EPA 0596
Health advisories for
other contaminants
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Other Contaminants Health Advisories
CONTS - 15.25
-Dichloromethane Health Advisory
D-284 - 1.50 . . •
-1,2-Dichloropropane Health Advisory
D-255 - 1 . 50 ' .
-Formaldehyde - Informal Guidance level fo
D-286 - 1.00 . '
-Lead Health Advisory
D-287 - 2.00
-p-Dioxane Health Advisory
D-288 - 1.00
-Zinc Chloride Health Advisory
D-289 - 8.25
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EPA 0596 March 31, 1987
RX000027824
DICHLOROMETHANE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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uicnioromethane March 31, 1987
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This Health Advisory is based upon information presented in the Office
of Health and Environment Assessment Criteria Document (CD) for Dichloromethan
(U.S. EPA, 1985a). Die HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CD. The CD is available
for a fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB85 191559. The toll-
free number is (800) 336-4700; in the Washington, D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 75-09-2
Structural Formula
Cl
I
H-C-C1
I
H
Synonyms
0 Methylene chloride, methylene dichloride, methylene bichloride, DCM
Uses
0 Solvent for insecticides, paints, varnish and paint removers and in
food processing; degreasing and cleaning fluids.
Properties (Verschueren, 1977; Windholtz, 1983)
Chemical Formula CH2C12
Molecular Weight 84.94
Physical State Colorless liquid
Boiling Point 40°C (760 mm Hg)
Melting Point -95 to -978C
Density 1.3255 (20/4°C)
Vapor Pressure 349 mm Hg (20°C)
Water Solubility 20 g/L (20°C)
Log Octanol/Water Partition
Coefficient
Odor Threshold
Taste Threshold
Conversion Factor —
Occurrence
* Dichloromethane (DCM) is a synthetic chemical with no known natural
sources.
0 Production of DCM was approximately 600 million Ibs in 1983 (U.S.
ITC, 1984). .
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Dichloromethane March 31, 1987
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0 The major sources of DCM released to the environment are from its
industrial uses where the majority of all DCM produced is released.
Most of the releases occur to the atmosphere by evaporation. However,
large amounts of DCM are disposed of by burial in landfills or dumping
on the ground or into sewers. Because DCM is involved in industrial
operations performed nationwide, releases occur in all urban areas.
Releases of DCM during its production are relatively minor in comparison
to releases during its use.
0 Dichloromethane released to the air is degraded in a matter of a few
days. Dichloromethane released to surface waters migrates to the
atmosphere in a few days or weeks where it also degrades. Volatiliza-
tion is the major transport process for its removal from aquatic
systems (U.S. EPA, 1979). Dichloromethane which is released to the
land does not sorb onto soil and migrates readily to ground water
where it is expected to remain for months to years. Dichloromethane,
unlike some other chlorinated compounds, does not bioaccumulate in
individual animals or food chains.
0 Because of the large and dispersed releases, DCM occurs widely in "the
environment. It is ubiquitous in the air with levels in the ppt
range and is a common contaminant in ground and surface waters with
higher levels found in ground water.
0 Very limited information is available on the occurrence of dichloro-
methane in food. Dichloromethane has been reported to occur in fish.
It is used as an extraction solvent for the decaffination of coffee
and other food processing operations. Low levels of DCM have been
reported to occur in some foods from these operations.
0 The major sources of exposure to DCM are from contaminated water.
Air and food are only a minor sources (U.S. EPA, 1980c).
III. PHARMACOKINETICS
Absorption
«*.
0 Dichloromethane is expected to be absorbed completely when ingested.
A single oral dose of 1 or 50 mgAg 14C-DCM administered to male rats
(3/dose) was exhaled as unchanged DCM (12.3 or 72.1%, respectively)
within 48 hours (McKenna and Zempel, 1981).
Distribution
c Tissue distribution after administration of 1 or 50 mgAg of 14c-DCM
in water by gavage to male rats (3/dose) was measured by McKenna and
Zempel (1981). The highest concentration of radioactivity was present
in liver and the lowest in fat, 48 hours after either dose.
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Dichloromethane. March 31, 1987
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Metabolism
0 The major metabolites of DCM are carbon monoxide and carbon dioxide.
McKenna and Zempel (1981) studied the metabolism of V4C-DCM after
gavage administration to groups of three male Sprague-Dawley rats
dosed at 1 or 50 mgAg- They metabolized about 88 or 28% of the
dose, respectively. The major metabolites exhaled after 48 hours
were carbon monoxide (30.9 and 11.9% of the 1 or 50 mgAg doses,
respectively) and carbon dioxide (35.0 and 6.3% of the 1 or 50 mgAg
doses, respectively).
Excretion
Metabolites of DCM are excreted in urine. McKenna and Zempel (1981)
reported that, in rats given 1 or 50 mgAg 14C-DCM, 4.52 +0.05% or
1.96 ±0.05% of the dose, respectively, was excreted in the urine
within 48 hours. The fecal elimination of DCM after oral or intra-
peritoneal administration of DCM is low (<1.0%) (DiVincenzo and
Hamilton, 1975; McKenna and Zempel, 1981).
IV. HEALTH EFFECTS
Humans
Bonventre et al. (1977) described a fatal intoxication with DCM
which was being used as a paint remover. Postmortem examination
revealed the presence of DCM in the liver (14.4 mg/100 g tissue),
blood (51 mg/dL or 510 mg/L) and brain (24.8 mg/100 g tissue).
The carboxyhemoglobin content was 3% saturated.
Animals
Short-term Exposure
Oral LD50s for DCM were reported as 1,987 mgAg for mice and 2,121
mgAg for rats (Kimura et al. 1971; Aviado et al. 1977).
Kimura e-t al. (1971) administered single oral doses of DCM to young
adult Sprague-Dawley rats and determined that an approximate dose
of 1.3 gAg body weight was the lowest dose to induce the first
observable signs of toxicity (dyspnea, ataxia, cyanosis and/or coma)
Long-term Exposure
Bornmann and Loeser (1967) administered DCM in drinking water at
2.25 g/18L (or 125 mg/L) to 30 male and 30 female Wistar rats for 13
weeks. This is equivalent to a dose of about 15 mgAg/day assuming
that 10 mL of water is consumed daily. The animals were examined
for changes in behavior, body weight, blood and urine chemistries,
reproductive function, organ to body weight ratios and histology.
No treatment-related effects were observed, even though some rats
may have consumed as much as 250 mg DCM (36.6 mg/kg/day) during this
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Dichloromethane March 31, 1987
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experiment. The urine albumin test was frequently positive; however,
the authors did not attach any biological significance to this obser-
vation. Prom this study, a NOAEL of 125 mgAg/day was identified.
0 Hazelton Labs (1982) reported on the toxicity and carcinogenicity of
DCM in a chronic two-year drinking water study in Fischer 344 rats.
Two control groups (85 and 50 rats/sex/group) received deionized
drinking water. Four groups of animals (85 rats/sex/group) were
given DCM in drinking water at target doses of 5, 50, 125 and 250
mgAg/day. A high-dose recovery group (25 rats/sex) was given DCM
in drinking water at a target dose of 250 mgAg/day for the initial
78 weeks and deionized drinking water subsequently for the remainder
of the study. At 26, 52 and 78 weeks of treatment, there were incre-
mental sacrifices of 5, 10 or 20 rats/sex/group, respectively. At
104 weeks of exposure, all survivors were sacrificed. Survival,
body weight gains, total food consumption, water consumption, clinical
observations; ophthalmoscopie findings, clinical pathology, absolute
and relative organ weights and gross and microscopic pathology were
examined to evaluate any compound-related effects. The dose of
5 mgAg was identified as the no-effect level based on the absence of
effects on body weight, hematological parameters and histopathological
changes in the liver (incidence of foci/areas of cellular alteration
and/or fatty changes).
Developmental Effects
0 No positive conclusion can be drawn regarding the potential for
developmental effects of DCM.
0 Maternal exposure of rats and mice to DCM (4337 mg/m3) on days 6
through 15 of gestation was associated with soft tissue abnormalities
in the offspring of rats and skeletal changes in the offspring of
both rats and mice (Schwetz et al., 1975).
0 Other workers have found no increased incidence of gross external,
skeletal or soft tissue anomalies in offspring after maternal exposure
of rats to DCM at 15,615 mg/m3 (6 hours/day, 7 days/wk) before and
during gestation. (Hardin and Manson, 1980).
Mutagenicity
0 DCM has been reported to be mutagenic in several bacterial and yeast
test systems, as well as in mammalian test systems. DCM was also
reported to be positive in a mammalian transformation test (U.S. EPA,
1985a).
garcinogenicity
0 In a pulmonary tumor response assay, DCM administered intraperitoneally
did not produce an increased incidence of lung tumors in mice (Theiss
et al. 1977).
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uicnj.orometnane March 31, 1987
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An inhalation bioassay conducted in male and female F344/N rats and
B6C3Fi mice indicated clear evidence of carcinogenicity in male and
female mice as shown by increased incidences of lung (alveolar/
bronchiolar adenoma and/or carcinoma) and liver (hepatocellular
adenoma and carcinoma combined) tumors (NTP, 1985, as cited in U.S.
EPA, 1985c). Some evidence of carcinogenicity in male rats and
sufficient or clear evidence of carcinogenicity in female rats was
indicated by an increased incidence of benign neoplasms of the mammary
gland. These animals were exposed at concentrations of 0, 1,000,
2,000 and 4,000 ppm for rats and 0, 2,000 and 4,000 ppm for mice,
6 hours/day, 5 days/week for 102 weeks.
Hazelton Laboratories (1982) studied the carcinogenicity of DCM in a
chronic two-year drinking water study in Fischer 344 rats, using the
protocol as described under longer-term exposure. Hepatic histological
alteration detected in the 50 to 250 mgAg/day dose groups (both
sexes) included an increased incidence of foci/areas of cellular
alteration. Fatty liver changes were detected in the 125 and 250
mgAg/day groups after 78 and 104 weeks of treatment. The authors
stated that DCM did not induce carcinogenicity under the conditions
of the study.
The U.S. EPA (1985b) performed an independent assessment of the data
from the Hazelton Laboratories (1982) study and determined that
incidences of hepatic neoplastic nodules and carcinomas (combined
in females exposed to 50 mgAg/day (4.8%), 250 mgAg/day (7.1%) and
250 mgAg/day, recovery group (8.0%) were significantly (P<0.05)
higher than that in matched controls (0%). No significant increase
in liver tumors was evident in any of the male dose groups. The U.S.
EPA (1985b) considered data on historical control values and concluded
that the 250 mgAg/day dose was borderline for carcinogenicity in
Fischer 344 rats.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) s /L ( „)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mgAg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
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Dichloromethane March 31, 1987
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UF * uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
__ L/day * assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
The study by Kiraura et al. (1971) has been selected to serve as the
basis for the One-day HA for the 10 kg child because no other acute oral
studies of appropriate duration or design were located in the literature.
This study identified a LOAEL in young adult Sprague-Dawley rats on the basis
of the first observable gross signs of toxicity (i.e., dyspnea, ataxia,
cyanosis and/or coma) following administration of a single oral dose of DCM
by gavage. The authors implied that multiple dose levels were administered
to define dose-response, although details were not reported. The calculations
for a One-day HA for a 10-kg child are given below:
One-day HA = 1'326 mg/kg/day) (10 kg) = 13.3 mg/L ('13,300 ug/L)
(1,000) (1 L/day)
where:
1,326 mg/ko/day = LOAEL, based on the first observable gross signs of
toxicity in rats.
10 kg = assumed body weight of a child.
1,000 = uncertainty factor, chosen in accordance with ODW/NAS
guidelines for use with a LOAEL from an animal study.
1 L/day = Assumed daily water consumption of a child.
Ten-day Health Advisory
The study by Bornmann and Loeser (1967) in which DCM was administered
in drinking water at 125 mg/L to Wistar rats for 13 weeks, has been selected
to serve as the basis for. the Ten-day HA for the 10-kg child because it was
the most comprehensive short-term oral toxicity study located.
The Ten-day HA for a 10 kg child is calculated as follows:
Ten-day HA = (15 mg/kg/day) (10 kg) . K5 mg/L (1 500 u /L)
(100) (1 L/day) *'
where:
15 mgAg/day = KOAEL, based on absence of effects on body weight gain,
blood and urine chemistries, reproductive function,
organ/body weight ratios, or histopathological changes
in Wistar rats.
10 kg = assumed body weight of a child.
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Dichloromethane March 31, 1987
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100 = uncertainty factor, chosen in accordance with ODW/NAS
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Longer-term Exposure
There were no suitable data available from which to calculate Longer-Term
Health Advisories.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water"is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Dichloromethane may be classified in Group B2: Probable Human Carcinogen,
according to EPA's guidelines for assessment of carcinogenic risk (U.S. EPA,
1986). Because of this, caution must be exercised in making a decision on
how to deal with possible lifetime exposure to this substance. The risk
manager must balance this assessment of carcinogenic potential against the
likelihood of occurrence of health effects related to non-carcinogenic end-
points of toxicity. In order to assist the risk manager in this process,
drinking water concentrations associated with estimated excess lifetime cancer
risks over the range of one in ten thousand to one in a million for the 70-kg
adult, drinking 2 liters of water per day, are provided in the following
section. In addition, in this section, a Drinking Water Equivalent Level
(DWEL) is derived. A DWEL is defined as the medium-specific (in this case,
drinking water) exposure which is interpreted to be protective for non-.
carcinogenic end-points of toxicity over a lifetime of exposure. The DWEL
is determined for the 70-kg adult, ingesting 2 liters of water per day. Also
provided is an estimate of the excess cancer risk that would result if exposure
were to occur at the DWEL over a lifetime.
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Dichloromethane March 31, 1987
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Neither the risk estimates nor the DWEL take relative source contribution
into account. The risk manager should do this on a case-by-case basis,
considering the circumstances of the specific contamination incident that has
occurred.
The study by Hazelton Laboratories (1982) is most appropriate from which
to derive the DWEL because it is an oral chronic (two year) study that admini-
stered DCM in drinking water in multiple dose levels to rats. This is the
most comprehensive chronic oral study available. There were sufficient
numbers of animals in the dose groups and a dose-response was demonstrated.
A NOAEL of 5 mgAg/day was identified in this study.
The DWEL for a 70-kg adult is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (5 mg/kg/day) a 0.05 mgAg/day
where:
5 mg/kg/day = NOAEL based on the absence of liver and blood effects
in rats.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.05 mg/kg/day) (70 kg) = U75 mg/L (1,750 ug/L) "
(2 L/day)
where:
0.05 mgAg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption by an adult.
Step 3: Determination of the Lifetime Health Advisory
Dichloromethane is classified in Group B2: Probable Human Carcinogen.
A Lifetime HA has not been calculated for DCM.
The estimated excess cancer risk associated with lifetime exposure to
drinking water containing DCM at 1,750 ug/L is approximately 3.7 x 10~4.
This estimate represents the upper 95% confidence limit from extrapolations
prepared by EPA's Carcinogen Assessment Group using the linearized, multistage
model. The actual risk is unlikely to exceed this value, but there is consid-
erable uncertainty as tc the accuracy of risks calculated by this methodology.
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Dichlororaethane March 31, 1987
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Evaluation of Carcinogenic Potential
0 IARC (1982) has classified DCM in group 3: Limited evidence of
carcinogenicity in animals.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), DCM may be classified in Group B2:
Probable human carcinogen. This category is for agents for which
there is inadequate evidence from human studies and sufficient evidence
from animal studies.
0 More recently, EPA's CAG (U.S. EPA, 1985c) estimated that the upper-
bound incremental unit carcinogenic risk for drinking water containing
1 ug/L DCM for a lifetime was 2.1 x 10-7 (ug/L)-1,. This risk estimate
was the mean of the derived carcinogenic risk estimates based on the
finding of liver tumors (not based on lung tumors) in the NTP (1985)
draft inhalation study in female mice and the suggestively positive
finding of liver tumors in the Hazelton (1982) unpublished ingestion
study in male mice. Since the extrapolation model is linear at low
doses, additional lifetime cancer risk is directly proportional to
the water concentration of DCM. Thus, levels of 10"4, 10"5 and 10-6
are 0.48, 0.048 and 0.005 mg/L, respectively.
0 The linear multistage model is only one method of estimating carcino-
genic risk. Using the 1O"6 risk level, the following comparisons in
micrograms/L may be made: Multistage, 4.8; Probit, 74,000; Logit,
4,000; Weibull, 10. Each model is based on differing assumptions. ,
No current understanding of the biological mechanism of carcinogenesis
is able to predict which of these models is more, accurate than another.
While recognized as statistically alternative approaches, the range of
risks described by using any of these modeling approaches has little
biological significance unless data can be used to support the
selection of one model over another. In the interest of consistency
of approach and in providing an upper bound on the potential cancer
risk, the Agency has recommended use of the linearized multistage
approach.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 ACGIH (1984) has recommended a time-weighted average threshold limit
value (TWA-TLV) of 100 ppm ( 360 mg/m3) in the absence of occupa-
tional exposure to carbon monoxide and is based upon experimental
data obtained from nonsmoking males at rest. A short-term exposure
level (STEL) of 500 ppm is also recommended.
0 The Occupational Health and Safety Administration (OSHA, 1979) has
established occupational exposure standards as follows: an eight-hour
time-weighted-average (TWA) of 1,737 mg/m3; an acceptable ceiling
concentration of 3,474 mg/m3; and an acceptable maximum peak above
the ceiling of 6,948 mg/m3 (five minutes in any two hours).
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Dichloromethane March 31, 1987
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0 Due to the metabolic formation of carboxyhemoglobin and the additive
toxicity with carbon monoxide, the National Institute of Occupational
Safety and Health (NIOSH, 1976) has recommended a ten-hour TWA exposure
limit of 261 mg/m3 and a 1737 mg/m3 peak (15 minute sampling), in the
presence of carbon monoxide concentrations less than or equal to 9.9
ng/m3 (TWA). Proportionately lower levels of DCM are required in the
workplace when carbon monoxide concentrations greater than 9.9 mg/m3
are present.
0 Based on noncarcinogenic risks, a water quality criterion of 12.4 mg/L
is the acceptable concentration of DCM in drinking water (U.S. EPA,
1980a). This calculation was performed by the U.S. EPA as part of the
overall process for developing a U.S. EPA Water Quality Criteria for
halomethanes as a group and uses a limit of 200 ppm (694 mg/m3) for
protection against excessive carboxy-hemaglobin formation. In that
calculation, the EPA assumed that the average person consumes approxi-
mately two liters of water and eats 6.5 g of contaminants in fish and
seafood per day, and that the estimated coefficient of absorption via
inhalation versus ingestion is 0.5.
0 The original U.S. EPA Suggested-No-Adverse-Response-Levels (SNARLs,
now referred to as Health Advisories) for DCM were set at 13, 1.5
. and 0.150 mg/L in drinking water for One-day, Ten-day and Longer-term
exposures, respectively (U.S. EPA, 1980b). The U.S. EPA-SNARLs were
established for a 10 kg body weight child and did not consider the
possible carcinogenic risk that may result from exposure to a chemical.
0 The NAS (1980) calculated one-day and seven-day NAS-SNARLs for DCM
in drinking water based on the minimal-effect acute oral dose in rats
reported by Kimura et al. (1971). The NAS concluded that data on the
no-effect dose do not exist. Using the 1 ml/kg (1.3'g/kg) minimal-
effect acute oral dose in the rat, assuming two liters/day of drinking
water as the only source (consumed by a 70 kg adult) and*employing a
safety factor of 1,000, the NAS (1980) calculated the one-day SNARL.
Since no appropriate data were available for the seven-day SNARL, the
one-day SNARL was divided by a factor of seven (days). However, the
NAS (1980) erroneously reported a value of 35 mg/L for the one-day
and 5 mg/L for the seven-day calculation. Re-examination of calcula-
tions indicated that the one-day and seven-day adult NAS-SNARLs
should be 45.5 mg/L and 6.5 mg/L, respectively.
VII. ANALYTICAL METHODS
0 Analysis of DCM.is by a purge-and-trap gas chromatographic procedure
used for the determination of volatile organohalides in drinking water
(U.S. EPA, 1985d). This method calls for the bubbling of an inert
gas through the sample and trapping DCM on an adsorbant material.
The adsorbant material is heated to drive off the DCM onto a gas
chromatographic column. This method is applicable to the measurement
of DCM over a concentration range of less than 1 to 1500 ug/L; however,
measurement of DCM at low concentrations is difficult due to problems
with contamination. Dichloromethane vapors readily penetrate tubing
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Dichloromethane March 31, 1987
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during the purge/trap procedure. Confirmatory analysis for DCM is
by mass spectrometry. (U.S. EPA 1985e). The detection limit for
confirmation by mass spectrometry is 0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Limited information is available concerning the removal of dichloro-
methane from drinking water. However/ evaluation of physical and
chemical properties and some experimental data suggest that adsorp-
tion by granular activated carbon (GAC) and aeration are feasible
technologies to remove this contaminant in drinking water supplies.
0 Dobbs and Cohen (1980) developed adsorption isotherms for several
organic chemicals, including DCM. This study reported that Filtrasorb*
300 exhibited adsorptive capacities of 1.3 mg and 0.09 mg DCM per gm
carbon at equilibrium concentrations of 1,000 mg/L and 100 mg/L,
respectively.
0 Another study reported activated carbon usage of 3.9 lb/1,000 gal of
treated water to maintain an effluent DCM concentration below 1 ug/L
from a raw water influent concentration above 20 mg/L (ESE, 1982).
This particular treatment scheme employed two activated carbon columns
operating in series with extremely long empty bed contact time (262
minutes).
0 The calculated Henry's Law constant for DCM is 2.5 x 10-3 atm-m3/mole
(ESE, 1982). In a bench-scale study, distilled water which was
spiked with 225 ug/L of DCM was passed through a diffused air aerator.
The results showed 82 percent reduction in DCM at an air-to-water
ratio of 15:1 (Love, 1983). Dichloronethane will, therefore, be
amenable to air stripping treatment. Actual field performance data,
however, have not been reported for this compound.
0 Air stripping is ah effective, simple and relatively inexpensive
process for removing DCM and other volatile organics from water.
However, use of this process then transfers the contaminant directly
to the air stream. When considering use of air stripping as a treatment
process, it is suggested that careful consideration be given to the
overall environmental occurrence, fate, route of exposure and various
hazards associated with the chemical.
0 Treatment technologies for the removal of DCM from water have not
been extensively evaluated except on an experimental level. Selection
of individual or combinations of technologies to attempt DCM reduction
must be based on a case-by-case technical evaluation, and an assessment
of the economics involved.
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Dichloromethane March 31, 1987
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IX. REFERENCES
ACGIH. 1984. American Conference of Governmental Industrial Mygienists.
Documentation of the threshold limit values. 4th ed. 1980-1984 supplement.
pp. 275-276.
Aviado, D.M., S. Zakhari and T. Hatanabe. 1977. Methylene chloride. In;
Non-fluorinated propellants and solvents for aerosols, L. Goldberg, ed.,
CRC Press, Inc., Cleveland, Ohio, pp. 19-45.
Bonventre, J., 0. Brennan, D. Jason, A. Henderson and M.L. Bastos. 1977.
Two deaths following accidental inhalation of dichloromethane and 1,1,1-
trichloroethane. J. Anal. Toxicol. 1:158-160.
Bornmann, G., and A. Loeser. 1967. Zur Frage einer chronisch-toxischen
Wirkung von Dichloromethan. Z. Lebensm.-Unters. Forsch. 136:14-18.
DiVincenzo, G.D., and M.L. Hamilton. 1975. Fate and disposition of carbon-14
labelled methylene chloride in the rat. Toxicol. Appl. Pharmacol. .
32:385-393.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600-8-80-023. Office of Research and Development/ MERL,
Wastewater Treatment Division, Cincinnati, Ohio.
ESE. 1982. Environmental Science and Engineering. Review of organic con-
taminants in ODW data base for summary of all available treatment tech-
niques, compound dichloromethane. Prepared for U.S. EPA, Office of
Drinking Water, EPA-68-01-6494.
Hardin, B.D., and J.M. Manson. 1980. Absence of dichloromethane teratogenicity
. with inhalation exposure in rats. Toxicol. Appl. Pharmacol. 52:22-28.
Hazelton Laboratories America, Inc. 1982. National Coffee Association
(prepared for the twenty-four month chronic toxicity and oncogenicity study
of methylene chloride in rats). Final Report, Vols. I-IV. Vienna, Va.:
2112-101.. August 11, 1982.
lARCi 1982. IARC monographs on the evaluation of the carcinogenic risk of
chemicals to humans. Supplement 4, Lyon, France.
Kimura, E.T., D.M. Ebert and P.W. Dodge. 1971. Acute toxicity and limits of
solvent residue for sixteen organic solvents. Toxicol. Appl. Pharmacol.
19:699-704.
Love, O.T., Jr. 1983. Treatment of volatile organic compounds in drinking
water. NTIS, U.S. Department of Commerce.
McKenna, M.J., and J.A. Zempel. 1981. The dose-dependent metabolism of
[14C]methylene chloride following oral administration to rats. Fd.
Ccsmet. Toxicol. 19:73-78.
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Dichloromethane March 31, 1987
-14-
NAS. 1980. National Academy of Sciences. Drinking Water and Health.
Vol. 3. National Academy Press, Washington, D.C.
NTP. 1985. National Toxicology Program. NTP technical report on the toxicology
and carcinogenesis studies of dichloromethane (methylene chloride)
in F344/N rats and B6C3F1 mice (inhalation studies) NTP TR 306. Draft.
Research Triangle Park, N.C. 94 pp. As cited in U.S. EPA, 1985c.
NIOSH. 1976. National Institute for Occupational Safety and Health. Criteria
for a recommended standard.. .occupational exposure to methylene chloride.
U.S. Department of Health, Education and Welfare (NIOSH). Washington,
D.C., pp. 1-3, 76-138, 142.
OSHA. 1979. Occupational Safety and Health Administration. General industry
standards. (OSHA) 2206, Revised January, 1978. U.S. Dept. of Labor,
Washington, D.C.
Schwetz, B.A., B.J. Leong and P.J. Gehring. 1975. The effect of maternally
inhaled trichloroethylene, perchloroethylene, methyl chloroform, and
methylene chloride on embryonal and fetal development in mice and rats.
Toxicol. Appl. Pharmacol. 32:84-96.
Theiss, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisberger. 1977. Test for
carcinogenicity of organic contaminants of United States drinking waters
by pulmonary tumor response in Strain A mice. Cancer Res. 37:2717-2720.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Water Related Environ-
mental Fate of 129 Priority Pollutants. Office of Water Planning and
Standards. EPA-440/4-79-029.
U.S. EPA. 1980a. U.S. Environmental Protection Agency. Ambient water
quality criteria for halomethanes. Office of Water Regulations and
Standards. Criteria and Standards Division. Washington, IX. C.
EPA 440/5-80-051.
U.S. EPA. 1980b. U.S. Environmental Protection Agency. Advisory opinion
for dichloromethane (methylene chloride) (Draft). Office of Drinking
Water. Washington, D.C.
U.S. EPA. 1980c. U.S. Environmental Protection Agency. Dichloromethane
occurrence in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Health assessment
document for dichloromethane (methylene chloride). Office of Health and
Environmental Assessment. EPA-600/8-82/004F.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Health assessment
document for dichloromethane (methylene chloride) (Final report). Office
of Health and Environmental Assessment. Washington, D.C.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Addendum to health
assessment document for dichloromethane (methylene chloride.) (Final
report). Office of Health and Environmental Assessment. Washington, D.C.
EPA 600/8-82-004FA.
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Dichloromethane March 31, 1987
-15-
U.S. EPA. 1985d. U.S. Environmental Protection Agency. Method 502.1.
Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas
Chromatography. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268.
U.S. EPA. 1985e. U.S. Environmental Protection Agency. Method 524.1.
Volatile Organic Compounds in Water by Purge and Trap Gas Chromatography/
Mass Spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Federal Register. 51(185):33992-34003.
September 24.
U.S. ITC. 1984. United States International Trade Commission. Synthetic
Organic Chemicals United States Production. USITC Publication 1422,
Washington, D.C. 20436.
Verschueren, K. 1977. Handbook.of Environmental Data on Organic Chemicals.
2nd ed. Van Nostrand Reinhold Company, NY. pp. 451-452.
Windholz, M. 1983. The Merck Index. 10th Edition. Merck and Co., Inc.,
Rahway, NJ. p. 869.
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EPA 0596 *«* 31' 1987
PX000027824
1,2-DICHLOROPROPANE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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1,2-Dichlorpropane . March 31, 1987
-2-
This Health Advisory is based on Information presented in the Office
of DriSJ^^Wa^ter's Health Effects Criteria Document (CD) for 1,2-Dichloro-
propane 4p#S. (kPA, 1985a). The HA and CD formats are similar for easy
referenceTff Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD.
The CD is available for review at each EPA Regional Office of Drinking Water
counterpart (e.g., Water Supply Branch or Drinking Water Branch)/ or for a
fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB #86-117850/AS.
The toll-free number is (800) 336-4700; in the Washington, D.C. area: (703)
487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 78-87-5
Structural Formula
H Cl Cl
Ml
HC—C--C-H
I I I
H H H
Synonyms
0 Propylene dichloride, 1,2-DCP
Uses
0 1,2-Dichloropropane has been used as a solvent for oils and fats,
dry cleaning and degreasing operations, and as a component of soil
fumigants.
Properties (U.S. EPA, 1985a)
Chemical Formula C3H6Cl2
Molecular Weight 112.99
Physical State (room temp) colorless liquid
Boiling Point 96.8° C
Vapor Pressure 50 (mm Hg at 20° C)
Specific Gravity 1.15
Water Solubility 2,700 mg/L
Log Octanol/Water Partition 2.28
Coefficient
Odor Threshold (air) 420 mg/m3
Occurrence
0 1,2-Dichloropropane (1,2-DCP) is a volatile synthetic compound with
no natural sources. The majcr release of 1,2-DCP to the environment
will be from its use as a soil fumigant (U.S. EPA, 1983).
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1,2-Dichlorpropane March 31, 1987
-3-
0 1,2-DCP is expected to be a persistent and mobile compound in soil.
The major route of removal of 1,2-DCP from soil and surface waters is
by volatilization (U.S. EPA, 1979). 1,2-DCP has been shown to be
stable in some soil for years (Roberts, 1976). 1,2-DCP has been shown
to migrate in soil and has been reported as a contaminant in ground
water (Cohen, 1983). 1,2-DCP is expected to be removed from surface
water by volatilization. 1,2-DCP also has been shown to biodegrade
in water over a number of weeks. There is no available information on
1,2-DCP's potential for bioaccumulation.
0 1,2-DCP has been identified as a contaminant of both ground and surface
water. 1,2-DCP has been surveyed for in the Ground Water Supply Survey
and has been found in approximately 1-2% of rural wells at levels
around 1 ug/L. Local monitoring has found levels as high as 1,200
ug/L in shallow wells njsar sites where 1,2-DCP has been used as a soil
fumigant (Cohen, 1983).' 1,2-DCP also has been reported in the Delaware
river at levels of 20-30 ug/L (U.S. EPA, 1983). 1,2-DCP has been
identified as a contaminant in fish. 1,2-DCP also has been reported
in urban air at low levels, approximately 100 ppt. The available
data are insufficient to show whether drinking water is the major
route of exposure for 1,2-DCP.
III. PHARMACOKINETICS
Absorption
0 The results of various studies suggest that the absorption of 1,2-DCP
is approximately 90 percent of the orally administered dose (Hutson
et al., 1971).
Distribution
0 Although no specific data were located which quantified the distribu-
tion of 1,2-DCP in animals, approximately 0.5% of a radioactive dose
was recovered from the gut of animals within 96 hours, 1 .6% was
recovered from skin and 3.6% was detected in the carcass (Hutson
et al., 1971).
