0013
  J
                                                                 January "1992
t
                   FINAL

QUANTIFICATION OF TOXICOLOGICAL EFFECTS

                    FOR

             DICHLOROMETHANE
                        Health and Ecological Criteria Division
                           Office of Science and Technology
                                  Office of Water
                        U.S. Environmental Protection Agency
                                 Washington, DC.
                             HEADQUARTERS LIBRARY
                             ENVIRONMENTAL PROTECTION AGENCY
                             WASHINGTON, D.C. 20460

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                                               January 1992
                   FINAL

QUANTIFICATION OF TOXICOLOGICAL EFFECTS

                    FOR

            DICHLOROMETHANE
      Health and Ecological Criteria Division
         Office of Science and Technology
               Office of Water
      U.S. Environmental Protection Agency
               Washington, DC.

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                         TABLE OF  CONTENTS

                                                                     Page

    LIST OF TABLES	    vi

    FOREWORD	vii

A.  PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS 	     2

    1.  Noncarcinoyenic Effects	     2
    2.  Carcinogenic Effects 	     4

B.  QUANTIFICATION OF NONCARCINOGENIC EFFECTS  FOR  DICHLOROMETHANE.  .     7

    1.  Toxic Effects in Humans	     ^

        a.  Short-term Exposure  	     7
        b.  Long-term Exposure 	     8

    2.  Toxic Effects in Animals	     8

        a.  Short-term Exposure  	  	     8
        b.  Long-term Exposure 	    11

    3.  Development of Health Advisories 	  	    16

        a.  One-day Health Advisory  	    17
        b.  Ten-day Health Advisory  	    IB
        c.  Longer-term Health Advisory	    18
        d.  Reference Dose and Drinking Water Equivalent Level  ...    21

C.  QUANTIFICATION OF CARCINOGENIC EFFECTS FOR DICHLOROMETHANE  ...    23

    1.  Categorization of Carcinogenic Potential 	    23
    2.  Quantitative Carcinogenic Risk Estimates 	    30

D.  EXISTING GUIDELINES AND STANDARDS  	    30

E.  SPECIAL CONSIDERATIONS 	    32

F.  SUMMARY	    32

G.  REFERENCES	' .  .    34

    APPENDIX

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LIST OF TABLES
Table No.
1
2
3
4
b
6
7
8
9
10

Summary of Hepatocellular Findings in the Livers of
Rats Given DCM in Drinking Water for 90 Days 	
Incidence of Liver Foci/Areas of Alteration in Rats
Given DCM in Drinking Water for 78 or 104 Weeks ....
Summary of Subchronic Oral Toxicity Studies Considered
for the Development of the Longer-term HA . . 	
Summary of Chronic Oral Toxicity Studies Considered for
the Development of the Reference Dose and Drinking Water
Summary of Findings for Liver Tumors in Rats Given DCM
in Drinking Water for 2 Years 	
Summary of Findings for Liver Lesions /Tumors in Male
Mice Given DCH in Drinking Water for 2 Years 	
Summary of Findings for Mammary and Subcutaneous Tumors
in Rats Exposed via Inhalation to DCM for 2 Years . . .
Summary of Findings for Lung and Liver Tumors in Mice
Summary of Findings for Mammary and Ventral Cervical
Tumors in Rats Exposed via Inhalation to DCM for
2 Years 	 ' 	
Summary of Quantification of Toxicological Effects for

Page
1 7
15
10
oo
cc.
•Jf.
26
28
OQ

33

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                                   FOREWORD


     Section 1412 (b)(3)(A) of the Safe Drinking  Water Act, as amended in 1986,
requires  the Administrator of the Environmental  Protection  Agency  to publish
Maximum Contaminant Level  Goals (MCLGs) and promulgate National Primary Drinking
Water  Regulations  for  each  contaminant,   which,   in  the  judgment  of  the
Administrator, may have an adverse effect on public health  and which  is known or
anticipated to occur in public water systems.  The MCLG  is  nonenforceable and is
set at a level  at which no  known or anticipated adverse  health effects in humans
occur and which allows for an adequate margin of  safety.   Factors considered in
setting the MCLG include health effects data  and  sources of exposure other than
drinking water.

     This  document provides  the  health  effects  basis   to  be considered  in
establishing the MCLG.  To achieve this objective,  data  on pharmacokinetics,
human exposure, acut? and chronic toxicity to animals and  humans, epidemiology,
and mechanisms  of toxicity  were evaluated.    Specific emphasis is  placed  on
literature data providing dose-response  information.  Thus, while the literature
search and evaluation  performed  in support of this document was comprehensive,
only the  reports considered  most pertinent  in the derivation of the MCLG are
cited in the document.  The comprehensive literature data base in  support of this
document includes information published up to April 1987;  however,  more recent
data have been  added during  the review  process and in response  to  public
comments.

     When adequate health effects data exist, Health Advisory values for less-
than-lifetime exposures (One-day, Ten-day, and Longer-term, approximately 10% of
an individual's lifetime) are included in this document.   These values are not
used in setting the MCLG, but serve as informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.

                                                                James R.  Elder
                                                                      Director
                                     Office of Ground Water and Drinking Water

                                                               Tudor T.  Davies
                                                                      Director
                                               Office of Science of Technology
                                      vii

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          QUANTIFICATION OF TOXICOLOGICAL EFFECTS FOR DICHLOROMETHANE

     The source documents for background information used to develop this
report on the quantification of toxicological  effects for dichloromethane  are
the health assessment document (HAD) for dichlormethane (U.S. EPA,  1985a)  and  a
subsequent addendum to the HAD (U.S. EPA, 1985b).  In addition,  some references
published since 1985 are discussed.

     The quantification of toxicological effects of a chemical  consists  of
                       /
separate assessments of noncarcinogenic and carcinogenic health  effects.
Chemicals that do not produce carcinogenic effects are believed  to  have  a
threshold dose below which no adverse, noncarcinogenic effects occur,  while
carcinogens are assumed to act without a threshold.

     To summarize the results of the quantification of toxicological effects,  a
One-day Health Advisory of 10,000 ug/L for a 10-kg child was calculated, based
on an acute oral study in rats reported by Kimura et al. (1971).  No suitable
data for the derivation of a Ten-day Health Advisory were found  in  the avail-
able literature.  A Longer-term Health Advisory of 2,000 was developed for a
10-kg child, based on a 90-day drinking water  study in rats  (Kirschman et  al.,
1986).  A Drinking Water Equivalent Level (DWEL) of 2,000 ug/L for  a 70-kg
adult was calculated based on a 2-year drinking water study  in rats (Serota et
al., 1986).  The DWEL is used as a conservative estimate for the Longer-term
HA for an adult.  Caution must be exercised when considering the risk  of lifetime
exposure to dichloromethane because, based on  a 2-year inhalation study  in rats
(NTP, 1986), this chemical 1s classified as a  Probable Human Carcinogen  (Group
B2).  The estimated excess cancer risk associated with lifetime  exposure to
drinking water containing 1,750 ug/L of dichloromethane is 4 x 10~4 based  on
the upper 95% confidence  limit of the linearized multistage  model.
                                      -1-

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A. . PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS

1.  Noncarcinogem'c Effects

     In the quantification of noncarcinogenic effects,  a Reference Dose  {RfD),
formerly termed the Acceptable Daily Intake (ADI), is calculated.  The RfD is
an estimate of a daily exposure to the human population that is likely to be
without appreciable risk of deleterious effects, even if exposure occurs over a
lifetime.  The RfD is derived from a No-Observed-Adverse-Effect Level  (NOAEL),
  •                    f
or Lowest-Observed-Adverse-Effect Level (LOAEL), identified from a subchronic
or chronic study, and divided by an uncertainty factor.  The RfD is
calculated as follows:
     RfD =   (NQAEL or LOAEL)
             Uncertainty factor
mg/kg bw/day
     Selection of the uncertainty factor to be used in the calculation of the
RfD is based on professional judgment while considering the entire data base of
toxicological effects for the chemical.  To ensure that uncertainty factors  are
selected and applied in a consistent manner, the Office of Drinking Water (ODW)
emplpys a modification to the guidelines proposed by the National Academy of
Sciences (NAS, 1977, 1980), as follows:

     o  An uncertainty factor of 10 is generally used when good chronic or
        subchronic human exposure data identifying a NOAEL are available and
        are  supported by good chronic toxicity data in other species.

     o  An uncertainty factor of 100 is generally used when good chronic
        toxicity data identifying a NOAEL are available for one or more animal
        species (and human  data are not available), or when good chronic or
        subchronic toxicity data identifying a LOAEL in humans are available.
                                      -2-

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     o  An uncertainty factor of 1,000 is generally used when limited or
        incomplete chronic or subchronic toxicity data are available, or when
        good chronic or subchronic toxicity data identify a LOAEL,  but not
        a NOAEL, for one or more animal species.

