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OCR for page 43
Toxicity of Selected Contaminants 43
concentration (2.9 mM) of cis-1,2-dichloroethylene; a 90~o survival oc-
curred at the highest concentration (2.9 mM) of trans-1,2-dichloroethyl-
ene used (Greim et al., 1975~.
Under the conditions of these studies neither the cis nor bans isomer of
1,2-dichloroethylene was observed to be mutagenic.
Teratogenicity No data were found by the committee.
Carcirzogenicity No data were found by the committee.
CONCLUSIONS AND RECOMMENDATIONS
Both cis- and trans-1,2-dichloroethylene demonstrate a potential for liver
and kidney damage. Little information is available on the effects resulting
from chronic administration of the materials. Long-term studies, espe-
cially those involving oral administration, are needed before a chronic
SNARL can be determined. In view of its structural similarity to vinyl chlo-
ride, a carcinogenesis bioassay is desirable. In addition, studies are needed
to determine the teratogenic and reproductive effects of these isomers, and
additional investigations should be conducted to examine their mutagenic
properties in mammalian cells.
DICHLOROMETHANE
methylene chloride; methane, dichIor~
CAS No. 75 09-2
CH2 C12
Dichloromethane was evaluated in the first and third volumes of Drinking
Water and Health (National Research Council, 1977, pp. 743-745; 1980,
pp. 124-128~. The following material, which became available after the
1980 report was prepared, updates and, in some instances, reevaluates the
information contained in the previous reviews. Also included are some ref-
erences that were not assessed in the earlier-report.
METAB OLI SM
DiVincenzo and Kaplan (1981) measured blood carboxyhemoglobin in
workers and volunteers exposed as long as 7.5 hours to atmospheric con-
centrations of 50, 100, 150, or 200 ppm (174, 347, 522, or 696 mg/m3) for
up to 5 consecutive days. As much as 34~o of the absorbed dichlorome-
thane was expired as carbon dioxide, and less than 5~o was exhaled as
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44 DRINKING WATER AND HEALTH
unchanged dichloromethane. Maximum carboxyhemoglobin levels of
6.8% were induced at exposure levels of 200 ppm, whereas the average
peak carboxyhemoglobin level in exposed workers was 3.9~o. The carboxy-
hemoglobin levels of workers exposed to carbon monoxide at the threshold
limit value (TLV) of 35 ppm (121 mg/m3) is approximately 6.5~o, or To
greater than those in workers exposed to dichloromethane.
The metabolism of orally administered ~4C-dichloromethane in rats re-
sulted in saturation kinetics up to 50 mg/kg, and both TACO and SCOT
was found in the expired air (McKenna and Zempel, 1981~. Eighty-eight
percent of a 1 mg/kg dose was metabolized. Ahmed et al. (1980) reported
that the metabolism of dichloromethane in vivo and in vitro was mediated
by the cytochrome P450-dependent mixed-function oxidase system.
HEALTH ASPECTS
Observations in Humans
No new data were found by the committee.
Observations in Other Species
New data found by the committee are summarized below.
Mutagenicity Dichloromethane was found to be mutagenic in the
Ames Salmonella' assay when tested in an open container inside a desicca-
tor, but not mutagenic when incorporated directly into the agar. Muta-
genic activity was detected with strains TA1535 and TA100 when used at
0.5 ml per desiccator, the only dose level used (Nestmann et al., 1980~. The
investigators did not specify whether or not the response was obtained in
the presence and/or absence of a mammalian metabolic activation system.
When 104 mM and 157 mM concentrations were incubated in suspension
with logarithmically growing Saccharomyces cerevisiae D7 cells for 1 hour
at 37°C, dichloromethane also induced gene mutation, recombination,
and mitotic gene conversion. No exogenous mammalian metabolic activa-
tion system was required to induce the genetic effects (Caller et al., 19801.
Nestmann et al. (1981) identified dichloromethane as the volatile muta-
genic component in six paint and Varnish removers assayed for mutagenic-
ity in 9-liter desiccators in the Ames Salmonella assay. Mutagenicity was
observed in strains TA1535, TA100, and TA98. All experiments were per-
fonned with an Aroclor 1254-induced rat liver metabolic activation system
only. Nestmann and colleagues found the chemical to be nonmutagenic
when assayed in the HGPRT forward mutation assay with Chinese ham-
OCR for page 45
Toxicity of Selected Contaminants 45
ster ovary cells, and it did not increase unscheduled DNA synthesis (UDS)
in cultured primary human fibroblasts (AH) and hamster (V79) cells. No
exogenous metabolic activation system was included in these experiments.
