HEALTH AND ENVIRONMENTAL
E F P E C
PROFILES
APRIL 30, 1980
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF SOLID WASTE
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2,4-OICHLOROPHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for 2,4-dichlorophenol (U.S. EPA, 1979).
2,4-Oichlorcphenol is a colorless, crystalline solid having the empiri-
cal formula C-H.C^Q and a molecular weight of 163.Q (Weast, 1975).
It has the following physical and chemical properties (Sax, 1975; Aly and
Faust, 1965; Weast, 1975; Kirk and Othmer, 1964):
Melting Point: 45° C
Boiling Point: 210° C at 760 mm Hg
Vapor Pressure: 1.0 mm Hg at 53.0° C
Solubility: slightly soluble in water at neutral pH;
dissolves readily in ethancl and benzene
2,4-Oichlorophenol is a commercially produced, substituted phenol used
entirely as an intermediate in the manufacture of industrial and agricultur-
al products such as the herbicide 2,4-dichlorcphenoxyacetic acid (2,4-0),
germicides, and miticices.
Little data exists regarding the persistence of 2,4-aichlorophenol in
the environment. Its lew vapor pressure, and non-volatility from aqueous
alkaline solutions would cause it to be only slowly removed from surface
water via volatilization (U.S. EPA, 1979). Studies have indicated low ab-
sorption of 2,4-dichlorophenol from natural surface waters by various clays
(Aly and Faust, 1964). 2,4-Dichlorpphenoi is photolabile in aqueous solu-
tions (Aly and Faust, 1964; Crosby and Tutass, 1966) and can be degraded
microbially to succinic acid in soils and aquatic environments (Alexander
and Alesm, 1951; Ingols, et al., 1966; Loos, et al., 1967).
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II. EXPOSURE
A. Water
Sources of 2,4-dichlorophenol in water are agricultural run-off (as
a contaminant and metabolic breakdown product of biocides) and manufacturing
waste discharges (U.S. EPA, 1979). Recant experiments under conditions sim-
ulating the natural environment have not demonstrated that 2,4-dichlorophe-
nol is a significant product resulting from chlorination of phenol-contain-
ing wastes (Glaze, et al. 1978; Jolley, et al. 1978).
8. Food
Contamination of food with 2,4-dichlorophenol would probably result
from use of the herbicide 2,4-0 (U.S. EPA, 1979).
The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor for 2,4-dichlorophenol to be 37 for the edible portions of
fish and shellfish consumed by Americans. . This estimate is based on the
octancl/water partition coefficient.
C. Inhalation
Pertinent information regarding direct evidence • indicating that
humans are exposed to significant amounts of 2,4-dichlorophenol through
inhalation has not been found in the available literature.
III. PHARMACOKINETICS
A. Absorption
Pertinent information regarding the absorption of 2,4-dichlorophe-
nol in humans or animals was not found in the available literature, although
data on toxicity indicate that 2,4-dichlorophenol -is absorbed after oral
administration (Deichmann, 1943; Kobayashi, et al. 1972). Due to its high
»
lipid solubility and low ionization at physiological pH, 2,4-dichlorophenol
is expected to be readily absorbed after oral administration (U.S. EPA,
1979).
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8. Distribution
Pertinent information dealing directly with tissue distribution
after 2,4-dichlorophenol exposure was not found in the available literature.
Feeding of 2,4-0 (300 - 2000 pg/g feed) to cattle and sheep (Clark, et al.
1975) and Nemacide (50 - 800 ug/g feed) to laying hens (Sherman, et al.
1972) did not produce detectible residues of 2,4-dichlorophenol in muscle or
fat. Cattle and sheep had high levels of 2,4-dichlorophenol in kidney and
liver; hens had detectible levels of 2,4-dichlorophenol in liver and yolk.
C. Metabolism
Pertinent information dealing directly with metabolism of admini-
stered 2,4-dichlorophenol was not found in the available literature. In
mice, urinary metabolites of 1AC-labellsd gamma or beta benzene hexacnlor-
ide (hexachlorocylohexane) included 2,4-dicnlcrcphenol and its glucuronide
and sulfate conjugates (as 4-6 percent of total metabolites) (Kurihara,
1575).
0. txcretion
Pertinent information dealing with excretion of administered 2,4-
dichlorophenol was not found in the available literature. After oral admi-
nistration of 1.6 mg Nemacide to rats over a 3-day period, 67 percent of
that compound appeared in urine as 2,4-dichlorophenol within 3 days. With a
dosage of 0.16 mg Nemacide, 70 percent of the compound appeared in urine as
2,4-dichlorophenol within 24 hours (Shafik, et al. 1973).
IV. EFFECTS
A. Carcinogenicity
Insufficient data exist to indicate that 2,4-dichlorophenor is a
carcinogenic agent. The only study performed (Boutwell and Bosch, 1959)
suggested that 2,4-dichlorophenol may promote skin cancer in mice after ini-
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tiation with dimethylbenzanthracene and when repeatedly applied at a concen-
tration high enough to damage the skin. An analysis of the data of Boutwell
and Bosch using the Fisher Exact Test indicated that 'the incidence of papil-
lomas in 2,4-dichlorophencl-treated groups was significantly elevated over
controls, while the incidence of carcinomas was not (U.S. EPA, 1979).
8. Mutagenicity, Teratogenicity and Other Reproductive Effects
No studies addressing the mutagenicity, teratogenicity or other
reproductive effects of 2,4-dichlorophenol in mammalian systems- were found
in the available literature. However, genotoxic effects of 2,4-dichlorophe-
nol have been reported in plants. Exposure of flower buds or root cells of
vetch, (Vicia -fabia)' to solutions of 2,4-dichlorophenol, 0.1M and 62.5 mg/1,
respectively, caused meiotic and mitotic changes including alterations of
chromosome stickiness, lagging chromosome anaphase bridges and fragmentation
(Arcer and -Ali, 1963, 1969, 1974). The relationship of such changes in plant
cells to potential changes in mammalian cells has not bean established (U.S.
EPA, 1979).
C.. Chronic Toxicity
One report (Blsiberg, et al. 1964) suggested that 2,4-dichlorophe-
noi was involved in inducing chloracne and porphyria in workers manufactur-
ing 2,4-dichlorophenol and 2,4,5-trichlorophenol and exposed to acetic acid,
phenol, monochloroacetic acid, and sodium hydroxide. Since various dioxins
(including one associated with chloracne) have been implicated as contami-
nants of 2,4,5-trichlorophenol, the role of 2,4-dichlorophenol in causing
chloracne and porphyria is not conclusive (Huff and Wassom, 1974).
In a study (Kobayaski, et al. 1972) in which male mice were fed
2,4-dichlorophenol at estimated daily doses of 45, 100 and 230 mg/kg body
weight, no adverse effects were noted except for some microscopic nonspeci-
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fie liver changes, after the maximum dose. Parameters evaluated included
body and organ weights and food consumption, as well as hematological and
histological changes.
D. Other Relevant Information
2,4-Qichlorophenol appears to be a weak uncoupler of oxidative
phosphorylation (Farquharson, et al. 1958; Mitsuda, et al. 1963). Values on
odor threshold for 2,4-dichiorophenol in water range from 0.65 to 6.5 ug/1,
depending on the temperature of water (Hoak, 1957).
V. AQUATIC TOXICITY
A. Acute Toxicity
Two 96-hour assays have been performed examining the acute effects
\
of 2,4-dichIcrcphanai in freshwater fish. An LC50 value of 2,020 jug/1 fo^ •-'
the bluegill, Lepomis macrcchir-js, (U.S. EPA, 1978), and an LC_n value of
<3,230 ug/1 for the juvenile fathead minnow, Pi^aphalss pro.T.aias, (Phipps. at
al. manuscript), have been reported. Two studies on the freshwater clatio-
ceran, Daohnia maona, have produced 48-hour static LC5Q values of 2,51---
and 2,600 ug/1 (Kcpperman, et al. 1974; U.S. EPA, 1978). , •
Only one marine fish or invertebrate species has been tested for
the acute effects of 2,4-dichlorophenol. Hi-tt, et al. (1953) observed cniy
a moderate reaction to a concentration of 20,000 pg/1 in mountain bass, a
species endemic to Hawaii.
B. Chronic Toxicity
Data for the chronic effects of 2,4-dichlorophenol for either
freshwater or marine organisms were not located in the available literature.
C. Plant Effects
Concentrations of 2,4-dichlorophenol that caused a 56 percent re-
duction in photosynthetic oxygen production or a complete destruction of
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chlorophyll were 50,000 or 100,000 ug/1, respectively, in algal assays with
Chlorella pyrenoidosa (Huang and Gloyna, 1963). An earlier study by Slack-
man, et al. (1955) reported a concentration of 2,4-dichlorophenol that
caused a 50 percent reduction in chlorophyll to be 53,320 jjg/1 in the duck-
weed, Lemna minor. No marine plant species have been examined.
D. Residues
A bioconcentration factor of 130 has been estimated from the octa-
nol-water partition coefficient of 2,4-dichlorophenol for aquatic organisms
having a lipid content of eight percent. The estimated weighted average
bioconcentration factor for the edible portion of aquatic organisms is 37.
E. Miscellaneous
Flavor impairment studies indicated that the highest concentration
of 2,4-c'ichiorcphenol in the exposure water which v/ould not causa tainting
•of the sdible portion of. fish ranged from 0.4 ug/1 for the iarcemcuth bass
(Microptarus- saL-oldes), to 14 ug/1 for the bluegill (Lepomis iiiacrochirus).
The value for the rainbow trout (Salrno gairdneri) was 1 pg/1 (Shumway and
Palansky, 1973).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived oy U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
Based upon the prevention of adverse organoleptic effects, the
*
draft interim criterion for 2,4-dichlorophenol in water recommended by the
U.S. EPA (1979) is 0.5 ug/1, although the recommended draft interim criter-
ion could be 371 ug/l based on calculations by the U.S. EPA (1979) from sub-
acute toxicity data in mice.
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8. Aquatic
The draft criterion for protecting freshwater organisms is 0.4 jug/1
as a 24-hour average concentration, not to exceed 110 yg/l. No criterion
was derived for marine organisms (U.S. EPA, 1979).
-907-
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2.4-OICHLOROPHENOL
REFERENCES
Alexander, M. and M.I.H. Aleem. 1961. Effect of chemical structure on
microbial decomposition of aromatic herbicides. Jour. Agric. Food Chem.
9: 44.
Aly, O.M. and S.O. Faust. 1964. Studies on the fate of 2,4-0 and ester
derivatives in natural surface waters. Jour. Agric. Food Chem. 12: 541.
Amer, S.M. and E.M. All. 1968. Cytological effects of pesticides. II.
Meiotic effects of some phenols. Cytologia 33: 21.
Amer, S.M. and E.M. Ali. 1969. Cytological effects of pesticides. IV.
Mitotic effects of. some phenols. Cytologia 34: 533.
Amer, S.M. and E.M. Ali. 1974. Cytological effects of pesticides. V. Ef-
fect of some herbicides on Soecia faba. Cytologia 33: 633.
Biackfiian, G.E., at al. 1955. The physiological activity of substituted
phenols. I.. Relationships between chemical structure and physiological
activity. Arch. Bicchem. Biophys. 54: 45.
Bleiberg, J.M., et al. 1964. Industrially acquired porphyria. Arch. Oer-
rnatol. 35: 793.
Scutweii, 3.K. arc O.K. Bcsch. 1959. The tumor-promoting sciicn of phenol
«^f* fo 1 —4- or* f^m^^.1 ir*He f OT rnoi <~O clC* ^ P
ai .U ^.^xawwU U*-t"!_^Ut ,^.O I Ul >i*Owww brN^-'i. W
Clark, D.E., et al. 1975. Residues of chlorophenoxy acid herbicides and
their phenolic metabolites in tissues of sheep and cattle. Jour. Agric.
Food Chem. 23: 573.
Crosby. O.G. and H.O. Tutass. 1966. Photodecomposition of ,2,4-dichlorophe-
noxyacetic acid. Jour. Agric. Food Chem. 14: 596.
Deichrnann, W.3. 1943. The toxicity of chlorophenols for rats. Fed. Proc.
2: 76.
Farquharson, M.E., et al. 1958. The biological action of chlorophenols.
Br. Jour. Pharmacol. 13: 20.
Glaze, W.H., et al. 1978. Analysis of new chlorinated organic compounds
formed by chlorination of municipal wastewater. Page 139 In: R.L. Jolley,
(ed.) Water chlorination - environmental impact and health effects. Ann
Arbor Science Publishers.
Hiatt,. R.W., et al. 1953. Effects of chemicals on schooling fish, -Kuhlia
sandvicensis. Biol. Bull. 104: 28. •
Hoak, R.D. 1957. The causes of tastes and odors in drinking water. Water
and Sew. Works. 104: 243.
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Huang, J. and E.F. Gloyna. 1968. Effect of organic compounds on photosyn-
tnetic oxygenation. I. Chlorophyll destruction and suppression of photosyn-
thetic oxygen production. Water Res. 2: 347.
Huff, J.E. and J.S. Wasscm. 1974. Health hazards from chemical impurities:
chlorinated dibenzodioxins and chlorinated dibenzofurans. Int. Jour. Envi-
ron. Studies 6: 13.
Ingols, R.5., et al. 1966. Biological activity of haiophenols. Jour.
Water Pollut. Control. Fed. 33: 629. "
Jolley, R.L., et al. 1978. Chlorination of organics in cooling waters and
process effluents. In Jolley, R.L., Water Chlorination environmental impact
and health effects. 1: 105. Ann Arbor Science Publishers.
Kirk, R.E. and.D.F. Othmer. 1964. Kirk-Cthmer encyclopedia of chemical
technology. 2nd ed. Interscience Publishers, New York.
Kobayashi, S., et al. 1972. Chronic toxicity of 2,4-dichlorophenol in
mice. Jour. Md. Soc. Toho, Japan. 19: 356.
Kopperman, H.L., et al. 1974. Aqueous Chlorination and ozonaticn studies.
I. Structure-toxicity correlations of phenolic compounds to Daphnia magna.
Chem. 3iol. Interact. 9: 245.
Kurihara, N. 1975. Urinary 'metabolites from and B-5HC in the mouse:
chlorcphenolic conjugates. Environ. Qual. Saf. 4: 56.
Loos, M.H., et al. 1967b. Phenoxyacetate herbicide detoxication by bacter-
ial enzymes. Jour. Agric. Food Chem. 15: 358.
Mitsuda, W., et al. 1963. Effect of chlorophenol analogues on the oxida-
tive phosphorylaticn in rat liver mitochondria. Agric. Siol. Chem. 27: 366.
Phipps, G.L., et al. The acute tcxicity of phenol and substituted phenols
to the fathead minnow. (Manuscript)
Sax, N.I. 1975. Dangerous properties of industrial materials. 4th ed. Van
Nostrand Rheinhold Co., New York.
Shafik, T.M., et al. 1973. Multiresidue procedure for haloand nitrophe-
nols. Measurement of exposure to biodegradable pesticides yielding these
compounds as metabolites. Jour. Agric. Food Chem. 21: 295.
Sherman, M., et al. 1972. Chronic toxicity and residues from feeding nema-
cide [o-(2,4-dichlorophenol)-o,o-diethylphosphorothioate] to laying hens.
Jour. Agric. Food-Chem. 20: 617.
Shumway, D.L. and J.R. Palensky. 1973. Impairment of the flavor of fish by
water pollutants. EPA-R3-73-010. U.S. Environ. Prot. Agency.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646. U.S. Environ. Prot.
Agency.
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U.S. EPA. 1979. 2,4-Oichlorophenol: Ambient Water Quality Criteria.
(Draft).
Weast, R.C., ed. 1975. Handbook of chemistry and physics. 55th ed. CHC
Press, Cleveland, Ohio.
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No. 76
2,6-Dichlorophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
2,6-OICHLOROPHENOL
Summary
There is no available information en the possible carcinogenic, terato-
genic, or adverse reproductive effects of 2,6-dichlorophenol.