     The uncertainty factor used for a specific risk assessment is  based prin-
cipally upon scientific judgment rather than on scientific fact and accounts  for
possible intra- and interspecies differences.  Additional considerations not  -
incorporated in the NAS/ODW guidelines for selection of an uncertainty factor
include the use of a less-than-lifetime study for deriving an RfD,  the signifi-
cance of the adverse health effect, and the counterbalancing of beneficial
effects.

     From the RfD,.a Drinking Water Equivalent Level (DUEL) can be  calculated.
The DWEL represents a medium-specific (i.e., drinking water) lifetime exposure,
at which adverse, noncarcinogenic health effects are not expected to occur.   The
DWEL provides the noncarcinogenic health effects basis for establishing a
drinking water standard.  For ingestion data, the DWEL is derived as follows:
     DWEL ~    {RfD)(body weight in kg)
            Drinking water volume in L/day
f
TL
mg/L (.
ug/L)
where:
              Body weight  - assumed to be 70 kg for an adult.
     Drinking water volume - assumed to be 2 L per day for an adult. •
     In addition to the RfD and the DWEL,  Health Advisories (HAs)  for exposures
of shorter duration (One-day, Ten-day, and Longer-term) are determined.   The HA
values are used as informal guidance to municipalities and other organizations
when emergency spills or contamination situations occur.  The HAs are calculated
                                      -3-

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using a similar equation to the RfD and DWEL;  however, the NOAELs or LOAELs  are
identified from acute or subchronic studies.  The HAs are derived as follows:

     HA = (NOAEL or LOAEL)(bw) =	mg/L (	ug/L)
            (    L/dayJW)

     Using the above equation, the following drinking water HAs are developed
for honcarcinogenic effects:

     1.  One-day HA for a 10-kg child ingesting 1 L water per day.
                       t
     2.  Ten-day HA for a 10-kg child ingesting 1 L water per day.
     3.  Longer-term HA for a 10-kg child ingesting 1 L water per day.
     4.  Longer-term HA for a 70-kg adult ingesting 2 L water per day.

     The One-day HA calculated for a 10-kg child assumes a single acute
exposure to the chemical and is generally derived from a study of less  than  7
days' duration.  The Ten-day HA assumes a limited exposure period of 1  to  2
weeks and is generally derived from a study of less than 30 days' duration.
A Longer-term HA is derived for both a 10-kg child and a 70-kg adult and
assumes an exposure period of approximately 7 years (or 10% of an individual's
lifetime).  A Longer-term HA is generally derived from a study of subchronic
duration (exposure for 10% of animal's lifetime).

2.  Carcinogenic Effects

     The EPA categorizes the carcinogenic potential of a chemical, based on  the
overall weight of evidence, according to the following scheme:

     o  Group A:  Known Human Carcinogen.  Sufficient evidence exists from
        epidemiology studies to support a causal association between exposure
        to the chemical and human cancer.
                                      -4-

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     o  Group B:  probable Human Carcinogen.   Sufficient evidence of  carcino-


        genicity in animals with limited (Group Bl) or inadequate (Group  82)


        evidence in humans.




     o  Group C:  Possible Human Carcinogen.   Limited evidence of carcinogeni-


        city in animals in the absence of human data.




     o  Group D:  Not Classified as to Human  Carcinogenicity.  Inadequate human


        and animal evidence of carcinogenicity or for which no data are
                      /

        available.




     o  Group E;  Evidence of Noncarcinogenicity  for Humans.   No  evidence of


        carcinogenicity in at least two adequate  animal  studies in different


        species or in both adequate epidemiologic and animal  studies.




     If toxicological evidence leads to the classification of the contaminant


as a known, probable, or possible human carcinogen, mathematical  models are used


to calculate the estimated excess cancer risk associated with the ingestion of


the contaminant in drinking water.  The data  used in these estimates  usually


come from lifetime exposure studies in animals.  To predict the risk  for


humans from animal data, animal  doses must be converted  to equivalent  human


doses.  This conversion includes correction for noncontinuous exposure, less-


than-lifetime studies, and for differences in size.  The factor that  compen-


sates for the size difference is the cube root of the ratio of the animal and


human body weights.  It is assumed that the average adult human body  weight is


70 kg and that the average water consumption  of an adult human is 2 liters of


water per day.




     For contaminants with a carcinogenic potential, chemical levels  are  corre-
                       j

lated with a carcinogenic risk estimate by employing a cancer potency (unit




                                      -5-

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risk) value together with the assumption  for  lifetime  exposure  via  inyestion of
water.  The cancer unit risk is usually derived from a linearized multistage
model, with a 95% upper confidence limit  providing  a low-dose  estimate;  that
is, the true risk to humans, while not identifiable, is not likely  to exceed
the upper limit estimate and, in fact, may  be lower.  Excess cancer risk esti-
mates may also be calculated using other models such as the one-hit, Weibull,
logit, and probit.  There is little basis in  the 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 any others.  Because each
model is based upon differing assumptions, the estimates that  are derived for
each model can differ by several orders of magnitude.

     The scientific data base used to calculate and support the setting of
cancer risk rate levels has an inherent uncertainty due to the systematic and
random errors in scientific measurement.  In most cases, only  studies using
laboratory animals have been performed.  Thus, there is uncertainty when the
data are extrapolated to humans.  When developing cancer risk  rate levels,
several other areas of uncertainty exist such as the incomplete knowledge
concerning the health effects of contaminants in drinking water; the impact of
the  laboratory animal's age, sex, and species; the nature of the target organ
system(s) examined; and the actual rate of exposure of the internal targets in
laboratory animals or humans.  Dose-response data usually are  available only
for  high levels  of exposure, not for the lower levels of exposure closer to
where a standard may be set.  When there is exposure to more than one contami-
nant, additional uncertainty results from a  lack of information about possible
synergistic or antagonistic effects.
                                      -6-

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B.  QUANTIFICATION OF NONCARCINOGENIC EFFECTS FOR DICHLOROMETHANE

     Exposure to dichloromethane (OCM) has resulted in hepatic, renal,  cardiac,
and central nervous system (CNS) toxicity in a variety of species.   DCM vapors
are irritating to the lungs, mucous membranes, eyes, and skin.  The most serious
effects of DCM (i.e., severe CNS depression/death) occur following  exposure  to
high vapor concentrations or when large doses are administered via  gavage or
injection.  Such severe effects are unlikely to occur in humans or  laboratory
animals by exposure to DCM via drinking water.

1.  Toxic Effects in Humans
     a.  Short-term jxposure

     Toxicity studies on DCM in humans are limited to inhalation exposure.
Behavioral and neurological symptoms such as light-headedness (Stewart  et al.,
1973), reduced scores on sensory/motor tests (Fodor and Winneke, 1971), and
eye/hand coordination depression (Putz et al., 1976) have been observed at
levels of 800 ppm for 1 hour, 300 ppm for 3 hours, and 200 ppm for 4 hours,
respectively.  These exposures correspond to approximate doses of 12 to 14
mg/kg (see Appendix for calculation).

     Reports of serious health effects from accidental/occupational exposure to
DCM (Moskowitz and Shapiro, 1952; Bonventre et al., 1977; Stewart and Hake,
1976) have not adequately determined the circumstances of exposure or quanti-
fied airborne DCM concentrations.
     After carbon monoxide was found to be a metabolite of DCM, Stewart et al.
 (1972b)  expressed concern that individuals with advanced cardiovascular disease      (j
 may  suffer severe effects from DCM exposure.  Elevated carboxyhemoglobin levels
                                       -7-

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followiny DCM exposure have been implicated  in  exacerbation of  cardiovascu-lar


effects (Welch, 1987), but no conclusive evidence linking DCM to cardiotoxicity


in humans has been shown.




     b.  Long-term exposure^

    *


     Hepatotoxicity and possible hematopoietic  effects have been implicated  in


chronic occupational exposure studies.  Ott  et  al. (1983c) studied 83 men and


183 women occupationally exposed to DCM levels  of 60 to 475 ppm (approximately
                       t

7.2 to 57 mg/kg/day; see Appendix).  Red blood  cell  counts were increased in


women, but not in men, exposed to approximately 475 ppm DCM, compared with no


increase among unexposed controls.