Metabolism
0 The metabolic end products of 1,2-DCP are predominantly N-acetyl-S-
(2-hydroxypropyl) cysteine and B-chloroacetate (Jones and Gibson,
1980).
Excretion
1,2-DCP was eliminated rapidly by rats dosed orally with 4 mgAg (Hutson
et al., 1971). Approximately 80% to 90% of the radioactivity was
excreted in thi. urine, feces and expired air of rats following dosing.
Urinary and fecal excretion accounted for 53% and 6%, respectively,
of the radioactivity recovered in the expired air of rats as carbon
dioxide; 23% was recovered as other volatile radioactivity.
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-4-
IV. HEALTH EFFECTS
Humans
Data on the toxicity of this compound to humans are limited to a
single case of acute poisoning, reported only as an abstract (Larcan
et al., 1977). Centro- and mediolobular hepatic necrosis were observed
in a man who died 36 hours after ingesting approximately 50 ml of
a cleansing substance. The toxic material was found to contain 1,2-DCP,
but it is unclear whether it contained other compounds as well.
Animals
Short-term Exposure
\
. The acute LD5o values for 1,2-dichloropropane are given .below:
Route Species LDe;n Value Reference
Inhalation Rat 9224 mg/m3 Smyth et al. (1969)
Oral Rat 2200 mgAg Smyth et al. (1969)
Rat 2200 mgAg Ekshtat et al. (1975)
Dermal Rabbit 10,200 mgAg Smyth et al. (1969)
The acute toxicity of 1,2-DCP was determined following single oral
administration to fasted dogs of unspecified age and sex (Wright and
Schaffer, 1932). Doses of approximately 250 to 350 mgAg in the dogs
produced gastrointestinal irritation without any histologic changes
in the kidney. A dose of 580 mgAg produced swelling of the epithelial
cells of the kidney tubules and fatty infiltration in the convoluted
tubules. At an approximate dose of 5800 mgAg* there was a lack
of coordination and partial narcosis followed by death in one dog.
Necropsy revealed congestion in the lungs, kidney, and bladder,
hemorrhage in the stomach and respiratory tract, and fatty degeneration
of the liver and kidneys.
Heppel et al. (1946) reported no apparent signs of toxicity following
single 7-hour inhalation exposures to 6900 mg/m^ in rats, rabbits and
guinea pigs.
Inhalation exposure for 1 hour at 10,400 mg/m3 showed evidence of
slight visceral congestion, fatty liver and kidneys, liver glycogen
storage and marked necrosis of the adrenals (Heppel et al., 1946).
Drew et al. (1978) measured SCOT, SGPT, glucose-6-phosphatase and
ornithine carbamyl transferase enzymes in the serum of male rats
following a single 4-hour inhalation exposure to 1,2-DCP at a concen-
tration of 4620 mg/m3. A significant increase in enzyme activities
was observed for SCOT, SGPT and ornithine carbamyl transferase at
24 and 48 hours.
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1 , 2-Dicloropropane March' 31, 1967
-5-
Longer-term Exposure
8 Heppel et al., (1948) reported the results of multiple inhalation
exposures to 1,2-DCP by rats, mice, guinea pigs and rabbits to daily
7-hour exposure periods in the concentration range of 4400 mg/m3 to
10,400 mg/m3. The concentration of 10,400 mg/m3 produced lethality in
over 50 percent of the animals. Gross and histopathological findings
included liver abnormalities such as visceral congestion, fatty
degeneration, extensive coagulation and necrosis in multilobular
areas. Renal tubular necrosis and fibrosis, splenic hemosiderosis,
pulmonary congestion, bronchitis, pneumonia and fatty degeneration of
the heart were observed among animals exposed to all concentrations.
0 The effects, of 1 , 2-DCP on the functional state of the liver in rats
has been studied by Kurysheva and Ekshtat (1975). The groups of
animals were given daily oral doses of 1,2-DCP at 14.5 mgAg or
360 mgAg for 30 days. t Levels of serum cholesterol, betalipoprotein
and gamma globulin increased after the 10th day following the daily
administration of both doses. By the 20th day of dosing, serum
cholinesterase activity was inhibited, whereas the fructose-1 -mono-
phosphate aldolase, SGPT and SCOT activities were increased; after
30 days of dosing, only SGPT activity was inhibited.
0 Ekshtat et al., (1975) orally administered 1,2-DCP to rats at daily
doses of 8.8, 44 or 220 mgAg for 20 days. The animals were reported
to have had disturbances in protein formation and hepatic enzyme and
lipid metabolism.
0 NTP (1983) dosed groups of female F344 rats and B6C3F1 male and
female mice with 1,2-DCP (0, 125 or 250 mg/kg/day) in corn oil by
gavage (5 days/week) for about 2 years (103 -weeks). Groups of male
Fischer 344 rats were administered 1,2-DCP at 0, 62 or 125 mg/kg/day
in the same manner. Observations included survival, body weight,
overt signs of toxicity and gross and histological appearance of a
wide range of organs and tissues. In rats, survival was decreased
only among the females of the 250 mgAg group. An increased incidence
of liver lesions (focal and centrilobular necrosis ) and decreased
mean body weight also were observed in this group. At the 125 mgAg
dose level, survival among rats was unaffected, but males had decreased
mean body weights and females had increased incidences of mammary
gland hyperplasia. No effects were observed in male rats given
62
In mice (NTP, 1983), there was a decrease in survival rates among
females receiving both 125 and 250 mgAg 1,2-DCP. This was attributed,
in part, to an increased incidence of severe infections of the
respiratory tract for both low- and high -dose groups. The only other
non-neoplastic effects in mice were increased incidences of liver
lesions (hepatomegaly and focal and centrilobular necrosis) in males
receiving 125 or 250 mgAg«
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iviarcn
-6-
Mutaqenicity
0 A positive dose-related mutagenic response at concentrations of 10,
20 or 50 mg/plate 1,2-DCP was observed in Salmonella typhimurium
strains TA 1535 and TA 100 (DeLorenzo et al., 1977). No increase
in mutagenicity was seen following the addition of the S-9 liver
microsomal fraction.
Carcinogenicity
0 The NTP (1983) chronic gavage study (discussed under longer-term
exposure) is the only adequately designed carcinogenicity study
available. The results show that 1,2-DCP may be carcinogenic for
mice as indicated by dose-related increased incidences of hepato-
cellular adenomas in male and female mice. The incidences of
• hepatocellular carcinomas were increased (not significantly) in males
and in females. Evidence of carcinogenicity in rats was equivocal.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) = _ « ( _ /L)
(OF) x ( _ L/day) *' y
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF as uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
There are insufficient toxicological data available in the published
scientific literature to derive a One-day HA.
Ten-day Health Advisory
Three studies in animals have been considered for use in the calculation
of a Ten-day HA; these are Kurysheva and Ikshtat (1975); Ekshtat et al. (1975);
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1,2-Dichloropropane March_31, 1987
-7-
and NTP (1983). However, these studies lack some relevant toxicological data
necessary for use in this calculation. Kurysheva and Ekshtat (1975) reported
the effect of 1,2-DCP on the functional state of the liver of rats. The
groups of animals were given daily doses of 1,2-DCP at 14.5 mg or 360 mgAg
orally for 30 days. Increases in the serum levels of cholesterol, lipoprotein,
and gamma-globulin were noted after the tenth day following the daily dosing.
By day 20 of dosing, serum cholinesterase was inhibited, whereas fructose-1-
monophosphate aldolase, SGPT and SCOT enzyme activities were increased; after
30 days of dosing, only SGPT was inhibited. Other information such as strain,
number of animals, weight and age, as well as which doses caused what effects
were not reported.
The study by Ekshtat et al. (1975) is selected as the basis for the
Ten-day HA. TJie authors reported the results of orally administered 1,2-DCP
at dose levels'of 8.8, 44 or 220 mgAg for 20 days. The investigators observed
disturbances in the animals' protein formation, hepatic enzyme levels and
lipid metabolism. The NAS (1979) in a request from the Office of Drinking
Water provided a 7-day Suggested-No-Adverse-Response-Level (SNARL) for 1,2-DCP
based on the Ekshtat et al. (1975) study in rats. The following formula was
used to derive a 7-day level for a 70 kg adult consuming 2 liters water/day.
The NAS SNARL can be used as an interim Ten-day HA as well. The HA is derived
as follows:
For a 10 kg child, the level of 1,2-DCP would be:
Ten-day HA = (8.8 mg/kg/day) (10 kg) = 0.088 mg/L = 0.090 mg/L
(1,000) (1 L/day)
or 90 ug/L
where:
8.8 mg/kg/day = minimal effect level from the subacute ingestion
studies in rats.
10 kg = assumed weight of a child.
1,000 = uncertainty factor,chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
1 L/day = assumed water consumption by a child.
Longer-term Health Advisory
There are no satisfactory toxicological data available from which to
calculate a Longer-term Health Advisory.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's cotal exposure
that is attributed to drinking water and is considered protective of
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-8-
noncarcinogenic adverse health effects over a lifetime exposure. The Life-
time HA is derived in a three step process. Step 1 determines the Reference
Dose {RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an
estimate of a daily exposure to the human population that is likely to be
without appreciable risk of deleterious effects over a lifetime, and is
derived from the NOAEL (or LOAEL), identified from a chronic (or subchronic)
study, divided by an uncertainty factor(s). From the RfD, a Drinking Water
Equivalent Level (DWEL) can be determined (Step 2). A DWEL is a medium-specific
(i.e., drinking water) lifetime exposure level, assuming 100% exposure from
that medium, at which adverse, noncarcinogenic health effects would not be
expected to occur. The DWEL is derived from the multiplication of the RfD by
the assumed body weight of an adult and divided by the assumed daily water
consumption of an adult. The Lifetime HA is determined in Step 3 by factoring
in other sources of exposure, the relative source contribution (RSC). The
RSC from drinking water is based on actual exposure data or, if data are not
available, a value of 20% is assumed for synthetic organic chemicals and a
value of 10% is assumed for inorganic chemicals. If the contaminant is
classified as a Group A or B carcinogen, according to the Agency's classifica-
tion scheme of carcinogenic potential (U.S. EPA, 1986), then caution should
be exercised in assessing the risks associated with lifetime exposure to this
chemical.
Only one chronic ingestion study (NTP, 1983) has been carried out for
1,2-DCP. This study was designed primarily to. investigate carcinogenic
effects. This study may provide some data on non-carcinogenic effects which
may be considered for a Lifetime HA in absence of other chronic animal studies.
However, it should be noted that the NTP (1983) study is recently audited and
there are some changes as a result of this audit. These changes are being
evaluated before its consideration for a Lifetime HA for 1,2-DCP.
Evaluation of Carcinogenic Potential
0 The dose-response data for hepatocellular adenoma and carcinoma in
B6C2F1 mice (NTP, 1983) are used for a quantitative assessment of
cancer risk from exposeure to 1,2-DCP. Based on these data and using
a linearized multistage model, a carcinogenic potency factor (q-|*) for
humans of 6.33 x 10~2 (mg/kg/day)"1 was calculated from the data for
male mice and a q.j* of 2.25 x 10~2 (mg/kg/day)~1 was calculated from
the data for female mice. The higher of the two values is the appropriate
basis for the estimation of cancer risk levels. The doses corresponding
to increased lifetime excess cancer risks for a 70 kg human of 10~4,
10-5 and 10-6 are 1.11 x 10-1, 1.11 x 10-2 and 1.11 x 10-3 mg/day,
respectively. Assuming a water consumption level of 2 liters per day,
the corresponding concentrations of 1,2-DCP in drinking water at 5.6 x
10-2, 5.6 x 10"3 and 5.6 x 10"4 mg/L,' respectively. However, it should
be noted that these risk assessments for 1,2-DCP are based on the
results of a carcinogenicity bioassay in animals reported in the NTP
(1983) draft report. An audit has been completed and minor changes
noted in the audit will be incorporated in the near future.
0 Cancer risk estimates (95% upper limit) with other models are presented
for comparison with that derived with the multistage. For example,
one excess cancer per 1,000,000 (10-6) is associated with exposure to
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1,2-DIchloropropane March 31, 1987
-9-
. 1,2-DCP in drinking water at levels of 0.5 mg/L (Probit), 0.002 mg/L
(Logit), and 0.0002 mg/L (Weibull).
0 IARC has not assessed 1,2-DCP for its carcinogenic potential.
° Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), 1,2-DCP is classified in Group C:
Possible human carcinogen. This category is for agents with limited
evidence of carcinogenicity in animals in the absence of human data.
(However, the Carcinogen Assessment Group upgraded the classification
of 1,2-DCP (to Group B2) on February 26, 1987. The final decision
be incorporated in the near future.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The ACGIH (1983) has adopted a TLV of 75 ppm ( 350 mg/m^) and STEL of
110 ppm { 500 mg/m3) for 1,2-DCP in workroom air. The TLV
represents A TWA concentration for an 8-hour day or 40-hour workweek.
The TLV and STEL are based primarily on the data of Heppel et al.
(1946, 1948).
0 The U.S. EPA (1980) concluded that data regarding the toxicity of
1,2-DCP were insufficient for the derivation of an ambient water
quality criterion for the protection of human health.
VII. ANALYTICAL METHODS
0 Analysis of 1,2-DCP is by a purge-and-trap gas chromatographic procedure
used' for the determination of volatile organohalides in drinking water
(U.S. EPA, 1985b). This method calls for the bubbling of an inert
gas through the sample and trapping 1,2-DCP on an adsorbant material.
The adsorbant ./material is heated to drive off the 1,2-DCP onto a gas
chromatographic column. The applicable concentration range for this
method has not been determined. Confirmatory analysis for 1,2-DCP
is by mass spectrometry (U.S. EPA, 1985). The detection limit for
confirmation by mass spectrometry is 0.2 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Treatment technologies which have been shown to be effective in
removing 1,2-DCP from drinking water are adsorption on granular
activated carbon (GAG) and ion exchange. Other methods which are
expected to be effective for removal of 1,2-DCP from water are air
stripping and boiling.
0 Granular activated carbon (GAC) and powdered activated carbon (PAC)
have been tested for their effectiveness in removing 1,2-dichloropro-
pane. Dobbs and Cohen (1980) developed adsorption isotherms for DCP.
They reported that Filtrasorb® 300 carbon exhibited adsorption capa-
cities of 5.9 mg of DCP per gram of carbon at equilibrium concentration
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1,2-Dichloropropahe March 31, 1987
-10-
of 1.0 mg/L and 1.5 mg of DCP per gram of carbon at equilibrium
concentration of 0.1 mg/L.
Isotherm studies using Filtrasorb* 400 carbon reported carbon loadings
of 240 mg DCP/gm of carbon and 480 mg DCP/gm of carbon at equilibrium
concentrations of 100 mg/L and 1,000 mg/L, respectively. No usage or
loading rates were available (U.S. EPA, 1985d).
Removal of DCP by air stripping is expected to be effective. Several
methods of air stripping have been tested. Air stripping in a column
packed with 1/4" Ceramic Intalox Saddle, proved to be effective in
removing chloroform with a Henry's Law Constant of 3.4 x 10~3 atm-m3/
mole and 1,2-dichloroethane with a Henry's Law Constant of 1.1 x 10-3
atm-m3/mole. Although no actual performance data have been provided
for removing DCP by this treatment system, its Henry's Law Constant of
2 x 1*0~3 atm-m3/mole is an indication that this chemical is amenable to
air stripping (Love & Eilers, 1982; Singley and Bilello, 1981; McCarty
and Sutherland, 1979).
-------
1,2-Dichloropropane March-31, 1987
-11-
IX. REFERENCES
ACGIH. 1983. American Conference of Governmental Industrial Hygienists.
Threshold limit values for chemical substances and physical agents in
the work environment with intended changes for 1983-1984. Cincinnati,
OH. p. 30.
Cohen, D.B., D. Gilmore, C. Fischer and G.W. Bowes. 1983. 1,2-Dichloropropane
and 1,3-dichloropropane. Prepared for State of California, Water Resources
Control Board, Sacramento, CA.
DeLorenzo, F., S. Degl'Innocenti, A. Ruocco, L. Silengo and R. Cortese.
1977. Mutagenicity of pesticides containing 1,3-dichloropropane.
Cancer Res. 37:1915-1917.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. U.S. EPA, Contract No. EPA-600/8-80-023.
Drew, R.T., J.M. Patel and F.N. Lin. 1978. Changes in serum enzymes in rats
after inhalation of organic solvents singly and in combination. Toxicol.
Appl. Pharmacol. 45:809-819.
Ekshtat, B. Ya., N.G. Kurysheva, V.N. Fedyanina and M.N. Pavlenko. 1975.
Study of the cumulative properties of substances at different levels of
activity. Uch. Zap.-Mosk. Nauchno-Issled. Inst. Gig.. 22:46-48.
Heppel, L.A., P.A. Neal, B. Highman and V.T. Potterfield. 1946. Toxicology
of 1,2-dichloropropane. I. Studies on effects of daily inhalations.
J. Ind. Hyg. Toxicol. 28:1-8.
Heppel, L.A., B. Highman and E.Y. Peake. 1948. Toxicology of 1,2-dichloro-
propane. IV. Effects of repeated exposures to a low concentration of
the vapor. J. Ind. Hyg. Toxicol. 30:189-191.
Hutson, D.H., J.A. Moss and B.A. Pickering. 1971. Excretion and retention
of components of the soil fumigant D-D and their metabolites in the rat.
Food Cosmet. Toxicol, 9(5):677-680.
Hwang, S.T., and P. Fahrenthold. 1980. Treatability of the organic priority
pollutants by steam stripping. The American Institute of Chemical
Engineers.
Jones, A.R., and J. Gibson. 1980. 1,2-Dichloropropane: Metabolism and fate
in the rat. Xenobiotica. 10:835-846.
Kurysheva, N.G., and B.Y. Ekshtat. 1975. Effect of 1,3-dichloropropylene
and 1,2-dichloropropane on the functional state of the liver in animal
experiments. Uch. Zap.-Mosk. Nauchno-Issled. Inst. Gig. 22:89-92.
(CA 86:115725).
Larcan, A., H. Lambert, M.C. Kaprevok and B. Gustin. 1977. Acute poisoning
induced by dichloropropane. Acta. Pharmacol. Toxicol. . 41:330. (Abstr.)
-------
i,^-uichloropropane • March 31, 1987
-12-
Love, O.T., Jr., and R.G. Eilers. 1982. Treatment of drinking water containirJ
trichloroethylene and related industrial solvents. AWWA. ™
McCarty, P.L., and K.H. Sutherland. 1979. Volatile organic contaminants
removal by air stripping. Paper presented at the Seminar on Controlling
Organics in Drinking Water, American Water Works Annual Conference, San
Francisco, CA.
NAS. 1979. National Academy of Sciences. Emergency Response Report on 1,2-
Dichloropropane.
NTP. 1983. National Toxicology Program. NTP technical report on the carcino-
genicity bioassay of 1,2-dichloropropane (CAS No. 78-87-5) in F344/N
rats and B6C3Ft mice (gavage study). May. NIH Publ. No. 83-2519. Draft.
Final Technical Report in Preparation (Management Status Report, 6/10/86).
Perry, R.H., and C.H. Chilton. 1973. Chemical Engineers Handbook, 5th
edition, McGraw Hill Book Company, New York.
Roberts, T.R., and G. Stoydin. Degradation of (Z) and (E) 1,3-Dichloropropane
and 1,2-dichloropropane in soil. Pestic. Sci. 7:325-335.
Singley, J.E., and L.J. Bilello. 1981. Advances in the development of design
criteria for packed column aeration. Environmental Science and Engi-
neering, Inc.
Smyth, H.F., Jr., C.P. Carpenter, C.S. Weil, U.C. Pozzani, J.A. Striegel and
J.S. Nycum. 1969. Ranges-finding toxicity data, VII. Am. Ind. Hyg.
Assoc. J. 30(5):470-476.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Water related environ-
mental fate of 129 Office of Water Planning and Standards. EPA-440/4-79-
-029.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Ambient water quality
criteria for dichloropropanes/ propenes. Environmental Criteria and
Assessment Office, Cincinnati, OH. EPA 440/5-80-043. NTIS PB81-117541.
U.S. EPA. 1983. U.S. Environmental Protection Agency. Philadelphia Geographic
Area Multimedia Pollutant Survey, Integrated Environmental Management
Division. Washington, DC.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Draft drinking
water criteria document for 1,2-dichloropropane. Office of Drinking
Water.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Method 502.1,
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory, Cin-
cinnati, OH. 45268.
-------
1,2-Dichloropropane _March 31, 1987
-13-
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Method 524.1,
Volatile organic compounds in water by purge and trap gas chromato-
graphy/mass spectrometry. Environmental Monitoring and Support Labora-
tory, Cincinnati, OH. 45268.
U.S. EPA. 1985d. U.S. Environmental Protection Agency. Treatment techniques
available for removal of 1,2-dichloropropane. (Draft) Science and
Technology Branch, Criteria and Standards Division, Office of Drinking
Water.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Federal Register. 51(185):33992-34Q03.
September 24.
Wright, W.H., and J.M. Schaffer. 1932. Critical antihelminthic tests of
chlorinated alkyl hydrocarbons and a correlation between the antihel-
minthic chemical structure and physical properties. Am. J. Hyg.
16:325-428.
-------
September 30, 1985
EPA 0596
RX000027824
LEAD
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
The Office of Drinking Water's non-regulatory Health Advisory Program
provides information on health effects, analytical methodology and treatment
technology that would be useful in dealing with contamination of drinking
water. Health Advisories also describe concentrations of contaminants in
drinking water at which adverse effects would not be anticipated to occur.
A margin of safety is included to protect sensitive members of the population.
Health Advisories are not legally enforceable Federal standards. They
are subject to change as new and better information becomes available. The
Advisories are offered as technical guidance to assist Federal, State and >
-------
Lead September 30, 1985
-2-
e,l~;*i A ..-»<•"/«
id.o.n|',^he' i
Office of HM*arch and Development's Air Quality Criteria for Lead (U.S. EPA
1984a) and^^e. Office of Drinking Water's Quantification of Toxicological
Effects (QTE) (U.S. EPA, 1985). Individuals desiring further information on
the toxicological data base or rationale for risk characterization should
consult the QTE. The QTE is available for review at each EPA Regional Office
of Drinking Water counterpart (e.g., Water Supply Branch or Drinking Water
Branch), or for a fee from the National Technical Information Service, U.S.
Department of Commerce, 5285 Port Royal Rd., Springfield, VA 22161,
PB #_, $ . The toll free number is (800) 336-4700; in Washington,
D.C. area: (703) 437-4650.
II. GENERAL INFORMATION AND PROPERTIES
Synonyms
Plumbum
Uses
Lead is used in the production of storage batteries , gasoline antiknock
additives, pigments and ceramics, ammunition, solder, cable coverings,
caulking lead, pipe and sheet lead, type metal, brass and bronze, and
bearing metals.
Properties
CAS # 7439-92-1
Molecular Weight 82
Oxidation States +2, +4
Density 11.35 g/cm3 at 20 C
Melting Point . 327.5°C
Boiling Point 1740°C
-------
Lead September 30, 1985
-3-
Occurrence
Ls a relatively rare metal which occurs in the earth's crust
at§j» average concentration of 15 ppm. Lead is ubiquitous in the
environment and occurs at low levels in most ground and surface
waters. While lead and its compounds are used in a number of
industrial processes, contamination of drinking water supplies is the
result of naturally-occurring mineral deposits. Lead also can enter
drinking water supplies as a result of the corrosion of lead pipe
and lead-containing solder.
0 Available data on the occurrence of lead in water supplies are
limited. Based upon EPA surveys, most water supplies are believed
to contain less than 20 ug/L. Currently, 59 ground water supplies-J
and 7 surface water supplies exceed the maximum contaminant level •
(MCL) of 50 ug/L. The major sources of lead exposure are from
food, where it occurs at low levels, and drinking water. Where
drinking water exceeds 20-30 ug/L, it is the major source of lead
exposure.
III. PHARMACOKINETICS
Absorption
0 Based on long-term metabolic studies with adult human volunteers,
Kahoe (1961a,b,c) estimated that approximately 10% of dietary lead is
absorbed from the human gut.
0 Heard and Chamberlain (1982) calculated a rate of 63.3% absorption by
humans after a fasting period. Isotope studies such as this support
the observations of Garber and Wei (1974) and Baltrop and Khoo (1975)
that lead in beverages consumed between meals is absorbed to a greater
extent than is lead from food.
-------
Lead September 30, 1985
-4-
Distribution
i a
"rthan 99% of blood lead in humans is associated, with the_ erythro-^
•'>•'•
cif£jiaT under typical conditions, but it is the very small fraction of
lead transported in plasma and extracellular fluid that provides
lead to various body organs (Baloh, 1974; DeSilva, 1981).
0 Whole blood lead in daily equilibrium with other compartments was
found to have a mean life of 35 days (25-day half-life) and an approxi-
mate total content of 1.9 mg in humans (Rabinowitz et al., 1976).
Chamberlain et al. (1978) established a similar half-life for 203Pb
in blood when volunteers were given the labeled lead by ingestion,
inhalation or injection.
0 Alterations in blood lead levels in response to abrupt changes in J
exposure apparently occur over somewhat different periods, depending
on whether the direction of change is greater or smaller. With
increased lead intake, the blood lead level achieves a new value in
approximately 60 days (Tola et al., 1973; Griffin et al., 1975). A
decrease may involve a'longer period of time depending on the magnitude
of the past higher exposure (Rabinowitz et al., 1977; Gross, 1981,
0'Flaherty et al., 1982).
0 There is an equilibrium between blood content in red blood cells and
plasma, such that the levels in the plasma rise with levels in whole
blood.
0 The relative percentage of blood lead in plasma versus red blood
cells is constant up to a blood lead level of about 50 to 60 ug/dL,
but becomes increasingly greater above this level.
-------
Lead September 30, 1985
-5-
Metabolism
Cen, particularly infants, retain a significantly higher amount
id than do adults [35 vs. 3.5 fold] (Barry, 1981).
0 Lead crosses the placenta beginning in the twelfth week of life and
continues until birth (Baltrop and Khoo, 1975).
Excretion
0 In adults, approximately 90 percent of ingested lead is eliminated in
the feces without prior gastrointestinal absorption (Kehoe 1961 a;
Wetherill et al., 1973).
0 The primary elimination route for lead is urine, representing about 95
percent of the total output of absorbed lead (Rabinowitz et al., 1973),
.1
0 Lead is excreted by the kidneys into the urine, by both glomerular-
filtration and transtubular flow (Goyer and Mahaffey 1972).
0 Renal effects of lead may compound lead toxicity by interfering with
urinary lead excretion.
IV. HEALTH EFFECTS
Humans
Short-term Exposure
0 Short-term or acute exposures to lead through drinking water of ten
days or less do not have any adverse effects (U.S. EPA, 1984a).
0 The health effects resulting from lead exposure become manifest only
after the blood lead level exceeds 15 ug/dL. It takes a minimum of
35 days to achieve that blood lead level and some unspecified time
after that to express the effect.
-------
Lead September 30, 1985
-6-
"
Longer-TerafegBd Chronic Effects
0 Ca^lgSjlJation of health advisory values for lead requires several
changes in the normal approach used for other Health Advisories or
RMCLs/MCLs. This is because most studies in humans evaluate the
degree of lead exposure by measuring the concentration of lead in the
blood (PbB) rather than by measuring ingestion. This requires that
the NOAEL be described first in terms of a PbB, and then an oral
exposure which produces that PbB must be calculated.
0 Lead interacts adversely with several key enzymes involved in heme
biosynthesis , i.e., delta-aminolevulinic acid dehydratase (ALA-D),
ferrochetalase and delta-aminolevulinic acid synthetase. The PbB ;
that will inhibit ALA-D is as low as 12 ug/deciliter in adults (Secchi
et al., 1974). Ferrochetalase inhibition produces measurable zinc
protoporphyrin (ZPP) after a lag of several weeks; ZPP will persist
long after the termination of exposure to lead. In children, the
threshold for ZPP accumulation is between 15.5 and 1.5 ug/dL
(Roels et al., 1976; Piomelli et al., 1976).
0 Lead also causes decreased red blood cell survival. Inhibition of
pyrimidine-5-nucleotidase (Py-5-N) occurs as a result of lead exposure
and decreases RBC survival by increasing membrane fragility (Angle
and Mclntire, 1978). Py-5-N inhibition occurs in children; no
threshold level has been determined.
0 Renal 1-hydroxylase mediates the final step in the synthesis of the
biologically active form of Vitamin D. Lead inhibits this enzyme at
a PbB level of 12 ug/dL (Mahaffey, 1982). Active Vitamin D is required
-------
Lead .September 30, 1985
-7- ff°*< .T~
f jg;-j|jMnnal intestinal calcium absorption. Vitamin D promotes differ-
of myeloid stem cells into macrophages; receptors for
Vitamin D have been found in monocytes and lymphocytes. Thus, active
Vitamin D appears to have functions involving cell differentiation
and immunoregulatory capacity.
0 Harlan et al. (1985) and Pirkle et al. (1985) examined the relation-
ship between PbB levels and blood pressure by statistical analysis
of the data base obtained during the National Health and Nutrition
Examination Survey (NHANES-II). They showed that PbB levels in
normotensive persons were significantly lower than in hypertensives.
0 Pirkle et al. (1985), using segmented regression analyses, indicaJ^ed
that there was no threshold below which blood pressure was not related
to PbB. In addition, the authors calculated that the 37% decrease in
average PbB in the white adult population from 16.7 to 10.5 ug/dL
which occurred in the United States between 1976 and 1980 will result
in 77,300 fewer myocardial infarctions and 27,500 fewer strokes over
a ten year period.
0 Considerable evidence exists that peripheral nerve dysfunction occurs
in adults at PbB levels as low as 30 to 50 ug/dL (Seppalainen and
Hernberg, 1980,1982).
0 Children's nervous systems appear to be more sensitive to lead than
those of adults. There is a significant linear relationship between
PbB and slow wave (SW) voltage beginning with a PbB of 7 ug/dL (Otto
et al., 1981). EEC gain, is altered in children whose PbB levels are
15 ug/dL or higher (Benignus et al., 1981). Two years later, there
were still measurable changes in central nervous systems of these
children (Otto et al., 1982).
-------
Lead September 30, 1985
-8- " ~ - -
.'• •< ,r.'i j\ r* •
^•j\^\r |
0 Prenatal exposure of the fetus to PbB levels below those causing
f«fS|iiniicity results in damage to the brain. PbB levels of mental
retairdates, measured during the second week of life, were found to be
significantly higher than those of control subjects (25.5 * 8.9 vs.
20.9 * 7.9 ug/dL) (Moore et al. 1977).
Teratogenicity/Reproductive Effects
0 Premature fetal membrane rupture occurs in term and preterm infants
in mothers whose PbB levels were 26 ug/dL (Fahim et al., 1976).
Normal deliveries occurred in mothers whose PbB levels were 14 ug/dL
and below.
Mutagenicity
0 Lead is a specific cellular poison. The short term tests that are
used to predict mutagenicity result in cellular toxicity before
mutagenicity can be expressed.
0 Fifteen studies of cytogenetic abnormalities in persons exposed to
lead have been reported (IARC, 1980). Positive results were reported
in nine of these studies. The incidence of abnormal metaphases
doubled in workers whose PbBs increased from an initial mean of 35 to
45 micrograms/dL (Forni et al., 1976).
Carcinogenicity
0 There are at least 12 positive carcinogenicity studies, eleven in
rat* and one in the mouse, using different lead salts.
