level which should  result in  less than one  additional  cancer
            per 100,000 population  (10~5)  for  a lifetime of  exposure assuming
            daily consumption of  two liters  of drinking water.

         0  The U.S.  EPA (1981) and  NAS  (1980) previously  calculated SNARLS
            (Suggested  No-Adverse-Response Levels)  for  CC14  in drinking water.
            These  guidelines  are  summarized  in Table  1.

     Carbon Tetrachloride                                       March  31,  1987


                                          TABLE 1

                          Summary of Existing Guidelines  for CC14

0.2 mg/L
0.02 mg/L
14 mg/L
2 mg/L
       au.S. EPA (1981)  used  a LOAEL of  20 mg/kg  (Korsrud  et al.,  1972)  as  the
        basis for their  calculations.
       t>NAS (1980)  used  a LOAEL of  400 mgAg  (Murphy  and Malley,  1969) as  the
        basis for their  calculations.
       cln the absence of subacute  oral  data,  the NAS (1980)  and  U.S.  EPA  (1981)
        calculated  7- and 10-day SNARLS  by dividing their  one-day  values by
        7 and 10, respectively.
       dThe U.S. EPA (1981) did not calculate  a long-term  SNARL due  to a lack
        of acceptable chronic oral  exposure data  at that time.
       eThe NAS (1980) did not determine a long-term  SNARL because of NAS  policy
        at that time not to calculate such values for animal carcinogens.
          0  The final RMCL by  the U.S.  EPA Office of  Drinking Water is  0,  the
             proposed MCL is 5  ug/L,  and the practical quantitation level is  5 ug/L
             (U.S. EPA, I985e).

          0  The U.S. EPA Office of Pesticide Programs has  published a notice of
             intent to cancel registrations of grain fumigation products containing
             CC14 (U.S. EPA, 1986b).

          0  The OSHA standard  in 10 ppm (TWA),  and the ACGIH (1983) has recommended
             a TLV of 5 ppm and an STEL  of 20 ppm.

          0  The U.S. EPA (1985d) has published a notice of intent to list CC14
             under Section 112  of the Clean Air Act.

          "  Analysis of  CC14 is by a purge-and-trap gas  chromatographic procedure
             used for the determination of  volatile  organohalides  in drinking water
             (U.S. EPA, I985b).   This method  calls for  the  bubbling of  an inert
             gas through  the sample and trapping CC14 on  an adsorbent material.
             The adsorbent material is heated to drive  off  the CC14 onto a gas
             chromatographic column.  This  method is applicable to the  measurement
             of CC14 over a concentration range of 0.03 to  1500 ug/L.  Confirmatory
             analysis for carbon tetrachloride is by mass spectrometry  (U.S.  EPA,

      Carbon Tetrachloride                                       March 31,  1987

              1985c).  The detection limit for confirmation by mass spectrometry is
              0.3 ug/L.


           0  Treatment techniques which will remove carbon tetrachloride from
              drinking water include granular activated carbon adsorption, boiling,
              and aeration (Combs,  1980).

           0  Pilot plant studies  by EPA's Drinking Water Research  Division have
              shown consistently that conventional treatment processes (coagulation,
              sedimentation,  filtration),  even when augmented by  the addition of pow-
              dered activated carbon,  provide little removal of carbon tetrachloride.

           0  The use of powdered  activated carbon was  only partially effective at
              doses as high as 30  ug/L (Love et al.,  1983;  Symons et al.,  1979;
              Lykins et al.,  1980).

           0  Carbon tetrachloride at a raw water concentration of  12 ug/L treated
              using Filtrasorb® 400 granular activated  carbon exhibited breakthrough
              after three weeks.  The empty bed contact time reported was  5 minutes.
              When the empty bed contact time was increased to 10 minutes, break-
              through occurred at  14 to 16 weeks (Symons,  1978).

           0  A full-scale installation investigation conducted by  Calgon  using twin
              granular activated carbon beds in series  (EBCT of 130 minutes)  reported
              that, along with other chemicals, carbon  tetrachloride  was removed to
              below detection from an influent concentration of 73  ug/L (O'Brien
              et al.,  1981).

           0  A study demonstrated  that the synthetic resin (Ambersorb XE-340)
              removed carbon tetrachloride from treated drinking  water with an
              effectiveness similar  to Filtrasorb® 400  (Symons et al.,  1979).  It
              should be noted that these resins are not commercially available.

           0  Boiling also is effective in eliminating  carbon tetrachloride from a
              solution.  Studies have shown that five minutes of  vigorous  boiling
              will remove upwards  of 99% of the carbon  tetrachloride  originally
              present (Combs, 1980;  Love and Eilers,  1981).

           0  Finally,  aeration may  be used to remove carbon tetrachloride from
              water.  Laboratory studies conducted by Love et al. (1983) showed
              that a diffused air  aerator  could remove  91% of the carbon tetra-
              chloride in the water  using  a 4:1  air to  water ratio.

           0  Air stripping is an  effective,  simple,  and relatively  inexpensive
              process  for removing carbon  tetrachloride and 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.

    Carbon Tetrachloride                                       March 31,  1987



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Carbon Tetrachloride                                       March 31, 1987

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Carbon Tetrachloride                                       March 31, 1987

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Carbon Tetrachloride                                       March 31, 1987


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