The compound did not show mutagenic activity in the Ames assay. A sin-
gle report has indicated that 2,6-dichlorophenol produced chromosome aberra-
tions in rat bone marrow cells; details of this study were not available for
evaluation.
Prolonged administration of 2,6-dichlorophenol may produce hepatoxic
effects. Pertinent data on the toxicity of 2,6-dichlorophenol to aquatic
organisms were not found in the available literature. However, EPA/ECAO
Hazard Profiles on related compounds may be consulted, including meta-
chlorophenol,.2,4.5-trichlorophenol, and 2,3,4,6-tetrachiorophenol.
-9/3-
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I. INTRODUCTION
2,6-Oichlorophenol, CAS registry number 87-65-0, exists as white nee-
dles and has a strong penetrating odor resembling o-chlorophenol. It has
the following physical and chemical constants (Weast, 1972; Hawlsy, 1971):
Formula: C6H4C12°
Molecular Weight: 163
Melting Point: 68°C - 69°C
Boiling Point: 219°C - 220°C (740 torr)
Vapor Pressure: 1 torr 1 59.5°C
pH: 6.79
Production: unknown
2,6-Oichlorcphsncl is produced as a by-product frcm ths dirsct chlcrinaticn
of phenol. It is used primarily as a starting. ->=-eriai for the manufacture
of trichlorophenols, tetrachlorophenols, and pentachlorophenols (Ooldens,
1964).
II. EXPOSURE
A. Water
y
Phenols occur naturally in the environment and chlorophenois are
associated with baa taste and odor in tap water \,.isk, 1957)'. 2,6-Oichicro-
phenol has a taste and odor threshold of 0.002 mg/1 and 0.003 mg/1, respec-
tively (McKee and .Wolf,. 1963). Piet and DeGrunt (1975) found unspecified
dichlorophenols in Dutch surface waters at 0.01 to 1.5 ug/1, and Burtt-
schell, et al. (1959) demonstrated that chlorination of phenol-containing
water produced, among other products, 2,6-dichlorophenol. in a 25-percent
yield after 18 hours of reaction.
8. Food
»
Pertinent data could not be located in the available literature.
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C. Inhalation
Qlie, et al. (1977) reported finding dichlorophenols in flue gas
condensates from municipal incinerators. The levels were not quantified.
0. Dermal
Pertinent data could not be located in the available literature;
however, it is known that dichlorophenols are- less toxic by skin contact
than monc-chlorophenols and less likely to be absorbed through the skin
(Dolcens, 1564).
III. PHARMACOKINETICS
A. Absorption
Pertinent data cculd not be located in the available literature.
By comparison with other chlorophenols, it is expected that 2,6-dichlcrcpna-
nol will be absorbed through the skin and from the gastrointestinal tract
(U.S. EPA, 1579).
3. Distribution
Pertinent data could not be located in the available literature.
The high lipid solubility of the compound would suggest that unexcreted com-
pound distributes .to adioose"tissues.
C. Metabolism and Excretion
Pertinent data could not be located in the available literature.
By comparison with other chlorophenols, it is expected that 2,6-dichlorophe-
nol is rapidly eliminated from the body, primarily as urinary sulfate and
glucuronide conjugates (U.S. EPA, 1979).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature.-
-7/.T-
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8. Mutagenicity
2,6-Oichlorophenol did not show mutagenic activity in the Ames
assay (Rasanen, et al. 1977). Chromosome aberrations in rat bone marrow
ceils have been observed following compound administration (route and dosage
not indicated) (Chung, 1978).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature.
D. Chronic Toxicity
Administration of 2,6-dichlorophenol to rats (route and dosage not
specified) has been reported to produce hepatic degeneration (Chung, 1978).
E. Other Relevant Information
In vitro tests have indicated that 2,6-dichlorophenol will inhibit
liver mitochondrial respiration (level not specified) (Chung, 1978).
V. AQUATIC TOXICITY
A. Acute
McLeese, et al. (1979) reported a 52-hour lethal threshold limit
of 15,100 ug/1 for marine shrimp (Cranqon seotemspinosa) exposed to 2,6-di-
chlorophenol.
B. Chronic .Toxicity, Plant Effects and Residues
Pertinent data could, not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
Sased on the organoleptic properties of 2,6-dichlorophenol, a
water quality criterion of 3.0 ug/1 has been recommended by the U.S. EPA
(1979).
B. Aquatic
NO existing criteria to protect fresh "and saltwater organisms were
found in the available literature.
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No. 77
2,4—Dichloropher.oxyacetic Acid (2,4-Q)
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential, health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-9/9-
-------
2,4-OICHLOROPHENOXYACETIC ACID
Summary
Oral administration of 2,4-Oichlorophenoxyacetic acid (2,4-0) failed to
produce carcinogenic effects in mice or dogs; however, feeding technical
grade 2,4-0 did produce tumors in a study with rats. Subcutaneous adminis-
tration of the isooctyl ester of 2,4-D has been reported to produce reticu-
lum cell sarcomas in mice.
A single study has indicated that 2,4-0 produced mutagenic effects in
Saccharomyces. Other investigations have failed to show mutagenic effects
of the compound Salmonella, Droscphila, Saccharomyces, or the dominant
'lethal assay with mice.
2,4-0 and several of its esters failed to snow teratogenic effects in
~iice; the prcDylene glycol butyl ether ester of the cornpounG produced an in-
crease in cleft palates in this study. Studies in hamsters orally acrninis-
i_ered ^.,4—u aHu derivatives 5~oweG i-eratccenic efrects. Oral aGiTiiniscrstion
of 2,4-0 to rats failed to indicate teratcgep.icity in cr.e study; ancther in-
vestigation using oral administration of 2,4-0 to rats found teratogenic ef-
fects. A three-generation feeding study of 2,4-0 to rats indicated feto-
toxic effects at a dosage of 1,500 ppm.
Toxicity tests on a variety of aquatic organisms generally have demon-
strated that various esters of 2,4-0 are more toxic than the 2,4-0 acid, di-
methyl amine, or sodium salt. Freshwater trout and bluegill sunfish were
adversely affected by the propylene glycol butylether. (PGEE) ester at con-
centrations of 900 to 2,000 jjg/1. Daphnids and freshwater seed shrimp were
sensitive to the PGBE ester at concentrations of 100 to 300 yg/1. Chrcnic
exposure of several species of fish to concentrations up to 310 jug/1 has not
demonstrated any toxic effect.
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2,4-OICHLOROPHENOXYACETIC ACID
I. INTRODUCTION
2,4-Oichlorophenoxyacetic acid, CAS Registry number 94-75-7, commonly
known as 2.,4-0, is a white or slightly yellow crystalline compound which is
odorless when pure. 2,4-0 has the following physical and chemical proper-
ties (Herbicide Handbook, 1979):
9CH2COOH
221.C
135°C-i36cC (technical);
140CC-141°C (pure)
15G0C 9 0.4 torr
Formula:
Molecular Weight:
Melting Point:
Boiling Point:
Density: i.565'"-J
Vapor Pressure: 0.4 ton
Solubility: Acetone, aicchci, aicxane ether,
isopropyl alcohol; slightly
soluble in benzene, solubility in
water 0.09g/100g, H7G
Production: unknown
2,4-0 is used as an herbicide along with its various salts and esters,
which .vary its solubility properties. It is used mainly to control broad-
leafed plants in pastures, and right-of-ways, and, and to keep lakes and
ponds free of unwanted submersed and emersed weeds.
II. EXPOSURE
A. Water
No estimates of average daily uptake of 2,4-0 from water. are
available; however, after treatment for water • milfoil in reservoirs in
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Alabama and Tennessee, the Tennessee Valley Authority found the concentra-
tion at downstream monitoring stations to be 2 ppb. 2,4-0 was not found in
the harvested beans of red Mexican bean plants after irrigation with contam-
inated water (Gangst, 1979).
S. Focd
The Food and Drug Administration, in monitoring milk and meat for
residues of 2,4-0 from 1963 to 1969, found no trace of the herbicide in
13,000 samples of milk and 12,000 samples of meat (Day, et al. 1978).
Cattle and sheep which were fed 2,000 ppm of 2,4-0 for 28 days had less than
0.05 ppm 2,4-0 in the fat and muscle tissue and no detectable amount of
2,4-dicnlcrcphenol. After seven days withdrawal from the 2,4-0 diet, these
tissue levels were drastically reduced (Clark, et al. 1975). Six species of
fish were monitored for three weeks after the water in a pond was treated
with a 2,4-D ester. The highest tissue concentration reached was 0.24 ppm
eight days after application. Subsequently, the herbicide or its metabolite
was eliminated rapiaiy. Cisms and oysters accumulate more 2,4-0 than cc
tish ar.o crabs. ~esidue pesKS occur rrc~i j. to 9 days ai u£r application sr.d
then rapidly decline (Gangst, 1979).
C. Inhalation
Pertinent data were net found in the available literature; ho.v-
ever, some 2,4-D esters which are much more volatile than the parent com-
pound have been monitored in air up to 0.13 ug/m3 (Farwell, et al. 1976;
Stanley, et al. 1971).
D. Dermal
Pertinent data were not found in the available literature.
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III. PHARMACOKINETICS
A. Absorption
Human absorption of 2,4-0 following oral intake is extensive;
Kohli et al. (1974) have determined absorption of 75 to 90 percent of the
total dietary intake of the compound. Animal studies have indicatec that
the gastrointestinal absorption of 2,4-0 esters may be less efficient than
that of the free acid or salt form of the compound (NRCC, 1978).
B. Distribution
The phenoxy herbicides are readily distributed throughout the body
tissues of mammals. Tissue levels of herbicide may be higher in the kidney
than in the blood; liver and muscle shew levels lower than these .determined
in the bloco .(MfiCC, 1978). withdrawal of dietary compound•produced almost
complete tissue loss of residues in seven days (Clark, et ai. 1975).
-^mal-i. 3fnu!jnk.s Ci p. isnoxy iisroici^ss srs passed LO uic young
through the .-ether's milk (3'jerke, et al. 1972). Transplacental transfer, of
2,4—0 has been reported in mice (Lincjcjuist and Uu-Ccry, i9/j.;.
C. Metabolism
Sauerhoff, et al. (1976) determined that following oral adminis-
tration of 2,4-D to human volunteers, the major amount excreted in the urine
was free compound; a smaller amount was excreted as 2 conjugate. Tissue
analysis of sheep and cattle fed 2 4-0 have shown unchanged compound and
2,4-dichlorophenol to be present (Clark, et al. 1975).
0. Excretion
Elimination of orally administered 2,4-0 by humans is primarily
through the urine (95.1 percent of the initial dose); the half-life of the
compound in the body has been estimated as 17.7 hours (Sauerhoff, et'al.
1976). Clark, et al. (1964) have reported urinary elimination of 96 percent
-------
of an oral dose of labelled 2,4-Q within-72 hours by sheep; approximately
1.4 percent of the administered dose was eliminated in the feces.
The plasma half-life of 2,4-0 has been estimated to be from 11.7
to 33 hours in humans (NRCC, 1978).
TV. ^FF^CTS
A. Carcincgenicity
Innes, et al. (1969) reported no significant increase in tumors
following feeding of mice with 2,4-D for 18 months. A two-year feeding
study in rats did indicate an increase in total tumors in females and malig-
nant tumors in males following feeding of technical 2,4-0; a parallel study
with dogs fed technical compound did not show carcinogenic effects (Hansen,
et al. 1971).
Mice were administered maximum tolerateo aoses of 2,4-0 and its
butyl, isooropyl, and isccctyl esters in a long-term carcinogenicity study.
Carcinogenic effects were seen after subcutaneous administration of cne iso-
octyl ester (reticulum cell sarcomas) (iCI, 1968).
B. Mutagenicity
No mutagenic effects of 2,4-0 in tests with Salmonella,
Saccharomvces, or Orosoohila were observed (Fahrig, 1974). Siebert and
Lemoerle (1?74) have recorted iryjtacenic effects ^ollo'-yinf ^"^c^T^nt — ^
Saccharomyces cerevisiae strain 04 with aqueous 2,4-0 solution (1,000 mg/1).
Gavage or intraperitoneal administration of 2,4-0 to mice failed
to show mutagenic effects in the dominant lethal assay (Epstein, et al.
1972).
C. Teratogenicity
Testing of 2,4-D and its n-butyl, isopropyl, and isooctyl esters
in pregnant mice produced no significant teratogenic effects. There was a
-------
significant increase in cleft palate deformities after administration of the
prooylene glycol butyl ether ester of 2,4-0 (Courtney, 1974).
Subcutaneous injection of the two isopropyl esters and the iso-
octyl ester of 2,4-0 in pregnant mice has been reported to produce terato-
genic effects (Caujolle, et al. 1967), although the DMSQ vehicle used is,
itself, a teratogen. Sage, et al. (1973) have also reported teratogenic ef-
fects in mice following injection of 2,4-0.
Oral administration of 2,4-0 to hamsters resulted in the produc-
tion of some terata (Collins and Williams, 1971). Studies with rats report-
ed that oral administration of the parent compound or its isooctyl and butyl
esters, and buto'xy ethancl and dimethylamir.e salts, produced teratcgenic ef-
fects (Khera and McKinley, 1972). However , Schv/etz, et al. (1971) v/ere un-
able L^ --'show teratogenic effects in rats following the oral administration
* ,-> — -^— -..-., ,-.r~
^J. uj. uo. wu y j-di 1
D. Other Reproductive Effects
Efflbryctcxic effscts following subcutaneous administration of 2,4-0
to preJKant mice have been reported (Caujolle, et al. 1967; ?sge, et al.
1573). ,; -
• J
Fetotoxic effects of the compound' and its esters have been repcrt-
— '" =fter o^si -^"i1' riist~2tion of :T2'-/i?T'3^1" toisrated clcs~s !'Sch'v?tz et si.
1971; Khera and McKinely, 1972).
Results of a three-generation study of rats fed 2,4-0 indicate
that at dietary levels up to 500' ppm, no reproductive effects are produced;
at levels of 1,500 ppm, a decrease in survival and body weights of weanlings
was observed (Hansen, et al. 1971). Bjorklund and Erne (1966) reported no
adverse reproductive effects in rats fed 1,000 mg/1 2,4-0 in drinking water.
-------
E. Chronic Toxicity
Animal studies with prolonged oral administration of 2,4-0 or its
amine salt have indicated renal and hepatic effects (Bjorklund and Erne,
1971; 3jorn and Northen, 1948); the chemical purity of the material adminis-
tered is not known. A feeding study in rats has reported histopatholcgical
liver changes at dietary levels of 2,4-0 equivalent to 50 mg/kg (Dow Chem-
ical, 1962).
V. AQUATIC TOXICITY
A. Acute Toxicity
«.
The National Research Council of Canada '(1978) has reviewed the
toxic effects of 2,4-0 to fish. For the bluegill sunfish (Lepcmis
macrochirus), 2,4-0 acid and 2,&-0 dimethyl amine producec ~oxic effects at
concentrations greater than.100,000 ug/1. At 2,4-0 concentrations of 50,000
pg/1 cr. 13S3, r.c increased mortalities were reported except in pink salr.cr,.
The iscprcpyi, butyl, ethyl, butcxy ethanci, and FGBE astars produced
43-hcur LC5Q values of 900, 1,300, 1,400, 2,100, and from 1,000 to 2,100
uc/1 rescectivelv.
For other fish species, the results follow a similar trend in that
the esters tend to be more toxic than other formulations. Meehan, et al.