0 The most useful study in establishing a quantitative relationship
between lead ingestion and frequency of renal tumors is reported by
Azar et al. (1973). A dose-dependent increase in renal tumor frequency
in rats was observed over the range of 500 to 2000 ppm Pb (as lead
acetate) in the diet. It should be noted that these effects also are
-------
Lead September 30, 1985
-9- " '
•' • V A r*r
.-^ , , f--.t *» I
" a J J
associated with moderate to severe non-carcinogenic effects in rats.
V. QUANTIFI<^jRlljl OF TOXICOLOGICAL EFFECTS
HealOT*»avi series are based upon the identification of adverse health
effects associated with the most sensitive and meaningful non-carcinogenic
end-point of toxicity. The induction of this effect is related to a particular
exposure dose over a specified period of time, most often determined from the
results of an experimental animal study. Traditional risk characterization
methodology for threshold toxicants is applied in HA development. The general
formula is as follows:
(NOAEL or LOAEL) (BW) _ ug/L
(UF(s)) ( L/day)
Where:
NOAEL or LOAEL = No-Observed-Adverse-Effeet-Level
or
Lowest-Observed-Adverse-Effect-Level
(the exposure dose in mg/kg bw)
BW = Assumed body weight of protected individual
in kg (10 or 70)
UF(s) = uncertainty factors, based upon
quality and nature of data
L/day = Assumed daily water consumption (1 or 2) in liters
One-day and Ten-day Health Advisories
The adverse'health effects resulting from lead exposure become manifest
only after the blood lead level exceeds 15 ug/dL. It takes a minimum of 35
days to achieve that blood lead level and some unspecified time after that
to express an effect. It is, therefore, inappropriate to determine One- or
Ten-day Health Advisories for lead.
Longer-term and Life-time Health Advisories
Because so many body systems are affected by chronic exposure to lead, and
and because so many studies provide data regarding the relationship between PbB
-------
Lead September 30, 1985
-10- " - - ...
levels and toxic effects, it does not seem appropriate to select a singlMstibdy
as the baag^^Rjr calculation of the long term or chronic level. RatherTit-
appears mofS*^ippropriate to identify a "consensus" PbB value that represents the
collective indication of the NOAEL based on all the relevant studies in children.
Although a number of the studies mentioned above suggest that there may
be no threshold for certain lead-induced effects, it does not seem appropriate
at present to conclude that a PbB value of zero must be achieved to avoid
adverse effects. Rather, it is judged that the effects at PbB values between
15 and 20 ug/dL do not constitute biologically significant adverse effects in
their own right, although they may be preclinical indicators of adverse
effects which could develop with increased exposure.
V*
In order to protect the fetus, however, it is advisable to limit the I&B
level in women of child-bearing age to between 15 and 20 ug/dL since
certain studies (Harris and Holley, 1972; Hubermont et al., 1978) indicate
that the ratio of fetal/maternal PbB values is close to 1:1. Thus, a NOAEL for
both children and adults is 15 ug/dL.
Since blood lead levels above 15 ug/dL will cause measurable adverse
health effects in children who are less than two years old, it seems
appropriate to set a single health advisory for all extended periods of
exposure.
Using-the relationship derived from the data of Ryu et al., (1983)
(PbB = 0.16 PbD), HA is calculated as follows:
Lifetime HA = (15 ug/dL) = 20 ug/day
(0.16H5)
-------
Lead September 30, 1985
-11- ••-•
• .blood lead level (PbB) at which no adverse effects are"
observed
0.16 = Proportionality constant between lead intake in the diet
(PbD) and blood lead level (PbB) in infants (Ryu et al.
1983). The units of this constant are (ug/dL)(ug/day).
5 = Uncertainty factor selected to account for intra-human
variability. The end-points measured are extremely subtle
and sensitive and do not require a full order-of magnitude
safety factor.
Evaluation of Carcinogenic Potential
0 Although some lead salts are associated clearly with increased renal
tumor frequency, no quantitative estimate of excess cancer risk has been
performed by the Carcinogen Assessment Group of the U.S. EPA.
0 IARC put lead in category 3 which means that there is sufficient
animal data to conclude that lead is a carcinogen in animals but
insufficient evidence of carcinogenicity in humans (IARC, 1980).
0 Applying the criteria described in EPA's proposed guidelines for
assessment of carcinogenic risk (U.S. EPA, 1984b), lead may be
classified in Group B2: Probabalt Human Carcinogen. This category
is for agents for which there is inadequate evidence from human studies
and sufficient evidence from animal studies.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The WHO European standard for lead is 100 ug/dl in blood.
0 The National Academy of Sciences (NAS 1977) concluded that the "no-
observed-adverse-health-effect level cannot be set with assurance at
any given value greater than 0.025 mg/L" (25 ug/L).
-------
Lead September 30, 1985
-12- - . _
VII. ANALYSIS
Lnation of lead is accomplished by atomic absorption. (AA) using
direct aspiration into a flame (Method 239.1. Atomic Absorption,
direct aspiration. U.S. EPA, 1979a) or a furnace technique (Method
239.2. Atomic Absorption, furnace technique. U.S. EPA, 1979b).
0 The direct aspiration AA procedure is a physical method based on the
absorption of radiation at 283.3 run by lead. The sample is aspirated
into an air-acetylene flame and atomized. A light beam is directed
through the flame into a monochromator and onto a detector that
measures the amount of light absorbed. Absorbance is proportional
to the concentration of lead in the sample. The detection limit is
100 ug/L using this procedure.
0 The furnace AA procedure is similar to direct aspiration AA except.
that a furnace, rather than a flame, is used to atomize the s'ample
The detection limit is 1 ug/L using this procedure.
VIII. TREATMENT
0 Experience indicates that direct filtration, coagulation/filtration,
lime softening, ion exchange and reverse osmosis can effectively
remove lead from source drinking waters.
0 Laboratory filtration tests, without coagulation, have been effective
on river water having a turbidity of 40 Jtu and a concentration of 0.15
mg/L lead. Lead removals of 85 to 90 percent were obtained through
removal of turbidity (EPA, 1977; Sorg, 1978).
0 Laboratory studies performed by Naylor, et al. (1975) on the removal
of lead by coagulation indicated that ferric sulfate and alum
coagulation can achieve better than 97% removal from river water
containing 0.15 mg/L of lead in the pH range of 6 to 10. Experiments
-------
Lead September 30, 1985
-1 3-
r
on well water under similar test conditions showed ferric sulfe
phieve the same high removal rate, greater than 97%, while altmt —"
obtained slightly lower removals, 80 to 90%.
0 Laboratory and pilot plant studies by Sorg (1978) indicate that lime
softening can be more effective for lead removal than coagulation
with alum or ferric sulfate. Over 98% removal was obtained throughout
the pH range 8.5 to 11.3 for well water containing 0.15 mg/L of
lead. Results of tests for conventional lime softening showed lead
removal below 0.05 mg/L in the pH range 9.2 to 10.4. Pilot-plant
work has achieved lead removal of 99% by lime softening for well
water at pH 9.5 and an initial lead concentration of 0.41 mg/L
(Sorg, 1978).
0 Patterson (1975) reported that ion exchange can be a successful
treatment in the removal of lead from industrial wastewaters. Highly
effective removal of lead has been reported for the cation exchange
resin clinopilolite (natural zeolite) (NAS, 1977).
0 In tests of home softeners with tap water spiked with 1.0 mg/L of
lead nitrate, the lead content was reduced to less than 0.05 mg/L
for 330 cycles before leakage (Personal communications, Ciccone
Engineers with Culligan Co., 1982). Pakalns, et al. (1978) reported
that lead removal may also be achieved by some chelating resins
which have been used increasingly in recent years to remove trace
metals from natural waters.
0 Bench scale reverse osmosis tests by Mixon (1973) showed excellent
removal of lead from spiked tap water by three types of cellulose
acetate membranes at a rejection pressure of 400 psi. Greater than
99% removal was observed for initial lead concentrations of 0.95
-------
Lead September 30, 1985
£.- while reductions of more than 94% were found for initial lead
of 9.3 mg/L. Rejections of 85.5 and 97.6% were observed for
two types of cellulose acetate membranes for distilled water spiked
with 10 mg/L of lead (Johnston, et al., 1978).
0 Protection against lead contamination from water distribution systems,
in general, may be achieved by a number of methods including pH
adjustment, addition of lime, increasing alkalinity or addition of
corrosion inhibitors. The city of Boston has successfully reduced
and maintained lead levels below 0.05 mg/L by increasing the pH
level of the water over 8.3 by the addition of sodium hydroxide.
Simultaneous elevation of pH and alkalinity achieved successful
control of lead contamination from the corrosion of lead pipes in
the Bennington, Vermont, water distribution system.
0 In Framingham, Mass., which uses the same water as Boston, adjustment
of pH levels above 7 by the addition of caustic compounds resulted
in low lead concentration levels (Karalekas, 1977). Lead concentration
levels below 0.05 mg/L are maintained at Providence, Rhode Island,
where lime is added to raise the water pH to 10.1, with the subsequent
increase of hardness to 40 mg/L and alkalinity to 20 mg/L (Karalekas,
et al., 1977).
0 In three Schuylkill/Carbon County water supply systems in Pennsylvania,
where lead contamination from corrosion of lead pipe was a problem,
addition of phosphate inhibitors successfully reduced lead levels to
below 0.05 mg/L.
0 Another method to prevent lead contamination of the drinking water is
to replace existing materials containing lead in the water supply
distribution system and to use lead-free materials such as lead-free
-------
Lead September 30, 1985
-15- ' "-• --_
in newly constructed plumbing. The feasibility of replacing
l
-------
Lead . September 30, 1985
-16- -- .
Goyer R.A., K.R. Mahaffey. 1972. Susceptibility to lead toxicit
Health Pcrspect. 5:73-80.
Griffin, IPlr F« Coulston, H. Willis, J.C. Russel and J.H. Knelson. 1975"." ""
?:studies on men continuously exposed to airborne particulate
lead. In: Griffin TB, Knelson, JH., eds. Lead. New York, NY. Academic
Press, pp. 221-240. (Coulston, F.; Korte, F., eds. Environmental
quality and safety: supplement v. 2).
Gross, S.B. 1981. Human oral and inhalation exposures to lead: Summary of
Kehoe balance experiments. J. Toxicol. Environ. Health. 8:333-377.
Harlan, W.R., R. Landis, R.L. Schmouder, N.G. Goldstein and L.C. Harlan.
1985. Blood lead and blood pressure. Relationship in the adolescent
and adult population. J. Am. Med. Assoc. 253:530-534.
Harris, P., and M.R. Holley. 1972. Lead levels in cord blood. Pediatrics.
49:606-608.
Heard, M.J., and A.C. Chamberlain. 1982. Effect of minerals and food on
uptake of lead from the gastrointestinal tract in humans. Hum. Toxicol.
1:411-445.
'i
Herrera, C.E., G.J. Kermeyer and B.P. Hoyt. Seattle Distribution System :
corrosion control study. Volume III: Potential for drinking water
contamination from tin/antimony solder. Environmental Protection Agency
Contract No. R806686-010.
Hubermont, G., J.P. Buchet, H. Roels and R. Lauwerys. 1978. Placental
transfer of lead, mercury and cadmium in woman living in a rural area:
importance of drinking water in lead exposure. Int. Occup. Environ.
Health. 41:117-124.
I ARC. 1980. International Agency for Research on Cancer. Lead and lead
compounds. In: IARC monographs on evaluation of the carcinogenic risk
of chemicals to humans: some metals and metallic compounds. October,
1979. Lyon, France. Geneva, Switzerland. World Health Organization/
IARC; pp. 325-416.
Johnston, H.K., and H.S. Lim. 1978. Removal of Persistent Contaminants from
Municipal Effluents by Reverse Osmosis. Volume III. Environment Canada,
Wastewater Technology Centre, Project No. 73-3-14.
Karalekas, P.C., Jr. 1977. Lead Corrosion Controls, Internal memorandum.
U.S. Environmental Protection Agency, Region I. March 28.
Karalekas, P.C., Jr., C.R. Ryan, C. Larson and F. Taylor. 1977. Alternative
methods for controlling the corrosion of lead pipe. Paper presented at
the Annual Conference of the New England Water Works Association, Boston,
Mass., September 13.
Kehoe, R.A. 1961 a. The metabolism of lead in man in health and disease.
Lecture I. The normal metabolism of lead. (The Harben Lectures, 1960).
J.R. Inst. Public Health Hyg. 24:81-97.
-------
Lead September 30, 1985
-17-
Kehoe, R.A. 1961b. The metabolism of lead in man in health and disease"." •
^^1. The metabolism of lead under abnormal conditions. .. (The
tures, 1960). J.R. Inst. Public Health Hyg. 24:129-143.
j?HV*~
Kehoe, R.A. 1961c. The metabolism of lead in man in health and disease.
Lecture III. Present Hygienic problems relating to the absorption of
lead. (The Harben Lectures, 1960). J.R. Inst. Public Health Hyg.
24:177-203.
Mahaffey, K.R., J.P. Rosen, R.W. Chesney, J.T. Peeler, C.M. Smith and
H.F. Deluca. 1982. Association between age, blood lead concentration,
and serum 1, 25-dihydrocalciferol levels in children. Am. J. Clin.
Nutr. 35:1327-1331.
Mixon, F.O. 1973. The removal of toxic metals from water by reverse osmosis.
U.S. Department of the Interior, Office of Saline Water. Research and
Development Progress Report No. 889.
Moore, M.R., P.A. Meredith and A. Goldberg. 1977. A retrospective analysis
of blood-lead in mentally retarded children. Lancet. 1(8014):717-719.
Murrel, N.E., Holzmacher, and McClendon. 1982. Lead in drinking water du^j
to lead-tin solder joints utilized in interior residential and other
plumbing. H2M Corp., Melville, NY.
NAS. 1977. National Academy of Sciences. Drinking Water and Health, Volumes
1 and 2. U.S. National Academy of Science.
Naylor, L.M., and R.R. Dague. 1975. Simulation of lead removal by chemical
treatment. J. AWWA. 67(10):560-565.
0'Flaherty, E.J., P.B. Hammond and S.I. Lerner. 1982. Dependence of apparent
blood lead half-life on the length of previous lead exposure in humans.
Fund. Appl. Toxicol. 2:49-54.
Otto, D.A., V.A. Benignus, K.E. Muller and C.N. Barton. 1981. Effects of
age and body lead burden on CNS function in young children. I: Slow
cortical potentials. Electroencephal. Clin. Neurophysiol. 52:229-239.
Otto, D.A., V.A. Benignus, C. Barton, K. Seiple, J. Prah and S. Schroeder.
1982. Effects of low to moderate lead exposure on slow cortical poten-
tials in young children: Two year follow-up study. Neurobehav. Toxicol.
Teratol. 4:733-737.
Pakalns, P., G.E. Batley, et al. 1978. The effect of surfactants on the
concentration of heavy metals from natural waters on Chelex-100 resin.
Analytica Chimica Acta. 99:333-342.
Patterson, J.W. 1975. Wastewater Treatment Technology. Ann Arbor Science
Publishers, Inc.
Personal Communication between V.J. Ciccone Engineers and Culligan Corporation,
August 4, 1982.
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Lead September 30, 1985
-18- ......
RAFT
Piomelli/ §», C. Seaman, D. Zullow, A. Curran and B. Davidow. 1982.
Thredjfijpi" for lead damage to heme synthesis in urban children* . .Prqc.
NatL||||pid. Sci. U.S.A. 79:3335-3339. '
Pirkle, J.L., J. Schwartz, J.R. Landis and W.R. Harlan. 1985. The relation-
ship between blood lead levels and blood pressure and its cardiovascular
risk implications. Am. J. Epidem. 121:246-258.
Rabinowitz, M.B., G. Wetherill, J.D. Kopple, 1973. Lead metabolism in normal
the human: Stable isotope studies. Science 182:725-727.
Rabinowitz, M.B., G.W. Wetherill and J.D. Kopple. 1976. Kinetic analysis of
lead metabolites in healthy humans. J. Clin. Invst. 58:260-270.
risk implications. Am J. Epidem. 121:246-258.
Rabinowitz, M.B., G.W. Wetherill and J.D. Kopple. 1977. Magnitude of lead
intake from respiration by normal men. J. Lab. Clin. Med. 90:238- 248.
Roels, H.A., J.P. Buchet, R. Lauwerys, G. Hubermont, p. Bruaux, F. Claeys-
Thoreau, A. LaPontaine and J. Van Overrschelde. 1976. Impact of air
pollution by lead on the heme biosynthetic pathway in school-age children.
Arch. Environ. Health. 31:310-316. 1
•\
Ryu, J.E., E.E. Ziegler, F.E. Nelson and S.J. Fomon. 1983. Dietary intake of
lead and blood lead concentration in early infancy. Am. J. Dis. Child.
137:886-891.
Secchi, G.C., L. Erba and G. Cambiaghi. 1974. Delta-aminolevulinic acid
dehydratase activity of erythrocytes and liver tissue in man: relation-
ship to lead exposure. Arch. Environ. Health. 28:130-132.
Seppalainen, A.M., and S. Hernberg. 1980. Subclinical lead neuropathy.
Am. J. Ind. Med. 1:413-420.
Seppalainen, A.M., and S. Hernberg. 1982. A follow-up study of nerve conduc-
tion velocities in lead exposed workers. Neurobehav. Toxicol. Teratol.
4:721-723.
Sorg, T.J., M. Csanady, et al. 1978. Treatment technology to meet the int.
primary drinking water regulations for inorganics: Part 3. J. AWWA.
70(12):680-691.
Tola, S., Si" Hernberg, S. Asp and J. Nikkanen. 1973. Parameters indicative
of absorption and biological effect in new lead exposure: a prospective
study. Br. J. Ind. Med. 30:134-141.
U.S. EPA. 1977. U.S. Environmental Protection Agency. Manual of treatment
techniques for meeting the interim primary drinking water regulations,
revised. EPA-600/8-77-005.
U.S. EPA. 1979a. U.S. Environmental Protection Agency. Method 239.1.
Atomic Absorption, direct aspiration. Methods for Chemical analysis of
water and wastes. EPA 600/4-79-020.
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O C £..-_:. ,1^,1= L J ^ , , 'JOJ
-19- '•••
U.S. EPA. 1979b. U.S. Environmental Protection Agency. Method 239.2." Atomic -'
Abso^jfejtton, furnace technique. Methods for chemical analysis of water
and «3lktB8. EPA 600/4-79-020.
U.S. EPA. 1979c. U.S. Environmental Protection Agency. Water related
environmental fate of 129 priority pollutants. Office of Water Planning
and Standards. EPA-440/4-79-029.
U.S. EPA. 1983. U.S. Environmental Protection Agency. Lead occurrence in
drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1984a. U.S. Environmental Protection Agency. Air quality criteria
for lead. Office of Health and Environmental Assessment for the Office of
Air and Radiation.
U.S. EPA. 1984b. U.S. Environmental Protection Agency. Proposed guidelines
for carcinogen risk assessment; Request for comments. Federal Register.
49(227):46294-46301. November 23.
U.S. EPA. 1985. U.S. Environmental Protection Agency. Quantification of
toxicological effects for lead (Draft). Office of Drinking Water. -T
••!
Wetherill, G.W., M. Rabinowitz, J.D. Kopple. 1974. Sources and metabolic5
pathways of lead in normal humans. Proc. Int. Symp. June 1974. Comnu'
Eur. Commun. U.S. EPA, World Health Organization, pp. 847-860.
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March 31, 193?
EPA 0596
RX000027824
p-DIOXANE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water.. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each aodel is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
OFC29 1093
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-2-
This Health Advisory is based upon information presented in the Office
of Drinking Water's Health Advisory Document for p-Dioxane (U.S. EPA, 1981).
The 1981 Health Advisory is available for review at each EPA Regional Office
of Drinking Water counterpart (e.g., Water Supply Branch or Drinking Water
Branch) .
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 123-91-1
Structural Formula
Synonyms
0 1,4-Dioxane; 1", 4-Diethylene dioxide
Uses^
0 Solvent for cellulose acetate, resins, oils and waxes.
Properties (Windholtz, 1983, Verschueren, 1977)
Chemical formula
Molecular weight 88.10
Physical state Colorless liquid
Boiling point 101.1°C ;
Melting point 11.8°C
Vapor pressure 30 mm (20°C)
Density 1.033 g/ml (20°C)
Solubility miscible in water at all concentrations
Taste/ odor threshold ~
Oceurrence
1,4-Dioxane is a synthetic organic compound with no known natural
sources. Production of dioxane in 1979 was 6 million Ibs.
Based upon dioxane's physical properties, it is expected to volatilize
from soil and surface waters. Dioxane also is expected to be mobile
in soil. No information on the bi ©degradation of dioxane has been
identified.
Dioxane has not been included in Federal and State surveys of drinking
water supplies. However, it has been reported to occur in both surface
and ground water (U.S. EPA, 1979). No information on the occurrence
of dioxane in food or air has been identified.
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p-Dioxane March 31, 1937
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III. PHARMACOKINETICS
Absorption
• Dioxane has been reported to be absorbed readily through the lungs,
skin and gastrointestinal tracts of mammals.
8 There is evidence that dioxane is absorbed after ingestion. Several
investigators administered dioxane in water to rats and observed
systemic adverse health effects (Argus *et al., 1965; Hoch-Ligeti
et al., 1970; Kociba et al., 1974). However, the quantities absorbed
following ingestion are not known. Based on the physico-chemical
properties of this compound, and for the purpose of HA estimation,
100% absorption will be assumed after ingestion.
Distribution
8 Woo et al. (1977b) studied the binding of H3-dioxane to tissue
macromolecules of animals. Male Sprague-Dawley rats, weighing 95 to
130 g, were administered a single intraperitoneal dose of H^-dioxane
at 500 uCi/100 g body weight, and sacrificed after 1, 2, 6 or 16
hours. Cystolic, microsomal, mitochondrial and nuclear fractions
were examined. The percent covalent binding, was highest in the
nuclear fraction followed by mitochondrial and microsomal fractions
and the whole homogenate. The binding of dioxane to the macromolecules
in the cytosol was mainly noncovalent. Pretreatraent of rats with
inducers of microsomal enzymes had no significant effect on the
covalent binding of dioxane to the various subcellular fractions of
the liver.
Metabolism/Excretion
8 Oioxane has been reported to be metabolized in animals to 2-hydroxy-
ethoxyacetic acid and 1,4-dioxan-2-one. After a single oral dose of
1,000 mgAg bw of 1,4-(14c)dioxane to rats, Braun and Young (1977)
recovered from the urine 85% of the dose as -hydroxyethoxyacetic
acid (HEAA) and most of the remainder as unchanged dioxane. Woo et al.
(1977a) isolated and identified p-dioxane-2-one from the urine of
rats given intraperitoneal doses of 100 to 400 mg dioxane/kg body
weight; the amount of p-dioxane-2-one excreted increased with the
dose level administered.
8 Humans exposed to 50 ppm dioxane for six hours eliminated it from the
body primarily by metabolism to HEAA, which was subsequently eliminated
rapidly in the urine (Young et al., 1977).
IV. HEALTH EFFECTS
Humans
The lowest oral lethal dose for humans has been recorded as 500
(NIOSH, 1978).
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p-Oioxar.e March 3', 19-5'
-4-
Johnstone (1959) described a fatal case of dioxane poisoning. The i
estimated exposure by inhalation in this case was 470 ppm (1,690 mg/ms
for one week; the extent of dermal exposure was not known. Postmortem
examination revealed hepatic and renal lesions as well as demyelination
and edema of the brain.
Animals
Short-term Exposure
0 Oral LD50 values for experimental animals are 4200 mgAg (rat), 5700
mgAg (mouse), 2000 mgAg (cat), 2000 mgAg (rabbit) and 3150 mgAg
(guinea pig) (NIOSH, 1978).
0 Pairley et al. (1934) intravenously injected four rabbits with a
single dose of either 1, 2, 3 or 5 mL of 80% dioxane diluted with
saline to a total volume of 10 mL. Three other rabbits each were
given two 5 mL intravenous injections of dioxane mixed with 5 mL of
saline with an interval of 48 hours between injections. One rabbit,
used as a control, received 10 mL of saline. The immediate effect of
dioxane injection in all of the rabbits was violent struggling, which
began as soon as the first few drops were injected.. With doses of
4 or 5 mL dioxane, the struggling was followed by convulsions and
collapse; the rabbits then rapidly returned to normal. The four
rabbits given the single doses of 80% dioxane were killed 1 month
later. Degeneration of the renal cortices with hemorrhages was
observed by microscopic examination. In the rabbit administered the
3 mL dioxane dose, the degenerative changes extended into the medulla
and the liver showed extensive cellular degeneration starting at the
periphery of the lobules. No abnormality was found in other organs.
The livers of the rabbits given the 1- and 5 mL doses showed no
microscopic abnormalities; areas of cloudy swelling were seen in the
liver of the rabbit given 2 mL of dioxane.
Longer-term Exposure
0 Kociba et al. (1974) reported liver and kidney damage in male and
female Sherman strain rats. The animals were given drinking water
containing 0, 1.0, 0.1 or 0.01% dioxane for up to 716 days. Toxico-
logical analysis included changes in body weights, survival rates,
blood chemistry (packed cell volume, total erythrocyte count, hemo-
globin, total and differential white blood cell counts) and complete
histopathological examination. There was no evidence of toxicity with
regard to the tested parameters in animals receiving 0.01% dioxane in
drinking water; however, liver and kidney damage was observed at 0.1%
dosage level. Decrease in body weight gains, survival rates, water
consumption and an increase in the incidence of tumors (hepatocellular
and nasal carcinomas) was observed at 1% dosage level.
Reproductive Effects
0 No reports were available on the reproductive effects of 1
in humans or other mammalian species.
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?-Dioxane . March 31, 1937
-5-
Developmental Effects
0 No reports were available on the developmental effects of 1,4-dioxane
in humans or other mammalian species.
Mutagenicity
•
* No reports were available on the mutagenic potential of 1,4-dioxane.
Carcinogenicity
0 Hoch-Ligeti et al. (1970) and Argus et al. (1973) observed a linear "
relationship between the total dose of 1,4-dioxane in drinking water
and the incidence of liver neoplasms in rats. The levels of 1,4-
dioxane in the drinking water were 0.75, 1.0, 1.4 and 1.8% for 13
months. A minimum effective tumor dose (105), 50% tumor dose (TDso),
and maximum effective dose (TDgs) were calculated for 1,4-dioxane.
These were 72, 149 and 260 g, respectively.
0 In a two-year study in Sherman strain rats (60/sex/level) given .
1,4-dioxane in drinking water, Kociba et al. (1974) reported that the
group receiving 1% 1,4-dioxane (calculated to be equivalent to approxi-
mately 1015 mg/kg/day and 1599 mgAg/day foe male and female rats,
respectively ) showed a significant increase compared to controls in
the incidence of hepatocellular carcinomas and squamous cell carcinomas
of the nasal cavity. At 0.01% (9.6 and 19.0 mgAg/day, respectively
for males and females) and 0.1% (94.0 and 148.0 mgAg/day, respec-
tively), there was no significant difference in the incidence of
neoplasms between the control and the experimental groups.
0 In a 90-week study in B6C3Fi mice (50/sex/level) on the oncogenic
effects of reagent-grade 1,4-dioxane in drinking water, a significant
increase in hepatocellular carcinomas over controls was reported in
both the 0.5 and 1% groups of both sexes (NCI, 1978). The average
daily low dose (0.5% v/v) was 720 (530 to 990) mgAg/day for males
and 380 (180 to 620) mgAg/day for females; at the 1% level, the
doses were 830 (680 to 1150) and 860 (450 to 1560) mgAg/day,
respectively.
0 In the NCI (1978) study, Osborne-Mendel rats (35/sex/level) exposed
to 1,4-dioxane in drinking water exhibited a dose-related, statisti-
cally significant incidence of squamous cell carcinomas of the nasal
turbinates in both sexes. Hepatocellular adenomas were observed in
female Osborne-Mendel rats at both dose levels* Average doses for
110 weeks for males were 240 (130 to 380) and 530 (290 to 780) mgAg
body weight; for females, the doses were 350 (200 to 580) and 640
(500 to 940) mgAg body weight.
Effects on Immunologic Status and Competence
* Thurman et al. (1978) reported on the in vitro effects of 1,4-dioxane
on the mitogenic stimulation of murine lymphocytes. At 2.5 and 5
g/L, 1,4-dioxane greatly enhanced lipopolysaccharide stimulation of
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p-Qioxane .March 31, 1967
-6-
lymphocytes as well as depressing phytohemagglutinin stimulation of
lymphocytes. These results were interpreted to indicate stimulation
of B-cell proliferation and suppression of T-cell responses. The
authors did not discuss the implications of the results in human
lymphocytes which appeared to be opposite to the findings with murine
lymphocytes. In vitro, at 25 g/L of 1,4-dioxane, a slight enhancement
of»phytohemagglutinin stimulation of human lymphocytes was seen, indi-
cating a stimulation of T-cell responses and an enhancement of the
immune response; little or no effect was seen at lower concentrations.
More data confirming this initial finding in murine lymphocytes are
necessary before any valid conclusions can be made on the immuno-
suppressive effects of 1,4-dioxane.
QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity,
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA - (NOAEL or LOAEL) X (BW) , _ mg/L ( _ u /L)
(UF) x ( _ _ L/day)
where: •
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day .
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF » uncertainty factor (10, 1 00 or 1,000), in
accordance with NAS/OCW guidelines.
_ L/day * assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
A study by Fairley et al. (1934) has been selected for calculating a One-
day HA. In this study, a single dose of 1, 2, 3 or 5 mL of 1,4-dioxane was
given intravenously to rabbits. Even though one rabbit was used per dose
level, the dose-response data generated by this study provide more useful
information concerning the toxic effects of dioxane than the other available
studies. Rabbits sacrificed one month later had degeneration of the renal
cortices with hemorrhages as observed by microscopic examination, with the
increasing dose levels, the degenerative change extended into the medulla
and the liver also showed extensive and gross cellular degeneration.
-------
-7-
A One-day HA for a 1 0 Jcg child is calculated as follows:
LOA£L (mgAg/day) = (1 "I/day ) (1.03 g/ml ) (0.80) (1000 mg/g) = 412 mg/kg/day
( 2 kg)
Where:
1 ml/day = Administered dose of p-dioxane (LOA£L)
1 .03 g/ml • Density of dioxane
*0.80 » Percent composition of dioxane solution
1000 mg/g « Conversion factor for grams to milligrams
2 kg - Assumed body weight of rabbit
One-day HA - (412 mg/kg/day ) (10 kg) « 4.12 mg/L (4,120 ug/L)
(1 L/day) (1,000)
Where:
412 mg/lcg/day » LOA£L for liver and kidney effects in the rabbit
10 kg » Assumed weight of a child
1 L/day » Assumed volume of water consumed daily by a child
1,000 a uncertainity factor, chosen in accordance with NAS/ODW.
guidelines for use with a LOAEL from an animal study .
Ten-day Health Advisory
In the absence of an acceptable study for the calculation of a Ten-day
HA, the One-day HA value is divided by ten; therefore, the Ten-day HA is
estimated as 0.412 mg/L (412 ug/L).
Longer-term Health Advisory^
No suitable data are available to determine a Longer-term HA. Kociba
et al. (1974) observed a no effect level of 9.6 mgAg/day based on a two-year
drinking water study in rats. This study, although scientifically sound,
should not be used for estimating a Longer-term HA because of the carcinogenic
potential of p-dioxane. p-Dioxane has been reported to be carcinogenic in
both sexes of rats and mice by several independent investigators. This may
be compared with trichloroethylene where only one species responded to the
carcinogenic effects of the chemical. Another reason for not calculating a
Longer-term HA for dioxane is its potential of being chlorinated in water,
thus producing a highly toxic chemical. Woo et al. (1980) showed that
chlorination of dioxane increased the toxicity by as much as 1,000 fold.