     Welch (1987) analyzed 141 cases of adverse health effects in workers


occupationally exposed to DCM.  Effects included neurotoxicity, respiratory


irritation, cardiotoxicity, and hepatitis.  Although the author linked these


effects to UCM, in none of these cases could it be conclusively demonstrated


that the effects were due to DCM exposure.  Confounding variables included


exposure to other solvents and cigarette smoking.   In addition, data on DCM


concentrations in workplace air and data on  the carboxyhemoylobin levels in the


blood of exposed individuals were  incomplete.




2.  Toxic Effects in Animals




     a.  Short-term exposure




     The only  acute oral toxicity  study found was that reported by Kimura et


al. (1971).   In this  study, 14-day-old  (16 to 50  g), young adult  (80 to 160 g),


and older adult (300 to  470 g) Sprague-Dawley rats were given single oral doses


of DCM  (undiluted) and  observed for 1 week for mortality and signs of toxicity.
                                      -8-

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LU50 values and 95% confidence limits for 14-day-old,  young  adult,  and  older
adult rats were 1.8 (1.3 to 2.3),  1.6 (1.3 to  1.9),  and  2.3  (1.7  to 3.2) ml/kg,
respectively.  Although few details were given,  the  authors  report  that the
lowest dose causing observable effects (i.e.,  dyspnea, ataxia,  cyanosis, and/or
coma} was 1 ml/kg (equivalent to 1,326 mg/kg,  based  on a density  of 1.326
g/mL).

     Short-term DCM exposure has also been shown  to  cause a  variety of  neuro-
toxic effects in laboratpry animals.  At concentrations  of 17,000 ppm for  6
hours, or 27,QUO ppm for 1.5 hours (approximately equivalent to 5,600 and  2,200
mg/kg/day; see Appendix), DCM induced coma and death in  rats (Thomas et al.,
1971).  Rats developed symptoms of depressed activity after  3 hours of  exposure
to concentrations of 1,000 ppm (approximately  165 mg/kg; see Appendix).
     Other neurotoxic effects have resulted from exposure to DCM via inhalation
or ip injection.  Effects on sleeping behavior such  as reduced  rapid eye move-
ment (REM) sleep were observed in rats (strain not specified) exposed continu-
ously for 24 hours to concentrations as low as 500 ppm (approximately equiva-
lent to 660 mg/kg; see Appendix; Berger and Fodor, 1968). Other neurological
effects include edema of the meninges of the brains  of female beagles exposed
continuously to 5,000 ppm DCM for 17 to 23 days  (MacEwen et  al., 1972), and  a
decrease in sciatic nerve conduction velocity in Wistar rats exposed to 85 and
510 mg/kg via ip injection (Pankow et al., 1979).
     Hepatotoxic effects of short-term inhalation exposure to DCM have been
demonstrated in several species.  Morris et al..(1979) observed increased
hepatic triglyceride and phospholipid levels in  guinea pigs  exposed to 5,200
ppm for 6 hours (approximately 1,400 mg/ky; see  Appendix).  Male Hartley guinea
pigs exposed via inhalation to 11,100 ppm for 6  hours, or 5,000 ppm for 6
                                      -9-

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hours/day for 5 days, also developed a variety  of hepatic histopathological
lesions such as fatty livers and vacuolization  (Balmer et al.,  1976).   Hepatic
fatty changes were also reported by Balmer et al. (1976) Jn  three of five male
Hartley guinea pigs exposed to DCM at levels  of 552 to 679 ppm  for 6 hours/day
for 5 days (approximately 188 mg/kg; see Appendix).
     Female mice (ICR strain) exposed continuously via inhalation to  5,000  ppm
of technical grade DCM (12,000 mg/kg/day; see Appendix) for  7 days exhibited
increased liver-to-body'weight ratios, increased liver triglyceride levels, and
decreased glycogen and protein synthesis.  A variety of histopathological
effects including breakdown of the endoplasmic  reticulum in  hepatocytes,
referred to as balloon degeneration, were also  observed.  Liver lesions were
initially noted after 12 hours of exposure or 6,000 mg/kg/day (Weinstein et
al., 1972).  Male Wistar rats, exposed to 500 ppm for 5 hours/day for  10 days
(approximately 140 mg/kg/day; see Appendix), exhibited microsomal enzyme induc-
tion (Norpoth et al., 1974).
     Klaassen and Plaa (1966) detected minor inflammatory changes to  the liver
(no details were specified) in male Swiss-Webster mice given a  single  intraperi-
toneal  (ip) injection of 2,519 mg/kg DCM in corn oil; no histopathological
changes were reported for mice administered 1,459 mg/kg.  In addition, no
changes in  SPGT activity were noted at either dose level.  Mongrel .dogs appeared
to be more  sensitive to DCM exposure, displaying slight hepatic changes such as
subcapsular necrosis, moderate neutrophilic infiltration, and organ dysfunction
characterized by increased serum glutamic-pyruvic transaminase  (SGPT)  activity
24 or 48 hours after receiving a single  ip injection of 663 or  995 mg/kg DCM in
corn oil.  The effective dose at which a 50% increase in organ  dysfunction
                                     -10-

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       occurred was estimated to be 796 mg/kg,  based on increased SGPT  activity
(Klaassen and Plaa, 1967).
      Cornish et al. (1973)  also reported  elevated serum glutamic-oxaloacetic
transaminase (SCOT) levels in groups of four Sprague-Dawley rats administered  ip
injections of 265, 663, and 1,326 mg/lcg DCM in  peanut oil.

     b.  Long-term exposure

     Long-term exposure to DCM has been shown to cause a variety of hepatotoxic
effects including carcinogenesis, which will be discussed in detail in  Section C
In a 90-day study conducted at Bio/dynamics, Inc. (Kirschman et al., 1986),
Fischer 344 rats were given DCM in the drinking water at target concentrations
of 0.15, 0.45, or 1.50%, which are equivalent to doses of 166, 420, or  1,200
mg/kg/day, respectively, in male rats, and 209, 607, or 1,469 mg/kg/day,  respec-
tively, in female rats, based on water consumption measurements.  Several
hepatocellular changes were observed after 90 days of exposure to DCM (Table 1).
A dose-related increase in the incidence of hepatocyte vacuolization (lipid
accumulation) was found.  Centrilobular necrosis, granulomatous foci, and some
evidence of ceroid and lipofuscin accumulation were noted in mid- and high-dose
animals, particularly females.  Slight decreases in body weight were noted in
mid-dose males and high-dose females, and several changes in clinical chemistry
parameters, such as increased SGPT, SGOT, and lactic dehydrogenase levels and
decreased serum protein levels, were noted, particularly in mid- and high-dose
females.  The NOAELs for male and female rats were 166 and 209 mg/kg/day,
respectively.
     Similarly, hepatocellular changes were observed in a companion study in
B6C3Fi mice  (Kirschman et al.,  1986).  DCM  concentrations of 0.15, 0.45, or
                                      -11-

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           Table 1.  Summary of Hepatocel lular Findings  in  the  Livers
                     of Rats Given DCM in  Drinking Water for  90 Days



Liver response
Number examined
Normal
Hepatocyte vacuolization
Hepatocyte degeneration
Pigment, Kupffer cells
Granuloma (focal)
Eosinophilic cytoplasmic
bodies {hepatocytes)
No. of
0
M
15
11
1
0
0
1
0

rats affected at DCM concentrations (%)a

F
15
4
6
0
0
0
0

0.
M
15
3
10
0
0
0
0

15
F
15
1
13
0
0
0
0

0
M
15
6
9
0
0
0
0

.45
F
15
0
15
0
0
4
0

1.
M
15
7
7
2
1
1
2

of:
50
F
15
0
.15
12
13
6
4


aihese concentrations correspond to doses of approximately 0, 166, 42U,  or 1,200
 my/kg/day for males and 0, 209, 607, or 1,469 mg/kg/day for females,  based on
 daily water consumption and body weights,

SOURCE:  Adapted from Kirschman et al. (1986).
                                       -12-

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1.50% in drinking water,  equivalent  to doses  of  226,  587,  or  1,911 mg/kg/day,
respectively, in males,  and 231,  586,  or  2,030 rag/kg/day,  respectively, in
females, were administered in mice for 90 days.   Livers  from  the  mid-  and
high-dose males and females exhibited  subtle  centrilobular fatty  changes.   In
addition, slight decreases in body weights were  noted in mid- and high-dose
animals during the second half of the  study.  Unlike  rats, male mice appeared
to be more sensitive to hepatocellular change compared to females.   The  NOAELs
for this study were 226 and 231 mg/kg/day for male and female mice,  respec-
                       f
tively.