(l?7^) conducted tests of various formulations of 2,4-D on echo saLr.cn fry
and fingerlings (Oncorhycus Kitutch), chum salmon fry (C3. keta), pink salmon
fry (0_. .gorbuscha), sockeye salmon smolts (Q_. nerka), Dolly Varden
(Salvelinus malma), and rainbow trout (Salmo gairdneri). The butyl ester
was the most toxic ester tested, with concentrations of 1,000 ug/1 or
greater producing nearly 100 percent mortalities in all species tested. The
PGBE ester was similar in toxicity to the butyl ester. Rainbow trout «ere
reported to have shown a 48-hour LC5Q vaiue of 1,100 ug/1 on exposure to
-------
the PGSE ester of 2,4-0. Harlequin fish (Rasbora heteromorpha) showed a
48-hour LC value of 1,000 ug/1 on exposure to the butoxyethyl ester of
2,4-0 (National Research Council of Canada 1978). Rehwoldt, et al. (1977)
have observed 96-hcur LC5Q values of 26,700; 40,000; 70,100; 70,700;
94,600; 96,500; and. 300,600 ug/1 for banded kiilifish (Fundulus diaphanus),
white perch (Roccus americanus), stripped bass (Morone sazatilis), guppies
(Libistes reticulatus), pumpkinseed sunfish (Lepomis gibbosus), carp
(Cvorinus carpio), and American eel (Anguilla rostrata), respectively,
exposed to commercial technical grade 2,4-0.
Sanders (1970) conducted a comparative study on the toxicities of
various iormulations o> 2,4—0 ior six species GI iresiiwa'-er crustaceans.
The PGSE ester was generally most toxic, while the dimethyiamine salt was
least toxic. The crayfish (Orconectes nails) was the most resistant species
tested, witn 48-nour static LC^ values greater than 100,000 /jg/1 for ail
for~jlaticr,s tested. The \vaterflea (Cacrr.ia fiiacna) s~d seec
-.-, — i r^o
(Cypricopsis vicua) '.vere tr.cst sensitive tc the PGSE estar, v/itn 48-hour
LC50 values of 100 and 320 jug/1, respectively. Scuds (Ganniarus
fasciatus), sowbugs (Ascellus brevicaudus), and freshwater grass shrimp
(Palaemonetes kadiakensis) were also moderately sensitive, with 43-hour
LC5g values ranging from 2,200 to 2,700 ,ug/l. Sanders and Cope (1563)
reported a 96-hour LC5Q value of 1,600 jug/1 for stonefly naiads
(Pteronarcy californica) exposed to the butoxyethanol ester of 2,4-0. Tech-
nical grade 2,4-0 produced a 96-hour LC5Q vaj.ue of 14,000 jug/1. Robertson
and Bunting (1976) reported 96-hour LC5Q values ranging from 5,320 to
11,570 jug/1 for copepods (Cyclops vernalis) nauplli exposed to 2,4-0 as free
»
acid. The range of 96-hour LC5Q values for nauplli exposed to 2,4-0 alko-
nolamine salt was 120,000 to 167,000 Aig/1.
-------
Among marine invertebrates, those of commercial significance have
been examined for toxic effects on exposure to 2,4-0 formulations. Butler
(1965) determined the 96-hour median effective concentration based on shell
growth for oysters as 140 ug/1 for the FGEE ester of 2,4-0. The 2,4-0 acid
had no detectable effect at exposures of 2,000 jug/1•for S6-hours. Sutler
(1963) observed paralysis of brown shrimp (Penaeus aztecus) exposed to 2,4-0
acid at a concentration of 2,000 ;jg/l for 48-hours. Sudak and Claff (1960)
found a 96-hour LC_0 value of 5,000,000 ,ug/l for fiddler crabs (Uca
pugmax) exposed to 2,4-0.
McKee and Wolf (1963) have reviewed the toxic effects of 2,4-0 to
aquatic organisms. Toxic concentrations as low as 1,COC ug/1 produced a 40
percent mortality for fingeriing biuegiils exposed to 2,4-0 butyl ester. In
general, esters of 2,4-0 were reported to be more toxic than sodium salts of
2,4-0.
3. Chronic Toxicity
Rehv/cict, et al. (1970) exposec several species of fish to ICO
ug/1 2,4-0 for ten months and observed no overt effects to any tested
species. The percent reduction of brain acetylcolinesterase ranged from 16
percent in white perch to 35 percent in American eels. In breeding experi-
ments with guppies, a 100 ug/1 concentration of 2,4-0 had no significant ef-
fect .on the reproductive process of the species under experimental condi-
tions. Cope, et al. (1970) examined the chronic effects of PGBE ester of
2,4-0 to bluegill sunfish. Fish were exposed to the herbicide in one-eighth
acre ponds containing initial concentrations of up to 10,000 ug/1. Altera-
tions in spawning activity, and the occurrence of pathological lesions of
the liver, brain, and vascular system were reported for a period of up to 84
-------
days. Mount and Stephan (1967) exposed 1-inch fathead minnows (Pimephales
promelas) to a continuous series of concentrations of the butoxyethanol
ester of 2,4-0 ranging from 10 to 310 ug/1 for a 10-month period. No deaths
of deleterious effects, including abnormal spawning activity and reduced
survival of eggs from exposed fish, were observed.
In static-renewal tests, Sigmon (1979) reported that the percent
pupation and the percent emergence of Chironomus larvae were significantly
reduced by exposure to 1,000 or 3,000 pg/1 1,4-0 (acid equivalent in Weedone
LV-4 formulation).
C. Plant Effects
The csnsra Microcwstis Scsnedesmus Chlcrel^s and Nitz^chp's
snowed no toxic resccnse when exposec to 2.000 ug/1 2,4-0 Lawrence .(1962).
Poorman (1973) treated cultures of Euglena gracilis with concentrations of
5G,GGG pg/1 2,4-0 for 24 hours and observed depressed .growth rates.
Valentine and Singhain (1974) demonstrated that at ICC.GCO pg/1, 2,4-0 re-
duced the cell numbers of Scenedesmus to one percent of control levels,
Chlareydsrncnas to 48 percent of control levels, Chlorella to 66 percent of
control levels, and--Euglena to 90 percent of control levels within 4 to 12
days. The bluegreen algae (Nostoc muscorum) displayed a 68-percsnt reduc-
tion in growth when exposed to 100 pg/1 2,^-0 (Cerci and Cavazzini, 1973).
Singh (1974) exposed Cylindrosoermum to 2,4-0 sodium salt at concentrations
ranging from 100,000 to 1,200,000 pg/1 and reported that concentrations
above 800,000 pg/1 caused growth to cease completely. McKee and Wolf (1963)
reviewed the effectiveness of 2,4-0• in control. of emergent aquatic plants
and reported that concentrations ranging from 6,000 to 100,000 /jg/1 have
been effective in controlling a number of species.
-------
0. Residue
Cope, et al. (1970) examined residues of the PG3E ester of 2,4-0
in the freshwater vascular plant, Potamogeten nodosus, in a one-eighth acre
pond treated with single 100 to 10,000 pg/1 applications of the chemical. A
gradual dspsleticn of the herbicide to insignificant levels v/as demonstrated
within three months.
Schultz and Gangstad (1976) reported that the flesh of fish ex-
posed to 2,4-0 dimethyl sodium salt in ponds treated with from 2.24 to 8.96
kg (as an acid equivalent) of the chemical did not attain the 100 jug/1 level
realized in the water two weeks after application.
The National Research Council of Canada (NRCC) (197S) has reviewed
the bioccncentraticn data and associated residues of 2,4-0 in a number of
studies. NRCC indicated that a relatively short half-life of less than two
days is round for fish and oyster. At water concentrations of IGO to 2GG
jug/1, the bioccncer.tration of 2,4-0 various aquatic invertebrates was one LO
two orders of magnitude greater than in the water. Oysters (Crassostica
virjjnica) v/ere reported to have a bioconcentraticn factor of ISO when ex-
posed to the butoxyethanol ester of 2,4-0. The freshwater bluegill and mos-
quito fish (Gambusia affinis) had bicconcentration factors ranging from 7 to
CC e^^^J.,'.,^ ^^ .,*,!* .-T* ^^,^^^^^-—^4--'«.-.,-. C"- -'— ?=,!-* ~ -I--.- ^^^J.-;^.,'.-^'-. ^ ' "^
-'-', L w~v^~w ^—. ^ uw -'lav-ij. i-wi i«~c; t c~a u-Lul ib • i _^>i t i %*o a uj-Ci- «-^i i wd^J 1 -Li i^ *_ , -r— u-
bioconcentrated the 2,4-0 .acid by less than 0.2.
VI. EXISTING GUIDELINES
A. Human
The acceptable daily intake of 2,4-D for humans has been estab-
lished at 0.3 mg/kg (FAO, 1969).
3. Aquatic
Pertinent data were not"found in the available literature.
-930-
-------
2.4-OICHLORQPHENOXYA.CETIC ACID
References
3age, et al. 1973. Teratogenic and embryotoxic effects of herbicides diand
trichlorcphenoxyacetic acids (2,4-0 and 2,4,5-T). Acta Pharmacol. Toxicoi.
32: 408.
Sjerke, E., et al. 1972. Residue studies of phenoxy herbicides in milk and
cream. Jour. Agric. Food Chem. 20: 963.
Sjorklund, N. and K. Erne. 1966. Toxicological studies of phenoxy acetic
herbicides in animals. Acta Vet. Scand. 7: 364.
Bjorklund, M. and K..Erne. 1971. Phenoxy-acid-induced renal changes in the
chicken. I. Ultra structure. Acta Vet. Scand. 12: 243.
Bjcrn, M. and H. Morthen. 1948. Effects of 2,4-dichlorcphenoxyacetic acid
on chicks. Science 108: 479.
Sutler, P.A. 1963 Commercial Fishery Investigations. U.S. Oept. Irtsricr
U.S. Fish arc Vdiuiife Service Circ. 167.: 11.
Sutler, P.A. 1953. • Effects of herbicides on estuarine fauna. Proc.
Southern Weed Conference 18: 576.
Caijjolle, F., st al. 1957. Limits cf ccxic and izeratcgenic tolerance of
dimethyl sulfcxide. Ann. ,\'.Y. Acad. .Sci. 141:. 110.
Cenci, P. and G. Cavazzini. 1973. Interaction between environmental micro-
flora anrj three heriicidal phencxy derivatives. Ig. Mod. 66: 451.
Clark, D., et al.. 1975. Residues of chlorophenoxy acid herbicides and
.their phenolic metabolites in tissues of sheep and cattle. Jour. Agric.
Food Chem. 22: 573.
Clerk, D., et ai. ' 1964. The fate of 2,4-dichlorophenoxyacetic acid in
sheep. Jour. Agric. Food Chem. 12: 43.
Collins, T., and C. Williams. 1971. Teratogenic studies with 2,4,5-T and
2,4-0 in the hamster. Bull. Environ. Contamin. Toxicoi. 6: 559.
Cope, O.B., et al. 1970. Some chronic effects of 2,4-D .in the bluegill
(Lgpamis macrochirus) Trans. Am. Fish Sec. 99: 1.
Courtney, K. 1974. in: The herbicide 2,4-0. U.S. Environmental Protec-
tion Agency, Office of Pesticides Programs, Washington, DC. 2C7 pp.
Day, B.E., et al. 1978. The phenoxy herbicides. Council for Agricultural
Science and Technology, Report 77.
-------
No. 78
1,2-Dichloropropane
Health : ..-d Environnental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-93S*-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts, presented by the
subject chemical. . This document, has undergone .scrutiny to
ensure its technical acc-uracy.
-936-
-------
1,2-DICHLOROPROPANE
Summary
The major environments! .source of dichloroprcpar.s is from the use of a
mixture of dichlo'ropropanes and dichlorcpropenes as a soil fumigant. On
chronic exposure of rats to dichloropropanes the only observed effect was a
lack of normal weight gain. There is no evidence that dichloropropanes are
carcinogens or teratogens. Oichloropropanes have produced mutations in bac-
teria and caused chromosomal aberrations in rats. ••
Aquatic toxicity tests of 1,2-dichloropropane are limited to four acute
investigations. Two observed 96-hour LCcp values for the bluegill are
280,000 and 320,000 jjg/1 and the 48-hour LC,.- value for Daohnia magna is
52,500 jjg/1. A saltwater fish has a reported 96-hour LCCO value of
^r l—'
240,000 jug/1.
-937-
-------
1,2-DICHLOROPROPANE
I. INTRODUCTION
This profile -is based on the Ambient Water Quality Criteria Document
for Dichloropropanes/Dichloropropenes (U.S. EPA, 1979).
1,2-Oichloropropane (1,2-POC, molecular weight 112.99) is a liquid at
environmental temperatures. This isomer of dichloropropane has a boiling
point of 96.4°C, a density of 1.156 g/ml, a vapor pressure of 40 mm Hg at
19.4°C and a water solubility of 270 mg/100 at 20°C (U.S. EPA, 1979).
Mixtures of 1,2-dichloropropane and cis-trans-L,3-dichloropropene are used
as soil fumigants. For the purposes of discussion in this hazard profile
document, dichlorcorooane refers to the 1,2-dichloroprooane isomer. When
heated to decomposition temperatures, 1,2-aichioropropane emits highly toxic
fumes of phosgene (Sax, 1975).
II. EXPOSURE
A. Water
frcrr. industrial and manufacturing processes, as run-off from agricultural
land, and from municipal effluents. This compound was identified'but not
quantified in New Orleans drinking water (uowty, ec ai. 1975).
B. Food
Information was not found, concerning the concentration of dichloro-
propane in commerical foodstuffs; therefore, the amount of this compound in-
gested by humans through food is not known. The U.S. EPA (1979) has esti-
mated the bioconcentration factor (BCF) of dichlorbpropane to be 20. This
estimate is based on the octanol/water partition coefficients of dichloro-
»
propane. The weighted average BCF for edible portions of all aquatic organ-
isms consumed by Americans is calculated to be 5.8.
-------
C. Inhalation.
Atmospheric levels of dichloropropane have not been positively
determined. However, it is known that 5-10 percent of the dichloropropane
which is applied to the soil as a fumigant is released to the air (Tncmas
and McKeury, 1973).
III. PHARMACOKINETICS
A. Absorption, Distribution and Metabolism
Pertinent data could not be located in available literature
searches regarding the absorption of dichloropropane.
B. Excretion
Pertinent data cculd not be located in available- literature
searches regarding excretion of dichioropropane. In the rat, approximately
50 percent of an orally administered dose of dichlorcorooane was eliminated
in the urine in 24 hours (Hutson, et ai. 1971).
IV. EFFECTS
A. Carcinogenicicy
Only one study is reported on the carcinogenicity of dichloro-
propane. Heppel, et al. (1943) repeatedly exposed mice (37 exposure
periods) to 1.76 mg dichloropropane per liter of air. Of the 30 mice, only
three survived the exposure and subsequent observation period; however, the
three survivors had multiple hepatomas at the termination of the experiment
(13 months of age). Due to the high mortality, an evaluation based on this
study cannot be made.
B. Mutagenicity
DeLorenzo, et al. (1977) and Bignami, et al. (1977) f showed
dichloropropane to be mutagenic in S. typhimurium strains TA 1535 and TA
100. Dichloropropane has also been shown to cause mutations in A. nidulans
•2-
-------
(Bignami, et al. (1977), and to cause chromosomal aberrations in rat bone
marrow (Oragusanu and Goldstein, 1975).
C. Teratogenicity
Pertinent information could not be located in available literature
searches regarding teratogenicity.
0. Other Reproductive Effects
Pertinent information could not be located regarding other repro-
ductive effects.
E. Chronic Toxicity
Pertinent information could not be located in available literature
searches regarding chronic toxicity studies of dichioroprocane exposure in
humans. In one study by Heppel, et al. (1948) rats, guinea pigs, and dogs
were exposed to 400 pom of dichioroprooane for 128 to 140 daily seven hour
period (given five oays per weeK). The only effect, observed was a decreased
weight in rats.
V. AQUATIC TOXICITY
A. Acute Toxicity
Two observed 96-hour LC5Q values for the bluegill, LeGomis
macrochirus, upon exposure to 1,2-dichloropropane were 280,000 and 320,000
ug/1•(Dawson, et al. 1977; U.S. EPA, 1978). In the only freshwater inverte-
brate study reported, the 48-hour . LC5Q for Daohnia maona is 52,500 ug/1
(U.S. EPA, .1979). . Tidewater silverside, (Menidia bevyllina), has an
observed 96- hour LC5Q of 240,000/jg/1 (Dawson, et al. 1977).
8. Chronic Toxicity
Chronic data are not available for any saltwater or fre.shwater
species.