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p-Dioxane ' March 31, 1937
-8-
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
* by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other, sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Because of its suspected carcinogenicity, a Lifetime Health Advisory for
p-dioxane is not recommended.
Evaluation of Carcinogenic .Potential
0 A number of studies show that p-dioxane is carcinogenic in more than
one animal species.
0 IARC has classified 1,4-dioxane in Group 2B, indicating sufficient
evidence of its carcinogenicity in animals (IARC, 1982).
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), p-dioxane may be classified
in Group B2: probable human carcinogen. This category is for
agenta for which there is inadequate evidence from human studies
and sufficient evidence from animal studies*
0 Drinking water concentrations estimated by EPA to increase the risk
by one excess cancer per million (10-6) would be 7 micrograms per
liter, assuming consumption of 2 liters of water per day by a 70-kg
adult over a 70-year lifetime and using the linearized multistage
model. The drinking water concentrations associated with a risk of
10-4 and 10-5 would be 700 and 70 ug/L, respectively.
0 The linearized multistage model is only one method of estimating car-
cinogenic risk. Using the 10~6 risk level, the following comparisons
in micrograms/L can be made: Multistage, 7; Logit, 10"7; and Weibull,
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?-Oioxane March 31, 1987
-9-
10-?. Each model is based on differing assumptions. No current
understanding of the biological mechanisms of carcinogenesis is able
to predict which of these models is more accurate than another.
0 While recognized as statistically alternative approaches, the range
of risks described by using any of these modelling approaches has
little biological significance unless data can be used to support
the selection of one model over another. In the interest of consistency
of approach and in providing an upper bound on the potential cancer
risk, the Agency has recommended use of the linearized multistage
approach.
•^
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
8 NIOSH has recommended an exposure standard of 1 ppm/30 M in air
(NIOSH, 1977).
0 TLV - 25 ppm; STEL » 100 ppm (ACGIH, 1980).
VII. ANALYTICAL METHODS
0 There is no standardized method for tKe determination of p-dioxane
in drinking water. However, p-dioxane can be determined by the purge
and trap gas chromatographic-mass spectrometric (GC-MS) procedure
used for determination of volatile organic compounds in industrial
and municipal discharges (U.S. EPA, 1984). In this method, a 5 mL
water sample is spiked with an internal standard of an isotopically
stable analog of p-dioxane and purged with an inert gas. The volat:.2
compounds are transferred from the aqueous phase into the gaseous
phase where they are passed into a sorbent column and trapped. After
purging is completed, the trap is backflushed and heated to desorb
the compounds on to a gas chromatograph (GC). The compounds are
separated by the GC and detected by a mass spectrometer (MS). The
labeled compound serves to correct the variability of the analytical
technique. The method detection limit is dependent upon the nature
of interferences*
VIII. TREATMENT TECHMOLOGIES
0 Treatment technologies which are capable of removing p-dioxane from
drinking water include adsorption by granular activated carbon (GAC) or
powdered activated carbon (PAC). The only data available demonstrating
removal of p-dioxane are for carbon adsorption. Further studies are
required to determine the effectiveness of 03 or 03-UV oxidation.
The available adsorption data are from laboratory bench-scale studies.
Field pilot studies or plant-scale data on p-dioxane are not.available.
0 McGuire et al. (1978) developed isotherms for a number of organic
chemicals, including dioxane. Based on the isotherm data, they
reported that the activated carbon Filtrasorb® 400 exhibited adsorptive
-------
xane March 31, "93"
-10-
capacities of 0.6 mg dioxane/g carbon and 3.5 mg dioxane/g carbon at
equilibrium concentrations of 1 mg/L and 10 mg/L. They also tested
the effectiveness of PAC treatment at 50 mg/L with 5-hour contact
time. The results showed poor removal efficiency. However, it was
concluded that greater removal of 1/4-dioxane could be achieved using
PAC at higher dosages.
Suffet et al. (1978) used a pilot-scale test column packed with an
experimental polymeric resin and compared its performance to granular
activated carbon. The resins showed poor performance with respect
to p-dioxane removal.
A batch laboratory study to demonstrate oxidation of p-dioxane by 100
mg/L chlorine and 100 mg/L permanganate showed no reductions after
12-hour and 3-hour contact times, respectively (McGuire et al.,
1978). A batch laboratory study showed diffused aeration to be
ineffective, achieving less than 3% removal at an 80:1 air-to-water
ratio over a 2.4-hour period (McGuire et al., 1978).
Treatment technologies for the removal of 1,4-dioxane from drinking
water have 'not been extensively evaluated (except on an experimental
level). An evaluation of some of the physical and/or chemical
properties of 1,4-dioxane indicates that the following techniques
would be candidates for further investigation: adsorbtion by activated
carbon and oxidation by ozone or ozone/ultraviolet light. Individual
or combinations of technologies selected to attempt 1,4-dioxane
reduction must be based on a case-by-case technical evaluation, and
an assessment of the economics involved.
-------
?-Dioxane ' . March 31, 1337
-1 1-
IX. REFERENCES
ACGIH. 1980* American Conference of Governmental Industrial Hygienists.
Documentation of the threshold limit values. 4th ed. Cincinnati, OH.
pp. 154-155.
Argus, M.P., J.C. Arcos and C. Hoch-Ligeti. 1965. Studies on the carcino-
genic activity of protein-denaturing agents: Hepatocarcinogenicity of
dioxane. J. Nat. Cancer Inst. 35:949-958.
Argus, M.F., R.S. Sohal, G.M. Bryant, C. Hoch-Ligesti and J.C. Arcos. 1973.
Dose-response and ultrastructural alterations in dioxane carcinogenesis.
Influence of methylcholanthrene on acute toxicity. Eur. J. Cancer.
9(4):237-243.
Braun, W.H. and J.D. Young. 1977. Identification of -hydroxyethoxyacetic
acid as the major urinary metabolite of 1,4-dioxane in the rat. Toxicol.
Appl. Pharmacol. 39:33-38.
Fairley, A., B.C. Linton and A.H. Ford-Moore. 1934. The toxicity to animals
of 1,4-dioxane. J. Hyg. 34:486-501.
Hoch-Ligeti, C., M.F. Argus and J.C. Arcos. 1970. Induction of carcinomas
in the nasal cavity of rats by dioxane. Brit. J* Cancer. 24(1):164-167.
IARC. 1982. International Agency for Research on Cancer. IARC monographs
on the evaluation of the carcinogenic risk of chemicals to humans.
Supplement 4. IARC, Lyon, France.
Johnstone, R.T. 1959. Death due to dioxane? AMA Arch. Ind. Health.
20:445-447.
Kociba, R.J., S.B. McCollister, C. Park, T.R. Torkelson and P.J. Gehring.
1974.* 1,4-Dioxane. I. Results of a 2-year ingestion study in rats.
Toxicol. Appl. Pharmacol. 30(2):275-286.
McGuire, M.J., I.H. Suffet and J.V. Radziul. 1978. Assessment of unit
processes for the removal of trace organic compounds from drinking water.
JAWWA. 10:565-572.
NCI. 1978* National Cancer Institute. Bioassay of 1,4-dioxane for possible
carcinogenicity. Washington, D.C.: U.S. Department of Health, Education
and Welfare, National Institute of Health. DHEW Pub. No. (NIH) 78-1330.
NIOSH. 1977. National Institute of Occupational Safety and Health. Criteria
for a recommended standard — occupational exposure to dioxane. Washing-
ton, D.C.: U.S. Department of Health, Education and Welfare. DHEW
(NIOSH) Pub. 77-226.
NIOSH. 1978. National Institute of Occupational Safety and Health. Registry
of toxic effects of chemical substances. U.S. Department of Health,
Education and Welfare. Washington, D.C.
-------
o-Dioxane ' March 31, 1937
-12-
Suffet, I.H., L. Brenner, J.T. Coyle and P.R. Cairo. 1978. Evaluation of
the capability of granular activated carbon and XAD-2 resin to remove
trace organics from treated drinking water. Environmental Science and
Technology. 1(12):1315-1322.
Thurman, G.B., B.C. Sinuns, A.L. Goldstein and D.J. Kilian. 1978. The
effects of organic compounds used in the manufacture of plastics on the c,,,,
responsivity of murine and human lymphocytes. Toxicol. Appl. Pharmacol.
44:617-641.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Chemical Hazard
Information Profile: Dioxane, Office of Toxic Substances.
U.S. EPA. 1981. U.S. Environmental Protection Agency. Health advisory
document for p-dioxane. Draft. Office of Drinking Water.
U.S. EPA. 1984. U.S. Environmental Protection Agency. Method 1624 Revision
B, Volatile Organic Compounds by Isotope Dilution GC/MS. Federal Register.
49(209):433407-433415.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Fed. Reg* 51{185):33992-34003.
September 24.
Verschueren, K. 1977. Handbook of environmental data on organic chemicals.
1st ed. Van Nostrand Reinhold Company, N.Y. p. 377.
Windholz, M., ed. 1983. Merck Index, 10th ed. Merck and Company, Inc.
Rahway, NJ. pp. 481-482.
Woo, Y-T, J.C. Arcos and M.F. Argus. 1977a. Metabolism in vivo of dioxane:
Identification of p-dioxane-2-one as the major urinary metabolite.
Biochem. Pharmacol. 26:1535-1538.
Woo, Y-T, M.F. Argus and J.C. Arcos. 1977b. Tissue and subcellular distri-
bution of 3H-dioxane in the rat and apparent lack of microsome-catalyzed
covalent binding in the target tissue. Life Sci. 21(10):1447-1456.
Woo, Y-T, B.J. Neuburger, J.C. Arcos, M.F. Argus, K. Nishiyama and G.w. Griffin.
1980. Enhancement of toxicity and enzyme-repressing activity of p-dioxane
by chlorination: Stereo-selective effects. Toxicol. Letts. 5:69-75.
Young, J.D., W.H. Braun, L.W. Rampy, M.B. Chenoweth and G.E. Blau. 1977.
Pharmacokinetics of 1,4-dioxane in humans. J. Toxicol. Environ. Health.
3(3):507-520.
-------
EPA 0596
KX000027824
Zinc Chloride Health Advisory
Health Advisory
Office of Water
U.S. Environmental Protection Agency
Washington, DC 20460
September 1992
-------
Zinc Chloride
Authors:
Joyce M. Donohue, Ph.D.
Lori Gordon, M.S.
Chris Kinnan, M.S.
Welford C. Roberts, Ph.D.
Project Officer:
Krishan Khanna, Ph.D.
Office of Water
U.S. Environmental Protection Agency
Washington, DC 20460
September 1992
-------
PREFACE
This report was prepared in accordance with the Memorandum of Understanding
between the Department of the Army, Deputy for Environmental Safety and
Occupational Health (OASA(IL&E)), and the U.S. Environmental Protection Agency
(EPA), Office of Water (OU), Office of Science and Technology, for the purpose
of developing drinking water Health Advisories (HAs) for selected
environmental contaminants, as requested by the Army.
Health Advisories provide specific advice on the levels of contaminants in
drinking water at which adverse health effects would not be anticipated and
which include a margin of safety to protect the most sensitive members of the
population. A Health Advisory provides health effects guidelines and
analytical methods and recommends treatment techniques on a case-by-case
basis. These advisories are normally prepared for one-day, ten-day, longer-
term, and lifetime exposure periods where available toxicological data permit.
These advisories do not condone the presence of contaminants in drinking
water, nor are they legally enforceable standards. They are not issued as
official regulations and they may or may not lead to the issuance of national
standards or Maximum Contaminant Levels (MCLs).
This report is the product of the Health Advisory Development process.
Available toxicological data (as provided by the Army and as found in open
literature sources) on the munitions chemical zinc chloride have been
reviewed, and relevant findings are presented in this report in a manner that
allows for evaluation of the data without continual reference to the primary
documents. Additional data on the properties of other soluble zinc compounds
are also presented. This report has been submitted for critical internal and
external review by the EPA.
I would like to thank the authors, who provided the extensive technical
knowledge required for the preparation of this report. I am grateful to the
members of the EPA Toxicology Review Panel who took time to review this report
and to provide their invaluable input, and I would like to thank Dr. Edward
Ohanian, Chief, Human Risk Assessment Branch, and Ms. Margaret Stasikowski,
Director, Health and Ecological Criteria Division, for providing me with the
opportunity and encouragement to be a part of this project.
The preparation of this Health Advisory was funded, in part, by Interagency
Agreement (IAG) 85-PP5869 between the U.S. EPA and the U.S. Army Medical
Research and Development Command (USAMRDC). This IAG was conducted with the
technical support of the U.S. Army Biomedical Research and Development
Laboratory (USABRDL), Dr. Howard T. Bausum, Project Manager.
Krishan Khanna, Project Officer
Officer of Water
-------
TABLE OF CONTENTS
PAGE
LIST OF TABLES ii
LIST OF APPENDICES ii
EXECUTIVE SUMMARY ES-1
I. INTRODUCTION 1-1
II. GENERAL INFORMATION AND PROPERTIES II-l
III. OCCURRENCE III-l
A. Zinc Chloride III-l
B. Other Zinc Compounds. . III-l
IV. ENVIRONMENTAL FATE IV-1
A. Zinc Chloride IV-1
B. Elemental and Ionic Zinc IV-1
V. TOXICOKINETICS V-l
A. Absorption V-l
1. Zinc Chloride V-l
2. Other Zinc Compounds V-2
B. Distribution V-3
1. Zinc Chloride V-3
2. Other Zinc Compounds V-5
C. Metabolism V-6
D. Excretion V-6
1. Zinc Chloride V-6
2. Other Zinc Compounds V-7
VI. HEALTH EFFECTS VI-1
A. Health Effects in Humans VI-1
1. Short-Term Exposure VI-1
a. Zinc Chloride VI-1
b. Other Zinc Compounds VI-2
2. Dermal/Ocular Effects VI-7
a. Zinc Chloride VI-7
b. Other Zinc Compounds VI-8
3. Long-term Exposure VI-8
a. Zinc Chloride VI-8
b. Other Zinc Compounds VI-8
B. Health Effects in Animals VI-9
1. Short-Term Exposure VI-9
a. Zinc Chloride VI-9
b. Other Zinc Compounds VI-11
2. Skin and Eye Irritation, Dermal Sensitization .... VI-12
a. Zinc Chloride VI-12
b. Other Zinc Compounds VI-12
3. Longer-Term Exposure VI-13
a. Zinc Chloride VI-13
b. Other Zinc Compounds VI-13
-------
Table of Contents - continued
PAGE
4. Reproductive Effects VI-14
a. Zinc Chloride VI-14
b. Other Zinc Compounds VI-14
5. Developmental Effects VI-15
a. Zinc Chloride VI-15
b. Other Zinc Compounds VI-16
6. Genotoxicity VI-16
a. Zinc Chloride VI-16
b. Other Zinc Compounds VI-18
7. Carcinogenicity VI-19
a. Zinc Chloride VI-19
VII. HEALTH ADVISORY DEVELOPMENT VII-1
A. Quantification of Toxicological Effects VII-2
1. One-Day Health Advisory VII-3
2. Ten-Day Health Advisory VII-3
3. Longer-Term Health Advisory VII-4
4. Lifetime Health Advisory VII-5
B. Quantification of Carcinogenic Potential VII-7
VIII. OTHER CRITERIA, GUIDANCE AND STANDARDS VIII-1
A. Zinc Chloride VIII-1
B. Other Zinc Compounds VIII-1
IX. ANALYTICAL METHODS IX-1
X. TREATMENT TECHNOLOGIES X-l
XI. CONCLUSIONS XI-1
XII. REFERENCES XII-1
LIST OF TABLES
TABLE PAGE
II-1 Chemical and Physical Properties of Zinc Compounds II-3
VI-1 Categories of Effects VI-3
VI-2 Acute Oral Studies of Zinc Chloride and Other Zinc Compounds . . VI-10
LIST OF APPENDICES
Data Deficiencies/Problem Areas and Recommendations for Additional
Data Base Development for Zinc Chloride and other Zinc Compounds . Al-1
11
-------
EXECUTIVE SUMMARY
Zinc is a naturally occurring element commonly found in the earth's crust.
Zinc is a bluish-white metal in its pure form, but also can exist as a number
of divalent inorganic compounds such as zinc chloride, zinc sulfate, and zinc
oxide. Although zinc occurs naturally in the environment, zinc may be
released to the environment from a number of industrial processes including
galvanization, wood preservation, soldering, -dry-battery cell production and
organic synthesis. In addition, zinc chloride may be introduced into the
environment through its use as a military screening smoke. In the
environment, zinc hydrolyzes when dissolved in water. Adsorption of zinc to
sediments and soils and the bioaccumulation of zinc have been reported to
occur.
The pharmacokinetics of zinc have been well studied in animals and humans.
Zinc is absorbed moderately well following oral intake. Absorption through
the skin is minimal while data on absorption following inhalation of
particulate zinc is limited. Radiolabeled zinc (administered as zinc
chloride) mainly distributes to the intestines, prostate, liver and kidney
with kidney levels remaining highest after intravenous administration.
Metallothionein plays an important role in regulating zinc homeostasis.
Excretion is mainly through the feces.
Following acute oral exposures of humans to high doses, up to 1,000 mg/kg, of
zinc, symptoms including vomiting, diarrhea, lethargy, and irritation of the
mouth, throat and stomach may occur. Acute symptoms of zinc toxicity from
exposure via inhalation include dyspnea, chest constriction, retrosternal and
epigastric pain, hoarseness, stridor, cough, lacrimation, expectoration and an
occasional hemoptysis. Pale grey cyanosis usually develops, pulse is
elevated, fever is present and bronchopneumonia can develop. Edema is
widespread. Death is usually due to respiratory insufficiency. Effects are
related to the hygroscopic nature of the inhaled zinc particles which combine
with moisture in the lungs to form caustic substances.
Oral exposures to zinc (as the gluconate) for longer periods of time
(6-12 weeks) were shown to reduce serum erythrocyte superoxide dismutase [E-
SOD] and ceruloplasmin (biomarkers of copper stakes) as well as HDL levels.
In animal studies, oral LDjgS as well as average lethal oral doses have been
reported for zinc compounds in several species. Zinc chloride causes both
skin and eye irritation, and percutaneous toxicity has been demonstrated.
Oral exposure to approximately 100 mg/kg/day of zinc chloride for up to
six weeks has been shown to precipitate a deficiency syndrome when combined
with a synthetic diet low in pantothenic acid. Renal damage was observed in
rats exposed orally to 190.6 mg/kg/day zinc acetate for 90 days. Several
studies indicate that high doses of various forms of zinc can interfere with
reproductive function at doses as low as 25 mg/kg/day and is fetotoxic.
Mutagenicity and carcinogenicity studies have largely yielded equivocal or
negative results. Zinc chloride was not mutagenic in a variety of bacterial
(Salmonella typhimumum. Escherichia coli. Saccharomyces cerevesiae) and rn
vitro mammalian (Chinese hamster ovary and embryo cells, human lymphocytes and
white blood cells) cell systems. Zinc chloride also did not cause chromosomal
ES-1
-------
aberrations in mouse bone marrow cells when administered to the animals in an
in vivo assay.
Health advisory values for zinc chloride are based upon measuring zinc (Zn**)
in water. Based on the available animal toxicity data, the HA for One-day and
Ten-days is 5 mg/L for the 10 kg child. The Longer-term HA for the 10 kg
child is 3 mg/L and for the 70 kg adult is 10 mg/L. The Lifetime HA is
2 mg/L. These values are considered protective against toxic effects for the
most sensitive members of the population. The essentiality of zinc was
considered in the derivation of these HA values. Currently, adequate
available data to assess the carcinogenic risk of zinc are inadequate. Using
the EPA criteria for classification of carcinogenic risk, zinc chloride and
other zinc compounds currently meet the criteria for category D, not
classifiable as to human carcinogenicity. This category is for agents with
inadequate human and animal evidence of carcinogenicity or for which no data
are available.
ES-2
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ZINC CHLORIDE AND OTHER ZINC COMPOUNDS
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Water (OW),
provides information on the health effects, analytical methodology and
treatment technology that would be useful in dealing with the contamination of
drinking water. Health Advisories describe nonregulatory concentrations of
drinking water contaminants at which adverse health effects would not be
anticipated to occur over specific exposure durations. Health Advisories
contain a margin of safety to protect sensitive members of the population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The Advisories are
subject to change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10 percent of an individual's lifetime) and
lifetime exposures based on data describing noncarcinogenic end points of
toxicity. For those substances that are known or probable human carcinogens,
according to the Agency's classification scheme (Group A or B), Lifetime HAs
are not recommended. The chemical concentration values for group A or B
carcinogens are correlated with carcinogenic risk estimates by employing a
cancer potency (unit risk) value together with assumptions for lifetime
exposure and the consumption of drinking water. The cancer unit risk is
usually derived from the linearized multistage model with 95% upper confidence
limits on risk. This provides a low-dose estimate of cancer risk to humans
that is considered unlikely to pose a carcinogenic risk in excess of the
stated values. Excess cancer risk estimates may also be calculated using the
One-hit, Weibull, Logit and Probit models. Current understanding of the
biological mechanisms involved in cancer do not suggest that any one of these
models is able to predict risk more accurately than another. Because each
model is based upon differing assumptions, the estimates that are derived can
differ by several orders of magnitude.
The major emphasis of this Health Advisory is on zinc chloride. However,
because in water zinc chloride and other zinc compounds hydrolyze to form
ionic zinc (Zn**), a review of zinc chloride health effects must include
observations and data associated with all forms of ionizable zinc compounds.
Throughout this document when the term "zinc" is used without identifying it
as a salt (e.g., chloride, acetate, sulfate, etc.) or other compound (e.g.,
zinc oxide), it refers to the ion.
1-1
-------
II. GENERAL INFORMATION AND PROPERTIES
Cas No.
Zn: 7440-66-6
ZnCl2: 7646-85-7
ZnS04-7H20: 7446-20-0
ZnO: 1314-13-2
Synonyms
Zn: Zinc
ZnCl2: Zinc chloride, butter of zinc;
ZnS04-7H20: Zinc sulfate heptahydrate, Op-Thal-Zin, Verazinc;
ZnO: Zinc oxide, flowers of zinc, philosopher's wool, zincite
Worldwide yearly production of zinc averages several million metric tons.
Annual industrial demand in the United States is 1.5 metric tons. Zinc metal
is used extensively in the United States in the machine, building and
automotive industries as a component of galvanized steel (NRC, 1979). Zinc
oxide, the most important inorganic zinc compound, is used in the rubber
vulcanizing process, pigments, paints, ceramics and Pharmaceuticals. Zinc
sulfate is used in plastics production; zinc chloride is used in batteries;
zinc sulfide and zinc silicate are used as phosphors in cathode ray tubes; and
zinc chromate is used as a wood preservative. Zinc chloride, zinc gluconate,
zinc oxide, zinc stearate, and zinc sulfate are used as additive nutrients in
foods and dietary supplements; zinc carbonate is used as a dietary supplement
for farm animals. Zinc borate is used as a fire retardant. Zinc sulfate and
zinc chloride are added to potable water to reduce corrosion.
Zinc chloride is a highly deliquescent, white, granular or crystalline
substance that is used commercially in textiles, adhesives, wood preservation,
embalming fluids, deodorants and numerous other commercial processes. It has
been used medicinally as a dentifrice, astringent and antiseptic and is used
by the military as a screening smoke. Zinc chloride is highly soluble in
water and several organic solvents. It fluoresces in solution, and the
hydrated form evaporates to produce a white, semi-solid mass similar in
consistency to butter, hence its synonym, butter of zinc. Its chemical and
physical properties are listed in Table II-l.
Zinc chloride is produced by the action of hydrochloric acid on zinc, zinc
oxide or zinc sulfide ore (Cumpston, 1983) and may be purified by
recrystallization. The commercial product is 95% pure with the remainder
being water and some oxychloride (ZnCl2-ZnO) (Hill et al., 1978). It is
trimorphic in nature with «-, £- and y-forms. The commercial product is
either «-, y-, °r «- plus -y-zinc chloride (Farnsworth and Kline, 1973 as cited
in Hill et al., 1978).
In its solid form, zinc chloride is odorless but corrosive; as an aqueous
solution it is highly acidic and may cause chemical burns. Its fumes act as
an irritant to the eyes and mucous membranes. Zinc chloride smoke, (the
military screening agent), is produced when mixtures of zinc oxide,
hexachloroethane (HCE) and 10% calcium silicide or, more recently, 9% grained
II-l
-------
aluminum is ignited. The resulting chemical reaction produces mostly
particulate zinc chloride along with free carbon, calcium carbonate and silica
(Macaulay and Mant, 1963). The highly hygroscopic zinc chloride combines with
the moisture in the air to produce hydrochloric acid and zinc oxychloride. In
an enclosed space, the particulate zinc chloride can be inhaled and hydrolyzed
in the lungs, resulting in widespread mucosal damage.
II-2
-------
Table 11-1
Chemical and Physical Properties of Zinc Compounds'
u>
Properties.
Chemical Formula
Atomic/Molecular Weight
Physical State (25'C)
Boiling Point
Melting Point
Density
Vapor Pressure
Water Solubility
Specific gravity (25'C)
Log Octanol/Water
Partition Coefficient
Taste Threshold (Water)
Odor Threshold (Water)
Zinc
Zn
65.38
Solid; bluish-white.
lustrous metal
908' C
419.5'C
7.U (25'C)
1 mm Hg (487* C)
Insoluble
7.U
Not applicable
None found
None found
Zinc chloride
ZnCl2
136.29
Solid, white hexagonal
crystals or powder,
deliquescent
732'C
290'C
2.91
None found
432 g/100 ml <25'C)
2.91
None found
None found
None found
Zinc sulfate
heptahydrate
ZnS04 -7H20
287.54
Solid, rhombic crystals
efflorescent
2BO'Cb
100'C
1.96
1 mm Hg (428*C)
96.5 g/100 mt (20'C)
1.96
None found
None found
None found
Zinc oxide
ZrO
81.4
Solid, white hexagonal
crystals
None found
1,975'C
5.67
None found
Insoluble
5.67
None found
None found
None found
"deferences: Budavarl, 1989; Weast, 1987; Sax, 1975)
Temperature at which the water of hydratlon is lost. No boiling point was available for ZnSo,.
-------
III. OCCURRENCE
A. Zinc Chloride
Zinc is ubiquitous in nature, found in most foodstuffs, water and air, and an
essential trace nutrient. Zinc in the soil is taken up by plants. The
average daily consumption is estimated at 12-15 mg, mostly from food (Klaassen
et al., 1986). Zinc chloride, an inorganic salt of zinc, is produced by the
action of hydrochloric acid (HC1) on zinc or zinc oxide. Its introduction
into the environment may result from industrial effluent from such processes
as galvanizing, wood preservation, soldering, dry-battery cell production, and
organic synthesis. It also may enter the environment via military screening
smokes, primarily hexachloroethane/zinc oxide smokes, where the principle end
product of combustion is zinc chloride.
When hexachloroethane (HCE) smoke, containing approximately 47.5% zinc oxide,
is detonated, the principle component of the reaction product is zinc
chloride. Cullumbine (1957), as cited in Hill et al. (1978), estimated that
for every 100 g of HCE smoke mixture used, approximately 40 g of zinc chloride
is released. Complete combustion of a typical HCE smoke pot, with an HCE
charge capacity of 13.6 kg would generate approximately 545 g of zinc
chloride. Helm et al. (1971), as described by Heimburger (1977), reported a
concentration in air of 4 g zinc chloride/m3 and 0.1 g ZnO/m3 following
detonation of a smoke flair.
Under conditions of high humidity, the highly deliquescent zinc chloride, with
a particle size of approximately 0.1 microns, reacts with water droplets to
form highly acidic, highly caustic zinc compounds with a particle size of up
to 3 microns. The reaction products are known as zinc oxychlorides. Further
hydrolysis can result in the formation of zinc hydroxide and hydrochloric acid
(Heimburger, 1977).
When smoke is generated in a closed environment, under conditions of low
humidity, the zinc chloride particles remain and may be inhaled, passing deep
into the respiratory passages. It is here that they react with the moisture
in the lungs to produce the highly corrosive products responsible for the
severe damage seen after inhalation exposure (Heimberger, 1977).
As a part of a risk analysis for exposure to high concentrations of zinc
chloride, air samples were collected following the burning of M5, HCE smoke
pots under controlled conditions Stocum and Hamilton (1976). Analysis of the
particles collected on membrane filters indicated a geonetrie mean
concentration of 1.1 g/m3. A maximum concentration of 8.5 g/m3 was calculated
for a 12 minute emission time.
When zinc chloride comes into contact with water, it dissociates to its ionic
form and combines with substances in the water to form various hydroxides as
well as insoluble precipitates with other ions (Hill et al., 1978).
B. Other Zinc Compounds
Zinc is a naturally occurring element found in the earth's crust at an average
concentration of 123 ppm (mg/kg) (Weast, 1987). The zinc concentration
averages about 70 ppm (mg/kg) in most rock-forming minerals. The zinc content
III-l
-------
in soil is highly variable, averaging about 54 ppm (mg/kg); it is generally
higher near industrial locations or highways owing to emissions and tire wear.
Zinc concentration in sea water averages about 8 ng/L; fresh water has varying
amounts of zinc but averages about 64 ng/L (NRC, 1979). The highest mean
value for dissolved zinc was found in the Lake Erie basin at a level of
205 ng/L while the lowest mean of 16 Mg/L was recorded in the California
basin. While it is present at only trace levels in most surface and ground
waters, it has been detected at levels as high as 50 mg/L in mining areas
(Hill et al., 1978).In natural waters, zinc can be found in several chemical
forms (e.g., as simple hydrated ions, as inorganic complexes or as
organometallic complexes) (Cotton and Wilkinson, 1972).
Zinc occurs chiefly as the minerals sphalerite (ZnS), smithsonite (ZnC03),
willemite (ZrijCrC^) and zincite (ZnO); it also replaces magnesium in silicate
minerals to some extent and is found in most igneous rock (Cotton and
Wilkinson, 1972).
Zinc is ubiquitous in all living cells, is a constituent of over 200
metalloenzymes and is involved in most major metabolic pathways (NAS, 1989;
McClain et al., 1985; Prasad, 1985).
Meats, fish and poultry are the richest sources of zinc in foods, and they
contribute 40-50% of the total daily intake of zinc to the diets of older
children and adults. Dairy products and grains are also good sources of zinc.
They each contribute 10-13% of the zinc in the adult diet. Dairy products
play a more important role as sources of zinc in the diets of young children
(Pennington and Young, 1991).
The National Research Council (1989) estimates that, in the United States,
typical mixed diets furnish between 10 and 15 mg zinc/day. A comprehensive
analysis, based on 3-day intake records of 150 individuals showed that the
average daily zinc intake from food was 12 ± 5.5 mg/day for men and 9.5 ±
0.8 mg/day for women (Bowerman and Harrill, 1983). Women in the 19- to
50-year-old groups had the lowest average zinc intake with only 8.7 ±
4.5 mg/day. Spencer and Gatza (1980) found an average daily intake of
12.5 mg/day from the analysis of institutional metabolic diets over a 10-year
period. In another analysis of dietary food composites from 22 subjects,
average zinc intake was 8.6 ± 0.5 mg/day (Holden and Wolf, 1979).
During the period from 1982 to 1989, the average zinc intake for United States
adults (as determined by the Food and Drug Administration Total Diet Study)
was 9-16 mg/day (Pennington and Young, 1991). The zinc in the diet was not
sufficient to meet the Recommended Dietary Allowance (RDA) for young children,
adolescent females or adult females. In addition, the zinc intake from the
diet was below the RDA for elderly males and females (Pennington and Young,
1991) . Recent surveys of the American population indicate that there is no
widespread occurrence of zinc deficiency in individuals consuming a balanced
diet selected from the available food supply, although zinc intakes are lower
than recommended, particularly in women (Pilch, 1989).