     Bornmann and Loeser (1967) reported  that no adverse effects  occurred  in
male and female Wistar rats after administration of 125 mg/L  or  15 mg/kg/day
(assuming daily consumption of 12 nt/100  g body  weight)  of DCM in the  drinking
water for 13 weeks.  The urine albumin test was  frequently positive, but no bio-
logical significance was attached to this observation.  Only  one dose  level was
tested, and this was identified as the NOAEL for this study.
     Weinstein and Diamond (1972) observed increased triglyceride levels,  cen-
trilobular fat accumulation, and decreased glycogen content in livers  of female
ICR mice exposed continuously to 100 ppm for up to 10 weeks.   Histologic effects
were first observed after  7 days (approximately 240 mg/kg/day; see Appendix).
Haun et al.  (1972) observed  vacuolization in the  livers of rats, dogs, and
monkeys  (strain  not specified) exposed to 100 ppm for 100 days (estimated to be
equivalent to  doses of 130, 84, and 42 mg/kg/day for rats, dogs, and monkeys,
respectively).   In this  study,  rats receiving 25  or  100 ppm exhibited some renal
tubular degeneration, but  this effect appeared to be transient with subsequent
regeneration.
                                       -13-

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     In a chronic study reported by Serota et al.  (1986a) and conducted  by
Hazleton Laboratories, Fischer 344 rats were given DCM in drinking water at
target doses of 0, 5, 50, 125, and 250 mg/kg/day  for 104 weeks.  At 50,  125,
or 250 mg/kg/day, an increased incidence of foci/areas of cellular alteration
(Table 2) and fatty change were observed in the liver.  These hepatic effects
were noted at 78 and 104 weeks of the study.   An  increased incidence of  hepatic
tumors (neoplastic nodules, and neoplastic nodules and hepatoce!lular carcino-
mas combined) occurred in females receiving 50 or  250 mg/kg/day, but not 125
                        t
mg/kg/day (see Section C).  In addition to hepatocellular effects, statisti-
cally significant decreases (p <0.05) in body weight, and in water and food con-
sumption, were observed in animals receiving  125  or 250 mg/kg/day compared  with
controls.  Because the increased incidence of hepatic tumors noted in females
was within the range of historical controls,  and  in the absence of a dose-related
effect, i.e., increased incidence in the 125-mg/kg/day group, this was not
considered to be attributable to DCM administration.  A NOAEL of 5 mg/kg was
identified.

     Mice appeared to be less sensitive to oral DCM exposure.  In a study in
which B6C3Fi mice were given 0, 60, 125, 185, and  250 mg/kg/day DCM in drinking
water for 104 weeks, an increase in hepatocellular alterations consisting of
slight increases in the amount of Oil Red-0 positive material (consistent with
increased fat content in the liver) was noted in  high-dose males and females.
A NOAEL of 185 mg/kg/day was identified (Serota et al., 1986b).  Increased
incidence of combined heptocellular adenomas/carcinomas was noted in male mice
given DCM at concentrations of 125 or 185 mg/kg/day but not at 250 mg/kg/day
(see Section C).  The authors considered this increase marginal because  there
was no dose-related response, and the incidence was within the historical
                                      -14-

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 Table 2.  Incidence of Liver Foci/Areas of Alteration in Rats
   .        Given DCM in Drinking Water for 78 or 104 Weeks

Sex
Males
Females
Males
Females
Incidence^
0

7/20
3/2U
t
27/36
17/31
of lesion
5

3/20
11/20
22/34
12/29
at DCM dose
50
78 weeks
15/20
14/20
104 weeks
35/38
30/41
(mg/kg/day)
12b

13/20
16/20
34/35
34/38
of:
2bO

20/20
17/20
40/41
31/34

"Number of rats affected/number examined.

SOURCE:  Adapted from Serota et al. (1986a).
                              -15-

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control range of 5 to 34% (mean 16.1%)  for this tumor type in B6C3Fi mice  at       t
Hazleton Laboratories (Serota et al., 19865).                                       1

     The National Toxicology Program (NTP, 1986)  reported that inhalation
exposure to 1,000, 2,000, or 4,000 ppm  DCM,  6 hours/day,  5 days/week for 102
weeks, resulted in increased incidences of hepatic hemosiderosis, cytomegaly,
cytoplasmic vacuolization, necrosis, granulomatous inflammation,  and bile  duct
fibrosis in both male and female F344/N rats.  In addition, increased inci-
dences of benign mammary tumors (primarily fibroadenomas) were noted in both
male and female rats exposed to 4,000 ppm DCM (see Section C, Table 7).   In  a
companion study {NTP, 1986), 2-year exposure to 2,000 or  4,000 ppm DCM 6 hours/
day, 5 days/week, resulted in hepatic cytologic degeneration in B6C3Fi mice.
Dose-related increases in the incidence of alveolar/bronchial adenomas and/or
carcinomas, and in the number of treated mice bearing multiple pulmonary tumors
or hepatocellular adenomas/carcinomas,  were  also  noted (see Section C).

     In another chronic inhalation study, 2-year  exposure of Sprague-Oawley  rats
to 500, 1,500, or 3,500 ppm DCM, 6 hours/day, 5 days/week,  resulted in hepatic
lesions characterized by increased vacuolization  in males and females at the 500-
ppm level (approximately 165 mg/kg/day; see  Appendix).  Increases in sarcomas
in and around the salivary glands were  observed in male rats at the 1,500- or
3,500-ppm exposure levels.  Also, female rats exhibited a dose-related increase
in total  numbers, but not incidence, of benign mammary tumors (see Section C).
No effects were noted in Golden Syrian  hamsters exposed for 2 years to 500 to
3,500 ppm DCM, 6 hours/day,  5 days/week (Burek et al., 1984).

3.  Development of Health Advisories

     The limited studies performed to date may not have identified the most
sensitive endpoint of DCM toxicity.  Available studies on human occupational
                                     -16-

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inhalation exposure focus primarily on behavioral/neurological  effects;  possible
toxicity to other tissues has not been investigated in  detail.   Hepatotoxicity
from short-term ingestion and inhalation exposure has been observed  in mice,
guinea pigs, and rats, but behavioral/neurotoxic effects  have  not  been well
studied at similar exposure levels.  The only report on the acute  oral toxicity
of DCM is the study of Kimura et al . (1971).   Details of  the toxic effects  and
doses tested were not provided.

     Long-term ingestion and inhalation studies of DCM  in rats have  identified
the liver as a target organ.   In addition, chronic occupational inhalation
exposure has been linked to increased bilirubin levels  (Ott et al.,  1983c),
which is suggestive of hepatotoxicity.  Oral  and inhalation exposures have  also
been found to cause kidney and CNS effects in laboratory  animals.

     a.  One-day Health Advisory

     The study by Kimura et al . (1971) was selected for derivation of the One-
day HA for DCM in a 10-kg child because no other adequate acute oral studies of
appropriate duration  or design were found in the literature.  This study identi-
fied a LOAEL of 1.0 ml/kg (1,326 mg/kg) in young adult  Sprague-Dawley rats on
the basis of gross signs of toxicity  (i.e., dyspnea, ataxia, cyanosis,  and/or
coma)  following the administration  of a single  oral dose of DCM.  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 =  t1*?2^ m&W. (.1U ^ * 13.3 mg/L  (rounded to 10,000 ug/L)
        j                 (I  L/day)
                                       -17-

-------
where:
         1,326 mg/kg
               10 kg
               1,000
LOAEL,  based on gross signs  of toxicity  in rats.
assumed body weight of a child.
uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an  animal  study.
             1 L/day « assumed daily water consumption of a child.