-------
C. Plant Effects
The phytotoxicity of 1,2-dichloropropane has not been investigated.
0. Residues
No information available.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by the U.S.
EPA (1979), which are summarized below, have gone through the process of
public review; therefore, there is a possibility that these criteria will be
changed.
A. Human
The TLV for dichlorcpropane is 75 ppm (350 rng/rr. ) (Am. Ccnf. Gov.
Ind. Hyg., 1977). The draft water criteria for dichioropropane is 203 ug/i
(U.S. EPA, 1979).
3. Aquatic
For 1,2-dichlcroprcpane, the proposed drs't criteria to prccsct
freshwater aquatic life are 920 jjg/1 a 24-hcur average and the ccr.csntraticn
should not exceed 2,100 ug/1 at any time. Criteria are not available for
saltwater species (U.S. EPA, 1979).
-------
1,2-DICHLOROPROPANE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1977. Documentation of the threshold limit values. 3rd.
ed.
Bignami, M., et al. 1977. Relationship between chemical
structure and mutagenic activity in some pesticides: The use
of Salmonella typhimurium and Aspergillus nidulans. Mutag.
Res"! 46: T~. ~~"
Dawson, G.W., et al. 1977. The acute toxicity of 47 indus-
trial chemicals to fresh and saltwater fishes. Jour. Hazard.
Mater. 1: 303.
DeLorenzo, P., et al. 1977. Mutagenicity of pesticides
containing 1,3-dichloropropene. Cancer Res. 37: 6.
Dcwty, B., et al. 1975. Halogenated hydrocarbons in New
Orleans drinking v.'ater and bleed plasma. Science 87: 75.
Dragusanu, 3., and I. Goldstein. 1975. Structural and nu-
merical changes of chromosomes in experimencai intoxication
with dichloropropane. Rev. Ig. Bacteriol. Virusol. Parazi-
tol. Epideir.iol. Pneumofitziol. Ig 24: 37.
Heppel, L.A., ec al. 1943. Toxicology of 1,2-dicnloropro-
par.e ' Cpropylene d ichloride; IV. Effect of repeated exposures
tc a low concentration of the vapor. Jour. Ind. Hyg. Toxi-
col. 20: 139
Hutson, D.H., et al. 1971. Excretion and retention of com-
ponents of the soil fumigant D-D^R' and their metabolites
in the rat. Food Cosmet. Tpxicol. 9: 677.
Leistra, M. 1970. Distribution of 1,3-Dichloropropene over
the phase in soil. Jour. Agric. Food Chem. 18: 1124.
Roberts, R.T., and G. Staydin. 1976. The degradation of (2)-
and (E)-l,3-dichloropropenes and 1,2-dichloropropanes in
soil. Pestic. Sci. 7: 325.
Sax, N.I. 1975. Dangerous properties of industrial mate-
rials. Reinhold Book Corp., New York.
Thomason, I.J., and M.V. McKenry. 1973. Movement and fate
as affected by various conditions in several soils. Part I.
Hallgardia 42: 393.
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No. 68-
01-4646.
-------
U.S. EPA. 1979a. Dichloropropenes/Dichloropropanes: Ambient
Water Quality Criteria. (Draft).
U.S. EPA. 1979b. Dichloropropenes/Dichloropropanes: Hazard
Profile.
-------
No. 79
Cichloropropane/Dichloropropenes
Health and Knvironaental iffsccs
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents...
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
DICHLOROPROPANES/DICHLOROPROPENES
SUMMARY
The major environmental source of dichloropropanes and
dichloropropenes is from the use of these compounds as soil fuiai-
gants. Some mild kidney damage has been observed in rats chroni-
cally exposed to 1,3-dichlorpropene. Both dichloropropane and
dichloropropene have been shown to be mutgenic in the Ames assay
test. Data are not available to prove conclusively that these
compounds are chemical carcinogens.
Aquatic toxicity studies suggest that the acute toxicity
r~\f ^h^ dic'"lo*"o^^ooa^es decr^sses as ^~he cM stance bstvs^n t^s
chlorine atoms increases. As an example, the reported 96-hour
LCsn values for the bluegill, Lepomis macrochirus, for 1,1-,
^ ,J —V^VMBBH^^^K^B w<^MMMM«nMBB««^Km^«M^« ,
1,2-, and 1,3-cicnloropropane are 97,300, 280,000, and greacer
char. 520,000 ug/1, respectively. For Daphnia magna, che corres-
ponding reported 43-hour LCeQ values are 25,000, 52,000, and
232,000 ug./l, respectively. Similar results have been obtained
with marine organisms.
The dichloropropenes are considerably more toxic in acute
exposure than the dichloropropanes. For 1,3-dichlorpropene,
the 96-hour LC_Q value for the bluegill is 6,060 ^g/1 compared
to 520,000 ug/1 for 1,3-dichloropropane. For Daphnia magna,
the corresponding values are 6,150 and 282,000 pg/I, respectively.
The ECCQ, based on chlorophyll a for a freshwater alga, is 4,950
pg/l for 1,3-dichloropropene, and 48,000 for 1,3-dichloropropane.
»
Data on measured residues could not be located in the available
literature for any saltwater or freshwater species.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Dichloropropanes/Dichloropropenes (U.S. EPA, 1979).
Dichlorcpropanes (molecular weight 112.99} and dichloropro-
penes (molecular weight 110.97) are liquids at environmental
temperatures. Their boiling points range from 76 to 120.4°C
depending on the compound and the isomer. They are slightly
denser than water, with densities ranging from 1.11 to 1.22.
The principal uses of dichloropropanes and dichloropropenes are
as soil fumigants for control of nematodes, in oil and fat sol-
vents, and in dry - cleaning and degraasing prccssses (Windhclz,
1976). When heated to decomposition temperatures, 1,2-dichloropro-
pane emits highly toxic fumes of phosgene, while 1,3-dichloropro-r
per.e gives off coxic fumes of chlorides (Sax, 1975). Production
of mixtures of dichloropropanes/dichloropropenes approached 60
million pounds per year prior to..1975 (U.S. SPA, 1979).
II. EXPOSURE
A. Water
Dichloropropanes and dichloropropenes can enter the
aquatic environment in discharges from industrial and manufactur-
ing processes, as run-off from agricultural land, and from munici-
pal effluents. These compounds have been identified but not
quantified in New Orleans drinking water (Dowty, et al. 1975).
B. Food
Information was not found in the available literature
*
concerning the concentrations of dichloropropanes and dichloro-
propenes in commercial food stuffs. . Therefore, the amount of
these compounds ingested by humans is not known. The U.S. SPA
-------
(1979) has estimated the weighted average bioconcentration fac-
tors (BCFs) of dichloropropanes and dichloropropenes to range
between 2.9 and 5.8 for the edible portions of fish and shellfish
consumed by Americans. This estimate is based on the ocuanol/
water partition coefficients of chese compounds.
C. Inhalation
Atmospheric levels of dichloropropanes and dichloro-
propenes are not known. However, from information on loss of
these compounds to the air after land application, it was esti-
mated that, in California alone, about 72 tons (8 percent of
the pesticide used) were released to the atmosphere in 1971 (Calif.
State Dept. Agric. 1971).
III. PHARMACOKINETICS
A. Absorption, Distrioution-and Metabolism
Pertinent information regarding the absorption, dis-
tribution, and metabolism of the dichloropropanes and dichloropco-
penes could not be located in the available information.
B. Excretion
No human data are available on the excretion of dichlor-
opropanes or dichloropropenes. In the rat, 80 to 90 percent
of an orally administered dose of dichloropropane or dichloropro-
pene was eliminated by all routes within 24 hours (Hutson, et
al. 1971). Approximately 50 percent of the administered dose
was eliminated in the urine within 24 hours.
IV. EFFECTS
A. Carcinogenicity
Information concerning the carcinogenicity of mixtures
of dichloropropanes and dichloropropenes could not be located
-------
in the available literature. However, cis-i,3-dichloropropane
has produced local sarcomas at the site of repeated subcutaneous
injections (Van Duuren, et al., in press). No remote treatment-
related tumors were observed.
B. Mutagenicity
Mixtures of 1,2-dichloropropane and 1,3-dichloropro-
pene are mutagenic to S_._ typhimurium strains TA 1535 and TA 100,
as are the individual compounds. The mixture, but not the in-
dividual compounds, is also mutagenic to TA 1978 (in the presence
of microsomal activation) indicating a frame-shift mutation not
caoable of beina oroduced by the individual ccm^cur.ds.
C. Taratogenicity and Other Reproductive Effects
Pertinent information could not be located in the ;
available -literature.
D. Chronic Toxic icy
Inhalation exposure of rats, guinea pigs, and -dcgs
to 400 ppm of 1,2-dichloropropane for 128 to 140 daily 7-hour
periods (5 days per week) decreased normal weight gain in rats
(Keppel, et al., 1948). Inhalation exposures of rats to 3 ppm
of 1,3-dichloropropene, 4 hours a day, for 125 co 130 days pro-
duced cloudy swelling in renal tubular epithelium which disap-
peared by 3 months after exposures ended (Torkelson and Oven,
1977) .
V. AQUATIC TOXICITY
A. Acute Toxicity
9
Exposures of bluegill, Lepomis macrochirus, to 1,1-,
1,2-, and 1,3-dichloropropane under similar conditions yielded
96-hour LC5Q values of 97,900, 280,000, and greater than 520,000
-------
rag/1, respectively (U.S. EPA, 1978). -These data suggest that
toxicity decreases as the distance between the chlorine atoms
increases. A reported 96-hour kC^n for 1,3-dichloropropene is
6,060 pg/i for -the bluegill, approximately two orders of magni-
tude lower than for 1,3-dichlorcpropane (U.S. EPA, 1979). Under
static test conditions, reported 48-hour LCcn values for 1,1-,
1,2-, and 1,3-dichloropropanes are 23,000, 52,500 and 282,000
p.g/1t respectively, (U.S. EPA, 1978) for the only freshwater
invertebrate species tested, Daphnia magna. The 48-hour LC5Q
value for 1,3-dichloropropene and Daphnia magna under static
conditions is 6,150 yg/1 (U.S. EPA, 1973).
The 96-hour I>C<-Q values for the saltwater sheepshead
minnow, Cyprinodon variegatus, exposed to 1,3-dichloropropane
and i, 3-dichloropropene were 36,700 ^ig/i and 1,770 jjg/i, respec-
tively (I7.3. EPA, 1573). Dav;son, et ai. (1977) obtained a 96-
hour LC.-Q of 240,000 jjg/'i for tne tidewacer silver side, rienidig
beryllina, for exposure to 1,2-dichloropropane.
For Mysidopsis oahia, the 96-hour LC-Q for 1,3-dichioro-
propene was one-thirteenth that for 1,3-dichloropropane, i.e.,
790 ug/1 and 10,300 ug/i, respectively (U.S. SPA, 1978).
B. Chronic Toxicity
Chronic studies are limited to one freshwater study
and one saltwater study. In an embryo-larval test, the chronic
value for fathead minnows, Pimeohales promelas, exposed to 1,3-
dichloropropene was 122 ug/1 (U.S. EPA, 1978). The chronic value
p
for mysid shrimp, Mysidopsis bahia, was 3,040 ug/1 for 1,3-di-
chloropropane in a life cycle study (U.S. EPA, 1978).
-------
C. Plant Effects
For 1,3-dichloropropene, the 96-hour SC^-Q values,
based on chlorophyll a concentrations and cell numbers of the
freshwater alga, Salanastrum capricornutum, were 4,350 ug/i and
4,960 ug/1, respectively. The respective values obtained for
1,3-dichloropropane were 43,000 and 72,200 jig/1. Thus, the pro-
pene compound is much more toxic than the propane compound, as
is true for the bluegill and Daphnia magna.
D. Residues
Measured steady-state bioconcentration factors (BCF)
are not available for any dichioropropane or dichioropropene
in any fresh or saltwater species. Based on octanol/water coef-
ficients of dichloropropanes and dichloropropenes, the U.S. SPA.
(1973) has estimated the bioconcentration factors for these com-
pounds to range between 10 and 35.
VI. -Other Pertinent Information
In the non-aquatic environment, movement of i,2-cichloro-
propane in the soil results from diffusion in the vapor phase,
as these compounds tend to establish an equilibrium between the
vapor phase, water and absorbing phases (Leistra, 1970). 1,2-
dichloropropane appears to undergo minimal degradation in soil
with the major route of dissipation appearing to be volatiliza-
tion (Roberts and Staydin, 1976).
Following field application, movement of 1,3-dichloropro-
pene in soil results in vapor-phase diffusion (Leistra, 1970).
The distribution of 1,3-dichloropropene within soils depends
on soil conditions. For example, cis-1,3-dichlorobenzene is
chemically hydroiyzed in moist soils to the corresponding cis-
-9ft-
-------
3-chloroalkyl alcohol, which can be microbially degraded to car-
bon dioxide and water by Pseudomonas sp. (Van Dijk, 1974).
VII. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gone through
the process of public review; therefore, there is a possibility
that these criteria may be changed.
A. Human
The TLV for dichloropropane is 75 ppm (350 mg/m )
(Am. Conf. Gov. Ind. Hyg., 1977). The draft water criterion
(U.S. E?A, 1379) for dichloropropane is 203 uc/I. The draft
water criterion for dichloropropenes is 0.63 ug/1 (U.S. EPA,
1979).
3. Aquatic
The draft criteria for the dichloropropanes and di-
chloropropenes to protect freshwater aquatic life are as follows
(U.S. SPA, 1979):
Concentration not
to be exceeded
Compound 24-Hour Average at any cime
1,1-dichloropropane 410 ^g/1 930 pg/1
1,2-dichloropropane 920 ug/1 2,100 ug/1
1,3 -dichloropropane 4> 800 pg/1 11,000 ug/1
1/3-dichloropropene 18 ^g/1 , 250 ug/1
The draft criteria to protect saltwater species are as follows
(U.S. EPA, 1979) :
-------
Compound
1,1-dichloropropane
1,2-dichloropropane
1,3-dichloropropane
1,3-dichloropropene
24-Hour Average
not derived
400 jjg/1
79 jig/1
5.5 pg/1
Concentration not
to be exceeded
at any time
not derived
910 Fg/l
180 pg/1
14
-9*3-
-------
DICHLOROPROPANES/DICHLOROPROPENES
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Documen-
tation of the threshold limit values. 3rd. 3d.
California Stats Department of Agriculture. 1971. State pesticide use
report.
Dawson, G.W., et al. 1977. The acute toxicity of 47 industrial chemicals
to fresh and saltwater fishes. Jour. Hazard. Mater. 1: 303.
Oowty, B.,.et al. 1975. Halogenated hydrocarbons in New Orleans drinking
water and blooa plasma. Science 87: 75.
Heppel, L.A., et al. 1948. Toxicology of 1,2-dichloropropane (propylene
dichloride). IV. Effect of repeated exoosures to a low concentration of the
vapor. Jour. Ind. Hyg. Toxicol. 30: 189.
Hutson. O.H., et al.. 1971. Excretion and retention of ccnncorient3 of the
soil fumigsnt D-0'>RX. and. their metabolites in the rat. Food Cosmet. Toxi-
col. 9: 677. .. )
Leistra, M. 1970. Distribution of 1,3-dichloropropene over the phase in
soil. Jour. Agric. .rooa Cnern. 15: 1124.
Rooerts, R.T. 2nd G. Stcycin. 1976. The degradation of (2)- and
(E)-l,3-di- chlorcpropenes and 1,2-dichloroprcpenes in soil. Pestic. Sci.
~>. ~o<:
/ . st.j. .^
- f
Sax, N.I. 1975. Dangerous properties of industrial materials. Reinhc.ld
Bock Corp., New York. .,
j
Torkelson, R.R. and F. Oyen. 1977. The toxicity of 1,3-dichloropropene as
determined by repeated exposure of laboratory animals. Jour. Am. Ind. Hyg.
Assee. 33: 217.
U.S. EPA. 1978. In-depth studies -on health and environmental impacts of
selected water pollutants. Contract No. 68-101-4646.