The average zinc concentration in tap water across the United States is
0.245 mg/L (Greathouse and Craun, 1978). The highest mean value reported for
tap water zinc concentrations from standing water in galvanized pipes is
1.979 mg/L (Sharrett et al., 1982).
III-2
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IV. ENVIRONMENTAL FATE
A. Zinc Chloride
Ignition of zinc-containing smokes results in the dispersion of additional
zinc chloride into the environment. Hydrolysis is the main transformation
process for zinc chloride in both air and water. In air, zinc chloride
hydrolyses with the available moisture to form hydrochloric acid and zinc
oxychlorides (ZnClj-ZnO). In high-temperature hydrolysis studies, zinc
chloride had a half-life of 17,000 minutes in the aerosol state. Similar
studies were not available for environmental temperatures at various relative
humidities (Spanggord et al., 1985).
Once introduced into the water, zinc chloride is rapidly transformed by
hydrolysis to zinc ions (Zn**) and chloride ions (Cl"*. The ionic zinc may
then react to form such chemical species as Zn(OH)*, Zn(OH)*3 and Zn(OH)2. In
very basic solutions, zincates may form. The zinc ion also forms insoluble
precipitates with carbonates, sulfides, phosphates and silicates present,
resulting in the immobilization of zinc in the water (Hill et al., 1978).
In soil, adsorption plays a major role. The fate of zinc in soil is highly
dependent upon pH and oxygen availability as well as various physical
characteristics of soil. Zinc chloride is not likely to be affected by
photolysis, vaporization, or biotransformation processes.
B. Elemental and Ionic Zinc
Zinc, as a trace element, is carried by prevailing winds from natural and
anthropogenic sources to remote marine environments. The transport of zinc in
the aquatic environment is controlled by the speciation of the ion. In most
unpolluted waters, zinc exists mainly as a divalent cation and is easily
absorbed by hydrous metal oxides and clay minerals. In polluted areas,
organic material has a significant effect on the chemical form of zinc.
Precipitation of zinc compounds appears to be important only in reducing
environments or highly polluted waters. Photolysis and volatilization of zinc
are not likely in an aquatic environment (Callahan et al., 1979).
Concentrations of zinc in suspended and bed sediments always exceed
concentrations in ambient waters (Angino et al., 1976), and an inverse
correlation exists between zinc concentration in the sediment and sediment
grain size (Perhac, 1974b; Pita and Hyne, 1975), which implies that sorption,
rather than precipitation, is responsible for this phenomenon.
The composition of the dissolved and suspended solids load has an important
effect on the mode of transport of zinc in ambient water. In cases where the
solids are primarily dissolved, most of the zinc in ambient water is
transported in solution as the hydrated cation or complex species (Perhac,
1972, 1974a; DeGrott and Allersma, 1975). In cases where suspended solids
make up a high proportion of the total solids load, most of the zinc
transported will be sorbed to the suspended and colloidal particles (Kubota
et al., 1974; Steele and Wagner, 1975). Residence in impoundments reduces the
concentration of dissolved zinc, apparently due to scavenging by suspended
solids and subsequent deposition (Pita and Hyne, 1975; Perhac, 1974b).
IV-1
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The tendency of zinc to be adsorbed is also affected by pH, salinity, and the
concentration of complexing ligands. In a study of heavy metal adsorption by
two oxides and two soils, zinc was completely removed from solution when the
pH exceeded 7; below pH 6, little or no zinc was adsorbed (Huang et al.,
1977). Helz et al. (1975) found that zinc was desorbed from sediments as
salinity increased; this, apparently, was due to displacement of the adsorbed
zinc ions by alkali and alkaline earth cations which are abundant in brackish
and saline waters. Addition of inorganic complexing ligands enhanced the
affinity adsorption of zinc (Huang et al., 1977).
Colloidal and suspended organic matter also adsorb zinc. Rashid (1974)
reported that about 26.1 mg of zinc were adsorbed per gram of sedimentary
organic matter added to a solution of zinc.
Holmes (1977) concluded that formation of zinc sulfide controls the mobility
of zinc in Corpus Christi Harbor (an estuarine system). Seasonal fluctuations
in dissolved zinc levels were attributed to variations in reduction-oxidation
potential. In studying an impoundment polluted with zinc (400 ng/L)
introduced by the dumping of mine wastes, Weatherley and Dawson (1973) found
that zinc was precipitated as an amorphous colloidal deposit of basic
carbonates and sulfates. Under oxidizing conditions, precipitation of these
zinc compounds is probably important only where high concentrations of zinc
exist.
Zinc is ubiquitous in soil with levels ranging from 10-300 mg/kg (Hill et al.,
1978). In general, Zn** is retained in the top few centimeters (5-10 cm).
Its movement through soil is affected by various factors, with movement
facilitated by anaerobic conditions and in acidic soil.
Adsorption of zinc ions in the soil is facilitated by the presence of hydrous
oxides of iron, aluminum and manganese, giving rise to hydrous -oxide zinc
compounds. Adsorption is also facilitated in finely divided soils such as
silt, clays and colloids. Zinc has been shown to precipitate near the surface
in soils containing calcium carbonate or lime or in soils high in organic
content. Zinc-soil complexes also are formed. At pH 7.7 and below, Zn** is
found in equilibrium with soil zinc while above that pH, Zn(OH)2 predominates
(Hill et al., 1978). Addition of a digested sewage sludge containing
4,300 mg/kg of zinc to soil during eight growing seasons showed that 46% of
the applied zinc was retained in the soil (Hinesly et al., 1977).
From its natural presence in water and soil, zinc has been shown to accumulate
in biological species. Application of a fertilizer containing 129 mg/kg of
zinc resulted in accumulation of the zinc in grains, leaves and legumes but
not in roots, squashes and tomatoes (Schroeder et al., 1967).
Hill et al. (1978) reported that marine species accumulate zinc, with tissue
levels measured at 6-1,500 mg/kg (EPA, 1976). Application of 10 millicurie of
65zinc by spraying a pond surface resulted in a rapid movement of the zinc
from water to sediments to organisms with 36% in sediment, 5% in biota and the
remaining 59%, mainly as suspended material, in water after the first 24 hours
(Duke, 1967). Maximum levels were reached in organisms after 2 days, while
0.6% was found in biota and 99.4% in sediment after 100 days.
Wildlife and domestic animals also accumulate zinc, mainly in muscle. Over a
45-year period, the human body accumulates zinc to levels of 30-60 mg
IV-2
-------
(Schroeder et al., 1967). As the infant body contains little or no zinc, an
accumulation rate of 0.67-1.3 mg/year has been calculated.
IV-3
-------
V. TOXICOKINETICS
The toxicokinetics of zinc have been well studied in animals and humans. Zinc
is absorbed moderately well following oral intake. Absorption through the
skin is minimal while data on absorption following inhalation of particulate
zinc is limited. Radiolabeled zinc was mainly distributed to the intestines,
prostate, liver and kidney with kidney levels remaining highest after
intravenous administration. Metallothionein plays an important role in
regulating zinc homeostasis. Excretion is mainly through the ^eces.
A. Absorption
1. Zinc Chloride
Payton et al. (1982) reported on a method for determining human zinc
absorption following oral administration. Intestinal absorption was
determined from the ratio of 65[Zn]-zinc chloride and a non-absorbed
radioactive marker, 51 [Cr] -chromic chloride. The marker had no effect on zinc
absorption and had a intestinal transit time similar to that of zinc.
Absorption was measured by both whole body and stool counting. Retention was
determined from the proportion of the dose remaining in the body 7-10 days
after administration. Doses were administered to 17 healthy adult volunteers
(sex not specified) ranging in age from 18-46 years. The individuals were
fasted overnight prior to dosing. An initial dose-response study indicated
that approximately 55% of the administered 65zinc chloride was absorbed at
doses of 18, 45 and 90 nmol of zinc. Absorption was reduced with increasing
dose, indicating that zinc absorption is saturable. At a test dose of
900 nmol, only 25% of 65Zn was absorbed.
Further studies were conducted by Payton et al . (1982) using a dose of 92
of 65zinc with the chromium marker. Results of zinc absorption, as measured
by dual isotope stool counting or whole body counting, and zinc body
retention, as measured by whole body counting 7-10 days after dosing, were
comparable. Among 16 healthy individuals, average initial absorption as
measured by body counting was 48% and by stool counting 50% , with a close
correlation between individual results by the two methods. No significant
differences were found between sexes . Absorption values corresponded closely
with the predicted mean absorption of 48%, corrected for endogenous excretion.
Similar studies were conducted in ostomy patients, patients with celiac
disease in relapse and in one patient with radiation injury of both small and
large intestine. There was no difference in absorption among the ostomy
patients but those with intestinal malabsorption showed a significant decrease
in absorption (average 30%). This finding indicated the importance of the
proximal intestinal mucosa in the absorption of inorganic zinc.
Hill et al. (1978) reviewed the absorption studies of zinc chloride in animal
species and concluded that there were conflicting results. In a study by
Feaster et al . (1955), only 5% of a single .tracer dose was absorbed in adult
female rats over 24 hours. In contrast, Methfessel and Spencer (1973)
reported that 25% of a dose of labeled 65zinc chloride was absorbed within 30
minutes of oral intubation. There was little increase in zinc uptake from the
gastrointestinal tract over the next 6 hours.
Four healthy men were given three different oral doses of tracer TOzinc
(expressed as mg 70zinc chloride) at weekly intervals against a background of
V-l
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15 mg/day dietary zinc. Absorption was 81% from a 4.52-mg tracer dose, 77%
from a 6.47-nig tracer dose, and 61% from a 24.52-mg tracer dose. For a 70 kg
man the doses were approximately 0.06 mgAg. 0.09 mg/kg and 0.35 mg/kg
respectively. A linear increase in absorption of dietary zinc within the
range 4.52 to 24.52 mg zinc and a decrease in fractional absorption with
larger zinc doses were observed. A reduction in dietary zinc from 15 to about
1.6 mg resulted in a significant (p<0.005) increase in fractional zinc
absorption of the fixed tracer dose (1.19 mg) from 81 to 92%. Thus, the dose
of zinc has a significant effect on its fractional absorption, and dietary
restriction of zinc results in prompt increase of zinc absorption (Istfan
et al., 1983).
In a study by Methfessel and Spencer (1973), 65zinc as the chloride salt was
instilled in vivo into ligated sacs formed from the duodenal portion of the
small intestines of rats. The absorption of 65zinc was significantly greater
from the duodenum than from the more distal portions of the small intestine.
The mid jejunum and ileum exhibited similar absorption; only minimal amounts
were absorbed from the stomach, cecum and colon.
Uptake of 65zinc from labeled zinc chloride was measured in four 10-cm
consecutive intestinal segments of weanling pigs starting 1 cm distal to the
pylorus. Data from a continuous-flow in vitro perfusion system for noneverted
sacs, revealed no significant differences attributable to gut segment position
(Hill et al., 1987).
Skog and Wahlberg (1964), indicated that absorption following percutaneous
application was minimal when solutions of 0.08-4.87 M aqueous "zinc chloride
were applied to the skin of guinea pigs. In these studies less than 1% of the
administered dose was absorbed over 5 hours.
Absorption following inhalation of particulate zinc chloride by five soldiers
from a smoke ammunition bomb was indicated by a slow (rate not reported)
increase in plasma zinc levels following exposure for two minutes or less
(Hjortso et al., 1988). Treatment with acetylcysteine, a heavy metal
chelating agent, by either intravenous infusion or nebulization resulted in
increased urinary zinc excretion.
2. Other Zinc Compounds
The absorption of zinc is similar in humans and other mammalian species and is
affected by the amount of zinc ingested, physiological need, the fiber content
of the diet, and the ratio of dietary zinc to other divalent cations (Davies
and Nightingale, 1975; Greger, 1992; NRC, 1989; Seal and Heaton, 1983;
Solomons and Jacob, 1981; Turnlund et al., 1984; U.S. EPA, 1987).
Numerous studies indicate that zinc absorption is regulated, in part, by the
zinc content in the intestinal mucosa, which, in turn, is regulated by the
zinc content of plasma (Evans et al., 1973; Ansari et al., 1976; Weigand and
Kirchgessner, 1978; Cousins, 1985). The zinc absorption process includes both
passive diffusion and a carrier-mediated process (Tacnet et al., 1990). A
cysteine-rich low molecular weight protein has been identified in the
intestinal mucosa which may be responsible for the carrier-mediated process
(Hempe and Cousins, 1991). This protein bound nearly 50% the radiolabeled
zinc entering the intestinal cells from the lumen in ligated loops of the
small intestine of anesthetized rats when the zinc concentration was 5 iiM, but
V-2
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only 25% of the label when the concentration was 300 ^M. This suggests that
the cysteine-rich protein has a limited binding capacity for zinc and is
saturated when the intestinal concentration of zinc is high.
The zinc in animal products has a higher coefficient of absorption than that
from vegetable products. Phytates (inositol hexaphosphate) present in whole
grains adversely affect the bioavailability of zinc by reducing its absorption
(Mason et al., 1990; Sandstead et al., 1990). The concentrations of iron and
calcium in the diet can also decrease zinc absorption (Dawson et al., 1989;
Sandstead et al., 1990; Solomons, 1982).
The typical American diet favors zinc absorption since it includes a high
consumption of meat and dairy products. Zinc absorption from different diets
(e.g., vegetarian, high fiber) can be considerably lower. Many studies report
zinc absorption of only 20-30% (Sanstead, 1973). Recent guidelines use an
absorption coefficient of 20% to account for the lower absorption of zinc from
fiber-rich diets (NRC, 1989).
Studies using everted sacs of rat duodenum and ileum revealed that zinc uptake
was greater in the duodenum than the ileum and was influenced by the pH of the
medium. Reducing the pH of the incubation medium from 7.3 to 6.4
significantly decreased zinc uptake (p<0.001) by the duodenal sacs from
23.4 ± 0.9 to 15.2 ± 1.5 ng/g dry tissue (mean ± SE) after 30 minutes of
incubation. Increasing the pH from 7.3 to 8.3 also significantly decreased the
uptake of zinc (p<0.001) by the ileal sacs from 13.0 ± 0.5 to 8.6 ± 1.1 ng/g
dry tissue (mean ± SE) per 30 minutes of incubation. Zinc uptake from salts
varied in the following order: zinc acetate>zinc sulfate>zinc chloride>zinc
phosphate> zinc citrate. Addition of aspartic acid and/or histidine to zinc
chloride increased the uptake, and addition of galactose and lactose decreased
it (Seal and Heaton, 1983).
B. Distribution
1. Zinc Chloride
Upon post-mortem examination of two victims (death from respiratory
complications) of inhalation exposure to a zinc chloride smoke bomb, Hjortso
et al. (1988) reported that the striated muscle showed elevated zinc levels
when compared to tissue of non-zinc chloride exposed trauma victims. Only one
of the victims showed elevated levels of zinc in lung tissue. All other
tissue zinc levels were within normal limits.
Average total body retention of 65zinc administered orally as zinc chloride
was measured after an overnight fast in 50 patients with taste and smell
dysfunction (Aamodt et al., 1986). There were no significant differences
(pX).25) in zinc retention between the first phase of the experiment (days
1-21) and the second "placebo" phase of the experiment (days 22-336). During
the third phase of the experiment (112-440 days, mean 307 days), 14 patients
were continued on the placebo and 36 patients received zinc sulfate (100 mg
Zn^/day). The latter group demonstrated an accelerated loss of total body
zinc (shortened biological half-time of 235 ± 8 days; mean ± SEM), which was
significantly different (p<0.001) from the placebo-treated group (biological
half-time of 384 ± 8 days; mean ± SEM). Accelerated loss of 65zinc from the
thigh muscle was apparent immediately; however, loss from the liver began
V-3
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after a mean delay of 107 days. There was no apparent effect on loss of
65zinc activity from red blood cells.
Feaster et al. (1955) reported that the highest concentrations of radio-
activity, were recovered in the kidney, liver and pancreas, 4 days following
the oral administration of a single tracer dose of 65zinc chloride to female
rats. Relatively little radioactivity was recovered from the muscle, hide and
hair, and bones.
Six hours after oral administration of 0.1 jiCi of 65zinc as zinc chloride to
30 Wistar rats (sex not reported), highest levels of radioactivity were found
in the small intestine followed by the kidney, liver and large intestine.
Smaller amounts were found in the lungs and spleen. At 14 days after
administration, highest levels of radioactivity could be found in the hair,
testicles, liver and large intestines (Kossakowski and Grosicki, 1983).
Following oral intubation of 65zinc (1 i»Ci of *5zinc chloride, specific
activity 0.81 jiCi/mg zinc) in the intact rat ingesting a diet containing
40 ppm zinc, maximum radioactivity (0.09% of the administered dose) was
attained in the whole blood at 30 minutes (Methfessel and Spencer, 1973). The
activity decreased to about 0.045% at 1 hour and to 0.01% at 24 hours. Liver
and pancreas both had a 6*zinc concentration of 0.1% (percent of dose/g wet
tissue) at 15 minutes which increased to 0.6% at 8 hours and decreased to 0.3
and 0.2%, respectively, at 24 hours. The uptake of 65zinc in femur and muscle
was generally low (0.01-0.17% over 24 hours).
Following intravenous administration of a single dose of 65zinc (as zinc
chloride) in mice, the liver contained 25%, and the pancreas, kidneys, and
small intestines contained about 1.7-2.4% of the administered label at
2-3 hours post-dosing (Sheline et al., 1943a). Levels in bone tissue
increased from approximately 4-10% of the 65zinc dose/g tissue during the
first week post-dosing.
In two dogs (sex not reported) administered a single IV dose of 65zinc (as
zinc chloride), radiolabeled-zinc levels in erythrocytes during the first
24 hours post-dosing ranged from 1.9 to 3.2% of recovered radioactivity and
were about 4% at the end of 1 week (Sheline et al., 1943a). Approximately
9.5% of the radiolabeled-zinc appeared in skeletal muscles 3-8 hours post-
dosing. The total radioactivity recovered 1 day after dosing was 13%; at
4 days, 35%; and at 7 days, 26%.
The tissue uptake of radiolabeled 15 yCi 65zinc (as the chloride salt) was
determined in adult male Vistar rats following a bolus intraperitoneal
injection (Pullen et al., 1990). For each of the 12 organs evaluated there
was a straight line relationship of uptake with time. The regression
coefficients for the uptake plots were calculated; the liver displayed the
greatest uptake of zinc (2.14 E-2 mL/min/g), followed by the kidney (1.30),
pancreas (1.25), spleen (1.03), ileum (0.91), lung (0.52), heart (0.43), bone
(0.42), testis (0.15). blood cells (0.12), muscle (0.06) and brain (0.05), all
in units of E-2 mL/min/g. Additional data on zinc uptake by the brain
indicate that the blood-brain barrier is minimally permeable to zinc.
Eight hours following intravenous administration of 65zinc chloride to
rabbits, tissue levels were highest in the liver, intestine and kidney with
levels reported as being 2 10%/g in tissue (Lorber et al., 1970). Sheline et
V-4
-------
al. (1943b) injected a total of 31 mice and 5 days (sex and strain not
reported for either species) with an unspecified dose of 65zinc chloride. In
mice, at 8 hours post-dosing, 17% of the dose was recovered from the liver,
while levels in the small intestine, colon, kidney, spleen and stomach were
between 10% and 1%. Percentage recovery from the liver remained high (3.3%)
up to 170 hours after injection. In dogs, levels in the liver (34%), small
intestine (10%) and skeletal muscle (9.6%) were highest followed by kidneys,
pancreas, stomach, colon and heart (i3.9%) at 8 hours after treatment. As in
mice, the liver levels of radioactivity remained elevated (il%) in the
170 hour assay.
2. Other Zinc Compounds
The body of a normal human male weighing 70 kg contains approximately 1.4 to
2.3 g of zinc. About 20% of this total is thought to be present in the skin.
The highest concentrations of zinc are found in the prostate (100 pg/g wet
tissue) and semen (100-350 ng/L). Typical zinc concentrations (expressed as
Hg/g fresh tissue) in other human tissues are: kidney, 55; liver, 55; muscle,
54; heart, 33; pancreas, 29; spleen, 21; testes, 17; lung, 15; brain, 14; and
adrenal gland, 12 (U.S. EPA, 1987).
About 98% of serum zinc is bound to proteins (85% to albumin; most of the
remainder to a-2-macroglobulin). Diffusible zinc in blood is associated with
albumin and amino acids and not with a-2 macroglobulin (U.S. EPA, 1987).
Normal human serum zinc values are 75-120 ng/dL (Monsen, 1987) and are not
particularly valuable as indicators of zinc status (Grider et al., 1990; King,
1986).
Zinc is present in erythrocytes (92.4% as cofactor for carbonic anhydrase
isoenzymes and superoxide dismutase), leukocytes (mostly as zinc
metalloprotein), and platelets (U.S. EPA, 1987).
Dietary supplementation of 600 ppm zinc as zinc oxide (a high, but not toxic,
level) in young Cherokee S-D albino male rats (9/treatment group), for periods
of 7-42 days, produced no change in the zinc levels of the tibia, liver,
kidneys, small intestines (first 15 cm), heart, muscle (semi-tendinous) and
whole blood (Ansari et al., 1975). However, when a single gavage dose of
labeled 65zinc chloride in acetate buffer (4 |*Ci) was administered along with
the supplement 7 days prior to sacrifice, label retention of the tissues
declined sharply in direct proportion to the duration of exposure in rats that
had received the supplement for periods of from 7 to 21 days. The decrease in
the level of label in the tissues of the zinc-supplemented animals indicates
that the turnover of body zinc stores increases when the zinc load increases.
There was no significant difference in the label retention in the animals
given the supplement for 21 or 42 days, suggesting that there are limits to
the body's ability to homeostatically adapt to continued exposure to excess
zinc.
In a different study, varying dietary levels of zinc were fed to rats for
21 days (Ansari et al., 1976). Zinc (as zinc oxide) was added to the diet at
levels of 1,200-8,400 ppm (in 1,200 ppm increments) for 21 days. There was an
increase (p<0.05) in the levels of zinc in the liver, kidney and tibia with
additions of 1,200 and 2,400 ppm to the diet. The tissue levels of zinc
remained relatively constant for the 3,660, 4,800, 6,000 and 7,200 ppm
V-5
-------
supplements but increased again with the 8,400 ppn supplement. Zinc levels in
the muscle and heart were unaffected by any dietary level of zinc.
After 14 days, the rats were administered a single dose of labeled *5zinc as
the chloride salt (29.8 i*Ci) 7 days before sacrifice (Ansari et al., 1976).
The label retention in all tissues was dramatically reduced by one to two
orders of magnitude in the animals receiving 1,200 ppm supplement as compared
to the controls, indicating that the animals increased the metabolic turnover
of zinc in response to the increased zinc intake. However, the presence of
additional zinc in the diet (up to 8,400 ppm) did not cause any additional
change in label retention. In contrast to the soft tissues, the zinc label in
bone increased when supplemental zinc was increased from 3,600 to 6,000 ppm
and remained fairly constant with still higher intakes. These results
indicate homeostatic adaptations in zinc turnover and absorption accompany
increases in dietary zinc to prevent the accumulation of zinc in the tissues.
Decreased absorption and increased turnover appear to regulate the body load
with dietary zinc concentrations of up to 1,200 ppm; decreased absorption is
more important than changes in turnover at dietary intakes higher than
1,200 ppm.
C. Metabolism
Zinc is an essential trace nutrient and is a cofactor for the function of as
many as 200 enzymes including DNA and RNA polymerase, carbonic anhydrase,
carboxypeptidase, aminopeptidase and superoxide dismutase (NAS, 1989). The
essentiality of zinc in the human diet was recognized as the result of a
series of studies in which inadequate dietary zinc was determined to be the
cause of retarded growth and development of children in Iran, Egypt and
Australia (Holt et al., 1980; Prasad, 1991). Inhuman and animal research,
adverse effects associated with inadequate dietary zinc include lethargy,
impaired taste acuity, impaired wound healing, delayed gonadal development,
abnormal dark adaptation, impaired immune response and dermatitis (Abernathy
et al., 1991; Prasad, 1991).
The protein metallothionein plays an important role in regulating zinc
homeostasis. This low molecular weight protein is found in the liver,
kidneys, intestines, erythrocytes and other tissues. It has binding sites for
cadmium, copper, mercury and zinc. Nearly one third of the 61 to 62 amino
acids in metallothionein are cysteines. Metallothionein synthesis is induced
by zinc exposure, stress, endotoxins, steroid hormones and interleukin-1
(Nutrition Reviews, 1989). Metallothionein is believed to act as a storage
protein for zinc and thereby help to maintain homeostasis.
D. Excretion
1. Zinc Chloride
Richmond et al. (1962) reported an average biological half life of 154 days in
four human subjects following a single oral dose of 0.6-1.0 yCi of 65zinc
chloride. The range was 149-161 days.
Sheline et al. (1943a) reported that mice intravenously injected with
radiolabeled zinc chloride (dose not specified) excreted over 50% of the dose
via the gastrointestinal (GI) tract. Approximately 20% of the dose was found
in the feces within the first 10 hours. In contrast, urinary excretion
V-6
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amounted to 2% of the dose over 170 hours of recovery. In dogs which also
were administered 65zinc chloride (dose not specified), excretion in the feces
was less, with only 25% of the dose recovered over a 15 day period. Less than
5% of the dose was excreted in the urine.
After intravenous administration of 65zinc chloride (dose not specified) to
male Wistar rats, Barrowman et al. (1973) reported that the feces was the main
route of excretion with the bile involved in this process. Over a period of
48 hours, 4% of the administered dose was recovered in the bile, largely
associated with a low molecular weight protein and with bile pigment.
Rats receiving a single intravenous injection of 65zinc chloride (0.012 or
0.020 mM zincAg) excreted 31-42% of the radioactivity in the feces within
75-92 hours of injection (Bruner, 1950). In mice, after a single IV injection
(0.33-1.6 |ig 65zinc chloride), more than 50% of the *5zinc dose was present in
the feces and 20% was present in the urine at the end of a 170-hour
observation period. Dogs administered a single IV injection of 65zinc (5.7 or
6.5 jig 65zinc chloride) excreted 25% of the radioactivity in the feces and
less than 5% in the urine over a 15-day observation period (Sheline et al.,
,1943b).
2. Other Zinc Compounds
In humans and other mammalian laboratory species, fecal excretion is the
predominant route of zinc loss (as much as 70-80% of the ingested amount), and
urinary excretion is a relatively insignificant route (1-2% of the ingested
amount) (U.S. EPA, 1987). A portion of the zinc excreted with the fecal
matter represents absorbed zinc that is lost from the body with the bile
(Wastney et al., 1991).
In one study of six healthy adult human males fed conventional foods, five
were able to maintain zinc balance in the tissue (equivalence between dietary
zinc and total excretory zinc) at an intake of as little as 5.5 mg/day (King,
1986). Balance apparently was achieved by a decrease in the fecal excretion
of zinc which may have resulted from either an increase in zinc absorption
and/or a decrease in the zinc lost in the gastrointestinal secretions.
Following dietary supplementation of rats with zinc (as zinc oxide) at 600 ppm
for 7-42 days (Ansari et al., 1975) or at 1,200-8,400 ppm for 21 days (Ansari
et al., 1976) and intubation with an oral tracer dose of 65zinc (4 pCi 65zinc
chloride, specific activity 2.1 |iCi/mg zinc), there was a linear increase in
fecal excretion of stable zinc in proportion to the dietary intake. The fecal
excretion of the labeled zinc increased as concentrations increased to
1,200 ppm and then remained relatively constant with the higher supplemental
doses.
Rats receiving the same amounts of different zinc salts in their diets
(53.2 ppm of either zinc chloride, zinc sulfate, zinc phosphate or zinc
citrate) over a 4-day period, excreted similar amounts of fecal zinc
(87.0-98.1% of intake) and urinary zinc (1.43-2.04% of intake) (Seal and
Heaton, 1983). Balance studies showed no differences in fecal excretion,
total excretion or retention of zinc among rats receiving diets containing
different forms of zinc.
V-7
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VI. HEALTH EFFECTS
A. Health Effects in Humans
Following acute oral exposures of humans to high doses of zinc, symptoms
including vomiting, diarrhea, lethargy, and irritation of the mouth, throat
and stomach may occur. Acute symptoms of zinc toxicity from exposure via
inhalation include dyspnea, chest constriction, retrosternal and epigastric
pain, hoarseness, stridor, cough, lacrimation, expectoration and an occasional
hemoptysis. Pale grey cyanosis usually develops, pulse is elevated, fever is
present and bronchopneumonia can develop. Edema is widespread. Death is
usually due to respiratory insufficiency. Effects are related to the
hygroscopic nature of the inhaled zinc particles which combine with moisture
in the lungs to form caustic substances. Zinc chloride is corrosive to skin
and mucous membranes. Oral exposures to zinc acetate for longer periods of
time (6-12 weeks) were shown to reduce serum erythrocyte superoxide dismutuse
(E-SOD) and ceruloplasmin (biomarkers of copper status) as well as HDL levels.
All of the reports of health effects in humans are based upon studies with
small numbers of subjects. Therefore, they may not reflect the responses of
the general population because of variabilities due to factors such as sex,
age, race, etc.
1. Short-Term Exposure
a. Zinc Chloride
Data concerning the effects of zinc chloride in humans after short-term oral
exposure are limited to a few case reports. These are described below.
In 1981, Potter reported on a single case of ingestion of 4 oz of an acid
soldering flux containing zinc chloride (11% as measured by atomic absorption
spectrophotometry) by a 28-month old child weighing 13.1 kg (approximately
1,000 mg/kg)• The child vomited twice within 5-10 minutes, before admission
to a hospital for emergency treatment. Subsequent vomitus contained Hematest-
positive material. Although the child was lethargic, no adverse effects were
noted upon physical examination except for an increase in serum zinc levels at
a high of 1,944 jig/dl approximately one hour after ingestion. Twelve hours
after the administration of a single dose of 150 mg of calcium disodium
ethylenediamine-tetra acetic acid (EDTA) in 75 mL of 1:5 normal saline, the
serum zinc level was 134 |ig/dl (normal values are 77-137 ng/dl).
Esophagoscopy was generally normal except for some minor bleeding from mucosal
abrasions. Radiologic examination of the skeleton, electrocardiographic
examination of the heart and detailed neurological evaluations were all within
normal limits. Two years after the incident, the condition of the child
remained unremarkable. It was felt that the powerful emetic properties of the
zinc chloride prevented absorption of the ingested dose thereby limiting
systemic effects.
In a similar incident reported by Chobanian (1981), a 24-year old male
ingested 3 oz of a solder flux containing zinc chloride (concentration not
specified). Symptoms were manifested as an immediate burning of the mouth and
throat and were accompanied by severe abdominal pain, nausea and vomiting.
While vital signs were normal, the patient developed indications of lethargy.
Abnormal laboratory findings included elevated white cell counts, blood sugar,
VI-1
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amylase and zinc while the serum calcium was mildly decreased. Urinalysis
disclosed a microhematuria without casts or other cellular elements. Physical
examination revealed erythema, edema and erosion of the pharynx and esophagus
without ulceration. A mild diffuse erythema of the stomach was evident.
Within 24 hours of chelation therapy serum zinc levels were normal,
50-90 ng/dl, while the microhematuria persisted over the next 72 hours with no
signs of renal dysfunction. Clinical signs, in this case, were suggestive of
acute pancreatitis. This is consistent with zinc in the pancreatic
secretions. Pancreatic damage might account for the increased serum glucose
levels encountered in this individual. The amount of zinc chloride ingested,
in mg/kg, could not be determined from the available information.