     b.  Ten-day Health Advisory
                        /
     The March 31, 1987, HA for dichloromethane gives a value for the Ten-day
HA of 1,500 mg/L, based on the study of Bornmann and Loeser (1967).  With the
availability of a more recent study, Kirschman et al. (1986), the Ten-day HA
value has been revised and is based on the Longer-term HA of 2,000 ug/L for a
10-kg child.

     c.  Longer-term Health Advisory
     Three studies were considered for the calculation of the Longer-term HA
(Table 3}.   In two studies conducted at Bio/dynamics, Inc., and reported by
Kirschman et al.  (1986),  Fischer  344 rats  and B6C3Fi mice were given nominal
concentrations of 0.15, 0.45, and 1.50% DCH  in the  drinking water  for 90 days.
These  levels are equivalent to doses of 166, 420, or 1,200 mg/kg/day, respec-
tively,  for  male  rats, and 209, 607, or 1,469 mg/kg/day, respectively, for
female rats; and  226,  587, or 1,911 mg/kg/day, respectively, for male mice, and
231, 586, or 2.U30 ing/kg/day, respectively,  for female mice.  Based on dose-
related  increases in hepatocyte  vacuolization in  both males and females and a
variety  of  histopathological  changes at the  mid-  and high-dose levels, a LOAEL
of 166 mg/kg/day  was identified.   In addition, slight decreases were observed
in body  weights  of  mid-dose  males and  high-dose  females, and degenerative changes
were observed  in the hepatocytes  of  high-dose  females.   The  authors  reported  a

                                       -18-

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    Table 3.  Summary of Subchronic Oral  Toxicity Studies  Considered for the
              Development of the Longer-term HA
Reference    Species   Duration
                                           Dose
                     Percent   (mg/kg/day)
                      (v/v)   Males  Females
                                           Effects
Ki rschman
et al.
(1986)
Rat
90 days
Ki rschman
et al.
(1986}

Bornmann
and Loeser
(1967)
Mouse
Rat
90 days
13 weeks
0.15
0.45
1.50
0.15
0.45
1.50

0.013
  166     209
  420     607
1,200   1,469
  226
  587
1,911

   15
  231
  586
2,030

   15
LOAEL
Dose-related increases
in hepatocyte vacuoliza-
tion; slight decreases
in body weight. In females,
hepatocellular degeneration
and increases in serum
glutamic-pyruvic transami-
nase, serum glutamic-oxalo-
acetic transaminase, total
serum protein, and lactic
dehydrogenase.

NOAEL
Centrilobular fatty
change in liver.

NOAEL
No effects noted.
                                      -19-

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NUAEL for mice of approximately 231 mg/kg/day, based on slight centrilobular
fatty changes in the livers of mid- and high-dose animals.

     Bornmann and Loeser (1967) exposed Wistar rats to DCM in drinking water
for 13 weeks and reported a NOAEl of 125 mg/L.  This is equivalent to a dose of
approximately 15 mg/kg/day» based on daily water consumption of 12 mL/100 g
body weight.

     The 9U-day study reported by Kirschman et al. (1986), in which DCM was
administered in drinking water at doses of 166 to 1,469 mg/kg/day to Fischer
344 rats, has been selected as the basis for the Longer-term HA because rats
proved to be slightly more sensitive to DCM administration than mice.  This
study was selected over the Bornmann and Loeser study primarily because a range
of doses was used to demonstrate a toxic effect, and a detailed description of
the study methods and results was provided.

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

     (166 mg/ky/day)(10 kg)  *  1.7 my/L (pounded to 2,UOO ug/L)
        (1 L/day)(1,000)
where:
     166 my/kg/day = LOAEL, based on dose-related increased histopathological
                     changes in the livers of rats.
             10 kg = assumed body weight of a child.
           1 L/day = assumed daily water consumption of a child.
             1,000 » uncertainty factor, chosen in accordance with NAS/ODW
                     guidelines for use with a LOAEL from an animal study.
                                      -20-

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     d*  Reference Dose and Drinking Vlater Equivalent Level

     Caution must be exercised in deciding how to consider possible lifetime
exposure to this substance because, based on the available carcinogenicity data,
dichloromethane may be classified in Group B2 {Probable Human Carcinogen), accord-
iny to the EPA guidelines for assessment of carcinogenic risk (U.S. EPA, 1986).
Consequently, the assessment of carcinogenic potential must be balanced against
the likelihood of occurrence of health effects related to noncarcinogenic end-
                       /
points of toxicity.

     The two chronic oral toxicity studies reported by Serota et al. (1986a,b)
were considered as the basis for calculation of the Reference Dose (RfD) and
Drinking Water Equivalent Level (DUEL) (Table 4).  Although both studies were
adequate, the study with rats is most appropriate for derivation of the DWEL
because rats are the more sensitive species.  A NOAEL of 5 mg/kg/day was iden-
tified in this study.  Effects on body weight, hematological parameters, and
histopathological changes in the liver (incidence of foci/areas of cellular
alteration and/or fatty changes) were observed at higher doses.

     The DWEL for a 70-kg adult is calculated as follows:
     Step 1:  Determination of the Reference Dose (RfD)

              RfD = (5 mg/kg/day) = 0.05 mg/kg/day
where:
     5 my/kg/day « NOAEL based on the absence of liver and blood effects in
                   rats.
             1UU = uncertainty factor, chosen in accordance with NAS/ODW
                   guidelines for use with a NOAEL from an animal study.
                                      -21-

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     Table 4.  Summary of Chronic Oral  Toxicity  Studies  Considered for the
               Development of the Reference Dose and Drinking Water Equivalent
               Level

Reference
Serota et
al. (1986a)
Species
(sex)
Rat
(M/F)
Duration
Route (weeks)
Oral 104
Dose
(mg/kg/day)
5
50
Effect
NOAEL
Hepatic fatty change,
                                                 125
                                                 250
Serota et
al. (1986b)
Mouse
(M/F)
Oral
104
 60
125
185
250
                                           hepatic tumors.
                                           Hepatic fatty change,
                                           decreased body weight
                                           and food consumption.
                                           Hepatic fatty change,
                                           hepatic tumors,
                                           decreased body weight
                                           and food consumption.
                                                           NOAEL
                                                           Hepatic lesions.
                                      -22-

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

      DUEL = (O.U5 mg/kg/day)(70 kg) - ^75 mg/L (pounded to 2,000  ug/L)
                     2 L/day

where:

     0.05 mg/kg/day = RfD.
              7U kg = assumed body weight of an adult.
            2 L/day = assumed daily water consumption by an adult.
C.  QUANTIFICATION OF CARCINOGENIC EFFECTS FOR OICHLOROMETHANE

1.  Categorization of Carcinogenic Potential

     DCM has been shown to be mutagenic in numerous test systems, including
Salmonella reversion assays using JS. typhimuriurn strains TA100,  TA1535, and
TA98 (U.S. EPA, 1985a).  The epidemiologic studies (Friedlander  et  al.,  1978;
Hearne and Friedlander, 1981; and Ott et al., 1983a,b,c,d,e) have not  demon-
strated any excessive cancer risk 1n occupationally exposed workers.  However,
because of the limitations of these studies (e.g., insufficient  followup
time), these findings were judged to be inconclusive (U.S. EPA,  1985b).

     Three groups have reported results of DCM carcinogenic!ty bioassays:
Scrota et al. (1986a,b, conducted by Hazleton Laboratories); the National
Toxicology Program (NTP, 1986); and Dow Chemical Company (Burek  et  al.,  1984;
Dow, 1982).  The results of these bioassays were considered in evaluating  the
carcinogenic potential of DCM.