U.S. EPA. 1979. Dichloropropanes/Dichloropropenes: Ambient Water Quality
Criteria. (Draft).
Van Dijk, J. 1974. Degradation of 1,3-dichloropropenes in the soil.
Agro-Ecosystems. 1: 193.
Van Duuren, 8.L., et al. 1979. Carcinogenicity of halogenated olsfinic and
alipahtic hydrocarbons. (In press).
Windholz, M., ed. 1976. The Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, N.J.
-------
No. 30
Dicnlorooronanol
Health and Environmental Zffects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference' documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-uracv.
-------
OICHLOROPROPANOL
Summary
There was no evidence found in the available literature to indicate
that exposure to dichloropropanol produces carcinogenic effects. Conclusive
evidence of mutagenic, teratogenic, or chronic effects of dichloropropanol
was not found in the available literature. Acute exposure results in toxi-
city similar to that induced by carbon tetrachloride, including hepato- and
nephrotoxicity. Data concerning the effects of dichloropropanol to aquatic
organisms was not. found in the available literature.
-9S7-
-------
I. INTRODUCTION
This profile is based on computerized searches of Toxline, Biosis, and
Chemical Abstracts, and review of other appropriate information sources as
available. Oichloropropanol (molecular weight 128.9), a colorless, viscous
liquid with a chloroform-like odor, refers to four isomers with the mole-
cular formula C-jHgOCl2. The physical properties of each isomer are
given below.
Soiling Point Density Solubility (Weast, 1976)
Water Alcohol Ether
2,3-Dichloro-l-propanol 182Qc 1.368 slight miscible miscible
l,3-Oichloro-2-propanol 1740c 1.367 very very miscible
3,3-Oichloro-l-oropanol 82-33°C . 1.316 net listed
1, l-Gicnicrc-2-prcpanoi 146-i45^C 1.3534 siicht very very
Additional physical data and synonyms of the above isomers are avail-
able in Heilbrcn (1965), Faircnild (1979), Sax-(1979), Windhaiz (1=75), ana
Vsrschusrsn (1977).
Pi^^ui—T»,^i~]T"^''*"^»""^'1 -*-» -,»» = ^,~—a;j £•.«,-,— — i . .-. _ — ^ i Q0_i.*^, _ _ • ,j • •_. _• .
— -.-.^.i-.'.-'-^.rf-wr-.aii*--. —^ w.k^uG.».du ij-om i^.L.j'^c.i.uJ.j aUc LJ.W GH-.I.U j 'diiu ny Ui L/'JCI •
chloride. It is used as a solvent for hard resins and nitrocellulose, in
the manufacture of photographic and Zapon lacquer, as a cement for cellu-
loid, and as a binder for water colors (winoholz, 1976). The compouno is
considered tc be a moderate fire hazard when exposed to heat, flame, or oxi-
dizers, and a disaster hazard in that it may decompose at-high temperatures
to phosgene gas (Sax, 1979).
II. EXPOSURE
Dichloropropanol was detectable in the air of a glycerol manufacturing
plant in the U.S.S.R. (Lipina and Belyakov, 1975). Unreacted dichloropro-
»
panol was also found in the wastewater effluent of a halchydrin manufactur-
ing plant (Aoki and Katsube, 1975). No monitoring data are available to
indicate ambient air or water levels of the compound.
-------
Human exposure to dichloropropanol from foods cannot be assessed, due
to a lack of monitoring data.
Bioaccumulation data on dichloropropanol was not found in the available
literature.
III. PHARMACOKINETICS
Pertinent data could not be located in the available literature on the
metabolism, distribution, absorption, or excretion of dichloropropanol.
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature.
3. Mutacenicity
2,3-Dichloropropanol and 1,3-dichloroprcpancl were evaluated for
Tiutagenicity by a modified Ames assay using S_._ tychi~urium strains. Seme
evidence of mutagenic activity was seen, but the authors felt that further
evidence and clarification of the metabolic activation pathway to mutagens
via haloalkanois were necessary (Nakamura, et al. 1979).
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Pertinent data could not be located in the available literature.
D. Acute Toxicity
2,3-Dichloropropanol was found to have an oral LD-a i_n tne rat
of 90 mg/kg. The lowest published lethal concentration (LCLQ) in rats is
500 ppm by inhalation for 4 hours. A dose of 6,800 ug in the eye of the
rabbit caused severe irritation (Fairchild, 1979). 1,3-Oichloropropanol was
.-
found to have an oral LD5Q in the rat of 490 mg/kg and lowest published
lethal concentration for inhalation exposure in rats of 125 ppm/4 hrs. .Ten
mg applied to the skin of the rabbit for 24 hours.produced mild irritation,
and 800 mg/kg was the LD5Q for the same route and species (Fairchild,
1979).
-------
Several references report the clinical indications of acute di-
chloropropanol intoxication as being similar to carbon tetrachloride poison-
ing, i.e., central nervous depression; hepatotoxicity, including hepatic
cell necrosis and fatty infiltration; and renal toxicity, including fatty
degeneration and necrosis of the renal tubular epithelium (Sax, 1979; Gos-
selin, et al. 1976).
V. AQUATIC TOXICITY
Data concerning the effects of dichloropropanol to aquatic organisms
were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Hunan
The maximum allowable concentration of dichloroprcpanol in the
working environment air in the U.S.S.R. is 5 mg/m^ .(Lipina and Bslyskov,
1975).
The rnaxiiTium allowable concentration in Class I Caters for the pro-
duction of drinking water is 1 mg/1 (Verschueren, 1977).
3. Aquatic.
The organoleptic limit in water set in the U.S.S.R. (1970) is 1.0
mg/1 (Verschueren, 1977).
-------
REFERENCES
Aoki, S. and E. Katsube. 1975. Treatment of waste waters from halohydrin
manufacture. Chem. Abs. CA/083/15875D.
Fairchiid, E. (ed.) 1979. Registry of Toxic Effects of Chemical Sub-
stances. U.S. Deoartrnent of Health, Education and Welfare, National Insti-
tute for Occupational Safety and Health, Cincinnati, Ohio.
Gosselin, et al. 1976. Clinical Toxicology of Commercial Products. Wil-
liam and Wilkins Publishing Co., Baltimore, Maryland.
Heilbron, I. (ed.) 1965. Dictionary of Organic Compounds. 4th edition.
University Press, Oxford.
Lipina, T.G. and A. A. Belyakov. 1975. Determination of allyl alcohol, al-
lyl chloride, epichlorohydrin and dichlorohydrin in the air. Gig. Tr. Prof.
Zabol. 5: 49.
r?., A., et al. 1979. The mutagenicity cf halcgensted alkancls and
their phosphoric acid asters for SalrnG.-.ella tychimuriurn. Mutat. Res.
66: 373.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials. Van Ncs-
trand Reinhold Co., New York.
Verschueren, K. 1577. Handbook of Environmental Data en Organic Chemicals.
Van Ncstrand Reinhold Co., New York, p. 659.
Weast, R.C. (ed.) 1976. Hancbook of Chemistry and Physics. CRC Press,
Cleveland, Ohio, p. c-454.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Railway,
New Jersey.
•961-
-------
No. 81
1,3-Dichloropropene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980.
-9 £3.-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
1 , 3-DICHLOROPROFENE
SUMMARY
The major environmental source of dichlorcoropenes is from the use of a
mixture of dichloropropenes and dichloropropanes as a soil fumigant. On
chronic exposure of rats to dichloropropene mild kidney damage was observed.
Oichloropropene has produced subcutaneous tumors at the site of injection,
and has been shown to be mutagenic in bacteria. However, not enough infor-
mation is available to classify this compound as a carcinogen.
The bluegill (Leoomis macrochirus) has a reported 96-hr LC_.^ value of
6C6G ug/1; Sasnnia ir.agna nas a ' reporzec 48-hr LC^n of 615C jug/i. For the
^ ^~— ' ^U
-l '-•t-- • >T--~—- "^° ne -T'e Ssh-'s 3 — annrfaH C
^O^-O LjCi* i— a , d ^.^(^wx^^^ ^
790 UQ/1. In the only lonn— term st'jdv available the v^lue nb^-insp fo^
1, 3-dichloroprcp3ne toxicity to fa^r.aad minr.-'/s (Pi.r.eohales prc~3l3s) in an
•cTnbr'/c-i3''~va "' '"sst is ' ^'~>r> ''—/!.' B-seG' on cnlor^^hv'' ''• 3. c~r^'=r''f"rs''""'cns -r'~
cell numbers, the 96-hr EC_n values for the freshwater alga Selenastrum
capricornutum are 4,950 and. 4, 960 jug/1, respectively; 'fcr .the
Skeletonema costatum, the respective values are 1,000 and 1,040 pg/1.
-------
1,3-OICHLOROPROP£.V€
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for DichlGrcprcpsnss/Oichloropropenes (U.S. EPA, 1579a).
1,3-dichloropropene (molecular weight 110.97) is a liquid at environ-
mental temperatures.• The isomers of 1,3-dichloropropene have boiling points
of 104.3°C for the trans-isomer and 112°C for the cis-isomer, and the
densities are 1.217 and 1.224 g/ml, respectively. The water solubility for
the two isomers is approximately 0.275 percent. When heated to
decomposition temperatures, 1,3-dichloropropene gives off toxic fumes of
chlorides (Sax. 1975). Mixtures of cis- and trans- l,3-dichioropropep,e and
1,2-dichioropropane are used as soil fumigants. In this document,
dichloroprcoene will refer to either cis- or trans-l,3-dichloropropene. For
more information regarding the dichioropropenes, the reader is referred to
tha EPA/ECAO Hazard Profile on Dichloropropanes/Dichioropropenes (U.S. EPA,
1979c).
II. EXPOSURE
A. Water
Oichloropropene can enter the aquatic environment in the discharges
from industrial and manufacturing processes, in run-off from agricultural
land, or from municipal effluents. This compound has been identified but
not quantified in New Orleans drinking water (Dowty, et al. 1975).
8. Food
Information was found in the available literature concerning the
concentration of dichloropropene in commercial foodstuffs. Thus, thefamount
of this compound ingested by humans is not known. The U.S. EPA (1979a) has
estimated the weighted average bioconcentration factor (8CF) of dichloropro-
pene to be 2.9 for the edible portions of fish and shellfish consumed by
-------
Americans. This estimate is based on the dctanol/water partition coeffi-
cient of dichloropropene.
C. Inhalation
Atmospheric levels of dichloropropene have not been measured. How-
ever, it is estimated that about 8 percent of the dichloropropene which is
applied to the soil as a fumigant is released to the atmosphere (U.S. EPA,
1979a).
III. PHARMACCKINETICS
A. Absorption
Data on the absorption, distribution and metabolism of dichloropro-
Data on the excretion of dichicrcproper.e by humans could not be
located in the available literature. In the rat, hcv/ever, approximately £G
percent of an orally administered dose of dichicrcprcper.e v/as eliminated in
the urine within 2
-------
addition of liver microsomal fraction. Neudecker, et al. (1977) found the
cis-isomer to be twice as reactive as the trans-isomer.
C. Teratogenicity and Other Reproductive Effects
Me pertinent information regarding the teratogenicity and other
reproductive effects could not be located in the available literature.
D. Chronic Toxicity
On exposure of rats to 3 ppm dichloropropene for period of 0.5, 1,
2 or 4 hours/day, 5 days a week for 6 months (Torkeison' and Oyen, 1977), or
rats, guinea pigs, and rabbits to 1 or 3 ppm of dfchloropropene, 7 hours per
day for 125-130 days over a 180-day period, only rats exposed 4 hours/day at
3.0 ppm shewed an effect (U.S. EFA, 1979a). The only effect observed was a
cloudy swelling . of the renal tubular epithelium which disaooesred by 3
months after exposures ended.
V. AQUATIC TCXICITY
A. Acute Toxicity
Tests or, the bluegiii, Lepomis macrochirus, yielded a 96-hr LC=n
value of 6060 }jg/l for 1,3-dichlorcprcpene exposure. For Daphnia maqna, the
48-hr LC-0 value is 6,150 jug/1 (U.S. EPA, 1973). The observed 96-hr
LC5Q for the saltwater rnyrid shrimp, Mysidopsis bahia, is 790 jug/1 (U.S.
SPA, 1978).
8. Chronic Toxicity
An embryo-larval test has been conducted with the fathead minnow
(Pimeohales promeles) and 1,3-dichloropropene. The observed chronic value
was 122.jjg/l (U.S. EPA, 1979a).
C. Plant Effects
Based on chlorophyll a concentrations and cell numbers, the 96-hr
EC50 values for the freshwater alga, Selenestrum caoricornutum, are 4,950
-$67-
-------
and 4,960 jug/1, respectively (U.S. EPA, 1978). The respective values for
the saltwater alga Skeletonema costatum were 1,000 and 1,040 jug/1 (U.S. EPA,
1973).
0. Residues
Measured steady-state bioconcentration factors (3CF) are not avail-
able for .1,3-dichloropropene. A BCF of 19 has been estimated based on the
octonol/water coefficient for 1,3-dichloropropene (U.S. EPA, 1979a).
£. Other Relevant Information
Following field application, movement •• of 1,3-dichloropropene in
soil results in vapor-phase diffusion (Leistra, 1970). The distribution of
1,3-uiohlcrcprcpsne within soils depends en sell conditions. Fcr exarcoie.
cis-l,3-dichioropropane is chemically hydroiyzed in moist soils to the cor-
responding cis-3-chloroalkyl alcohol, which can be microbially degraded to
carbon dioxide ana water oy .-seuoornonas sp. (Van Oijk 1574).
VI. EXISTING GUIDELINES AND STANDARDS
^either the human health nor cr.e aquatic criteria cerivec by U.S. EPA
(1979a), which are summarized below, have gone through the process of public
review: therefore, there is a possibility that these criteria will cs
changed.
A. Human
The draft, water criterion for 1,3-dichloropropene is 0.63 /jg/1
(U.S. EPA, 1979a).
8. Aquatic
The draft,criterion to protect freshwater species is 18 jug/1 as a
24-hr average not to exceed 250/jg/1 at any time. For marine species, the
value is 5.5 -jug/1 as a 24-hr average not to exceed 14 jug/1 at any time (U.S.
EPA, 1979).
-------
1.3-OICHLOROPROPENE
REFERENCES
DeLorenzo, F., gt al. 1977. Mutagenicity of pesticides containing 1,3-di-
chloropropene. Cancer Res. 57: 5
Oowty, 3., et al. 1975. Halogenated hydrocarbons in New Orleans drinking
water and blood plasma. Science 87T75.
Hu-tson, O.H.,'et al. 1971. Excretion and retention of components of the
soil fumigant D-0>R) and their metabolites in the rat. Food Cosmet.
Toxicol. 9: 677.
Leistra, M. 1970. Distribution of 1,3-dichloropropene over the phase in
soil. Jour. Agric. Food Chem. 18: 1124.
Neudecker, T., et al. 1977. _In vitro mutagenicity of the soil nematocide,
1,3-dichlorcpropene. Experientia 33: 8.
Sax, N.I. 1975. Dangerous. Drrcarti3S of Industrial Materials. Reir.hold
Book Corp., New York. ')
Torkelscn, R.R, and F. Oven. 1977. The toxicity of 1,3—dichlorcpropene as
determined by repeated exposure of laboratory animsls. Hour. Am. Ind. Hvo.
Assoc. 38: 217.
U.S. EPA. 1973. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646.
U.S. EPA.. 1979a. Cicnloroprdpanes/Dichloropropenes: Ambient Water Quality
Criteria (Draft) .
. ) '
U.S. EPA. 1979b. Dichloropropanes/Dichloropropenes: EPA/ECAO Hazard Pro-
file.
Van Oijk, J. 1574. Degradation of i,3-dicnloropropenes in the soil. Agro-
Ecosystems. 1: 193.
Van Duuren, et al. 1979. Carcinogenicity at halogenated olefinic and
aliphatic hydrocarbons. (In press).
-96?-
-------
No. 82
Dleldrin
U.S. ENVIRONIiENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-970-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracv.