Markwith (1940) reported on a single case of industrial intoxication occurring
in a closed environment due to exposure to solders that contained copper and
zinc chloride. Clinical symptoms included malaise, headache, chills and pain
on swallowing. Physical examination revealed a reddening and loosening of the
mucous membranes of the mouth and throat, followed by the membranes becoming
dry and leathery until swallowing became impossible. On the 10th day
following exposure, a carbuncle formed on the chin. The patient died on the
13th day with clinical signs of sepsis.
A number of studies reported toxic effects in humans following the inhalation
of particulate zinc chloride smoke in military and industrial environments.
Toxic symptoms mainly involved the mucous membranes of the nasopharynx and
respiratory tract. Damage to the lungs was minimal, with little or no venous
congestion. Symptoms associated with inhalation exposures to zinc chloride
include inflammation of the respiratory tract, respiratory difficulty,
bronchopneumonia, sore throat, metallic taste, cough, chest pain, fever,
headache, fatigue, nausea, vomiting, edema, and necrosis and hemorrhage of
mucous membranes (Evans, 1945; Milliken et al., 1963; Macauley and Mant, 1963;
Hjortso et al., 1988; Matarese and Hatthews, 1986; Schenker et al., 1981).
Death may occur following serious exposures (Evans, 1945; Milliken et al.,
1963; Macauley and Mant, 1963; Hjortso et al., 1988). Following less serious
exposures, full recovery may occur within 1-6 weeks (Evans, 1945; Schenker
et al., 1981). Although these studies generally did not provide quantitative
information on exposure, Stocum and Hamilton (1976) analyzed the dose-response
effects from several reports of inhalation injuries due to exposure to zinc
chloride smoke. Based on the concentration and exposure duration, these
authors categorized inhalation effects as indicated in Table VI-1.
b. Other Zinc Compounds
Data on adverse health effects in humans exposed to excessive amounts of zinc
are limited. Since zinc is an essential element for human growth and
nutrition, most of the available studies on humans relate to functional
consequences of zinc deficiency, pharmacologic use of zinc supplements,
accidental exposure (mostly to zinc fumes) in occupational settings, or cases
involving suicide (Cousins, 1986; McClain et al., 1985; Prasad, 1985; Prasad
et al., 1978; U.S. EPA, 1987).
King (1986) conducted a study in which dietary zinc was reduced from 16.5 to
5.5 mg/day in the diets of 6 men over an 8-week period. Several metabolic and
physiological changes were observed: serum albumin, prealbumin and retinal-
binding protein concentrations decreased. Also, the levels of thyroid-
stimulating hormone (TSH), T4 (thyroxine), free T4, and the basal metabolism
VI-2
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Table VI-1
Categories of Effects Due to the Inhalation of Zinc Chloride Smoke"
Dosageb
g-min/m3 Effect Grade
NAe Essentially no effect, some awareness
of presence
0.16 to 0.24 Noticeable irritation of nose, throat
and chest
1.7 to 2.0 Marked irritation, hospitalization
and treatment required
20 Severe irritation, chemical pneumonia,
hospitalization and treatment
required
50 Massive injury, may be fatal
8 Reference: Stocum and Hamilton, 1976.
b Concentration x exposure time
e NA - not applicable
VI-3
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rate decreased. Fasting plasma glucose levels increased. While none of the
changes were large and may not be clinically significant, the author surmised
that 5.5 ing/day is probably below the amount required for good tissue status.
Short-term, high-level intake, resulting in acute gastroenteritis, can result
from consuming foods improperly stored in zinc-containing vessels (NRC, 1989).
It has been reported that the emetic dose of zinc is 225-450 mg in humans
(Brown, 1964). Approximately 300-350 persons developed intestinal symptoms
such as severe diarrhea with abdominal cramping (about 50% developed gross
blood in the feces) within 24-48 hours after ingesting food which became
contaminated with zinc during preparation and storage in galvanized containers
(Brown, 1964). The concentration of zinc in the fecal matter collected from
several subjects during the investigation of the food poisoning episode ranged
from 59 to 1,200 mg/kg as compared to a normal value of 90-100 mg/kg. The
available data do not present enough information for an exposure calculation.
In another episode, individuals consuming a zinc-contaminated alcoholic fruit
punch developed a hot taste and dryness in the mouth, nausea, vomiting and
diarrhea from 20 to 90 minutes after ingestion (Brown, 1964). In the post-
acute phase, the individuals reported general discomfort and muscular pain.
All of the victims recovered from the acute adverse effects within 24 hours of
exposure. The zinc concentration of a 5 oz serving of the punch was 325 mg or
a dose of 4.6 mg zinc/kg for a 70-kg person. The dose increased with the .
number of glasses of punch consumed.
Gastrointestinal distress has also been reported in individuals receiving zinc
supplements (as the acetate or sulfate) of 50-150 mg/day over a period of
6 weeks to 2 years (Freeland-Graves et al., 1982; Prasad et al., 1978; Samman
and Roberts, 1988).
An accidental parenteral administration of 7.4 g zinc sulfate over a 60-hour
period (approximate dose 2.96 g/day or 289 mg zinc/kg/day in a 60-kg female)
to a Crohn's disease patient produced hypotension, pulmonary edema, diarrhea,
vomiting, jaundice, oliguria, high serum zinc (4.184 mg/100 mL; normal serum
zinc is 0.075-0.124 mg/100 mL) and death (Brocks et al., 1977).
Chandra (1984) reported on the effects of administering 150 mg of dietary zinc
(as the sulfate salt) twice daily (300 mg zinc/day) to 11 adult males for
6 weeks. Average dietary zinc during the supplementation period was
10.1 mg/day, based on 24-hour recall data and 11.2 mg/day in the pretest
period. Thus, the daily zinc intake was 311 mg/day (or 4.4 mg/kg/day for a
70-kg male) during the supplementation period. Fasting serum cholesterol,
high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-
cholesterol and triglycerides were measured on a biweekly basis for 6 weeks;
follow-up measurement of these parameters was conducted at 2 and 10 weeks
after the supplement use ended. Total lymphocytes, T-lymphocytes and
B-lymphocytes also were measured. Lymphocyte activity was monitored through
polymorphonuclear migration response to chemotactic phytohemagglutinin (PHA)
stimulation and phagocytosis of opsonized bacteria.
Plasma zinc values increased during the supplement administration period.
There was a significant decrease in serum HDL values during weeks 4 (p<0.1)
and 6 (p<0.01) with a return to baseline levels at week 16 (Chandra, 1984).
LDL-cholesterol levels were significantly increased (p<0.05) at week 6, but
there were no significant changes in serum cholesterol and triglycerides.
VI-4
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There were no significant changes in lymphocyte counts during the period of
zinc supplementation, but polymorphonuclear response to PHA stimulation
(chemotactic migration) and phagocytosis were diminished (Chandra, 1984),
suggesting that there was some functional impairment in immunological response
which accompanied the zinc supplementation. This study indicates a Lowest-
Observed-Adverse-Effect-Level (LOAEL) for zinc of 4.4 mg/kg/day.
Supplementation with 160 mg zinc (as zinc sulfate) was found to lower HDL-
cholesterol values in 11 healthy males when administered over a 5-week period
(Hooper et al., 1980). A control group of eight subjects received a placebo.
Fasting cholesterol, HDL-cholesterol and triglycerides were determined on a
weekly basis for 7 weeks and again 11 weeks after the end of supplementation.
Dietary zinc levels were not measured. The total zinc intake was 176 mg/day
(or 2.5 mg/kg/day f°r an individual with a 70-kg body mass and a dietary
intake of 16 mg zinc/day). After an initial HDL increase during the first
2 weeks of supplementation, HDL levels became significantly lower than those
for the controls during weeks 4 through 7 (p-0.002 to 0.0001) (Hooper et al.,
1980). HDL levels returned to normal 11 weeks after supplementation ended.
Serum cholesterol, LDL-cholesterol and triglycerides did not change
significantly during the study; serum zinc levels increased during the
supplementation period. Serum cholesterol values were normal. This study
suggests a LOAEL of 2.5 mg/kg/day for zinc.
Groups of 15 healthy white males were administered 0, 50 or 75 mg/day zinc (as
zinc gluconate) for a 12-week period (Black et al., 1988). The subjects were
given instructions to avoid foods high in calcium, fiber and phytic acid,
dietary constituents which have a negative impact on zinc absorption.
Subjects also were told to restrict their intake of zinc- and copper-rich
foods. Three-day dietary records were collected on a biweekly basis. These
records indicated that the zinc intakes of the three treatment groups were
12.5, 14.0 and 9.5 mg/day, respectively. Based on the average body weights
for each treatment group, the doses for diet plus supplement correspond to
zinc intakes of 0.16, 0.85 and 1.10 mg/kg/day.
Biweekly fasting blood samples were collected from all subjects and analyzed
for total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, zinc
and copper. Urinary zinc and copper values were also determined. There was a
general decline in the mean serum HDL-cholesterol for the 75 mg supplement
group between weeks 6 and 12. HDL values for this group were significantly
lower than those for the placebo group at weeks 6 and 12 (p>0.05). There was
also a decline in the HDL values for the 50 mg group from weeks 8 through 12.
However, this decline was not significantly different from that for the
controls until the 12th week of treatment (p<0.05). Serum zinc, copper, total
cholesterol, LDL-cholesterol, and triglycerides did not appear to be affected
by treatment.
Samman and Roberts (1988) administered 150 mg zinc (as the sulfate salt) to a
group of 21 healthy young male and 20 female volunteers in a 12-week double
blind cross-over trial. The subjects were instructed not to change their
lifestyle, including their diet, alcohol consumption and exercise patterns
during the study. No other dietary directions were given. The subjects were
seen at 3-week intervals. The duration of the zinc exposure period was
6 weeks; subjects were given a placebo for the other 6 weeks. Non-fasting
blood samples were collected for determination of plasma lipoproteins (LDL,
HDL, HDLj, HDLj) and indicators of copper status (hematocrit, ceruloplasmin,
VI-5
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E-SOD, Cu-Zn-SOD). There was a slight, but nonsignificant, decline in the HDL
values for both males and females. There also appeared to be a shift in HDL
distribution from HDLj to HDLj. There was a slight nonsignificant increase in
LDL levels in males after 6 weeks of supplemental zinc, but there was a
significant decrease in the LDL values for females. Accordingly, the exposure
to zinc appeared to have no influence on the cardiovascular risk for the male
subjects and a benefit for the females. There was considerable variability in
the LDL response of the females since only about 50% of the study population
exhibited a decrease in LDL values; the remainder of the subjects had LDL
values that remained constant or increased.
A study of HDL response to zinc in premenopausal females suggests that
supplemental zinc does not appear to have the sane effect on females that it
has on males. Healthy adult females were given supplemental zinc doses of 0,
15, 50 and 100 mg/day zinc as zinc acetate for 60 days (Freeland-Graves,
1982). Three-day dietary records kept at weekly intervals were used to
evaluate the nutrient content of the diet including values for dietary lipids,
zinc (8.1-8.5 mg/day) and copper (2.6-2.7 mg/day). Fasting plasma
cholesterol, HDL-cholesterol and zinc were monitored at biweekly intervals.
Cholesterol values were not reported and there was no measurement of LDL
values. A transitory decrease in HDL values was noted at 4 weeks only in the
group receiving the 100 mg/day supplement and 8.1 mg/day zinc in the diet
(diet records) (or 1.8 mg/kg/day based on a 60-kg body weight). This decrease
in HDL values was not apparent at 6 and 8 weeks. Serum zinc levels were also
highest in these subjects at 4 weeks.
A very slight but statistically significant (p-0.04) 2 mg/dL increase in HDL
cholesterol was seen in a group of 22 elderly male and postmenopausal female
subjects (sex ratio unknown) 8 weeks after they ceased using zinc supplements
(Goodwin et al., 1985). Serum zinc values fell from 92 to 86 |ig/dL during the
same period. The average supplement intake was 29.1 mg/day (with a range of
17.5-52.2 mg/day). The increase in HDL values seemed to be greatest for the
subjects with the highest ratings for physical activity. Although the data in
this study are far from conclusive with regard to the relationship between
zinc and HDL values, they do add to the weight-of-evidence which suggests that
supplemental zinc can impact HDL levels.
Healthy adult males given 25 mg of zinc (as the gluconate) twice daily for a
6-week period, displayed a significant decrease (p<0.05) in E-SOD activity at
the end of 6 weeks of exposure (Fischer et al., 1984). The decreased
concentration of E-SOD is indicative, not only of a copper deficiency, but
also of a diminished capacity of the cells to respond to oxidative stress.
There were no differences in serum copper levels or ceruloplasmin activity in
the 13 members of the supplement group as compared to the controls. Serum
zinc levels were significantly increased in the supplement group after
2 weeks. Dietary zinc was not measured. The diet plus supplement intake was
66 mg/day or a LOAEL of 0.96 mg/kg/day for a 70-kg male with a dietary intake
of 16 mg/day.
Almost identical results were obtained from a 10-week study of zinc
supplementation in 18 healthy adult females given supplements of 50 mg
zinc/day (as zinc gluconate) (Yadrick et al., 1989). E-SOD concentrations
declined over the 10-week supplementation period and, at 10 weeks, were
significantly different (p<0.05) from values during the pre-treatment period.
Ceruloplasmin concentrations were not altered, but serum zinc was
VI-6
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significantly increased. There was also a significant decline in serum
ferritin and hematocrit values at 10 weeks. However, neither ferritin nor
hematocrit values were altered when iron (50 ing/day) was added to the zinc
supplement which corrected the iron-zinc imbalance but not the copper-zinc
imbalance. The zinc plus supplement intake for the females was 59.7 ag/day or
a LOAZL of 1.0 mg/kg/day for a 60-kg female with a dietary copper intake of
9.7 mg/day.
Several indicators of a copper deficiency were noted in the 20 females
administered 150 mg zinc/day for 6 weeks during a double blind placebo study
(Samman and Roberts, 1988). Ceruloplasmin, E-SOD and Cu-Zn-SOD concentrations
were all significantly decreased during the zinc supplement period when
compared to the values during placebo administration. There was a 20%
decrease in E-SOD and a 23% decrease in Cu-Zn-SOD at the end of 6 weeks. The
same parameters were very slightly decreased in the males, changes were not
significant.
Nine healthy men (21-27 years of age) were given daily diets containing
2.63 mg copper/day (0.13 mg from the diet and 2.5 mg from copper sulfate) and
1.8, 4.0, 6.0, 8.0, 18.5 or 20.7 mg zinc (1.8 mg from the diet and the
remainder as zinc carbonate) for 1- or 2-week periods randomized over 9 weeks
(Festa et al., 1985). The purpose of this protocol was to examine the effect
of zinc on copper excretion and retention. The weekly mean (± SEM) plasma
copper concentrations (81 ± 3.3 to 100 ±5.8 jig/dL) remained within the normal
range with all zinc doses. On two occasions, the 18.5 mg zinc/day dose was
administered for 2 consecutive weeks after 1 week on a lower zinc dose
(1.8-8 mg/day). In each instance, the mean fecal copper excretion was
increased during the second week as compared to the first (from 1.92 mg/day to
approximately 2.62 mg/day), and copper balance became more negative. This
study demonstrated that feeding 18.5 mg zinc/day (an amount only 3.5 mg above
the recommended dietary allowance (RDA) which is 15 mg zinc/day for adult
males) resulted in elevated fecal copper excretion and reduced copper
retention during a 2-week period.
Some data suggest that supplemental zinc impacts iron absorption. Crofton
et al. (1989) administered solutions of 23.5 mg of ferrous iron (as the
hydrated sulfate salt) either alone or combined with zinc (as the sulfate
salt) (27.5 or 68.5 mg zinc) to a group of seven subjects and measured the
area under the plasma time curves. The minerals were administered after an
overnight fast and testing episodes were separated by 35 days. There was an
incremental decrease in the area under the curve (AUC) for iron at 3 and
6 hours when the combination of zinc and iron was used. The lower zinc
concentration decreased the AUC for iron by 66% at 3 hours and 72% at 6 hours;
the higher dose decreased the value by 80% at 3 hours and by 90% at 6 hours.
2. Dermal/Ocular Effects
a. Zinc Chloride
Contamination of the eye with concentrated solutions of zinc chloride causes
severe damage to both the cornea and the lens. In 1973, Houle and Grant
reported on a case of splash injury with concentrated zinc chloride
galvanizing solution (pH 3.53) to both eyes and the nasal passages of a
38-year old male. Despite extensive irrigation with water, the initial
ophthalmic examination revealed a reduced visual acuity, puffy swelling of the
VI-7
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eyelids, pale and markedly chemotic conjunctiva and epithelial edema of the
cornea. The cornea remained permanently scarred with persistent gray spots
present beneath the anterior lens capsule. Prior to this injury, uncorrected
visual acuity was 20/20. Two years later, visual acuity in the more severely
damaged right eye was 20/200 correctable by refraction to 20/60 while the left
eye was correctable to 20/30.
Examination of the nasal passages revealed whitish speckled eschar-like
lesions on the anterior mucosa with complete bilateral nasal obstruction. The
patient permanently lost all sense of smell from the zinc chloride injury
(Houle and Grant, 1973).
Du Bray (1937) described symptoms of fatigue, anorexia, weight loss and pain
in the long bones of a man exposed to aqueous zinc chloride solution by
frequent and long-term immersion of the hands. Concentration of the aqueous
solution was not reported.
b. Other Zinc Compounds
No information was found in the available literature regarding dermal/ocular
effects in humans of other zinc compounds.
3. Long-term Exposure
a. Zinc Chloride
No information was found in the available literature regarding long-term
health effects in humans of zinc chloride.
b. Other Zinc Compounds
Anemia and neutropenia developed in a 44-year-old male patient who had taken
43 mg zinc/day (as zinc gluconate) for a 2-year period (Simon et al., 1988).
Serum zinc was elevated (262 jig/dL) while serum copper (15 ng/dL) and
ceruloplasmin (2 ng/dL) values were low; hemoglobin (9 g/dL), hematocrit
(25.7%) and white cell count (2,000/(»L; 6% neutrophils) were also depressed.
At 7 weeks after discontinuing the supplement, all physiological measurements
of copper and zinc status returned to normal and the patient's anemia was
resolved.
A 35-year-old woman with a history of gastrointestinal problems (gastric
ulcers, reflux gastritis, intestinal obstruction and ulceration) was
prescribed a zinc supplement for ulcers of the mouth and tongue (Hoffman
et al., 1988). For a 10-month period she ingested 142-197 mg zinc/day as the
sulfate salt. Although the oral ulcers responded to the zinc treatment, the
patient developed a microcytic hypochromic anemia which did not respond to
6 months of iron therapy. After 10 months of the zinc therapy combined with
iron for 6 months to resolve the anemia, the patient's serum copper and
ceruloplasmin values were extremely low (0.15 yg/dL for copper and 0 for
ceruloplasmin). (Normal is 0.75-1.45 jig/dL for copper and 22.9-43.1 mg/dL for
ceruloplasmin.) The use of the zinc supplement was then discontinued and the
patient was given 2 mg/day copper for 2 months. Although there was some
initial increase in serum copper and ceruloplasmin, the patient's
hematological parameters did not improve, and zinc excretion continued to be
high. Over a 5-day period, a total dose of 10 mg copper (as the chloride
VI-8
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salt) was given intravenously. Within 2 weeks, ceruloplasmin increased to
19.5 mg/dL. Oral copper therapy (2 mg/day) was continued. The patient's
anemia was resolved, serum copper and ceruloplasmin, and white cell count
returned to normal after 5 months.
Prasad et al. (1978) reported the occurrence of a microcytic anemia and
neutropenia in a sickle-cell anemia patient who had received 75-200 mg/day
zinc (as either the acetate or sulfate salt) as an antisickling agent for a
period of 2 years. The patient's condition was discovered when he enrolled in
a study involving the use of zinc to control pain in sickle-cell patients.
Based on plasma zinc and copper data which had been collected over the 2-year
period, the zinc supplement caused an initial increase in plasma zinc values
which gradually decreased with time; plasma copper values continuously
decreased during the zinc supplementation period but increased when 1 g of
copper (as copper sulfate) was added to the therapy. As a result of these
findings, 13 other individuals who were taking part in a study of pain in
sickle-cell patients were surveyed. Ceruloplasmin levels were below normal
for seven patients. The addition of copper to the therapeutic program for
'these individuals resulted in normalization of the ceruloplasmin values.
B. Health Effects in Animals
In animal studies, oral LD50s as well as average lethal oral doses have been
reported for zinc compounds in several species. Zinc chloride causes both
skin and eye irritation, and percutaneous toxicity has been demonstrated.
Oral administration of zinc chloride to rats for up to 6 weeks precipitated a
deficiency syndrome when combined with a synthetic diet low in pantothenic
acid. Renal damage was observed in rats exposed orally to zinc for 90 days.
Several studies indicate that high doses of zinc can interfere with
reproductive function and can be fetotoxic. Mutagenicity and carcinogenicity
studies have yielded equivocal or negative results.
1. Short-Term Exposure
a. Zinc Chloride
Limited data are available on the toxic effects of zinc chloride following
acute oral exposures in animals (Table VI-2). In 1941, Voodard and Calvery,
as cited in Calvery (1942), reported acute median oral lethal doses of
350 mg/kg for rats, 350 mg/kg for mice and 200 mg/kg for guinea pigs. These
data suggest that the guinea pig may be slightly more sensitive to the acute
toxicity of zinc chloride than other laboratory animals. In 1974, Yakuri
indicated an oral LD50 of 502 mg/kg in male dd-K mice. Hahn and Schunk (1955)
reported an average oral lethal dose of 750 mg/kg in rats and 1,000 mg/kg in
rabbits (cited in Hill et al., 1978). Rats were given a single oral dose by
gavage of zinc chloride in solution at 500, 750 or 1,000 mg/kg. Approximately
40% of the dosed rats died within 24 hours. Upon necropsy, perforations of
the stomach or penetration into the liver tissue, as well as pyloric stenosis,
were evident. Mucosal damage was less prevalent among animals dying early,
but ataxia, tremor, dyspnea and a drop in body temperature were evident. A
dose response was not indicated. Doses in rabbits were reported to be 250,
500 or 1,000 mg/kg. Similar effects were reported upon necropsy. Mortality
rate was not specified. Domingo et al. (1988) reported oral LD50 values for
zinc chloride of 528 mg/kg in rats and 605 mg/kg in mice.
VI-9
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Table VI-2
Acute Oral Studies of Zinc Chloride and Other Zinc Compounds
Chemical
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc chloride
Zinc sulfate
Zinc sulfate
Zinc sulfate
Zinc acetate
Zinc acetate
Zinc nitrate
Zinc nitrate
Species
Rat
Rat
Rat
Mouse
Mouse
Mouse
Guinea pig
Rabbit
Rat
Rat
Mouse
Rat
Mouse
Rat
Mouse
Effect
Median lethal dose
LD50
Average lethal dose
LD50
Median lethal dose
LD50
Median lethal dose
Average lethal dose
L050
LD50
LD50
LD50
L050
LD50
LD50
Dose
(ing/kg)
350
528
750
1,000
350
502
200
1,000
623
920
337
237
86
293
204
Reference
Woodward and Calvery, 1941
Domingo et at., 1988
Hahn and Schunk, 1955
Domingo et al., 1988
Woodward and Calvery, 1941
Yekurl, 1974
Woodward and Calvery, 1941
Hahn and Schunk, 1955
Domingo et al., 1988
Fabrlclo, 1974
Domingo et al., 1988
Domingo et al., 1988
Domingo et al., 1988
Domingo et al., 1988
Domingo et al., 1988
-------
Gross et al. (1941) studied the effects of orally administered zinc chloride
in young female rats (40 g average weight) fed a synthetic diet. The animals
were orally intubated with a vitamin-supplemented filtrate fraction low in
pantothenic acid. Oral intubation with zinc chloride in cod liver oil at
4 mg/day (approximately 100 mg/kg/day for a 40-g rat) occurred at 4 hours
after the vitamin supplement, 6 days/week for up to 6 weeks. Deficiency
symptoms characterized by growth retardation, severe alopecia, rusting and
ruffling of the fur, and crusting of the nose, chin and eyelids, were reported
in i50% of the rats after 5 weeks of treatment. Control animals grew at a
slightly suboptimal rate and had some rusting of the fur which cleared
spontaneously, but developed no other symptoms. Black rats similarly treated
with 5-6 mg/day of zinc chloride in olive oil developed alopecia and a severe
graying of the coat as well as crusting of the nose, chin, tail and eyelids.
Oral supplementation of the daily regimen with 150 pg of synthetic calcium
pantothenate reversed the progress of the deficiency symptoms, even with
continued intubation of the zinc chloride. Neither a No-Observed-Adverse-
Effect-Level (NOAEL) nor a LOAEL could be determined.
b. Other Zinc Compounds
The acute oral LD50 value for zinc sulfate in rats was 920 mg/kg (Fabrizio,
1974) . LDeo values were calculated in rats and mice (10/dose group) for four
zinc salts using the Litchfield-Wilcoxon method after intragastric
administration of a single dose of the salt in solution (Domingo et al.,
1988) . The LD50 for zinc (as zinc acetate dihydrate) in rats was 237 mg/kg
and in mice, 86 mg/kg. The LD50 value for zinc nitrate hexahydrate in rats
was 293 mg/kg and in mice it was 204 mg/kg. Zinc sulfate dihydrate had an
LD50 of 623 mg/kg in rats and 337 mg/kg in mice.
Two studies on the homeostasis and tissue distribution of zinc in male
Cherokee Sprague-Dawley rats weighing 100-120 g have been described (Ansari
et al., 1975, 1976). In the 1975 study, one control group (seven rats) and
four experimental groups (nine rats/group) were fed zinc oxide in the diet at
0 or 600 ppm for 7, 14, 21 or 42 days (Ansari et al., 1975). In the 1976
study, zinc oxide was fed to groups of 6-8 rats at 1,200, 2,400, 3,600, 4,800,
6,000, 7,200 or 8,400 ppm for 21 days (Ansari et al., 1976). There was
increased excretion when zinc added to the diet was elevated above the
1,200 ppm level. This finding, as well as the observed sharp increases in
stable zinc in the liver, kidney, and tibia at the highest dietary zinc intake
(8,400 ppm), suggested some breakdown in zinc homeostasis. However, body
weight gain and food consumption were similar in controls and zinc-treated
groups, and gross clinical signs of toxicity such as skin lesions, diarrhea
and muscular incoordination were not observed in any of the treated groups.
Several case studies of dogs which have swallowed zinc-containing coins or
metal objects report hemolytic anemia in the affected animals (Latimer et al.,
1989; Luttgen et al., 1990; Torrance and Fulton, 1987). In these cases, it is
impossible to determine the dose of zinc received by the animal in order to
unequivocally attribute the symptoms to zinc since zinc was not the only metal
present in the objects swallowed.
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2. Skin and Eve Irritation. Dermal Sensitization
a. Zinc Chloride
In a test for dermal irritation, 0.5 ml of a 10% solution of zinc chloride was
applied to the skin of six male albino rabbits (Williams, 1984). The
application area was prepared for testing by clipping the area free of hair.
The area was covered and occluded for 24 hours prior to scoring for erythema
and edema. The authors reported that zinc chloride caused severe edema and a
necrotic erythema in the test area. When 0.1 ml of the 10% zinc chloride
solution was instilled into the lower conjunctival sac of one eye,
conjunctivitis and a moderate, penetrating corneal opacity were observed.
Recovery from these effects occurred after 7-14 days.
Percutaneous administration of 2 ml of 0.239 moles of aqueous zinc chloride to
a 3.1 cm2 area of the skin of guinea pigs (mean weight 375 g) resulted in a
cessation of weight gain after 1 week. Mortality was unaffected over the
four-week observation period. A low absorption rate of less than 1.0 % per
5 hour exposure period was indicated (Wahlberg, 1965).
Experiments were conducted in albino rabbits (Johnstone et al., 1973) to
evaluate the effects of zinc chloride on the eye with the possibility of
developing more specific treatment techniques for use in human injuries.
Corneal injuries were obtained by exposure for one minute to a 50% solution of
zinc chloride followed by a ten second irrigation with water to remove excess
test solution. One group of rabbits received no further treatment, while a
second group received a 15 minute eye irrigation with either 0.9% sodium
chloride or 0.05 M neutral sodium ethylenediamine-tetra acetic acid (EDTA) at
one minute post-exposure. A third group received the same two treatments
starting at 15 minutes after exposure to the 50% zinc chloride. Zinc content
of the cornea was measured at various time intervals following injury.
Neither treatment was effective in its rate of removal of zinc when compared
to the untreated cornea injured by exposure. While treatment with 0.05 M EDTA
did not prevent the corneal opacification seen following injury with zinc
chloride, treatment within one minute following injury did result in a
progressive improvement. By 2 weeks after injury the corneal opacity in the
EDTA treated eyes was 1+, a marked improvement over those treated with normal
saline. If treatment was delayed for 15 minutes, neither procedure resulted
in improvement.
Johnstone et al. (1973) also conducted experiments with excised bovine corneal
buttons. They found that zinc chloride acts as a fixative or denaturant of
the cornea and that EDTA acts to some degree to reverse this denaturation when
the exposure is relatively mild.
b. Other Zinc Compounds
No reports were found on the toxic effects of zinc following dermal exposure,
although zinc may be absorbed across the broken and unbroken epithelial
membrane (NRC, 1979).
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3 . Longer-Term Exposure
a. Zinc Chloride
All data on the longer-term administration of zinc chloride are associated
with reproductive, developmental or carcinogenic screening studies. Details
are presented in the related sections.
b. Other Zinc Compounds
Weanling COX-SP rats of both sexes (180 control rats and 40 rats/experimental
group) were administered zinc phenolsulfonate (a cosmetic product) for 91 days
at dietary levels of 62.5, 250 or 1,000 mg/kg/day (corresponding to calculated
doses of 1, 4 and 16 mg zinc/kg/day, respectively, based on 200-g weight and
20 -g/ day food consumption). There was no unusual variation in food
consumption, body weight gain or hematological parameters between the control
and treated groups. One mg zinc/kg/day produced minor, randomly distributed
variations in organ-to-body weight ratios and increased testicular fluid at
the 4-week necropsy. The 4-week necropsy also revealed hydropic changes at
the intermediate dose and increased vacuolar changes at the high dose in the
seminiferous tubules. These effects were absent at the 8 -week necropsy and at
the end of the study, suggesting a temporary failure of zinc homeostasis and a
subsequent endogenous repair (Elder, 1986). The influence of the organic
cation on toxicity, if any, cannot be determined from the results presented in
this study. Usefulness of this study for the calculation of an HA value is
questionable, given the type of compound used.
Doses of 0, 47.6, 95.3 or 190.6 mg zinc/kg/day (as the acetate salt) were
administered to groups of 10 female Sprague-Dawley rats in drinking water for
90 days (Llobet et al., 1988). The animals were observed daily for clinical
signs, food and water consumption, and urine and fecal excretion; body weights
were determined weekly. Prior to sacrifice, blood samples were collected and
analyzed for biochemical indices and hematological parameters. After
sacrifice, the major organs were weighed and examined histologically. There
were no differences for food consumption, body weight or fecal matter
production between the dose groups. The animals in the highest dose group
exhibited apathy, decreased water consumption and urine production, increased
serum urea and creatinine. There were no differences in hematocrit,
hemoglobin or serum enzymes between groups. At the two highest dose levels
there were significant increases in the zinc concentration in the liver,
kidneys, heart, bone and blood but no significant differences in organ weights
for the liver, kidney and heart. Lesions were seen in the kidneys of the
animals exposed to the highest dose. Bowman's capsule epithelial cells were
flattened and there was loss of some of the surface epithelial cells in the
proximal tubules along with pyknotic nuclei in the tubular epithelial cells.