     Serota et al. (1986a,b) describe studies in which Fischer 344  rats and
B6C3Fj mice were exposed to DCM in drinking water at concentrations equivalent
to doses of 0, 5, 5U, 125, or 2bO mg/kg/day (rats) and 0, 60, 125,  185, or 25U
                                      -23-

-------
my/kg/day (mice).  A significant increase (p <0.05)  in the incidence  of  neo-
plastic nodules/hepatocellular carcinomas was observed in female rats exposed
to 50 and 250 mg/kg/day compared to matched controls (Table 5).   These increases
were within the range of historical controls and were considered marginal.
Similarly, increases in combined hepatocellular adenomas/carcinomas  in male
mice were also considered borderline with increases significantly different (p
<0.05) from controls in the 125- and 185-mg/kg/day,  but not the  2bO-mg/kg/day,
                      >
dose groups (Table 6).  Based on the incidence of hepatocellular adenomas/car-
cinomas in male mice, an upper-bound risk estimate for ingestion of  DCM in
drinking water was calculated (U.S. EPA, 1985b).  Using the multistage model,
the incremental unit risk estimate for drinking water was estimated  to be 3.5 x
10-7
     An inhalation study conducted by NTP (1986) serves as the basis for both
the qualitative ranking (Group B2, Probable Human Carcinogen) and the quantita-
tive risk assessment.  In this study, Fischer 344/N rats and B6C3Fi mice of both
sexes were exposed to DCM concentrations of 0, 1,000, 2,000, or 4,000 ppm
(rats) and 0, 2,000, or 4,000 ppm (mice) for 6 hours/day, 5 days/week, for 2
years.  Significant  increases in the benign mammary tumors (primarily fibro-
adenomas) were observed in high-dose male and female rats from all DCM-dosed
groups (Table 7).  Significant positive trends for mammary adenoma or fibroade-
noma were also noted in male and female groups.  The significance of other tumor
incidence increases  (combined hepatocellular neoplastic nodules/carcinomas,
mononuclear  cell  leukemia, mesotheliomas, adrenal pheochromocytomas and intersti-
tial cell tumors, and combined pituitary glarid adenomas/carcinomas) varied with
the type  of  statistical  analysis  used to evaluate the results.  For mice, increasecL
incidences of al veolar/bronchiolar adenonomas and/or carcinomas as well as signifiu
cant positive trends were  found  for  both sexes  (Table 8), and the  number of

                                        -24-

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      Table 5.  Summary of Findings for Liver Tumors  in  Rats Given DCM in
                Drinking Water for 2 Yearsa
                                              Dose (mg/kg/day)
      Lesion
50
125
250
25U&
Males
Neoplastic nodules
Hepatocellular carcinomas
Combined nodules/
carcinomas
Females
Neoplastic nodules
Hepatocellular carcinomas
Combined nodules/
carcinomas

4(S)c
2(2)
6(7)
0(0)
0(0)
0(0}

5(10)
2(4}
7(14)
0(0)
0(0)
0(0)

2(2)
0(0)
2(2)
KD
0(0)
KD

3(4)
0(0)
3(4)
2(2)
2(2)
4(5)*

3(3)
0(0)
3(4)
1(1)
0(0)
KD

HD
KD
2(2)
4(5)
2(2}
6(7)*

4(16}
0(0)
4(16)
2(8)
0(0}
2(8)*

aLifetime totals.
bRecovery group, exposed to DCM for 78 weeks  followed by  a  recovery  period  of
 26 weeks.
CNumber of animals affected (percent incidence).
*Significantly different from controls (p <0.05)  using a  combined  control
 incidence of 0/134.

SOURCE:  Adapted from Serota et al. (1986a).
                                      -25-

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           Table 6.  Summary of Findings for Liver Lesions/Tumors in
                     Male Mice Given DCM in Drinking Water for 2 Yearsa
      Lesion
                                               Dose (mg/ky/day)
                    60
185
ZbU
Focal hyperplasia
4(7)a    6(9)     14(7)    4(4)     10(10)   13(10)
Hepatocellular adenoma      6(10)    4(6)     20(10)   14(14)   14(14)   15(12)     I
Hepatocellular carcinoma    5(8)   ;9(14)    33(17)   18(18)   17(17)   23(18)     .
Hepatocellular adenoma
and/or carcinoma
11(18)   13(20)    51(26) 30(30)*  31(31)*  35(28)
aNumber of animals affected (percent incidence).
*Significantly different from controls (p <0.05) using a combined incidence of
24/25.

SOURCE:  Adapted from Serota et al. (1986b).
                                      -26-

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       Table 7.  Summary of Findings for Mammary and Subcutaneous  Tumors
                 in Rats Exposed via Inhalation to DCM for 2 Years

Dose (ppm)
Site/tumor
Hales
Mammary gland: adenoma or fibroadenoma
Subcutaneous tissue: ftbroma
Mammary yland or subcutaneous tissue:
adenoma, fibroadenoma, or fibroma
Fema 1 es
Mammary gland: fibroadenoma
Mammary gland: adenoma or fibroadenoma
0
0(0)a*
1(2)
1(2)*
5(10)*
5(10)*
1,000
0(0)
1(2}
1(2)
11(22)*
11(22)*
.2,000
2(4)
2(4)
4(8)
' 13(26}*
13(26)*
4,000
5(10)*
4(8)
9(18)*
22(44)**
23(46)**

 ^Number of animals affected (percent incidence),
 *Significant1y different from controls (p <0.05).
**Significant1y different from controls (p <0.01).
Note:  A positive trend denoted at control level  by an asterisk using incidental
       tumor tests (actual tests used were not reported).

SOURCE:  Adapted from NTP (1986).

-------
           Table 8.   Summary of Findings  for Luny and Liver Tumors  in
                     Mice Exposed via Inhalation to DCM for 2 Years
1
Site/ tumor
Males
Alveolar/bronchiolar adenoma
Alveolar/bronchiolar carcinoma
t
Alveolar/bronchiolar adenoma or carcinoma
Hepatocellular adenoma
Hepatocellular carcinoma
Hepatocellular adenoma or carcinoma
Females
Alveolar/bronchiolar adenoma
Alveolar/bronchiolar carcinoma
Alveolar/bronchiolar adenoma or carcinoma
Hepatocellular adenoma
Hepatocellular carcinoma
Hepatocellular adenoma or carcinoma

0

3(6)a*
2(4)*
5(10)*
10(20)
13(26)*
22(44)* -
2(4)*
1(2)*
3(6)*
2(4.)*
1(2)*
3(6)*
Dose (£pm)
2,000

19(38)**
10(20)*
27(54)**
14(29)
15(31)
22(49)
23(48)**
13(27)**
30(63)
6(13)
11(23)**
16(33)**

4,000 i
;
1
24(48)** j
i
28(56)**
\
40(80)** |
14(29) j
26(53)* j!
33(67)* |!
,!
i
28(58)** I
29(60)** ;
41(85)
22(46)** jl
32(67)**
40(83)** i
i
I
t
 aNumber of animals affected (percent incidence).
 *Significantly different from controls (p <0.05)
**Significant1y different from controls (p <0.01).
Note:  A positive trend denoted at control level  by an asterisk using incidental
       tumor tests (actual tests used were not reported).

SOURCE:  Adapted from NTP (1986).
                                      -28-

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treated animals bearing multiple pulmonary tumors was also increased over controls.
In addition, the incidence of mice with multiple hepatocellular adenomas/carci-
nomas increased significantly in a dose-related matter.  On the basis of these
results, NTP concluded that there was some evidence of the carcinogenicity of
DCM for male Fischer 344/N rats as shown by an increased incidence of benign
neoplasms of the mammary gland; there was sufficient or clear evidence of the
carcinogenicity of OCM for female Fischer 344/N rats as shown by an increased
incidence of benign neoplasms of the mammary gland; and there was clear evidence
of carcinoyenicity in male and female B6C3Fi mice as shown by increased incidence
of lung and liver tumors.  The increased incidence of hepatocellular adenomas/
carcinomas was used as the basis for computing the unit risk estimate for
inhalation of UCM: .7.5 x 10-8 (ug/l)-l (U.S. EPA, 19855).

     In the study described by Burek et al. (Dow Chemical, 1983), Sprague-
Dawley rats and Golden Syrian hamsters  (both sexes) were exposed via inhalation
to levels of 0, 500, 1,500, or 3,500 ppm DCM, 6 hours/day, 5 days/week, for 2
years.  No effects were noted in hamsters.   Increases in two tumor types were
observed in rats:  (1) ventral cervical sarcomas, probably of the salivary
gland (male rats only, 1,500- and 3,500-ppm dose groups); and (2) benign mammary
tumors (female rats only, increase in total number of tumors, not incidence)
(Table 9).  In a second study (Dow,  1982), Sprague-Dawley rats were exposed to
0, 50, 200, and SOU ppm DCM.  No significant Increase in tumor incidence was
found.