-9-71'
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
dieldrin and has found sufficient evidence to indicate that
this compound is carcinogenic.
-973.-
-------
DIELDRIN
SUMMARY
Dieldrin is a compound belonging to the group of cyciodier.e
insecticides. The chronic toxicity-of low dcses of dieidrin
includes shortened life span, liver changes ana teratogenic effects,
The induction of hepatocellular carcinoma in mice by dieidrin
leaas to the conclusion that it is likely to be a human carcinogen.
Dieidrin has been found to be non-mutagenic in several test sys-
tems. The WHO's acceptable daily intake for dieidrin is 0.0001
mg/kg/day.
The toxicity of dieidrin to aquatic organisms has been
investigated in numerous studies. The 96-hour LC,-g values for
the common freshwater fish range from 1.i.to 3oO ug/1. Tha acute
tcxicity is considerably more varied for f reshv/ater inver titrates,
witn 96-hour ^C-~ values ranging from 0.5 ug/i for the stonefiy
to 7
-------
DIELDRIN
I. INTRODUCTION
This profile is based on the draft Ambient Water Quality
Criteria Document for Aldrin and Dieldrin (u.S. SPA, 1979).
Dieldrin is a -white crystalline substance with a melting point
of 176-177°C and is soluble in organic solvents (U.S. EPA, 1979).
The chemical name for dieldrin is 1, 2 , 3 ,.4 ,10 ,10-hexachlor-6 , 7-
epoxy-i, 4,4a,5,6,7,8 ,8a-octohydro-endo/ exo-1, 4 : 5 , 8-dimethanor.aph-
thalene.
Dieldrin is extremely stable and persistant in the envircn-
men.t. Its persistance is due to its extremely low volatility
(1.78 x 10~7 mm Hg at 2Q°C) and low solubility in water (186
ug/1 at 25-29°C). The time required for 95 percent of the dieldrin
to disappear from soil has been estimated to vary from 5 to 25
years depending on the microbial flora of the soil (Edwards,
1966;.' Patil, et al. (1372; reported that dieidrin was not de-
graded or metabolized in sea water or polluted water.
Dieldrin was .primarily used as a broad spectrum insecticide
until 1974, when the U.S. EPA restricted its use to termite con-
trol by direct soil injection, and non-food seed and plant treat-
ment (U.S. EPA, 1979). From 1966 to 1970, the amount of dieldrin
used in 'the United States decreased from 500 to approximately
335,000 tons '(U.S. EPA, 1979). This decrease in use has been
attributed primarily to increased insect resistance to dieidrin
and to development of substitute materials. Although the produc-
tion of dieldrin. is restricted in: the' United States, formulated
products containing dieldrin are imported from Europe (U.S.
EPA, 1979).
-------
II. EXPOSURE
A. Water
Dieldrin has been applied to vast areas of agricul-
tural land and aquatic areas in the united States, and in most
parts of the world. As a result, this pesticide is found in
most fresh and marine waters. Dieldrin has been measured in
many freshwaters of the United States, with mean concentrations
ranging from 5 to 395 ng/1 in surface water and from 1 to 7 ng/1
in drinking water (Epstein, 1976) . Levels as high as 50 ng/1
have been found in drinking water (Harris, et al. 1977) . The
half-life of dieldrin in water, 1 meter in. depth, has been esti-
mated to be 723 days (MacKay and Wolkoff, 1973).
B. Food
Dieldrin is one of the most scable and persistant
orcancchiorine pesticides (Mash and Woolson, 1967), ar.d because
it is iipophilic, it accumulates in the food chain (Wurster,
1971). Its persistence in soil varies with the .type of soil.
(Matsumura and Boush, 1967).
The U.S. EPA (1971) estimated that 99.5 percent of
all human beings have'dieldrin residues in their tissue. These
residues are primarily due to contamination of foods of animal
origin. The overall concentration of dieldrin in the diet in
the United States has been calculated to be approximately 43
ng/g of food consumed (Epstein, 1976). The U.S. EPA has estimated
the weighted average bioconcentration factor for dieldrin to
be 4,50.0 in the edible portion of fish and shellfish consumed
by Americans (U.S. EPA, 1979). This estimate is based on measured
-------
steady-state bioconcentration studies in several species of fish
and shellfish.
C. Inhalation
Dieldrin enters the air through various mechanisms,
such as spraying, wind action, water evaporation, and adhesion
to par ticulates. The U.S. EPA detected dieldrin in more than
85 percent of the air samples tested between 1970-1972, with
the -mean levels ranging from. 1 to 2.3 ng/m (Epstein, 1976).
From these levels, the average daily intake of dieldrin by respi-
ration was calculated to be 0.035 to 0.098 ug.
Although dieldrin is no longer 'jssd in the United
States, there is still the possibility, of air-borne contamination
from other parts of the world.
D. Dermal
Dermal exposure to dieldrin is limited to those in-
volved in its manufacture or application as a pescicids.. vvcifa,
et al. (1972) reported that exposure in workers was mainly through
dermal absorption rather than inhalation. The ban on the manufac-
ture of dieldrin in the United States has greatly reduced the
risk of exposure.
III. PHARMACOKINETICS
A. Absorption
The absorption of dieldrin by the upper gastrointes-
tinal tract- begins almost immediately after oral administration
in rats and has been found to vary with the amount of solvent
»
used (Heath and Vandekar, 1964). These authors also demonstrated
that absorption takes place via the portal vein, and that dieldrin
-------
couid be recovered from the stomach, small intestine, large intes-
tine and feces one hour after oral administration.
B. Distribution
The distribution of dieldrin has been studied in numer-
ous feeding experiments. Dieldrin has an affinity for fat, but
high concentrations are also reported in the liver and kidney,
with moderate concentrations in the brain one and two hours after
administration in rats (Heath and Vandekar, 1964). . Deichman,
et al. (1968) fed dieldrin to rats for a'- period of 183 days.
The mean concentration in the fat was 474 times that in the blood,
while the concentration in the liver was approximately 29 tiT.es
the blood concentration.
Additional animal studies on the distribution of diel-
drin have shown that concentrations in tissues are dose related
and rr.ay vary with the sex of the animal (Walker, et al. 1963).
Matthews, et al. (1971) found that female rats administered oral
doses of dieldrin had higher tissue levels of the compound than
male rats. The females stored the compound predominatly as diel-
drin. In males, other metabolites, identified as keto-dieldrin
trans-hydro-aldrin and'a polar metabolite, were detected.
The concentrations of dieldrin in human body fat were
found to be 0.15 + 0.02 pg/g for the general population and 0.3S
ug/g in one individual exposed to aldrin (aldrin is metabolized
*•
to dieldrin) (Dale and Quinby, 1953). The mean concentrations
of dieldrin in the fat, urine, and plasma of pesticide workers
were 5.67, 0.242 and 0.0185 mg/g, respectively (Hayes and Curley,
1968). Correlations between the dose and length of exposure
to dieldrin and the concentration of dieldrin in the blood and
-97
7-
-------
other tissues have been reported (Hunter, et al. 1969). Dieldrin
residues in the blood plasma of workers averaged approximately
four times higher than that in the erythrocytes (Mick, et al.
1971) .
C. Metabolism
The epoxidation of aldrin to dieldrin has been reported
in many organisms, including man (U.S. EPA, 1979). The reaction
is. NADPH-dependent, and the enzymes have .been found to be heat
labile (Wong and Terriere, 1965).
The metabolism of dieldrin has been studied in several
species, including mica, rats,, rabbits, and sheep. Dieldrin
metabolites have been identified in the urine and feces in the
form of several compounds more polar than the parent compound
'{U.S.. EPA, 1379). Bedford and Hutson .(1976) summarized the four
.
-------
as in the feces. Robinson, et al. (1969) found that 99 percent
of the dieldrin fed to cats for 8 weeks was excreted during a
subsequent 90-day observation period. The half-life of dieldrin
in the liver and blood was 1.3 days for the period of rapid elimi-
nation and 10.2 days for a later, slower period. The half-life
of dieldrin in adipose tissue and brain were 10.3 and 3.0 days,
respectively.
The concentration of dieldrin in the urine of the
general human population is 0.3 mg/1 for man and 1.3 mg/1 for
women as compared to 5.3, 13.8, or 51.4 mg/1 for men with low,
medium, or high exposure (Ceuto and Biros, 1967). The half-life
ifor dieldrin in the blood of humans ranges from 141-592 day '-• \
with a mean of 369 days (Hunter, et al. 1969). Jager (1970)
reported -the half-life tc be .265 days. Because there is a rela-
tionship between the concentration of dieldrin in the ciood and
that ir. adipose and ether tissues, it seems likely that the hai£-\._
) "
life in the blood may reflect the over-all half-life in other
tissues (U.S. EPA, 1979). ' - -{
IV EFFECTS
A. Carcinogenic!ty
Dieldrin'has produced liver tumors in several strains
of mice according to six reports of chronic feeding studies (NCI,
1976 (43 FR 2450); Davis and Fitzhugh, 1962; Davis, 1965; Song
and Harville, 1964; Walker, et al. 1972; Thorpe''and Walker, 1973).
In rats, dieldrin has failed to induce a statistically significant
f
excess of tumors at any site in three strains during six chronic
feeding studies (Treon and Cleveland, 1965; Cleveland, 1966;
-------
Fitzhugh, et al. 1964; Deichman, et al. 1967; Walker, et al.
1969; Deichmann, et al. 1970).
The only information concerning the carcinogenic poten-
tial of dieldrin in man is an occupational study by Versteeg
and Jager (1973) . The workers had been employed in a plant pro-
ducing aldrin and dieldrin with a mean exposure time of 6.6 years.
An average of 7.4 years had elapsed since the end of exposure.
No permanent adverse effects, including cancer, were observed.
B. Mutagenicity
Microbial assays concerning the mutagenicity of aldrin
and dieldrin have yielded negative results even when some type
of accivacicn system was added (Fahrig, 1973; Bidweii •- et al.
1975; Marshall, et al. 1976). A host-mediated assay and a domi-
nant lethal test, also yielded negative resuics (oidweil, et
al. 1975). Majumdar, et al. (1577), .however, found dieldrin
tc be rr.utagenic in 5. cyph iph iaur i urn , although these --positive
~~ '• j'
results were .questioned because several differences existed- be-
tween their procedures and those recommended (U.S. EPA, ii .}}.
A decrease in the mitotic index was observed in vivo
•filth mouse bone marrow ceils and _iri vitro wicn human lung cells
treated with 1 mg/kg and 1 jjg/ml dieldrin, respectively (Majumdar,
et al. 1976).
D. Teratogenicity
14
In 1967, Hathaway, et al. established that C-diel-
drin could cross the placenta in rabbits. Dieldrin caused signifi-
cant increases in fetal death in hamsters, and increased fetal
anomalies (i.e.. open eye, webbed foot, cleft palate, and others)
-------
in hamsters and mice when administered, in single oral doses dur-
ing gestation (hamsters 50, 30, 5 mg/kg and mice 25, 15, 2.5
mg/kg) {Ottolenghi, et al. 1974).
However, in subsequent studies no evidence has been
found that dieldrin causes teratogenic effects in mice and rats
(Chernoff, et al. 1975) or mice (Dix, et al. 1977).
D. Other Reproductive Effects
Deichmann (1972) reported that aldrin and dieldrin
(25 mg/kg/diet) fed to mice for six generations affected ferti-
lity, gestation, viability, lactation, and survival of the young.
However, no changes in weight or survival of fetuses v:ere fcund
in mice administered dieldrin for day 6 through 14 of gestation
at doses already mentioned in this report (Ottoler.ghi, et al.
1974) .
E. Chronic Toxicity
The other effects produced by chronic administration
of dieldrin to mice, rats, and dogs include shortened life span,
increased liver to body weight ratio, various changes in liver
histology, and the induction of hepatic enzymes (U.S. EPA, 1979).
F. Other Relevant Information
Since aldrin and. dieldrin are metabolized by way of
the mixed function oxidase (MFO) system and dieldrin has been
found to induce the production of these enzymes, any inducer
or inhibitor of the MFO enzymes should affect the metabolism
of dieldrin (U.S. EPA, 1979). Dieldrin fed in low doses pjrior
to an acute dose of dieldrin alters its metabolism (Baldwin,
et al. 1972). Dieldrin can effect the storage of DDT (U.S. EPA,
* -9*1-
-------
1979) and induce a greater number of tumors in mice when admini-
stered with DDT as compared to DDT alone (Walker, et al. 1972).
V. AQUATIC TOXICITY
A. Acute Toxicity
The acute toxicity of dieldrin has been investigated
in numerous studies. Reported 96-hour LC^Q values for freshwater
fish are 1.1 to 9.9 ug/1 for rainbow trout, Salmo gairdneri (Katz,
1961; Macek, et al. 1969); 16 to 36 ug/1 for fathead minnows,
Pimephales promelas (Henderson, et al. 1959; Tarzwell and Henderson,
1957); and 8 to 32 pg/1 for the bluegill, Lepomis macrochir us
(Henderson, et al. 1959; Macek, et al. 1959; Tar2we11. and Henderson,
1957) .. . Freshwater invertebrates appear to be more variable in
their sensitivity to acute dieldrin toxicity. The 96-hour LC-M
values range from 0.5 /ig/1 for the stone fly (Sanders ana Cope,
1963-} to 740 ug/1 for the crayfish (Sanders, 1972).
The acute .'LCcg values for eight saltwater fish species
range from 0.66 to 24.0 pg/l in flow-through tests (Butler, 1963;
Earnest and Benville, 1972; Korn and Earnest, 1974; Parrish,
et al. 1973; Schoettger, 1970; and Lowe, undated). LC-^ values
ranging from 0.7 to 240.0 ug/1 have been reported for estuarian
invertebrates species, with the 'most sensitive species tested
being the commercially important pink shrimp, Penaeus duorarum
(U..S. EPA> 1978) .
B. Chronic Toxicity
Chronic toxicity has been studied in two species of
freshwater fish. The chronic value for steelhead trout (S aImp
gairdneri) from an embro-larval study is 0.11 ug/1 (Chadwick
-------
and Shumway, 1969) . For the guppy, Poecilia reticulata,- in a
life-cycle test, the chronic value is 0.4 yg/l (Roelofs, 1971).
C. Plant Effects
Freshwater plants are less sensitive to dieldrin than
freshwater fish or invertebrates. For example, a concentration
of 100 /ag/1 caused a 22 percent reduction in the biomass of the
alga Scenedlesmus quadr icaudata (Stadnyk and Campbell, 1971),
and 12,300 ug/1 reduced growth by 50 percent in the diatom, Navi-
cula seminulum after 5 days of exposure (Cairns-, 1968). In a
saltwater plant species growth rate was reduced, at concentrations
of approximately 950 pg/i (Batterton, et al. 1971).
~" /
D. Residues
Bioconcentration factors (3CF) have been determined
for 9 freshwater species (U.S. EPA, 1973). Representative 5CF
values are 123 for ens alga, See.nee a sinus obliguua (Reinert, 1972,
1395 for Dap'nnia magr.a (Reir.ert, 1972), 2335-2993 for the channel
catfish, _Ictalurus punc ta tug (Shannon, 1977a; 1977b) and 68,258
for the yearling lake trout, Salvelinus namaycusb. (Reinert, ec
al. 1974). The edible tissue of the Eastern oyster, Crassostrea
virginica, had a 3CF value of 3000 after 392 days of exposure
(Parrish, 1974). Spot, Leiostomus xanthurus, had a BCF of 2,300
after 35 days exposure to dieldrin (Parrish, et al. 1973).
VI. EXISTING GUIDELINES AND STANDARDS
.-
Neither the ' human health nor the aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gone through
the process of public review; therefore, there is a possibility
that these criteria will be changed.
-------
A. Human
The current exposure level for dieldrin set by OSKA
is an air time-weighted average of 250 ug/m for skin absorption
(37 FR 22139). In 1953, the U.S. Public Health Service Advisory
Committee recommended that the drinking water standard for diel-
drin be 17 ug/1 (Mrak, 1969) . The U.N. Food and Agricultural
Organization/World Health Organization's acceptable daily intake
for dieldrin is 0.0001 mg/kg/day (Mrak, 1959).