There were no adverse effects associated with the 95.3 mg/kg/day dose (NOAEL) ,
but there were some indications of renal damage at the LOAEL of
190.6
Male and female C3H mice were provided with zinc sulfate (0.5 g/L) in
distilled drinking water ad libitum for up to 12 months. The outward
appearance, appetite and activity were similar to controls (Aughey et al . ,
1977). A total of 150 mice, including an unspecified number of controls, was
used. Plasma zinc levels in the zinc -supplemented mice rose to a peak of
2.1 jig/mL at day 3 of ingestion while the control level was 1.02 |ig/mL;
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thereafter, a plateau with minor fluctuations was evident over the 34-day
observation period. (On day 34, plasma zinc was about 1.5 ng/mL.) No
significant difference in zinc content between the control and zinc-
supplemented groups was observed for the liver, spleen, or skin over a 6-month
observation period; no sex difference was observed with respect to zinc
content of these tissues. Plasma insulin and glucose levels were unaffected
by dietary zinc supplementation. However, some histological and
ultrastruetural changes were noticed in tissues of zinc-supplemented groups as
compared to tissues of controls. Individual beta cells of the pancreas were
larger than in controls. The zona fasciculata of the adrenal cortex was
hypertrophied and highly positive to lipid staining at 3 months of zinc
ingestion; at 6 months or more, the glomerulose and reticularis zones also
gave strongly positive reactions for lipid staining. Cells of the anterior
lobe of the pituitary showed morphological changes consistent with
hyperactivity. It was not possible to derive a LOAEL or a NOAEL from this
study for the following reasons: only one dose was used, the amount of
ingested zinc could not be estimated because water spilled during drinking,
intestinal absorption was uncertain, and data on body weights were
unavailable. However, assuming an approximate water consumption of 10 mL/day
and a mean body weight of 25 g, the daily dose in this study corresponds to
about 200 mg zinc sulfate/kg/day.
4. Reproductive Effects
a. Zinc Chloride
In general, results of oral administration indicate maternal toxicity
evidenced by a decrease in weight gain when zinc chloride administered by
gavage at a dose of 150 mgAg/day. In contrast, administration in the diet
during reproduction revealed no toxic effects at levels up to 250 mg/kg/day.
Heller and Burke (1927) reported no toxic effects on growth, reproduction or
offspring of rats following the ingestion of zinc chloride in the diet. Diets
containing 0.25 or 0.5% of zinc as zinc chloride were administered during
breeding and continued for one generation after the parental FQ animals. This
is equivalent to approximately 12.5 or 25.0 mg/kg/day, assuming normal dietary
intake of 20 g/day for a 0.4 kg rat (Lehman, 1959). The 0.25% group consisted
of 2 rats/sex; the 0.5% group had two males and 7 females. A control group of
3 males and 1 female were fed a diet that did not have added zinc. It appears
that growth, mating and number of offspring were not affected by zinc
chloride. The offspring, continued on the same treatment, also produced
normal, vigorous offspring. No lesions or pathological conditions were seen.
Tissue zinc levels (which were reported as average zinc concentration and
included tissues from animals fed zinc carbonate, zinc oxide, and zinc dust)
were comparable to controls. Results from this study are difficult to
interpret due to its design and lack of experimental detail; therefore, a
LOAEL and NOAEL are not identified. No other data were found in the available
literature on the reproductive effects of exposure to zinc chloride in
animals.
b. Other Zinc Compounds
Kumar (1976) orally administered 150 mg/kg/day zinc (as 2% zinc sulfate) in
drinking water to 13 pregnant rats. Zinc content of the diet was 30 ppm. All
animals were sacrificed on day 18 of pregnancy and examined. Eight
VI-14
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experimental animals showed 11 resorptions out of 116 implantations. Two
control animals revealed a total of 2 resorptions out of 101 implantations.
Data suggest that moderately high levels of zinc may have harmful effects on
pregnancy.
In a study in which groups of 10 female Sprague-Dawley rats were maintained on
diets containing 2,000 and 5,000 ppm zinc oxide for 35-38 days (from day 1 of
gestation to day 14 of lactation), no malformations were observed; however,
fetal mortality was noted (Ketcheson et al., 1968). A dietary level of
2,000 ppm corresponds to a calculated dose of 200 mg zinc/kg/day, assuming a
body weight of 200 g and a dietary intake of 20 g/day while the 5,000 ppm dose
is equivalent to 500 mg zinc/kg/day. Among the 10 litters given 2,000 ppm, 4
dead pups were observed; in the 8 litters given 5,000 ppm, 2 litters consisted
entirely of dead pups (the number of dead pups in these 2 litters was not
mentioned).
Dietary supplementation with zinc carbonate at 1,000, 5,000 or 10,000 ppm
(corresponding to calculated doses of 100, 500 and 1,000 mg/kg/day) for
10-16 weeks resulted in an increase in stillbirths at 5,000 ppm and no
reproduction at 10,000 ppm in groups of five young rats (three females and two
males; strain not reported) (Sutton and Nelson, 1937). Three females on the
5,000-ppm diet had 6/11 dead pups from their first pregnancies; during their
second pregnancies, all 23 pups died. No effects were observed at 1,000 ppm.
The effect of zinc on the male reproductive organs was evaluated in male
Sprague-Dawley rats (number not specified) over a 3- to 6-week period (Saxena
et al., 1989). The experimental animals received a diet containing 500 ppm
zinc. The control animals were fed a diet with adequate zinc to support
nutritional needs. The water used for both groups of animals contained 2 mg/L
zinc. The total zinc intake of the experimental animals was 25 mg/kg/day.
Animals were sacrificed at 3 and 6 weeks for examination of their reproductive
organs. Spermatogenesis was found to be impaired in the exposed animals at 3
and 6 weeks.
No effect on embryonic mortality, male fertility, or pregnancies/ effective
mating was produced by zinc chloride in the dominant lethal mutation assay
using mice [Fl hybrids (CBA/X/C57BL)] and a single intraperitoneal dose
(15 mgAg) in males (Vilkina et al., 1978).
5. Developmental Effects
a. Zinc Chloride
No effects were found on reproductive parameters, but zinc chloride may be a
teratogen.
Seidenberg et al. (1986) screened 55 chemicals, including zinc chloride, for
possible teratogenicity, utilizing the Chernoff/Kavlock developmental toxicity
screen. This method identifies developmental toxicity, including potential
teratogenicity, based on growth and viability of embryonic, fetal, and
postnatal mice. The screen was designed to prioritize chemicals for
subsequent, more detailed, conventional study and may not be appropriate to
classify chemicals as developmental toxicants.
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In the zinc chloride screen, 28 timed-pregnant mice received by gavage an oral
dose of 150 mg/kg/day in water on Day 8 through Day 12 of gestation. The mice
were weighed on Days 7 and 13 of gestation and at one day postpartum. Dams
were allowed to deliver, litters were counted and weighed on day of birth and
on Day 3. Dead pups were examined for external abnormalities. Dams not
delivering by Day 2.1 or 22 were necropsied and uteri were examined. One of
the maternal animals died at this dose, and average weight gain was
significantly reduced as compared to controls (p<0.01). Eleven litters were
produced with no resorptions. No significant differences were found in the
average number of neonates/litter, % survival Days 1-3, or average neonatal
weight on Days 1 and 3 (Seidenberg et al., 1986).
Based on the Chernoff/Kavlok method, Seidenberg and Becker (1987) reported
that zinc chloride caused a significant reduction in litter size and thus
classified it as a teratogen. This parameter was not significantly different
when only the litters that came to term by Day 22 of gestation were counted.
Given the limitations of the method zinc chloride should be considered a
potential developmental toxin. A NOAEL or LOAEL could not be determined
because only one dose was tested.
One intraperitoneal study suggests that zinc chloride is teratogenic. Chang
et al. (1977) injected zinc chloride intraperitoneally in mice (number not
clearly specified for each dose group) in single doses of 0, 12.5, 20.5 and
25 mg/kg on days 8, 9, 10 or 11 of gestation. Dams were sacrificed on
gestation day 18 (1 day prior to expected delivery). Thereafter, the number
of fetuses and resorption sites was determined. Fetuses were weighed, sexed
and examined for skeletal and visceral anomalies. Quantitative data on
maternal toxicity and fetotoxic effects were not provided by the author for
evaluation. Skeletal anomalies, including delayed ossification, were seen at
dose levels of 20.5 mg/kg/day or greater beginning on gestation day 8. Ripple
ribs, an unusual skeletal anomaly, first appeared when zinc chloride was given
on day 9 of gestation. For the most part, the severity of the skeletal
lesions was dose and time dependent. There were no significant differences in
soft tissue anomalies at any dose level. Skeletal anomalies were observed at
doses of 20.5 mg/kg and above but not at 12.5 mg/kg.
b. Other Zinc Compounds
Dietary zinc deficiency (0.3-100 ppm zinc carbonate) in Sprague-Dawley rats
(10-20/group) and Long-Evans hooded rats (10-17/group) produced reproductive
and developmental effects including testicular lesions, abnormal estrous
cycles, embryotoxicity and malformed fetuses (most organ systems and the
skeleton were involved) (Hurley, 1969; Hurley and Swenerton, 1966; Rogers
et al., 1985; Hurley et al., 1971).
6. Genotoxicitv
a. Zinc Chloride
Mutagenicity studies produced mixed results in which some cytotoxicity was
indicated.
In an in vitro assay for detection of potential carcinogens and mutagens,
Casto et al. (1979) used hamster embryo cells (HEC) to detect the ability of
zinc chloride to enhance the transformation of Simian adenovirus SA7.
VI-16
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Enhancement occurred in only 50% of the six assays. The lowest concentration
producing a positive response was 0.18 mM with a transformation ratio of 8.7
(transformation frequency (TF) of treated cells/TF of controls). Because of
.the 50% response, the authors reported that the results of this study were
inconclusive.
Results of in vitro studies in normal stimulated human lymphocyte cultures did
not demonstrate the mutagenic potential of zinc chloride. At a concentration
of 3xlO~5 M, severe chromosome aberrations were manifested as dicentric
chromosomes but the incidence was not significant against controls using the
chi-square analysis. At a level of 3x10"^ M, zinc chloride was cytotoxic to
human lymphocytes (DeKnudt and Deminatti, 1978).
No evidence of DNA damage was observed in human white blood cells at the zinc
chloride concentration of 5xlO"5 M (McLean et al., 1982).
Mutagenicity tests conducted with SL typhimurium strains TA1535, TA1537,
TA1538, TA98 and TA100 indicated that zinc chloride was not mutagenic in any
strain either with or without S-9 mix, although zinc chloride was toxic at the
higher exposure levels (McGregor, 1980). Sokolowska and Jongen (1984)
indicated that zinc chloride was not mutagenic in any strain at doses up to
5 mg/plate. In contrast, Kalinina and Polukhina (1977) indicated that zinc
chloride produced frame shift mutations in the indicator strains (not
specified) of S. tvphimurium in the Ames test. The effect was measured by the
ability of the chemical to induce reversions from histidine auxotrophy to
prototrophy and was described as species-specific with respect to liver
homogenates, with the highest mutagenic activity evident in the mouse liver.
In the E. coli DNA repair test, zinc chloride did not show preferential
toxicity for the polymerase-deficient strain at 10 mg/plate, with or without
S-9 mix (McGregor, 1980). In the S. cerevisiae mitotic recombinogenic
activity test, zinc chloride did not show a reliable indication of toxicity to
the yeast cells during the 150 minute incubation. An 18 hour incubation did
result in a reduced viability at 0.75 mg/ml. In the presence of S-9 mix
toxicity was severe at kl mg/ml. At lower concentrations in which moderate
toxicity was observed, there was no sign of an increase in recombinant
frequency. In the absence of S-9 mix, results were not clear.
In an in vivo system using male and female F1 hybrid mice, Vilkina et al.
(1979) studied the effects of a single intraperitoneal dose of 15 mg/kg of
zinc chloride in aqueous solution on chromosome aberrations in bone marrow
cells. While single fragment rearrangements were most commonly encountered in
this system, no statistically significant differences in frequency were seen
in treated animals compared to controls. The authors also tested the ability
of zinc chloride to induce dominant lethal mutation in the germ cells of male
mice. Three intact females were mated to zinc chloride injected mice for one
week at time periods corresponding to the influence of the zinc chloride on
mature sperm, late and early spermatids, late and early spermatocytes and
spermatogonia. There were no zinc chloride-related effects on mortality
before or after implantation. Also the percentage of effective matings, and
numbers of corpora lutea, implantation sites, and live embryo were not
affected.
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Zinc chloride was studied for its ability to cause DNA strand breaks using the
fluorescence analysis of DNA unwinding (FADU) technique with freshly isolated
human white blood cells. McLean et al. (1982) reported that zinc chloride
gave no firm evidence of DNA damage at a concentration of 5xlO"5 M. In a
similar study using the average molecular weight of DNA to determine strand
breaks in Chinese Hamster Ovary (CHO) cells, Robison et al. (1982) also
reported that zinc chloride caused no significant changes.
Rivedal and Sanner (1981) reported that zinc chloride was not an inducer of
transformations in hamster embryo cells, and it had no effect on the frequency
of transformation when tested in combination with benzo(a)pyrene.
When tested for induction of Y prophage in L coli WP2s(y), Rossman et al.
(1984) reported that zinc chloride produced a two-fold increase (+/-)
in Y prophage at a concentration of 3.2xlO"3. In this system, positive
inducers produced increases ranging from 3 to 75 times that of controls.
Zinc chloride did not produce preferential inhibition of DNA repair-deficient
Bacillus subtilis M45 as compared to the DNA repair-competent parental strain,
H17 (Nishioka, 1975).
b. Other Zinc Compounds
Zinc compounds were generally negative in in vitro reverse bacterial mutation
assays with Salmonella tvphimurium (Marzin and Vo Phi, 1985; Thompson et al.,
1989); in mouse-mediated assays (Fabrizio, 1974); in the Escherichia coli
assay (Nishioka, 1975); the mouse lymphoma forward mutation assay (Amacher and
Paillet, 1980); and in in vivo rodent somatic and germinal cell cytogenetic
assays (Fabrizio, 1974).
Zinc acetate (10-1,000 ng/mL) did not cause unscheduled DNA synthesis in
cultured rat hepatocytes (Thompson et al., 1989).
Dose-related positive responses to concentrations of 1.3-13 jig/mL zinc acetate
were seen in the TK*'" mouse lymphoma assay and in the in vitro Chinese
Hamster Ovary (CHO) cell cytogenic assay both in the presence and absence of
microsomal activation (Thompson et al., 1989).
Acceptable evidence of zinc sulfate-induced genotoxicity in yeast has been
presented (Fabrizio, 1974). Oral administration of 2.75, 27.5, and
275.0 mg/kg zinc sulfate in both acute (one exposure) and subacute (five
consecutive daily exposures) mouse host-mediated assays induced dose-related
recombinogenic effects in Saccharomvces cerevisiae D3. For the acute study,
recombinant frequencies (RF) ranged from 8.22xlO"5 at the low dose to
13.22xlO"5 at the high dose (RF for negative control, 4.06xlO"5). For the
subacute study, more pronounced effects were observed. The highest dose was
both cytotoxic (30% reduction in total survivors) and recombinogenic (four-
fold increase in the RF) . The remaining doses were not cytotoxic, but the RF
was increased 2-fold at the low dose and 2.8-fold at the intermediate dose.
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7. CarcinoE.eni.citv
a. Zinc Chloride
Administration of zinc chloride in drinking water did not promote kidney or
liver lesions when administered in drinking water for 25 weeks.
Kurokawa et al. (1985) treated a group of 7-week old male F344 rats (15/group)
with zinc chloride (96% pure) at 450 ppm in drinking water (equivalent to «
28 mg/kg/day based on body weight and intake data provided) for 25 weeks.
Prior to zinc chloride exposure, another treatment group received 500 ppm of
N-ethyl-N-hydroxy-ethylnitrosamine (EHEN) in drinking water for 2 weeks. Two
additional groups either received drinking water (DW) alone or DW following
initiation with EHEN. Mean final body weight for the EHEN-zinc chloride group
were significantly lower (p<0.01) than the group receiving drinking water
alone, but were not significantly different from the EHEN-DW controls. Mean
final body weight for the DW-zinc chloride group were comparable to both
control groups. There were no significant differences in absolute kidney or
.liver weights in either of the zinc chloride groups. The relative kidney
weights of both the initiated and uninitiated zi'nc chloride groups were
significantly increased as compared to the DW only controls (p<0.05).
However, these differences were minor (0.61 versus 0.60). Mean intake of
drinking water (mL/rat/day) were slightly lower in both groups receiving zinc
chloride as compared to either control group.
The EHEN-DW controls exhibited the same significant increase in relative
kidney weight when compared to the DW controls. Renal tissue was examined for
preneoplastic and neoplastic lesions. The lesions were classified as
dysplastic foci (DF) or renal cell tumor (RCT). Dysplastic foci were defined
as proliferation of lining epithelium of solitary tubules ranging from a focal
increase in cell numbers to complete obliteration of the tubules and included
dilated tubules with multilayered epithelium or the projection of lining cells
into the lumen (Kurokawa et al., 1985). While there was no significant
difference in the incidence of DF between the EHEN-zinc chloride and EHEN-DW
rats, the mean number of DF/cm2 was significantly increased (p<0.01) in the
EHEN-zinc chloride group as compared to the control group. There were no
significant differences in either the incidence or the mean number of RCTs of
the EHEN-zinc chloride or EHEN-DW groups. Renal cell tumors were single or
multiple nodules usually with a solid growth pattern but occasionally
presenting as cystic formations with papillary-like ingrowth or tumors with
trabecular morphology. All RCTs were benign. Neoplastic nodules and
hepatocellular carcinomas were observed in the livers of both the zinc
chloride and DW rats initiated with EHEN but no significant differences were
found between these two treatment groups. No lesions were observed in the
rats receiving only DW or zinc chloride without prior initiation. Based on
the results of this study, the authors concluded that zinc chloride could not
be considered a promoter of kidney lesions.
Testicular tumors (embryonal carcinomas) were observed in 2 of 49 Syrian
hamsters administered 2 mg zinc chloride by a single intratesticular injection
at 8-14 weeks (during rapid gonadal growth) (Guthrie and Guthrie, 1974). All
but six animals exhibited testicular pathology, such as fibrous-walled
cavities near the epididymis and areas of coagulative necrosis in testes
surrounded by a zone of pigmented and foamy macrophages. The two tumors arose
adjacent to the area of necrosis (Guthrie and Guthrie, 1974).
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VII. HEALTH ADVISORY DEVELOPMENT
Zinc is an essential trace element which is a constituent of a number of
enzymes involved in key biological processes. Zinc deficiency is associated
with loss of appetite, growth retardation, skin changes, inmiunological
abnormalities, wound healing retardation, and developmental effects (HAS
1989). The development of a health advisory is complicated by the fact that
there appears to be a narrow range of doses between the amount of zinc needed
to fulfill physiological needs (5.5 mg/day) and the amount that will produce
minimally adverse effects (depressed E-SOD at 60 mg/day) (King, 1989; Fischer
et al., 1986; Yadrich et al., 1989). The Recommended Dietary Allowance for
zinc ranges from 5 mg/day for infants to 19 mg/day for lactating women (NAS,
1989). These values were used as a guide for Health Advisory derivation.
Available data on the oral exposure of humans and animals to various forms of
zinc compounds have been reviewed. In animals (rats, mice, and guinea pigs),
oral LD50's and average lethal doses range between 200 and 1,000 mg/kg.
Results of exposure to zinc chloride while being fed a synthetic diet
deficient in pantothenic acid, as well as those following exposure via
drinking water for 25 weeks are reported. Both reproductive and teratogenic
effects have been evaluated. No bioassay for carcinogenicity has been located
in the literature, but a study of the tumor-promoting potential of zinc
chloride is discussed. Human exposure to zinc chloride, both by ingestion and
inhalation, are reported. Tissue damage has been indicated upon both ocular
and dermal exposure, and a low dermal absorption rate has been indicated.
Oral intake of an estimated zinc chloride dose of 1,000 mg/kg in humans
resulted in gastrointestinal (GI) symptoms which included burns of the mouth
and throat, abdominal pain and vomiting with blood in the vomitus and urine
(Markwith, 1940; Chobanian, 1981; Potter, 1981). Vomiting and diarrhea
occurred in people who ingested approximately 225 mg (3.2 mg/kg) or greater of
zinc leached from galvanized containers. (Brown, 1964). Gastrointestinal
distress is associated with doses of 50-150 mg/day (0.7-2.1 mg/kg/day of zinc
acetate or sulfate) (Freeland-Graves et al., 1982; Prasad et al., 1978; Saoman
and Roberts, 1988). A number of human studies have reported that zinc
(sulfate or gluconate) doses ranging from 29-311 mg/kg (0.4-4.4 mg/kg/day) for
longer-term exposures decrease serum HDL, erythrocyte superoxide dismutase,
copper, and ceruloplasmin levels (Black et al., 1988; Chandra 1984; Fischer
et al., 1984; Goodwin et al., 1955; Hooper et al., 1980; Samman and Roberts,
1988). In addition anemia and neutropenia have been reported in some people
following doses of 43-200 mg/day zinc (sulfate or acetate) (0.6-2.8 mg/kg/day)
for longer-term exposures (Hoffman et al., 1988; Prasad et al., 1978; Simon
et al., 1988).
Mucosal damage is the most consistent effect reported after exposure to high
doses of zinc chloride by both the oral and inhalation route. Rats and
rabbits receiving single oral doses of zinc chloride solution at doses between
250 and 1,000 mg/kg developed perforations of the stomach, penetration into
the liver and pyebric stenosis (Hahn and Schunk, 1955). The only notable
effect reported following short-term exposure of animals to zinc chloride were
symptoms of pantothenic acid deficiency. This effect was evidenced mainly by
severe alopecia and weight loss in rats maintained on a synthetic diet and
orally administered approximately 100 mg/kg/day zinc chloride and a
pantothenic acid-deficient vitamin supplement (Gross et al., 1941). A slight
decrease in the intake of drinking water was reported in rats exposed to
VII-1
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28 mg/kg/day zinc chloride in that medium for 25 weeks (Kurokawa et al . ,
1985). Histological changes were reported in the kidneys of rats exposed to
190.6 mgAg/day zinc chloride for 90 days (Llobet et al., 1988).
No effects on reproductive parameters were seen in rats exposed to 125 or
250 mg/kg/day zinc chloride as the acetate salt in the diet during breeding
and through production of one generation (Heller and Burke, 1927). Offspring
were also treated and bred without notable effects. Zinc chloride
(150 mg/kg/day) was considered an equivocal teratogen based on a slight but
significant reduction in live litter size, but only when the live litters
found in utero were included in the determination of litter size (Seidenberg
et al., 1986). Treatment of parental females on days 8-12 of gestation
resulted in a significant decrease in average weight gain, as well as death of
one of the maternal animals. Increases in resorption and fetal mortality have
been reported in animals orally exposed to 150-1,000 mg/kg/day of zinc oxide,
sulfate, or carbonate (Ketcheson et al. , 1968; Kumar, 1976; Sutton and Nelson,
1937). Zinc deficiency also adversely affects reproductive function, and
fetal development (Hurley, 1969; Hurley and Swenerton, 1966; Hurley et al .
1971; Rogers et al. 1985).
Dermal irritation studies resulted in the development of severe edema and
necrotic erythema following application of a 10% solution of zinc chloride to
the shaved skin of rabbits. Mild conjunctivitis with moderate corneal opacity
developed after instillation of this solution into the eye (William, 1984).
Johnstone et al. (1973) indicated that zinc chloride solution acted as a
denaturant or fixative when applied to the cornea. Evidence of dermal
absorption was indicated by a reduced weight gain in guinea pigs after
percutaneous administration of an aqueous solution (Wahlberg, 1965). An
absorption rate of <1% over a five hour period was indicated.
No evidence of tumor promotion was reported in male F344 rats given 28
mg/kg/day zinc chloride in drinking water for 25 weeks (Kurokawa et al. ,
1985) . Equivocal evidence of testicular tumors was reported in hamsters
intratesticularly injected with 2 mg zinc chloride (Guthrie and Guthrie,
1974) . Mutagenicity studies were inconclusive although most test results were
negative. Some evidence of cytotoxicity was seen during mutagenic assays
(DeKnudt and Deminatti, 1978; McGregor, 1980).
A. Quantification of lexicological Effects
Health Advisories are generally determined for one-day, ten-day, longer-term
(approximately 7 years) and lifetime exposures if adequate data are available
that identify a sensitive noncarcino genie end point of toxicity. The HAs for
noncarcino genie toxicants are derived using the following formula:
(NOAEL or LOAEL) (BW)
(UF(s)) ( L/day)
where:
NOAEL or LOAEL - No- or Lowest-Observed-Adverse-Effect Level
in mg/kg bw/day.
BW - assumed body weight of a child (10 kg) or
an adult (70 kg).
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UF - uncertainty factor (10, 100 or 1,000), in
accordance with NAS/EPA guidelines.
L/day - assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
The health advisory levels which follow were derived with both the
essentiality and toxicity of zinc in mind. In doing so, the most recent set
of Recommended Daily Allowances (RDAs) for zinc, derived by NRC (1989), were
used as a guide in the overall risk assessment analysis. If traditional
procedures for developing RfDs are applied to the available data (uncertainty
factors of 100-1,000 applied to less-than-lifetime human study end points),
the resulting RfDs for zinc would be considerably lower than the RDAs. With
these parameters in mind, the following numbers were derived.
1. One-Day Health Advisory
The oral LD50 for zinc sulfate in rats was 920 mg/kg, and the oral LD50 for
zinc chloride in rats, mice and guinea pigs ranged from 200 to 502 mg/kg
(Fabrizio, 1974; Calvery, 1942; Yakuri, 1974). One-time ingestion of zinc in
beverages at 4.6 mg/kg produced severe abdominal and gastric symptoms in adult
humans (Brown et al., 1964). However, since this value was derived from a
case study of zinc-induced food illness in adults, the accuracy of the dose
information is questionable. Thus, the LD50 values and food poisoning doses
are not appropriate for the calculation of the One-day Health Advisory for
zinc. Therefore, the RDA for a 1-year-old, 9-kg infant (5 mg/day) is used as
the basis of the One-Day HA value calculated below.
(0.56 mgAg/day) (10 kg)
One-day HA - - 5.6 mg/L (rounded to 5 mg/L
(1) (1 L/day) to correspond to infant RDA)
where:
0.56 mgAg/day - RDA for a 9-kg infant.
10 kg - assumed weight of child.
1 - uncertainty factor, chosen in accordance with
NAS/EPA guidelines for use with an RDA which
provides adequate zinc for human growth and
nutrition (NAS, 1989).
1 L/day - assumed daily water consumption by a 10-kg child.
This value is expected to be without any adverse effect even when the diet
contains zinc. The RDA for the slightly heavier 13-kg child is 10 mg/day.
2. Ten-Day Health Advisory
No suitable information was found in the available literature for determining
the Ten-day HA for zinc for a 10-kg child. The One-day Health Advisory of
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5 mg/L, based on the RDA for a 9-kg infant is suitable for use as the Ten-day
HA.
3. Longer-Term Health Advisory
Studies by Fischer et al. (1984) and Yadrick et al. (1989) concerning the
effects of zinc on copper homeostasis were used as the basis of the Longer-
tern Health Advisory. In these studies, healthy adults were given 25 mg of
zinc as the gluconate twice daily for 6 or 10 weeks. There was a significant
decrease in erythrocyte-superoxide dismutase (E-SOD) activity or concentration
at both 6 and 10 weeks of exposure (Fischer et al., 1984; Yadrick et al.,
1989). The decreased concentration of E-SOD is indicative of a copper
deficiency and a diminished capacity of the cells to respond to oxidative
stress. There were no differences in serum copper levels or ceruloplasmin
activity as compared to the controls. Serum zinc levels were significantly
increased; dietary zinc was not measured. The total zinc intake of 66 mg/day
(dietary intake of 16 mg zinc/day plus a zinc supplement of 50 mg/day)
resulted in a LOAEL of 0.94 mg/kg/day for a 70 kg male (Fischer et al.,
1984). For females, the total zinc intake was 59.7 mg/day or a LOAEL of
1.0 mg/kg/day for a 60-kg female with a dietary intake of 9.7 mg/day (Yadrick
et al., 1989).
Similar findings were seen in females, but not males, administered 150 mg
zinc/day for 6 weeks during a double blind placebo study (Samman and Roberts,
(1988) . Ceruloplasmin, E-SOD and Cu-Zn-SOD concentrations were all
significantly decreased during the zinc supplement period when compared to the
values during placebo administration. There was a 20% decrease in E-SOD and a
23% decrease in Cu-Zn-SOD at the end of 6 weeks. The same parameters were
very slightly (but not significantly) decreased in the males.
The results from several case studies, in which zinc supplementation for
periods of 10 months to 2 years resulted in symptoms of a copper deficiency,
support the data by Fischer et al. (1984); Samman and Roberts, (1988); and
Yadrick et al. (1989). Male and female patients experienced anemia and
neutropenia with ingestion of 43-200 mg zinc per day for 10 months to 2 years.
(Hoffman et al., 1988; Prasad et al., 1978; Simon et al., 1988). Serum zinc
levels were high and ceruloplasmin values were low. Both the anemia and
neutropenia were resolved after zinc supplementation ceased.
The LOAEL from the study by Yadrick et al. (1989) in adult females was used to
calculate the Longer-term HA for a 10-kg child as follows:
(1.0 mgAg/day) (10 kg)
Longer-term HA - - 3.33 mg/L (rounded to 3 mg/L)
(3) (1 L/day)
where:
1.0 mg/kg/day - LOAEL, based on a depression of E-SOD concentrations
in human subjects following exposure to zinc for
10 weeks (Yadrick et al. , 1989).
10 kg - assumed weight of child.
V1I-4
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3 - uncertainty factor, chosen in accordance with
NAS/EPA guidelines for use with a LOAEL from a
human study. This factor also takes into account that
zinc is essential for human growth and nutrition.
[The RDA for a child ranges from 5 to 10 mg zinc/day
(NRC, 1989).]
1 L/day - assumed daily water consumption by a 10-kg child.
Using the Yadrick et al. (1989) LOAEL, the Longer-term HA for a 70-kg adult is
calculated as follows:
(1.0 mgAg/day) (70 kg)
Longer-term HA - - 11.6 mg/L
(3) (2 L/day) (rounded to 12 mg/L
or 12,000 (tg/L)
where:
1.0 mg/kg/day - LOAEL, based on a depression of E-SOD concentrations
in human subjects following exposure to zinc for
10 weeks (Yadrick et al., 1989).
70 kg - assumed weight of adult.
3 - uncertainty factor, chosen in accordance with
NAS/EPA guidelines for use with a LOAEL from a
human study This factor also takes into account that
zinc is essential for human growth and nutrition. [The
RDA for an adult ranges from 12 to 19 mg zinc/day (NRC,
1989).]
2 L/day - assumed daily water consumption by a 70-kg adult.
4. Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure that
is attributed to drinking water and is considered protective of noncarcino-
genic adverse health effects over a lifetime exposure. The Lifetime HA is
derived in a three-step process. Step 1 determines the Reference Dose (RfD),
formerly called the Acceptable Daily Intake (ADI). The RfD is an estimate of
a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e.,
drinking water) lifetime exposure level, assuming 100% exposure from that
medium, at which adverse, noncarcinogenic health effects would-not be expected
to occur. The DWEL is derived from the multiplication of the RfD by the
assumed body weight of an adult and divided by the assumed daily water
consumption of an adult. The Lifetime HA is determined in Step 3 by factoring
in other sources of exposure, the relative source contribution (RSC). The RSC
VII-5
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from drinking water is based on actual exposure data or, if data are not
available, a value of 20% is assumed.