2.  Quantitative Carcinogenic Risk Estimates

     The two risk estimates based on hepatocellular adenomas/carcinomas in mice
(Serota et al., 1986a,b; NTP, 1986) are similar, with a mean value of 2.1 x 10-7
(ug/L)-l (U.S. EPA, 1985b).  The estimated excess cancer risk associated with
                                      -29-

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         Table 9.  Summary of Findings for Mammary and Ventral  Cervical
                   Tumors in Rats Exposed via Inhalation to OCM for 2 Years

Site/tumor
Mal_es
Mammary tumor (benign)
Total number benign mammary tumors
Ventral cervical sarcoma
Females
.Mammary tumor (benign)
Total number benign .mammary tumors
Ventral cervical sarcoma b
Dose (ppm)
0 500 1,500

7{8)a 3(3) 7(7)
8 6 11
1(1} 0(0) 5(5)
79(82) 81(85) 80(83)
165 218 245
-_

3,500

14(14)
17
11(11)*
83(86)
287
--

aNumber of animals affected (percent incidence).
bNot reported.
*Significantly different from controls (p <0.05).

SOURCE:  Adapted from Burek et al. (1984). .
                                      -30-

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lifetime exposure to drinking  water containing  DCM at  1,750  ug/L  (the OWEL) is

approximately 3.7 x 10-4.  This estimate represents the upper 95% confidence
                      I
limit from extrapolations prepared  by  the U.S.  EPA 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.


0.  EXISTING GUIDELINES  AND STANDARDS
                       /


     The U.S. EPA (1980a) criterion for  DCM in  drinking water is  12.4 mg/L

based on noncarcinogenic risk.  The original U.S.  EPA  (1980b) Suggested-No-

Adverse-Response Levels  (SNARLS, presently referred to as Health  Advisories)

in drinking water were calculated as 13, 1.5, and  0.150 mg/L for  One-day, Ten-

day, and Longer-term exposures, respectively.  The National  Academy of  Sciences

(HAS, 198U) reported One- and Seven-day  NAS-SNARLS of  35 and 5 mg/L,  respec-

tively, for DCM  in drinking water.  Recalculation  of these data resulted  in

One- and Seven-day values of 45.5 and 6.5 mg/L, respectively (U.S. EPA,  1987).


     The American Conference  of Governmental Industrial Hygienists (ACGIH,

1984} recommended a Time-Weighted Average-Threshold Limit Value (TWA-TLV) of

100 ppm (360 my/m3) in the absence of exposure to  carbon monoxide and a short-

term exposure  level of 500 ppm.  The Occupational  Safety and Health Administra-

tion (OSHA,  1979) established an occupational exposure  standard of 1,737  mg/m3

for 8 hours  (TWA) with a 3,474 mg/m3 ceiling concentration  (5 minutes in any 2

hours).  The National Institute of Occupational Safety  and Health (NIOSH, 1976)

recommended  an exposure  limit of 261 mg/m^  for.10  hours  (TWA).
                                       -31-

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E.  SPECIAL CONSIDERATIONS



    High-Risk Populations


     Carbon monoxide is a known metabolite of  DCM,  causing  elevated  carboxyhemo-

globin levels in humans (Ott et al., 1983c,e).  The increased concentrations  of

carboxyhemoglobin may compound cardiovascular  effects  as  suggested by  Welch

(1987).  Thus, although there is no conclusive evidence linking DCM  to cardio-
                        t
toxicity in man, those suffering from advanced cardiovascular disease  may  con-

stitute a potential high-risk population (Stewart et al., 1972).

                                                    !

F.  SUMMARY


     The recommended One-day, Ten-day, and Longer-term HA values, the  DWEL,  and

the estimated excess cancer risks are summarized in Table 10.
                                      -32-

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             Table 1U.  Summary of Quantification of lexicological
                        Effects for Dichloromethane
                                 Drinking water
                                 concentration

                                     (ug/L)
                       Reference
One-day HA for 10-kg child

Ten-day HA for 10-kg child

Longer-term HA for 10-kg child

Longer-term HA for 70-kg adult

DWEL (100% from drinking
water)

Excess cancer risk
 .10-4
  10-5
  10-6
10,000
    a


 2,000
    b


 2,000
   476
    48
     5
Kimura et al. (1971)

Kirschman et al. (1986)

Kirschman et al. (1986)

Kirschman et al. (1986)

Scrota et al. (1986)
U.S. EPA (1985b)
U.S. EPA (19855)
U.S. EPA (1985b)
aThe Longer-term HA is used as a conservative estimate of the Ten-day HA.
bThe OWEL value is used as a conservative estimate of the Longer-term HA value
 for a 70-kg adult.

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                                  G.   REFERENCES


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

 Balmer MF,  Smith FA,  Leach  LJ, Yuille CL.   1976.   Effects  in the  liver of
 methylene chloride inhaled  alone and with  ethyl alchohol.  Am.  Ind. Hyg.
 Assoc. J.  37:34b-352.

 Berger M, Fodor GG.   1968.   CNS disorders  under the influence of  air mixtures
 containing dichloromethane.  Zentralbl.  Bakteriol.  215:517.

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

 Bornmann  G,  Loeser A.   1967.   Zur frage  einer chronisch-toxischen wirkung von
 dichloromethan.  Z.  Lebensm.-Unters.  Forsch,  136:14-18.

 Burek  JU,  Nitschke KD,  Bell  TJ,  Wackerle DL, Childs RC, Beyer JE, Dittenber DA,
 Rampy  LW, McKenna  MJ.   1984.   Methylene  chloride:  A two-year inhalation toxi-
 city and  oncogenicity study  in  rats and hamsters.  Fund. Appl.  Toxicol.  4:30-47.

 Cornish HH,  Ling BP,  Barth  ML.   1973,  Phenobarbital and organic solvent toxi-
 city.  Am.  Ind. Hygiene Assoc. J.  34:487-492.

 Dow Chemical Company.   1982.   Nitschke KD, Bell  TJ, Rampy LW, McKenna  MJ.
 Methylene chloride:  A two-year inhalation toxicity and oncogenicity study in
 rats.  Toxicology  Research  Laboratory, Health and Environmental Sciences, Dow
 Chemical Company,  Midland, MI.  October 11, 1983.

 Fodor GG, Winneke  H.  1971.  Nervous system disturbances in men and animals
 experimentally exposed to industrial  solvent vapors.   Proceedings  of the 2nd
 International Clean Air Congress.  New York:  Academic Press, pp.  238-243.

 Friedlander BR, Hearne FT, Hall S.  1978.  Epidemiologic investigation  of
 employees chronically exposed to methylene chloride.   J. Occup. Med. 20:657-666.

 Haun CC, Vernot EH, Darmer KI, Jr., Diamond SS.   1972.   Continuous animal
 exposure to low levels of dichloromethane AMRL-TR-130,  paper  No. 12.  In:
 Proceedings of the 3rd Annual Conference  on Environmental Toxicology, Wright-
 Patterson Air Force Base, Ohio, Aerospace Medical  Research  Laboratory,,pp. 199-
 208.

 Hearn FT,  Friedlander BR.  1981.  Follow-up of methylene chloride  study.  J.
Occup.  Med. 23:660.

Kimura  ET, Ebert DM,  Dodge PW.   1971.  Acute toxicity and limits of  solvent
 residue for sixteen organic  solvents.  Toxicol. Appl.  Pharmacol.  19:699-704.
                                      -34-

-------
Klaassen CD, Plaa GL.  1966.  The relative effects  of various  chlorinated
hydrocarbons on liver and kidney function in mice.   Toxicol. Appl.  Pharmacol.
9:139-141.

Klaassen CO, Plaa GL.  1967.  Relative effects of various chlorinated  hydro-
carbons on liver and kidney function in dogs.  Toxicol. Appl.  Pharmcacol.
10:119-131.

Krischman SC, Brown NM, Coots RH, Morgareidge K.   1986.  Review of  investiga-
tions of dichloromethane metabolism and subchronic  oral toxicity as the basis
for the design of chronic oral studies in rats and  mice.   Food Chem. Toxicol.
24:943-949.

MacEwen JD, Vernot EH, Haun CC.  1972.  Continuous  animal exposure  to  dichloro-
methane AMRL-TR-72-28, SysteMed Corporation report  No. W-71005.  Wright-
Patterson Air Force Base, Ohio, Aerospace Medical Research Laboratories.

Morris JB, Smith FA, Garman RH.  1979.  Studies on  methylene  chloride  induced
fatty liver.  Exp. Mol. Pathol.  30:386-393.

Moskowitz S, Shapiro H. M952.  Fatal exposure to methylene chloride vapor.
Arch. Ind. Hyg. Occup. Med.  6:116-123.