The carcinogenicity data of Walker, et al. (1972)
were used to calculate the .draft ambient water quality criterion
_2
for dieldrin of 4.4 •-: 10 ng/i (U.S. EPA, L^l?} . This Isvel
keeps the lifetime cancer risk for humans below 10~D.
B. Aquatic
The draft criterion to protect freshwater life is
0.0019 uc/'i as a 24-hour average; the concentration should r.c-~
exceed 1.2 ^ug at any time. To protect saltwater aquatic life,
the draft criterion is O.OCS9 jjg/1 as. a 24-hour average; the
concentration should not exceed 0.15 ^5/1 at any tirr.e.
-------
DI ELDRIN
REFERENCES
Baldwin, M.K., et al. 1972. A comparison of the metabolism
of HEOD (dieldrin) in the CFI mouse with that in the CFE rat.
Food Cosmet. Toxicol. 10: 333.
Batterton, J.C., et.al. 1971. Growth response of bluegreer.
algae to aldrin, dieldrin, endrin and their metabolites.
Bull. Environ. Contam. Toxicol. 6: 589.
Bedford, C.T., and D.H. Hutson. 1976. The comparative me-
tabolism in rodents of the isomeric insecticides dieldrin and
endrin. Chem. Ind. 10: 440.
Bidwell, K., et al. 1975. Comprehensive evaluation for mu-
tagenic activity of dieldrin. Mutat. Res'; 31: 314.
Butler, P.A. 1963. Commercial fisheries investigations. I_n
Pesticide and wildlife studies: A review of Fish and Wildlife
Service investigations during 1951 and 1962. U.S. Fish
Wildl. Serv. Circ. 157: 11."
Cairns, J., et al. 1968. The effects of dieldrin on dia-
toms. Mosquito News 28: 177.
Chadwick, G.G., and D.L. Shumway. 1969. Effects of dieidrin
on the growth and development of steelhead trout. Page 90 in
The Biological impact of pesticides in the environment. En~
viron. Health Sci. Ser. No. 1 Oregon Stare University.
Chernoff, N., et al. 1975. Prenatal effects of dieldrin and
photodieldrin in mice and rats. Tcxicol. Acol. Pharmacol.
31: 302.
Cleveland, F.P. 1966. A summary of work on aldrin and diel-
drin toxicity at the Kettering Laboratory. Arch. Environ.
Hea-i.cn 13: 195.
Cole, J.F., et al. 1970. Endrin and dieldrin: A comparison
of hepatic excretion in the rats.. Toxicol. Appl. Pharmacol.
16: 547.
Cueto, C., Jr., and F.J. Biros. 1967. Chlorinated insecti-
cides and related materials in human urine. Toxicol. Appl.
Pjharmacol. 10: 261.
Dale, W.E., and G.E. Quinby. 1963. Chlorinated insecticides
in the body fat of people in the United States, Science 142:
593.
-------
Davis, K.J. 1965. Pathology report on mice for aldrin,
dieldrin, heptachlor, or heptachlor epox ide for two years.
Inc. Food and Drug Admin.
Davis, K.J., and O.G. Fitzhugh. 1962. Tumorigenic potential
of aldrin and dieldrin for mice. Toxicol. Appl. Pharmacol.'
4: 187. .
Deichmann, W.B. 1972.. Tox icplogy- of DDT and related chlor-
inated hydrocarbon pesticides. Jour. Occup. Med . 14: 285.
Deichmann, W.B., et al. 1967. Synergism among oral carcino-
gens in the simultaneous feeding of four tumorigens to rats.
Toxicol. Appl. .Pharmacol. 11: 88.'
Deichmann, W.B., et. al. 1968. .Retention of dieldrin in
blood, liver, and fat of rats fed dieldrin for six months.
Ind. Med. Surg. ' 37: 837.
Deichmann, W.B., et al. 1970.. Tumorigenic ity of aldrin,
• d i° ^ d ^ in ^ pd ond r ^ n "* P ' t he a ^ b ^ no r a t . T p d . Med. S u r ~ . 39:
Dix, K.M., et al. 1977. Toxicity studies wich dieidrin:
Teratolog ical studies in mice cosed orally with HEOD. Tera-
tology . 15: 57.
Earnest, R.D., and ?.I. Benville, Ju. 1972. Acuce toxicicy
of four ore -nochlorine in-secticides tc two species of surf
Edwards, C,A. 1966. Insecticide residues in soils. Residue
Rev. 13: 83.
Epstein, S ,.S. 1976. Case study 5: Aldrin and dieldrin sus-
pension based on experimental evidence and evaluation and so-
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Fahrig, R. 1973. Comparative mutagenicity studies with pes-
ticides. Chem. Carcinogenesis Essays 10: 161.
Fitzhugh, O.G., et al. 1964. Chronic oral toxicity of al-
drin and dieldrin in rats and dogs. Food Cosmet. Toxicol.
2: 551.
Harris, R.H., et al. 1977. Carcinogenic hazards of organic
chemicals in drinking water. Page 309 in H.H. Hiath, et al.
eds. Origins of human cancer. Cold Springs Harbor Lab. Mew
York.
»
Hathaway, D.E., et al. 1967. Transport of dieldrin from
mother to blastocyst and from mother to foetus in pregnant
rabbits. Eur. Jour. Pharmacol. 1: 167.
-------
Hayes, W.J., and A. Curley. 1968. Storage and excretion of
dieldrin and related compounds: Effect oif occupational expo-
sure. Arch. Environ. Health 16: 155.
Heath, D.F., and M. Vandekar. 1964. Toxicity and metabolism
of dieldrin in rats. Br. Jour. Ind. Med. 21: 269.
Henderson, C., et al. 1959. Relative toxicity of ten chlor-
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Trans. Am. Fish. Soc. 88: 23.
Hunter, C.G., et al. 1969. Pharinacodynamics of dieldrin
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Jager, K.W. 1970. Aldrin, dieldrin, endrin and telodrin: An
epidemiological and toxicological study of long-term occupa-
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Katz, M. 1961. Acute toxicity of some organic insecticides
to three species of salmonids and to the threespine sticle-
back. Trans. Am. Fish. Soc. 90: 264.
Korn, S., and R. Earnest. 1974. Acut-2 toxicity of twenty
insecticides to striped bass, Morone sax.atilis. Calif. Fish
Game. 60: 128.
Lowe, J.I. Results of toxicity tests with fishes and macro
invertebrates. Data sheets available from U.S. Environ.
Prot. Agency, Environ. Res. Lab., Gulf Breeze, Fla.
Macek, K.J., et al. 1969. The effects of temperature on the
susceptibility of bluegills and rainbow trout to selected
pesticides. Bull. Environ. Contain. Toxicol. 4: 174.
MacKay, D., and A.W. Wolkoff. 1973. Rate of evaporation of
low-solubility contaminants from water bodies to atmosphere.
Environ. Sci. Technol. 7: 611.
Hajumdar, 5.K., et ai. 1976. uieidrin-induced chromosome
damage in mouse bone-marrow and WI-38 human lung cells.
Jour. Hered. 67: 303.
Majumdar, S.K., et al. 1977. Mutagenicity of dieldrin in
the Salmonella-microsome test. Jour. Herd. 68: 194.
Marshall, T.C., et al. 1976. Screening of pesticides for
mutagenic potential using Salmonella typhimurium mutants.
Jour. Agric. Food Chem. 24: 560.
Matsumura, F., and G.M. Bousch. 1967. Dieldrin: Degradation
by soil microorganisms. Science 156: 959.
-------
Matthews, H.B., et al. 1971. Dieldrin metabolism, excre-
tion, and storage in male and female-rats. Jour. Agric.
Food Chem. 19: 1244.
Mick, D.L., et al. 1971. Aldrin and dieldrin in human blood
components. Arch. Environ. Health 23: 177.
Mrak, 'E.M. 1969. Chairman 1969 report on the secretary's
commission on pesticides and their relationship to environ-
ment health. U.S. Dept. Health Edu. Welfare, Washington,
D.C.
Nash, R.G., and E.A. Woolson. 1967. Persistence of chlori-
nated hydrocarbon insecticides in soils. Science 157: 924.
Ottolenghi, A.D., et al. 1974. Teratogenic effects of al-
drin, dieldrin and endrin in hamsters and mice. Teratology
9: 11.
Parrish, P.R. 1974.. Arochlor 1254, DDT and DDD, and diel-
drin: accumulation and loss by American oysters, Crasscstrea
v i r c: i rs i c 5 sxccssd continuously for 55 weeks. ?roc. Nc.-_I.
She II i: _5r. Assoc. 64.
Parrish, P.R., et al. 1973. Dieldrin: Effects on.several
estaurine organisms. Pages 427-434 in ?roc. 27th Annu. Conf.
S.E. Assoc. Game Fish Comm.
Patil, i'. C . , et al. 1972. Metabolic transf ormat icr. of DDT,
dieldrin, aldrin, and endrin by-marine microorganisms. Envi-
ron. Sci. Technol. 6: 631,
Reinert, R.E. 1972. Accumulation of dieldrin in an alga
Soenedesmus obiiqus, Daphnia maqna and the guppy, Poecilia
reticulata. Jour. Fish Res. Board Can. 29: 1413.
Reir.ert, R.E., et al. 1974. Dieldrin and. DDT: Accumulation
from water and food by lake trout, Salvelinus namaycush, in
the laooracory. Proc. 17th Conf. Great Lakes Res. 52~7~
Robinson, J., et al. 1969. The pharmacokinetics of HEOD
(dieldrin) in the rat. Food Cosmet. Toxicol. 7: 317.
Roelofs, T-.-D. 1971. Effects of dieldrin on the intrinsic
rate of increase of the guppy, Peocilia reticulata Peters.
Thesis. Oregon State University, Corvallis.
Sanders, H.O. 1972. Toxicity of some insecticides to four
species of malacostracan crustaceans. Bur. Sport Fish. Wild.
Tech. Pap. No. 66.
-m-
-------
Sanders, H.O., and O.B. Cope. 1968. The relative toxicities
of several pesticides to naiads of three species of stone-
flies. Linnol. Oceanogr. 13: 112.
Schoettger, R.A. 1970. Progress in sport fishery research.
Fish-Pestic. Res. Lab. U.S. Dep. Inter. Bur. Sport Fish Wild.
Resour. Publ. 106.
Shannon, L.R. 1977a. Accumulation and elimination of diel-
drin in muscle tissue of channel catfish. Bull. Environ.
Contain. Toxicol. 17: 637.
Shannon, L.R. 1977b. Equilibrium between uptake and elimi-
nation of dieldrin by channel catfish, Ictalurus punctatus.
Bull. Environ. Contam. Toxicol. 17: 278.
Song, J., and W.E. Harville. 1964. The carcinogenicity of
aldrin and dieldrin on mouse and rat liver. Fed. Proc. 23:
336.
Stadynyk, L., and R.S. Campbell. 1971. Pesticide effect on
growth and c assimilation in a freshv/ater alga. Bull.
Environ. Contam. Toxicoi. 6: 1.
.Tarzwell, C.M., and C. Henderson. 1957. Toxicity of diel-
drin to fish. Trans. Am. Fish. Soc. 86: 245.
Thorpe, Z., and A.I.T. v-Jalker. 1973. The toxicology of
dieldrin (HSOD). Part II. Comparative long-term oral coxic-
ifcy studies in mice with dieldrin, DDT, phenobarbitone, bsia-
3HC and ga-jna-BKC . Food Ccsmet. Toxicol. 11: 433.
Treon, J., and F.D. Cleveland. 1955. Toxicity of certain
chlorinated hydrocarbon insecticides for laboratory animals
with special reference to aldrin and dieldrin. Agric. Food
Chem. Jour. 3: 402.
U.S. EPA. 1971. Reasons underlying the registration deci-
sion concerning products containir.g DDT, 2,4,5-T, aldrin and
dieldrin.
U.S. EPA. 1979. Aldrin/Dieldrin: Ambient Water Quality Cri-
teria (Draft).
Versteeg, J.P.J., and K.W. Jager. 1973. Long-term occupa-
tional exposure to the insecticides aldrin and dieldrin, en-
drin, and telodrin. Br. jour. Ind. Med. 30: 201.
Walker, A.I.T., et al. . 1969. The toxicology and pharmacody-
namics of dieldrin (HEOD): Two-year oral exposures of rats
and dogs. Toxicol. Appl. Pharmacol. 15: 345.
iff
-------
Walker, A.I.T., et al. 1972. The toxicology of dieldrin
(HEOD). Long-term oral toxicity studies in mice. Food Cos-
met. Texicol. 11: 415.
Winteringham, F.P.W., and J.M. Barnes. 1955. Comparative
response of insects and mammals to certain halogenated hydro-
carbons used as pesticides. Physiol. Rev. 35: 701.
Wolfe, H.R., et al. 1972. Exposure of spraymen to pesti-
cides. Arch. Environ. Health 25: 29.
Wong, D.T., and L.C. Terriere. 1965. Epoxidation of aldrin,
isodrin, and heptachlor by rat liver microsomes. Biochem.
Pharmacol. 14: 375.
Wurster, C.F. 1971. Aldrin and dieldrin. Environment 13:
33.
•990-
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No. 83
o,o-Diethyl Dithiophosphoric Acid
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information -contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-992-
-------
0,0-OIETHYL DITHIOPHOSPORIC ACID
Summary
There is no available information to indicate that o,o-diethyl dithio-
phosphoric acid produces carcinogenic, mutagenic, teratogenic, or adverse
reproductive effects.
A possible metabolite of the compound, o,o-diethyl dithiophosphoric
acid, did not show mutagenic activity in Drosophila, £. coli, or Saccha-
romyces.
The pesticide phorate, which may release o,o-diethyl dithiophosphoric
acid as a metabolite, has shown some teratogenic effects in developing chick
embryos and adverse reproductive effects in mice.
An acute value of 47.2 pg/1 has been reported for rainbow trcut exposed
to a diethyl dithicphosphoric acid analogue, dioxathion. A synergistic
toxic effect with the latter chemical and malathion is succested.
-------
I. INTRODUCTION
o,o-0iethyl hydrogen dithiophosphate, CAS registry number 298-06-6, al-
so called o,o-diethyl phosphorodithioic acid or o,o-diethyl dithiophosphoric
acid, is used primarily as an intermediate in the synthesis of several pest-
icides: azinphosmethyl, carbophenothion, dialifor, dioxathion, disulfoton,
ethion, phorate, phosalone and terbufos. It is made from phosphorus penta-
sulfide (SRI, 1976).
II. EXPOSURE
A. Water
Pertinent data were not found in the available literature; how-
ever, if found in water, its presence would most likely be due to microbial
action on phorace or disulfoton (Daugnton, et al. 1375), or as a contaminant
of any of the above pesticides for which it-is a starting compound.
8. P"ood
Pertinent data were net fc-u.-.d in the available literature; ho•-•,•-
ever, if present in feed, the cc~pcund would probably originate frc~ the
same sources discussed above. Organophosphorus pesticide residues have been
found in food (Vettcrazzi, 1975).
C. Inhalation
Pertinent data were net found in the available literature; how-
ever, major exposure could come from fugitive emissions in manufacturing
facilities.
0. Dermal
Pertinent data were'not found in the available literature.
-------
III. PHARMACOKINETICS
A. Absorption
Information relating specifically to the absorption of o,o-diethyl
dithophosphoic acid was not found in the available literature. Acute toxi-
city studies with the pesticides disulfoton and phorate indicate that these
related organophosophorous compounds are absorbed following oral or dermal
administration (Gaines, 1969).
B. Distribution
Pertinent data were not found in the available -literature. Oral
administration of labelled phorate, the S-(ethyl thio)methyl derivative of
o,o-diethyl dithiophosphoric acid, to cows accumulated in liver, kidney,
lung, alimentary tract, and glandular tissues: fat samples showed very low
residues (Bowman and Casida, 1956).