If the contaminant is classified as a known, probable or possible carcinogen,
according to the Agency's classification scheme of carcinogenic potential
(U.S. EPA, 1986), then caution must be exercised in making a decision on how
to deal with possible lifetime exposure to this substance. For human (A) or
probable human (B) carcinogens, a Lifetime HA is not recommended. For
possible human carcinogens (C), an additional 10-fold safety factor is used to
calculate the Lifetime HA. The risk manager must balance this assessment of
carcinogenic potential and the quality of the data against the likelihood of
occurrence and significance of health effects related to noncarcinogenic end
points of toxicity. To assist the risk manager in this process, drinking
water concentrations associated with estimated excess lifetime cancer risks
over the range of 1 in 10,000 to 1 in 1,000,000 for the 70-kg adult drinking
2 L of water/day are provided in the Evaluation of Carcinogenic Potential
section.
In establishing an RfD for zinc, the data on essential needs were combined
with the human data on toxic responses in studies of limited duration in order
to define a transition level which would meet the physiological requirements
of nearly all healthy persons without causing a toxic response in the most
sensitive population subgroup when consumed daily for a lifetime.
There appears to be only an order of magnitude between the amount of zinc that
will satisfy physiological need (5.5 mg/day; King, 1989) and the amount that
is associated with the appearance of minimally adverse effects (depress E-SOD
at 60 mg/day) with 6- to 10-week daily exposures (Fischer et al., 1986;
Yadrich et al., 1989). Since an appropriate lifetime duration study was not
available and the animal data from the 12-month duration study by Aughey
et al. (1977) did not evaluate the sensitive end points of zinc toxicity
identified in the human studies, the LOAEL of 1.0 mg/kg/day which was used for
the Longer-term HA is also used for determination of the .RfD and DWEL as
follows:
Step 1. Determination of the Reference Dose (RfD)
(1.0 mgAg/day)
RfD - T-=T - 0.33 mg/kg/day (rounded to 0.3 mg/kg/day)
where:
1.0 mg/kg/day - LOAEL, based on a depression of E-SOD concentrations in
human subjects following 10-week exposure (Yadrick et
al., 1989)
3 - uncertainty factor, chosen in accordance with
NAS/EPA guidelines for use of a LOAEL from a human
exposure study (of an essential nutrient) in which
minimally adverse effects were observed.
This RfD was compared to the RDA expressed on a mg/kg/day basis for each age
and sex group. For 79% of a 70-year lifetime, the RDA corresponds to a daily
zinc intake of 0.23 mg/kg/day or less, a value which provides the functional
and metabolic zinc requirements for over 99% of the population (NAS, 1989).
VII-6
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The RfD of 0.3 mg/kg/day supplies adequate zinc to meet these requirements
over a lifetime without any concurrent physiologic impairment. It does not
supply the RDA for infants, preadolescent children and pregnant women and,
therefore, does not apply to these groups. The RfD dose is expected to be
without adverse effect when consumed on a daily basis over an extended period
of time. It neither induces a nutritional deficiency in healthy nonpregnant
adult humans consuming the average American diet nor causes undesirable
inhibition of copper absorption. ,
Step 2. Determination of the Drinking Water Equivalent Level (DWEL)
(0.3 mgAg/day) (70 kg)
DWEL - - - 10.5 mg/L (rounded to 10 mg/L)
(2) (1 L/day)
where :
0.3 mA/day - RfD.
70 kg - assumed weight of adult.
2 L/day - assumed water consumption by 70-kg adult.
Step 3. Determination of the Lifetime HA
Lifetime HA - (10 mg/L) (0.2) - 2.0 mg/L
where :
10.0 mg/L - DWEL.
0.2 - assumed percentage of the daily exposure (20%)
contributed by the ingestion of drinking water.
According to NAS (1989), approximately 70% of the zinc consumed in human diets
comes from animal products. Drinking water in the U.S. generally contains
less than 0.1 mg zinc/liter.
B. Quantification of Carcinogenic Potential
Due to the absence of toxicological evidence for classifying zinc as a
potential carcinogen, a quantification of carcinogenic risks for zinc is
inappropriate .
Groups of male F344 rats (15/group) were given 450 ppm (approximately 28
mg/kg/day) of zinc chloride in drinking water for 25 weeks to evaluate the
promoting effect on renal tumor igen'e sis (Kurokova et al. , 1985). Some animals
were pretreated with N-ethyl-N-hydroxyethylnitrosamine (EHEN) (500 ppm) as an
initiator. Four groups were compared: controls (no EHEN or zinc chloride),
EHEN-DW, EHEN-zinc chloride and DW-zinc chloride. There were no significant
differences in the incidence of dysplastic foci (DF) between the EHEN-zinc
chloride and EHEN-DW groups. The mean number of DF/CM* was increased
significantly (p<0. 01) in the EHEN-zinc chloride group compared to controls.
There were no significant differences between groups for the occurrence of
renal cell tumors and hepatocellular carcinoma. Even though this study is
VII-7
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limited by duration and use of one sex, it did not demonstrate that zinc
chloride is a promoter of kidney lesions.
Other limited available information on the carcinogenic potential of zinc
(testicular tumors in 2/49 hamsters from intratesticular injection) is
particularly relevant to zinc exposure via drinking water.
Applying the criteria described in EFA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), zinc *nd zinc salts are assigned to Group
D: not classifiable as to human carcinogenicity. This category is for agents
with inadequate animal evidence of carcinogenicity.
VII-8
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VIII. OTHER CRITERIA. GUIDANCE AND STANDARDS
A. Zinc Chloride
The ACGIH (1986) 8-hour time weighted average threshold limit value (TWA-TLV)
for exposure to zinc chloride is 1 mg/n3. This limit is protective against
the irritative effects that result from exposure to zinc chloride fume. A
short-term exposure limit (STEL) of 2 ag/nr also has been recommended. The
Occupational Safety and Health Administration (OSHA) permissible exposure
limit (PEL) for zinc chloride fume also has been set at 1 mg/m3 averaged over
an 8-hour work shift (Mackison et al., 1981). An initial or pre-employment
medical examination is recommended to detect pre-existing conditions with
examination of the respiratory system stressed. In 1978, the exposure limit
in Sweden was also 1 mg/m3 (ACGIH, 1986).
Cullumbine (1957) calculated "safety distances" for exposure to zinc chloride
screening smoke for set time periods under the differing meteorological
conditions of day and night exposure. For daytime exposure, a distance of
91 meters from the source for 43 minutes is considered safe while at
914 meters exposure could last up to 37 hours. Estimated zinc chloride
concentrations at these distances are 47 and 0.9 mg/m3, respectively. Under
night time conditions, a distance of 183 meters from the source would be
considered safe for up to 24 minutes and 914 meters would be a safe distance
for exposures up to 2.5 hours. Zinc chloride levels at these two distances
are estimated at 85 and 13 mg/m3, respectively (cited in Hill et al. , 1978).
B. Other Zinc Compounds
The current EPA-recommended secondary standard based on taste and odor for
zinc in drinking water is 5 mg/L (NRC, 1979).
Although standards for public exposure are not reported (NRC, 1979), air
quality standards for zinc and its compounds have been established for
occupational exposures in many countries, including the United States. For
example, the American Conference of Governmental Industrial. Hygienists
recommends a Threshold Limit Value-Time Weighted Average (TWA) of 1 mg/m3 for
zinc chloride fumes and a Threshold Limit Value-Short-Term Exposure Limit
(STEL) of 2 mg/m3 (ACGIH, 1990). The corresponding values for zinc oxide
fumes are 5 mg/m3 and 10 mg/m3 and there is a TWA of 10 mg/m3 for zinc oxide.
The Recommended Daily Allowance for zinc is 5 mg for infants under 1 year of
age; 10 mg for children under 10 years; 15 mg for adult males; 12 mg for adult
females; 15 mg for pregnant women; and 16-19 mg for lactating women (NRC,
1989).
No other criteria, guidelines or standards pertaining to zinc exposure via
drinking water were found.
VIII-1
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ANALYTICAL METHODS
The concentrations of zinc in environmental media can be determined by several
methods based on either emission or absorption spectroscopy. Each of these
methods can be used for the determination of a number of metals and is not
specific for zinc or zinc chloride. In each of the methods the metal is
dissolved using acid digestion and is then thermally excited. All elements,
when excited, emit or absorb light frequencies characteristic of that element
and those frequencies can be used to identify the element. Most metal
analysis is done in the ultraviolet and x-ray regions of the spectrum.
EPA Method Number 289.1 uses atomic absorption (AA) spectroscopy to determine
the zinc concentration in water and wastewater. In this method the dissolved
metals are aspirated into a flame source and excited to the point that the
metals are dispersed to a mono-atomic state. A light source, whose cathode is
the metal of interest, passes through the flame; the resulting absorption of
light by the element of interest is directly proportional to concentration.
The disadvantage of this technique, when multiple metal ions are present in
the solution, is the fact that only one metal can be detected during an
analysis. The detection limit of this technique is 5.0 ng/L for zinc (EPA,
1979).
EPA Method Number 289.2, Graphite Furnace Atomic Absorption (GFAA), is an
alternate atomic absorption technique for use with water and wastewater. In
this approach, a specific amount of liquid is dried on a thermal source to
concentrate the sample. The sample is then electrothermally excited for
analysis and identification. The detection limit for zinc is 0.05 ng/L (EPA,
1979).
Inductively-Coupled Plasma Atomic Emission Spectroscopy (EPA Method Number
200.7) is a method which is applicable for the analysis of dissolved and/or
suspended metals in water or wastewater. In this technique the liquid sample
is aspirated into the flace source which is a plasma torch of argon excited to
super hot levels by radio-frequency (RF) radiation. The metals are excited to
the level where they emit radiation. By using classical dispersion grating
optics, the intensities of the spectral lines are monitored by a
photomultiplier tube. The spectral lines and their intensities are used to
, identify the metal and its concentration in the sample. One advantage of this
techniques is that a large number of metals can be determined simultaneously;
however, in samples with multiple analytes, interferences between analytes can
sometimes limit the accuracy of the results. The detection limit for zinc in
this method is 2.0 ng/L (EPA, 1982).
In EPA Method Number 6020, Inductively-Coupled Plasma Mass Spectroscopy
(ICP/MS), the excitation of the metal is again by a radio-frequency plasma,
but the excited atoms are then interfaced into a mass spectrometer (MS) where
they are sorted according to their mass/charge ratios for identification and
quantification. The use of the mass spectrometer makes the method applicable
for determination of a large number of elements in water and wastewater at low
concentrations. The detection limit for zinc is 0.08 (ig/L. Quantification is
achieved by computerized software programs similar to those used in EPA-MS
methods for analysis of organic compounds. By using appropriate filtration
and digestion steps, this method can be used to measure both dissolved and
particulate metals in water samples (EPA, 1990).
IX-1
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Neutron activation is used to determine the concentration of zinc in
biological samples (Greenberg et al., 1979; Jurgensen and Behne, 1977; Lievens
et al., 1977). The samples are irradiated by exposure to a high neutron flux
to form radioactive **Zn and then wet-ashed with concentrated sulfuric acid
and extracted with a diphenylthiocarbazone solution. The zinc concentration
is determined by a measurement of gamma ray emissions with a scintillation
counter used in conjunction with a pulse height analyzer and then quantified
by comparison with a standard containing a known amount of wZn (Lieberman and
Kramer, 1970). The detection limit of this method for zinc varies with the
medium analyzed. A detection level of 5E-5 jig/100 mL has been reported for
blood samples (Jurgensen and Behne, 1977).
IX-2
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TREATMENT TECHNOLOGIES
Zinc chloride in water is rapidly hydrolyzed to zinc ions (Zn~) and chloride
ions (Cl"5; no specific treatment of water for removal of zinc chloride is
necessary. The ionic zinc reacts to form various hydroxides and zincates.
Removal of zinc from water can be accomplished by standard water treatment
techniques, such as coagulation and filtration.
Available data indicate that reverse osmosis (RO), chemical coagulation and
possibly ion exchange (IX) will significantly reduce zinc levels in drinking
water.
Foster et al. (1980) applied RO treatment to saline water with a zinc
concentration of 0.26 mg/L in Alamogordo, New Mexico. The RO system consisted
of hollow fiber (HF) and spiral wound (SW) elements. The HF was operated at
515 psi with a water recovery rate of 78%, while the SW was operated at
430 psi with a water recovery rate of 79%. The HF element removed 73% of zinc
while the SW removed 92%.
Fox and Sorg (1987) tested the effectiveness of home-use reverse osmosis
devices in removing zinc. RO systems typically consist of prefilters,
dechlorinators, a RO module and an activated carbon filter. The RO module, a
spiral-wound polyamide filter, was operated at a pressure of 42 ± 2 psig.
Zinc was reduced by 99% from an influent concentration of 5.42 mg/L.
Harries (1985) described the performance of a seeded RO pilot plant used to
desalinate gold mine water nearly saturated with CaSO^. The pilot plant was
operated for 5,000 hours at a water recovery rate of 92-96%. Tubular cellulose
acetate membranes were operated at 400 psi. Zinc was reduced by 81.8% from an
influent concentration of 2.2 mg/L.
Terril and Neufeld (1983) reported data from a RO unit used to treat blast
furnace scrubber effluent which, in this case, had a zinc concentration of
27 mg/L. The RO unit contained cellulose acetate (CA) membranes and was
operated at pressures of 350-450 psi and a water recovery rate of 70-80%. The
system achieved 99% reduction in zinc levels.
Hrubec et al., (1979) reported the results of wastewater treatment by RO for
water reuse. The RO system contained CA membranes in tubular configuration
and was operated at 580 psi and a water recovery rate of 60-80%. Zinc was
reduced by 75% from an influent concentration of 40 mg/L.
Hrubec et al., (1979) reported that wastewater treatment by lime softening
reduced zinc by 92% from an influent concentration of 119 mg/L. Lime [at
250-600 mg Ca(OH)2/L] and polyelectrolyte (at 0.5 mg/L) were added to the
rapid mix and flocculator influent at a pH of 11.2. Retention time for the
clarifier was 1.5 hours. Recarbonation was carried out in columns designed
for an optimum hydraulic time. Filtration was accomplished on a double-layer
filter bed.
Adams et al. (1975), demonstrated that when dissolved zinc was added to the
influent of a wastewater treatment plant at levels of 2.5 to 20 mg/L, primary
treatment removed only about 8 to 14% of the zinc. After activated sludge
treatment, however, 74 to 96% of the zinc was removed. It is uncertain
whether the zinc was bioaccumulated by the microorganisms, or if further
X-l
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removal of solids by sludge formation was responsible for the dramatic
reduction in zinc concentration. Nevertheless, it is clear that in the
biodensity ranges found in sewage treatment plants, zinc is effectively
removed from solution, and bioaccumulation probably plays an important role in
such removal.
Laboratory jar tests were conducted to develop data on the removal of metal
ions, including zinc, from aqueous solutions (Uestbrook and Grohse, 1979).
Sodium sulfide was added at stoichiometric ratios of 1.1 and 1.5. From an
initial concentration of 5 mg/L, zinc was reduced to below 1 mg/L by
precipitation with sodium sulfide.
The performance of natural zeolite clinoptilolite, used as an ion exchange
resin, was studied in a pilot plant by Blanchard et al. (1984). Two columns,
each approximately 8 inches in diameter and packed with 40 inches of zeolite,
were operated in series. The breakthrough concentration was set at 50 pg/L
for zinc, after which the zeolite was regenerated with NaCl solution at a flow
rate of 10 bed volumes (BV) per hour. Zinc breakthrough occurred after 220 BV
with a leakage rate of 8 pg/L at an influent concentration of 0.235 mg/L.
X-2
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I. CONCLUSIONS
Based on the available animal toxicity data, the HA for One-day and Ten-days
is 5 mg/L for the 10 kg child. The Longer-term HA for the 10 kg child is
3 ag/L and for the 70 kg adult is 10 mg/L. The Lifetime HA is 2 mg/L. These
values are considered protective against toxic effects for the most sensitive
members of the population. The essentiality of zinc was considered in the
derivation of these HA values. Currently, adequate available data to assess
the carcinogenic risk of zinc are inadequate but in view of its physical and
chemical properties, and considering that zinc is an essential element, it
seems unlikely that zinc chloride will present a carcinogenic risk to humans
at the levels considered safe for consumption. Using the EPA criteria for
classification of carcinogenic risk, zinc chloride and other zinc compounds
currently meet the criteria for category D, not classifiable as to human
carcinogenicity, This category is for agents with inadequate human and animal
evidence of carcinogenicity or for which no data are available.
A companion report, "Data Deficiencies/Problem Areas and Recommendations for
Additional Data Base Development for Zinc Chloride" (Appendix 1), summarizes
the scope of existing data reviewed for this HA. Recommendations are made for
additional studies to assess the short term effects of zinc chloride in
drinking water as well as developmental toxicity studies to clarify the issue
of the teratogenicity of zinc chloride.
XI-1
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XII. REFERENCES
Aamodt, R.L., W.F. Rumble, A.K. Babcock, D.M. Foster and R.I. Henkin. 1982.
Metabolism 31:326-334.
Abernathy, C.O., R. Cantilli, J.T. Du and O.A. Levander. 1991. Essentiality
versus toxicity: considerations in the risk assessment of essential trace
elements. U.S. EPA, Office of Science and Technology, Human Risk Assessment
Branch and U.S.D.A., Human Nutrition Research Center.
ACGIH. 1986. American Conference of Governmental Industrial Hygienists, Inc.
Documentation of the threshold limit values and biological exposure indices.
Cincinnati, OH: p. 643.
Adams, C.E. Jr., W.W. Eckenfelder and B.L. Goodman. 1975. The effects and
removal of heavy metals in biological treatment. In: Krenkel, P.A., ed.
Heavy metals in the aquatic environment. Oxford, England: Pergamon Press,
pp. 277-292.
Amacher, D.E. and S.C. Paillet. 1980. Induction of trifluorothymidine
resistant mutants by metal ions in L5178Y1 TK +/- cells. Mutat. Res.
78:279-298.
Angino, E.E., L.M. Magnuson and T.C. Waugh. 1976. Mineralogy of suspended
sediment and concentration of Fe, Mn, Ni, Zn, Cu, and Pb in water and Fe, Mn,
and Pb in suspended load of selected Kansas streams. Water Res. 10:1187-1191.
Anonymous. 1989. Interleukin-1 regulates zinc metabolism and metallothionein
gene expression. Nutr. Rev. 47(9):285-287.
Ansari, M.S., W.J. Miller, J.W. Lassiter, M.W. Neathery and R.P. Gentry.
1975. Effects of high but nontoxic dietary zinc on zinc metabolism and
adaptations in rats. Proc. Soc. Exp. Biol. Med. 150:534-536.
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APPENDIX 1
Data Deficiencies/Problem Areas and Recommendations for
Additional Data Base Development for Zinc Chloride and
other Zinc Compounds
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INTRODUCTION
The Office of Water (OW), Environmental Protection Agency (EPA), in
conjunction with the Department of the Army, has reviewed the available data
on zinc and zinc chloride for the purpose of developing a Health Advisory (HA)
useful in dealing with contamination of drinking water, to include "state-of-
the-art" information on environmental fate, health effects and analytical
methodology.
OBJECTIVES
The objective of this appendix is to provide an evaluation of the data
deficiencies and/or problem areas encountered in the review process for zinc
and to make recommendations, as appropriate, for additional data base
development. This document is presented as an independent analysis of the
current status of zinc technology, as related to its possible presence in
drinking water, and includes a summary of the background information used in
the development of the HA. For greater detail on the toxicology of zinc, the
Health Advisory on Zinc Chloride should be consulted.
BACKGROUND
Zinc is an essential trace element which is a constituent of a number of
enzymes involved in key biological processes. Zinc deficiency is associated
with loss of appetite, growth retardation, skin changes, immunological
abnormalities, wound healing retardation, and developmental effects (HAS,
1989). The development of a health advisory is complicated by the fact that
there appears to be a narrow range of doses between the amount of zinc needed
to fulfill physiological needs (5.5 mg/day) and the amount that will produce
minimally adverse effects ( depression of erythrocyte superoxide dismutase, E-
SOD, at 60 mg/day) (King, 1989; Fischer et al., 1986; Yadrich et al., 1989).
The Recommended Dietary Allowance for zinc ranges from 5 mg/day for infants to
19 mg/day for lactating women (NAS, 1989). These values were used as a guide
for Health Advisory derivation.
In water, zinc compounds readily dissociate to its ionic form, combining with
substances in the water to form hydroxides and insoluble precipitates. It has
been detected only as trace amounts in most ground and surface waters (Hill
et al., 1978). Hydrolysis is its main transformation process in the
environment.
Few data are available on the pharmacokinetic properties of zinc in animals.
Measurement of zinc chloride absorption in humans following jimol doses of zinc
indicates that approximately 50-55% of the dose was absorbed (Payton et al.,
1982). Minimal absorption was indicated following percutaneous application in
guinea pigs (Skog and Wahlberg, 1964). Absorption following inhalation by
five soldiers was indicated by an increase in plasma zinc levels (Hjortso
et al., 1988). Distribution of zinc chloride to the tissues has been reported
in both human (Hjortso et al., 1988) and animal studies (Feaster et al., 1955;
Lorber et al., 1970; cited in Hill et al., 1978; Kossakowski and Grosicki,
1983) with levels highest in liver, kidney and intestines. Distribution to
striated muscle also has been indicated (Sheline et al., 1943b). No data on
the excretion of zinc following oral administration of zinc chloride was
located in the literature but intravenous studies in aice, rats and dogs
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indicated that most excretion takes place in the feces (Sheline et al.,
1943a).
Data on the exposure of humans to zinc chloride, both orally and by
inhalation, indicate that it is highly irritating to the mucous membranes
(Potter, 1981; Chobanian, 1981). Death has been reported following inhalation
of zinc chloride in a closed environment (Markwith, 1940; Evans, 1945;
Milliken et al., 1963; Macaulay and Mant, 1963; HJortso, 1988), usually as a
result of toxicity to the respiratory tract. Toxic signs include inflammation
with edema, bronchopneumonia with engorgement and necrosis (Evans, 1945).
Sloughing of the epithelium also has been reported (Milliken et al., 1963;
Macaulay and Mant, 1963). Exposure by inhalation in open spaces results in
milder respiratory symptoms such as cough, hoarseness and sore throat, and
also may include nausea, vomiting, fatigue and headache (Schenker et al.,
1981). Reduced visual acuity and loss of the sense of smell has resulted from
splash injuries from zinc galvanizing solutions (Houle and Grant, 1973).
In humans oral doses of zinc, approximately 225 mg (3.2 mg/kg) or greater
leached from galvanized containers produce vomiting and diarrhea (Brown,
1964). Gastrointestinal distress is associated with doses of 50-150 mg/day
(0.7-2.1 mg/kg/day as zinc acetate or sulfate) (Freeland-Graves et al., 1982;
Prasad et al., 1978; Samman and Roberts, 1988). A number of human studies
have reported that zinc sulfate or gluconate doses ranging from 29-311 mg/kg
(0.4-4.4 mg/kg/day) for longer-term exposures decrease serum HDL, erythrocyte
superoxide dismutase, copper, and ceruloplasmin levels (Black et al., 1988;
Chandra 1984; Fischer et al., 1984; Goodwin et al., 1955; Hooper et al., 1980;
Samman and Roberts, 1988). In addition anemia and neutropenia have been
reported in some people following doses of 43-200 mg/day (0.6-2.8 mg/kg/day as
zinc gluconate, -sulfate, or -acetate) for longer-term exposures (Hoffman
et al., 1988; Prasad et al., 1978; Simon et al., 1988).
An oral LD50 and average lethal doses for zinc chloride were reported in
animals. Yakuri (1974) reported an LD50 of 502 mg/kg in male mice while
Woodard and Calvery (1941) as cited in Calvery (1942) reported acute oral
median lethal doses of 350, 350 and 200 mg/kg in rats, mice and guinea pigs,
respectively. Oral average lethal doses of 750 and 1,000 mg/kg were reported
in rats and rabbits, respectively (Hahn and Schunk, 1955).
Dermal application of a 10% solution of zinc chloride to the skin of albino
rabbits produced severe edema and necrotic erythema while mild conjunctivitis
and moderate penetrating corneal opacity was evident after application to the
conjunctival sac (Williams, 1984). Percutaneous administration of an aqueous
solution of zinc chloride to guinea pigs resulted in a cessation of weight
gain (Wahlberg, 1965). Johnstone et al. (1973) indicated that zinc chloride
acted as a fixative and denaturant on excised bovine corneas.
Perforation of the stomach, penetration to the liver and pyloric stenosis
occurred in rats and rabbits following a single oral dose in the
250-1,000 mg/kg zinc chloride range (Hahn and Schunk, 1955). Signs of vitamin
deficiency evidenced by severe alopecia, growth retardation and rusting of the
coat were precipitated after five weeks by the oral administration of zinc
chloriac to female rats at a dose equivalent to approximately 100 mg/kg/day
for a 40 kg rat (Gross et al., 1941). During this study, rats were maintained
on a synthetic diet and orally administered a vitamin-supplemented filtrate
fraction low in pantothenic acid.
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No effects were seen in rats on reproductive parameters, offspring and the
subsequent reproductive cycle of the offspring while exposed to 2.5-5% of zinc
in the diet. A NOAEL of approximately 250 mg/kg/day was indicated (Heller and
Burke, 1927). Seidenberg et al. (1986) reported that zinc chloride could be
considered a teratogen based on a slight but significant reduction in live
litter size, but only when live litters found in utero were included in the
calculations. The oral dose in this study was 150 mg/kg/day in the drinking
water and was administered on Days 8-12 of gestation. Average weight gain of
the maternal rats was also significantly decreased at this dose level when
compared to the controls. However, the study method was designed to screen
chemicals for additional, more detailed, conventional evaluation; therefore,
zinc chloride should be considered a potential teratogen.
In a study conducted to measure the tumor-promoting potential of zinc
chloride, Kurokawa et al. (1985) treated young male rats at 450 ppm
(approximately 28 mg/kg/day) in drinking water for 25 weeks, both with and
without a prior two week initiation period with N-ethyl-N-
hydroxyethylnitrosamine (EHEN). While the mean number of dysplastic foci were
significantly increased at this dose level in the EHEN-initiated rats
receiving zinc, there were no significant differences in the incidence of
these lesions nor in the incidence or mean number of renal cell tumors. No
effects were seen on final body weight and liver and kidney weight, nor were
any lesions seen in the zinc-treated rats not initiated with EHEN.
Genotoxicity studies were somewhat inconclusive with most studies indicating
no mutagenic effects with zinc chloride. Kalinina and Polukhina (1977)
reported the occurrence of frame shift mutations. DeKnudt and Deminatti
(1978) reported cytotoxicity in human lymphocytes and McGregor (1980) reported
toxicity at high levels in S. typhimurium strains and in S^. cerivisea.
Dominant lethal mutation studies were negative (Vilkina et al., 1979).
Analysis for zinc can be accomplished by atomic absorption spectrophotometry
.(AAS), flameless AAS and neutron activation analysis. Calorimetric methods
are also available. A detection limit of 10 ng/L in body fluids has been
reported using AAS (Hill et al., 1978).
Based on the available animal toxicity data, the HA for One-day and Ten-days
is 5 mg/L for the 10 kg child. The Longer-term HA for the 10 kg child is
3 mg/L and for the 70 kg adult is 10 mg/L. The Drinking Water Equivalent
Level (DWEL) is 10 mg/L. The Lifetime HA is 2 mg/L. These values are
considered protective against toxic effects for the most sensitive members of
the population. The essentiality of zinc was considered in the derivation of
these HA values. Currently, adequate available data to assess the
carcinogenic risk of zinc are inadequate but in view of its physical and
chemical properties, and considering that zinc is an essential element, it
seems unlikely that zinc chloride will present a carcinogenic risk to humans
at the levels considered safe for consumption. Using the EPA criteria for
classification of carcinogenic risk, zinc chloride and other zinc compounds
currently meets the criteria for category D, not classifiable as to human
carcinogenicity. This category is for agents with inadequate human and animal
evidence of carcinogenicity or for which no data are available.
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DISCUSSION
Available data on the toxicokinetics, health effects, analysis and treatment
of zinc have been reviewed.
While the toxicokinetic properties of zinc have not been extensively studied,
available data indicate that humans absorb between 50-55% of an oral dose in
the pool range. Measurable zinc is distributed to the tissues with the
largest amounts in the liver, kidney and intestines and lesser amounts in
other tissues, including striated muscle. Excretion is primarily via the
feces. Since zinc is an essential trace nutrient, its presence in the body is
expected. Removal of excess quantities of zinc has been accomplished with the
use of chelating agents. Further studies are not required for development of
a HA.
Available studies on the toxicity of zinc include LD50 and average lethal
doses. However, little data is available on the short-term exposure of
animals to zinc by the oral route. Inadvertent ingestion of zinc soldering
solutions has resulted in toxicity in humans. It is, therefore, recommended
that studies be carried out in animals over periods ranging from several days
to several weeks to determine a short-term NOAEL or LOAEL for zinc.
Oral exposure to zinc (various compounds) for longer periods of time indicate
that doses of 29-311 mg/day (0.4-4.4 mg/kg/day) can produce marginally adverse
effects on several blood chemistry parameters including decreased levels of
HDL, erythrocyte superoxide dismutase, copper, and ceruloplasmin. Anemia and
neutropenia may develop in more severe cases. Weight loss and vitamin
deficiency have been demonstrated under conditions not routinely encountered,
i.e. special synthetic diets. Available data is considered sufficient for
development of a Longer-term and Lifetime HA.
While no bioassay for carcinogenicity of zinc has been conducted, preliminary
studies to evaluate the tumor-promoting properties indicate that zinc chloride
is not a promoter of tumors in the two organs in which zinc is readily
distributed. Most genotoxic studies indicate that zinc is negative for
mutagenicity.
Zinc chloride had no effect on the reproductive parameters nor on the
offspring in a reproduction study. Mating of the litters of this study were
also negative for reproductive effects. No further reproductive studies are
recommended for HA development. Because zinc is a potential teratogen, based
on a reduction of litter size when in utero live litters were counted, further
studies on possible developmental effects should be undertaken.
Zinc is an essential trace element, and as a constituent of a number of
enzymes, a participator in numerous biological processes. The National
Academy of Sciences (HAS, 1989) has developed Recommended Dietary Allowances
(RDAs) of 5-19 mg/day (0.3-0.6 mg/kg/day) for various populations.
Several methods for analysis of zinc in various matrices appear adequate for
use in the detection of zinc in drinking water. No further studies are
recommended. Similarly, development of techniques for the removal of zinc
from water are not considered necessary at this time.
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RECOMMENDATIONS
Based on the above discussion, the following recommendations are made:
1. The available studies on the short-tern toxicity of zinc are
limited. It is recommended that short-term exposure studies in one
or more animals species be conducted to confirm safe exposure levels
to zinc in water for development of One-day and Ten-day HAS.
2. Available data on the developmental effects of zinc in animals
indicate that it is an equivocal teratogen. It is recommended that
further studies be conducted to clarify its developmental effects.
3. A lifetime bioassay in male and female rodents, at least five
species, should be conducted to determine the carcinogenic potential
of zinc.
4. Aside from the aforementioned data gaps, no further studies on zinc,
as related to its possible presence in drinking water, are deemed
necessary at this time.
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Vilkina, G.A., M.D. Pomerantseva and L.K. Ramaiya. 1979. Absence of the
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