A marginal increase in sister chromatic exchange (SCE) was observed in
V79 cells with and without a rat liver metabolic activation system when
tested at concentrations of 1%, Two, Two, and 4% for 1 hour at 37°C
(Jongen et al., 1981~. An aspecific (nongenetic) inhibition of DNA synthe-
sis was observed in cultured primary human fibroblasts (AH) and hamster
(V79) cells. These experiments were performed with concentrations rang-
ing from 0.5% and 5~O. The cells were examined between 30 minutes and
3.5 hours after treatment. The investigators did not state whether the DNA
synthesis experiments were performed with and/or without an exogenous
metabolic activation system.
In summary, dichloromethane is a volatile mutagenic substance in two
bacterial test systems. It was nonmutagenic when tested in several mam-
malian test systems.
Carcinogenicity In a National Toxicology Program (1982c) bioassay,
dichloromethane was tested for carcinogenicity in both sexes of the
B6C3F ~ mouse and the Fischer 344 rat. Dichloromethane doses of 500 or
1,000 mg/kg in corn oil were administered by gavage to 50 rats of each sex
per dose level; doses of 500 or 1,000 mg/kg were similarly administered to
mice for 5 days/week for 2 years. There were also corresponding vehicle
and untreated control groups of 50 rats and 50 mice of each sex.
Dichloromethane was carcinogenic in both male and female rats. He-
patic neoplastic nodules and adrenal cortical adenomas were observed in
both sexes, and pancreatic acinar-cell adenomas were found in males. The
compound caused hepatocellular carcinomas in both sexes of mice. There
may have been an association of thyroid C-cell carcinomas in male rats and
leukemia and alveolar/bronchiolar adenomas in female mice. The Na-
tional Toxicology Program Technical Review Subcommittee, which evalu-
ated this bioassay, concluded that there may have been excessive mortality
due to gavage errors and also that the maximum tolerated dose may have
been exceeded.
Teratogenicity Hardin and Manson (1980) exposed rats via inhalation
to 4,500 ppm (15,620 mg/m3) for 6 hours/day before and during the first
17 days of gestation. Some fetal weight reduction occurred, but no in-
creases in malformations were found. In the same treatment group, be-
havorial studies were done by Bornschein et al. (1980~. Postnatal growth,
activity, and avoidance learning were not impaired, but behavorial habitu-
ation was more rapid in the exposed group.
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46 DRINKING WATER AND HEALTH
These limited data indicate that dichloromethane is not teratogenic to
rats.
CONCLUSIONS AND RECOMMENDATIONS
Because dichloromethane was carcinogenic in both rats and mice, no
chronic SNARL has been calculated. Some of the uncertainties involving
the cancer bioassay must be resolved before a final assessment is made
concerning the potential risk to humans.
Dichloromethane is mutagenic in two bacterial test systems, but is not
considered to be teratogenic to rats. Its metabolism is mediated by mixed-
function oxidases with saturation kinetics exhibited by doses up to 50 ma/
kg. This dose-dependent metabolism may necessitate a closer look at the
pharmacokinetics, especially with respect to the doses used in the carcino-
genicity bioassays.
DINOSEB
phenol, 2-sec-butyl4,6~initr~
CAS No. 88-85-7
OH
NO/< CH-C2 Hs
lo CH3
NO2
Dinoseb has been in use since 1945 as a herbicide and insecticide. Its pri-
mary application is in the control of annual weeds in many cereal and vege-
table crops. This compound is slightly soluble in water (52 mg/liter at
25°C), but it can form salts with inorganic and organic bases, some of
which are more soluble in water.
METAB OLI SM
Dinoseb is believed to enhance metabolic activity by uncoupling oxidative
phosphorylation and disrupting adenosine triphosphate synthesis (Brody,
1955), culminating, in extreme cases, in hyperthe~n~ia. In ruminants,
dinoseb, an organonitro compound, is reduced to an amine, which may
then cause the oxidation of hemoglobin to me/hemoglobin. There have
been several reports that dinoseb causes methemoglobinemia and hemoly-
Representative terms from entire chapter:
dna synthesis