NAS.  1980.  National Academy of Sciences.  Drinking Water and Health.  Vol.  3.
National Academy Press, Washington, DC.

National Toxicology Program.  1986.  NTP technical  report on the toxicology and
carcinoyenesis studies of dichloromethane (methylene chloride) (CAS No. 75-U9-2)
in F344/N rats and B6C3Fj mice (inhalation studies).  Final report. NIH publi-
cation No. 86-2i>62,  National Toxicology Program, Research Triangle Park,  NC.

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, DC,  pp.  1-3,
76-138, 142.

Norpoth K, Witting U, Springorum M, Witting C.  1974.  Induction of microsomal
enzymes in the rat liver by inhalation of hydrocarbon solvents.  Int.  Arch.
Arbeitsmed.  33(4):315-321.

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

Ott MG, Skory LK, Holder BB, Bronson JM, Williams PR.  1983a.   Health  evalua-
tion of employees occupationally exposed to methylene chloride.  General study
design and environmental considerations.  Scand.  J. Health 9(Suppl. 1):1-17.

Ott MG, Skory LK, Holder BB, Bronson JM, Williams PR.  1983b.   Health  evalua-
tion of employees occupationally exposed to methylene chloride.  Mortality.
Scand. J.  Work Environ. Health 9:8-16.
                                      -35-

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Ott MG, Skory LK, Holder BB, Bronson JM, Williams  PR.   1983c.   Health evalua-
tion of employees occupationally exposed to methylene  chloride.  Clinical
Laboratory Evaluation.  Scand. J. Work Environ.  Health 9:17-25.

Ott MG, Skory LK, Holder BB, Bronson JM, Williams  PR.   1983d.   Health evalua-
tion of employees occupationally exposed to methylene  chloride.  Twenty-four
hour electrocardiographic monitoring.  Scand. J. Work  Environ.  Health 9:26-30.

Ott MG, Skory LK, Holder BB, Bronson JM, Williams  PR.   1983e.   Health evalua-
tion of employees occupationally exposed to methylene  chloride.  Metabolism
data and oxygen half-saturation pressures.   Scand. J.  Work  Environ.  Health
9:31-38.                            '       •

Pankow D, Gutewort R, Pansold W, Glatzel W, Tietze K.   1979.  Effect of
dichloromethane on the sciatic motor conduction  velocity of rats.  Experientia
35:373-374.       .                                :

Putz VR, Johnson BL, Setzer JV.  1976.  A comparative  study of  the effect of
carbon monoxide and methylene chloride on human  performance.  J.  Environ.
Pathol. Toxicol.  2:97-112.

Serota DG, Thakur AK, Ulland BM, Kirschman  JC, Brown NM, Coots  RH.  1986a.  A
two-year drinking-water study of dichloromethane in rodents.   I.  Rats.  Food
Chem. Toxicol.  24:959-963.

Serota DG, Thakur AK, Ulland BM, Kirschman  JC, Brown NM, Coots  RH.  1986b.  A
two-year drinking-water study of dichloromethane in rodents.   II. Mice.  Food
Chem. Toxicol.  24:959-963.

Stewart RD, Fisher TN, Hosko MJ, Peterson JE, Baretta  ED, Dodd  HC.  1972a.
Carboxyhemoglobin elevation after exposure  to dichloromethane.   Science
176(4032):295-296.

Stewart RD, Fisher TN, Hosko MJ, Peterson JE, Baretta  ED, Dodd  HC.  1972b.
Experimental  human exposure to methylene chloride.  Arch. Environ. Health
25:342-348.

Stewart RD, Forester HV, Hake CL, Lebrun AJ,  Peterson  JE.   1973.   Human
response to controlled exposure of methylene  chloride  vapor.  Report No. NIOSH-
MCOW-ENVM-MC-73-7.  Milwaukee, WI, Dept. Environmental  Medicine,  December.
p. 82.

Stewart RU, Hake CL.  1976.  Paint remover'hazard. J.  Am.  Med. Assoc.
235(4):398-401.

Thomas AA, Pinkerton MK, Warden JA.   1971.   Effects of  dichloromethane exposure
on the spontaneous  activity of mice.  AMRL-TR72-130,  paper No. 13.   _In_: Pro-
ceedings of the 3rd Annual  Conference on Environmental  Toxicology,  pp.  223-
227.

U.S. EPA.  1980a.  U.S. Environmental  Progection Agency. Ambient water quality
criteria for halomethanes.   EPA 440/5-8U-051. Office  of Water  Regulations and
Standards.  Criteria and Standards Division.   Washington, DC.
                                      -36-'

-------
U.S. EPA.  198U5.  U.S. Environmental  Protection Agency.   Advisory  opinion  for
dichloromethane (methylene chloride).   Draft.  Office of  Drinking Water.
Washington, DC.

U.S. Environmental Protection Agency.   1985a.  Health assessment document for
dichloromethane (methylene chloride).   Final  report.   EPA-700/8-82-004F.
Prepared by the Office of Health and Environmental Assessment, Washington,  DC.

U.S. Environmental Protection Agency.   1985b.  Addendum to the health assess-
ment document for dichloromethane (methylene  chloride); updated carcinogen
assessment of dichloromethane.  Draft.  EPA-600/8-82-004FA.   Prepared by the
Office of Health and Environmental Assessment, Washington, DC.
Weinstein RS, Boyd DD, Back KC.  1972.  Effects  of  continuous  inhalation
dichloromethane in the 'mouse - morphologic and functional  observations.
Toxicol. Appl. Pharmacol.  23:660-679.
                                                                         of
Weinstein RS, Diamond SS.  1972.  Hepatotoxicity  of dichloromethane (methylene
chloride) with continuous inhalation exposure at  a low-dose level.  AMRL-72-
130, paper No. 13.  In;  Proceedings of the 3rd Annual  Conference on Environ-
mental Toxicology, Wright-Patterson Air Force Base, Ohio, Aerospace Medical
Research Laboratories, pp. 209-222.

Welch L.  1987.  Reports of clinical disease secondary  to methylene chloride
exposure - a collection of 141 cases.  FYI-OTS. 0487-0537.  George Washington
University School of Medicine.  Prepared for the  Office of Toxic Substances,
U.S. Environmental Protection Agency, Washington, DC.
                                      -37-

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APPENDIX?

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   Estimations of Dose From Studies of Inhalation Exposure to Dlchloromethane
Species
Concen-
tration
 (pom)
Duration of
 exposure
 (hr/day)
  Estimated
absorbed dose
 (mg/kg/day)a
      Reference
Human:  (70 kg; U.6 m3/hr)
Controlled
exposures


Occupational
exposures
    2UO
    300
    800

     6U
    475
     4
     3
     1

     8
     8
Rat:  (0.25 ky; 0.0792 m3/hr)
Mouse;  (0.025 kg; 0.0144 m3/hr)
               5,000
                 100
              12
              24
Guinea pig;  (0.50 kg; 0.133 m3/hr)

               5,200        6

Dog;  (10 kg; 0.20 m3/hr)

                 100       24

Monkey;  (10 kg; 0.1 m3/hr)

                 100       24

Hamster:  (0.10 kg; 0.0366 m3/hr)

                 500        6
       12
       14
       12

        7.2
       57
25
100
500
500
500
1,000
17,000
27,000
24
24
5
6
24
3
6
1.5
33
130
140
165
660
165
5,600
2,200
                  6,000
                    240
                           14,400
                               84
                               42
                            1,900
Putz et al. (1976)
Fodor and Winneke (1971)
Stewart et al. (1973b)

Ott et al. (1983a,c)
Ott et al. (1983a,c)
                                                      Haun et al. (1972)
                                                      Haun et al. (1972)
                                                      Norpoth et al. (1974)
                                                      Dow (1980)
                                                      Berger and Fodor (1968)
                                                      Thomas et al. (1971)
                                                      Thomas et al. (1971)
                                                      Thomas et al. (1971)
                 Weinstein et al. (1972)
                 Weinstein and Diamond (1972)
                               Morris et al. (1979)



                               Haun et al. (1972)



                               Haun et al. (1972)



                               Dow (1980)
 Estimated absorbed dose was calculated as follows:
 Dose *
[Conc.(ppm) x 3.47 mg/m3 ppm-l][Exposure(hr)][Resp.
                                       rate(mg/m3)][50% absorption]
                                 body weignt (kg)

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