C. Metabolism
Pertinent data '.vere not found in the available literature. Metab-
Gj..i3rri Si-Uoies wi-.ti uj.suJ.iGi.cn v,oUj.J., i^c^> CLMU pisorsuc v.ocwfiian and uss-i—a,
1958) indicate that both compounds are converted to diethyl phosphcrodithio-
ate, diethyl phcrphorothioate, and diethyl phosphate.
D. Excretion
Pertinent d?.ts were not found in t^e available literature. 5.a.cad
on animal studies with related organophosphorous compounds, the parent com-
pound and its oxidative metabolites may be expected to eliminated primarily
in the urine (Matsumura, 1975).
IV. EFFECTS
A. Carcinogenesis
The dioxane s-s diester with o,o-diethyl dithiophosphoric acid,
dioxathion, has been tested for carcinogenicity in mice and rats by
-------
long-term feeding. No carcinogenic effects were noted in either species
(NCI, 1978).
8. Mutagenicity
Diethyl phosphorothioate, a possible metabolite of the parent com-
pound, did not shew mutagenic activity in Drosophila, E_. coli, or Saccha-
romyces (Fahrig, 1974).
C. Teratogenicity
Pertinent data were not found in the available literature. In-
jection of phorate into developing chick embryos, has been reported to
produce malformations (Richert and Prahlad, 1972).
0. Other Reproductive Effects
Pertinent data were not found in the available literature. An
oral i ceding study conducted in mice with pnorstc \,G.5 to .?.u pprn^ indicated
^"h° h^^h0^^" 1 =a\'a ] Q "P f^rn^C''Pd ^^^ Q-rr-^jjpa SCiTlS ad^'^^S" •r-o^-r^^''^1--*^^)
effects (American Cyanamid, 1566). Chronic feeding of mica ,vith technical
dicxathian at levels of 45G to 6CG pprn produced seme testiscular atrophy
(NCI, 1978).
E. Chronic Toxicity
Chronic feeding of technical dioxathicn produced hyperplastic
ncrules '• n livers of fale mice. o c— Die^nvl cithicn'nosc:~cric acic ''ike
other organophosphates, is expected to produce cholinesterase inhibition
(MAS, 1977).
V. AQUATIC TOXICITY
A. Acute
Marking (1977) reports on |_C5Q value of 47.2'/jg'/l for rainbow
trout (Salmo qairdneri) exposed to the dithiodioxane analogue • of
bis(o,o-diethyl dithiophosphoric acid), dioxathion, and an LC5Q value of
-------
3.44 ug/1 when this latter compound is applied in combination with mal-
athion. The synergistic action with malathion suggests that the combination
is more than eight times as toxic as either of the individual chemicals.
B. Chronic, Plant Effects, and Residues.
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES
Existing guidelines or standards were not found in the available lit-
erature.
-9?7-
-------
REFERENCES
American Cyanamid 1966. Toxicity data on 15 percent Thimet granules.
Unpublished report. In: Initial Scientific and Minieconomic Review of
Phorate (Thimet) Office of Pesticide Programs, Washington.
Bowman, J. and J. Casida 1553. Further studies on the metabolism of Thimet
cy plants, insects, and mammals. J. Econ. Entomoi. 51: 338.
Bull, 0. 1965. Metabolism of di-systox by insects, isolated cotton leaves,
and rats. J. Econ. Entomoi. 58: 249.
Oaughton, C.G., A.M. Cook, M. Alexander 1979. Phosphate and soil binding
factors limiting bacterial . degradation of ionic phosphorus-containing
pesticide metabolites. App. Environ. Microbio. 37: 605.
Fahrig, R. 1974. Comparative . mutagenicity studies .with pesticides.
Chemical Carcinogenesis Assays, IARC Scientific Publication #10, p. 161.
Gaines, T. 1969. Acute toxicity of pesticides. Toxicol. Appl. Pharmacol.
Marking, L.L. 1977. Method- for asssessing additive toxicity of chemical
mixtures. In: Aquatic Toxicology and Hazard Evaluation. STP 634 ASTM
^O'sn i a 1 Torino -| ^Q 1 P» i^l i njsi" *' ori n QQ
^•* w -rf _ — _ • v v^> i> ' J. w w* > ^w-fc-vUtdu^v^'l. H* • s s •
Matsumura, F. 1975. Toxicolcay of Insecticides. New Ycrk: Pler.ur1 °~ess,
p. 223.
Naticr.ai Academy of Sciences 1977. Drinking Water ?nd Health, national
Researcn Council, Washington, p. 615.
National. Cancer Institute 1978. Sicsssay of Dioxathion for Possible
Carcinoaenicity. . U.S. DHEW, NCI Carcinocenesis Technical Recort Series
#125, 44 pp.
Richert, E. and K. Prahlad 1972. Effect of the oraancDhosohate c.c-diethvl
s-C (ethyitnio)metnyl] pnospnorcaithioate on tne cnick. Poult. Sci. 51: 513.
SRI 1976. Chemical Economics Handbook. Stanford Research institute.
Pesticides, July 1976.
vettorazzi, G. 1976. State of the art en the toxicologies! evaluation
carried out by the joint FAO/WHO meeting on pesticide residues. II.
Carbamate and organophosphorus pesticides used in acriculture and public
health.. -Res. Rev. 63: 1.
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No. 84
0,0-Dlethyl-^-methyl Phosphorodithioate
Health and Environnental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources, and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This" document has undergone scrutiny to
ensure its technical accuracy.
-1000
-------
o,o-OIETHYL-S-METHYL PHOSPHORODITHIOATE
Summary
There is no available information on the possible carcinogenic, muta-
genic, teratogenic or adverse reproductive effects of o,c-diethyl-S-methyl
phosphorodithioate. Pesticides containing the o,o-diethyl phosphoro-
dithioate 'moiety did not show carcinogenic effects in rodents (dioxathion)
or teratogenic effects in chick embryos (phorats). The possible metabolite
of this compound, o,o-diethyl phosphorothioate, did not show mutagenic
activity in Drosoohila, E. coli, or Saccharomyces. o,o-Oiethyl-S-oiethyl
phosphcrodithioate, like other organophosphate compounds, is expected to
produce cholinesterase inhibition in humans.
There is no available data on the aquatic toxicity of this compound.
-1001-
-------
0,0-OIETHYL-S-METHYL PHOSPHORODItHIOATE
I. INTRODUCTION
0,0-Oiethyl-S-methyl phosphorodithioate (CAS registry number 3288-58-2)
is described in German oatents 1.768,141 (CA 77:151461s) and 1,233,390 (CA
66:115324p). The latter states the compound has "partly insecticidal,
acaricidal and fungicidal activity" and is useful as an intermediate for
organic synthesis. It has the following physical and chemical properties:
Formula: C5H13
Molecular Weight: 200
Soiling Point: lOOoc to 102°C (4 torr)
(CA 55:8335h)
Density: 1.192420
(CA 55:3335h) " '-.,3
Pertinent data were not found in the available literature with respect
to production, consLirnption or the current use of this ccmoound.
II. EXPOSURE
•'v
Pertinent data were not found in the available lite. 'cure.
III. PHARMACOKINETICS
.'-' "}
A. Absorption
Information relating specifically to the absorption of o,o-di-
sthyl-S-methyl phosphorodithioate was not found in the available liter-
ature. Oral administration of the S-ethylthio derivative of this compound,
the insecticide.phorate, indicates that this, derivative is absorbed from the
gastrointestinal tract (Bowman and Casida, 1958).
.3. Distribution
Pertinent data were not found in the available literature.
Studies with 32p radiolabelled phorate in the cow indicated that following
oral administration, residues were found in the liver, kidney, lung,
-IQOSL-
-------
alimentary tract, and glandular tissues; fat samples showed very low
residues (Bowman and Casida, 1953).
C. Metabolism
Pertinent data were not found in the available literature. Based
on metabolism studies with various orgsncpnosphstas in mammals, o,c-diethyl-
S-methyl phosphorodithioate may be expected to undergo hydrolysis to diethyl
phosphorodithioic acid, diethyl phosphorothioic acid, and diethyl phosphoric
acid (Matsumura, 1975).
D. Excretion
Pertinent data were not found in the available literature.
Related metabolites (0,0-diethyl .phosphorodithioic, phosphorothioic, and
phosphoric acids) have been identified in the urine of rats fed phcrate
(Bowman and Casida, 1958).
IV. EFFECTS
A. Carcinoaenicity
• Pertinent data were not found in the available literature. The
dioxane-S-3-diester with. o,o-diethyl pnosonorodithioate, dioxathion, has
been tested for csrcinogenicity in.mice and rats by long-term feeding. No
carcinogenic effects were noted in either species (NCI, 1978).
b. Mu oagenicii.y
Pertinent data were not found in the available literature.
Diethyl phosphorothioate, a possible metabolite of the parent compound, did
not show mutagenic activity in Drosphila, Ei. coli, or Saccharomyces (Fahrig,
1974).
-------
C. Teratogenicity
Pertinent data were not found in the available literature. In-
jection of phorate into developing chick embryos has been reported to pro-
duce malformations (Richert and Prahlad, 1972).
0. Other Reproductive Effects
Pertinent data were not found in the available literature. An
oral feeding study conducted in mice with phorate (0.6 to 3.0 ppm) indicated
that the highest level of compound did produce some adverse reproductive ef-
fects (American Cyanamid, 1966). Chronic feeding of rats with technical
dioxathion at levels from 450 to 600 ppm produced some testicular atrophy
(NCI, 197S).
E. Chronic Toxicity
Pertinent oata were not founo in the available literature.
Chronic feeding of technical dioxathion procuced nycerpiastic nodules in the
livers of ,T,aie-mice. o,o-DiethyI-5-.r1ethyi phcsohoroaithioace, iixe other
organopnosphates, is expected to produce choiinesi:ersse inhibition (MAS,
1977).
V. AQUATIC TQXICITY
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Existing guidelines, and standards were not found in the available
literature.
-------
0,o-OIETHYL-S-METHYL PHOSPHORODITHIOATE
References
American Cyanamid. 1966. Toxicity data en 15 percent Thimet granules. Un-
published report. In: Initial Scientific and Minieconomic Review of
Phorate (Thimet) Washington, DC: Office of Pesticide Programs.
Bowman, J. and J. Casida. 1958. Further studies on the metabolism of
Thimet by plants, insects, and mammals. Jour. Eccn. Entcm. 51: 338.
Fahrig, R. 1974. Comparative mutagenicity studies with pesticides. Chem-
ical Carcinogenesis Assays, IARC Scientific. Publication NO. 10. p. 161. •
Matsumura, F. 1975. Toxicology of Insecticides. Plenum Press, New York
p. 223.
National Academy of Sciences. 1977. Drinking Water and Health. National
Researcn Council, Washington, DC. p. 615.
National Cancer Institute. 1573. oioassay of Oioxathion for Possible Car-
cinogenicity. CHEW. Nat-'.o-al Cancer Institute, Carcinogenesis Technical
Report Series No. 125: 44.. J
Richert, E.P. 2nd K.V. Prshlsd. 1972. Effect of •i'h0 c""3nochccpr;-''"0
o,a-disthyl-5-L(ethyithio)rr.etnyi ] pnospnorcaitniate on the chick. Pcuit.
Sci. 51: 513.
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No. 85
Diethvl Phthalate
sslC"T, ^nc Hnvi.ronnsT.£3l Z^^sc^
U.S. ENVmOciMENTAL PROTECTION AGENCY
.WASHINGTON, D.C. 20460
APRIL 30, 1980
-/006-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available .reference documents,
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
'/007-
-------
DISTHYL PHTHALATS
SUMMARY
Diethyl phthalate has been shown to produce mutagenic
effects in the Ames Salmonella assay.
Teratogenic effects were reported following i.p. admin-
istration of diethyl phthalate to pregnant rats. This same
study has also indicated fetal toxicity and increased resorp-
tions after i.p. administration of DEP.
• Evidence that diethyl phthalate produces carcinogenic
effects- has not. been found.
A single clinical report indicates that the development
of hepatitis in several hemodialysis patients may have been
related to leaching of diethyl phthalate from the plastic
tubings utilised.
Diethyl phthalate appears to be more toxic foe marine
species acutely tasted, with a concentration of 7,590 ug/1
being reported as the LC^Q in marine invertebrates. The
data base for the toxic effects of diethyl phthaiates to
aquatic organisms is insufficient to draft criterion for:
their protection.
-------
DIETHYL PHTHALATE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Phthalate Esters (U.S. EPA, 1979a).
Diethyi phthalate (DEP) is a diester of the ortho form
of benzene dicarboxylic acid. The compound has a molecular
weight of 222.23, specific gravity of 1.123, boiling point
of 296.1°C', and is insoluble in water (U.S. EPA, 1979a) .
DEP is used as a plasticizer for cellulose ester plas-
tics and as a carrier for perfumes.
The 1977 current production of diethyl phthalate was:
3.75 x 10 tons/year (U.S. EPA, I979a).
Phthaiates have been detected in soil, air, and water
samples; in animal and human tissues; and in certain vegeta-
tion. Evidence from _in_ vitro studies indicate that certain
bactsrisl flora mav be capable of metaboiizinn phthaiates
to the monoester form (Engelhardt, et al. 1975).
II. EXPOSURE
Phthalate esters appear in all areas of the environ-
ment. Environmental release of tne phthaiates may occur
through leaching of plasticizers from plastics, volatiliza-
tion of phthaiates from plastics, and the incineration of
plastic items. Human exposure to phthaiates includes contami-
nated foods and fish, dermal application -in cosmetics, and
parenteral administration by use of plastic blood bags,
»
tubings, and infusion devices (mainly DEHP release) (U.S.
EPA, 1979a).
-/oof-
-------
Monitoring studies have indicated that most water phthal-
ate concentrations are in the ppra range, or 1-2 pg/1 (U.S.
EPA, 1979a). Industrial air monitoring studies have mea-
sured air levels of phthalates from 1.7 to 66 mg/m (Milkov,
et ai. 1975). Information on levels of DEP in foods is
not available. The U.S. EPA (1979a) has estimated the weighted
average bioconcentration factor for DEP to be 270 for the
edible portions of fish and shellfish consumed by Americans.
This estimate is based on measured steady-state bioconcen-
tration studies in bluegills.
III. PHARMACOKINETICS
Specific information is not available on the absorp-
tion, metabolism, distribution, or excretion of DEP. The
reader is referred to a general coverage of phthalate metabo-
lism in the phthalate ester hazard profile (U.S. SPA, IS79b).
IV. EFFECTS
A. Carcinogenicity
Pertinent information could not be located in
the available literature.
3. Mutacenicitv
Diethyi phthalate has been shown to produce muta-
genic effects in the Ames Salmonella assay (Rubin, et al.
1979).
C. Teratogenicity
Administration of DEP to pregnant rats by i.p.
»
injection has been reported to produce teratogenic effects
(Singh, et al. 1972).
-/oio
-------
D. Other Reproductive Effects
Fetal toxicity and increased resorptions were
produced following i.p. injection of pregnant rats with
DEP (Singh, et al. 1972).
£. Chronic Toxicity
A single clinical report has been cited by the
U.S. EPA (1979a) which correlated leaching of DEP from hemo-
dialysis tubing' in several patients with hepatitis. Char-
acterization of all compounds present in the hemodialysis
fluids was not done.
V. AQUATIC TOXICITY
A. ACUCS Toxic icy
Among aquatic organisms, the bluegiil sunfish, ;
Lepomis macrochirus, has been shown co be acutaiv sensitive
to diethyl chthaiate; a 36-hour static LC,--, of 98,200 ^ig/i
is reported (U.S. EPA., 1978) . For the freshwater inverte-
brate, Daphnia magna, a 48-hour static LC^Q of 51,100 pg/1
was obtained. Marine organisms proved to be more sensitive,
with the sheepshead minnow, Cyprinodon var iegacus, showing
a 96-hour static LC5Q of 29,600 ;jg/l, while the raysid shrimp,
Mysidopsis bahia, showed an 96-hour static LC^n of 7,590
ug/1 (U.S. EPA, 1978).
B. Chronic Toxicity
Pertinent information could' not be located in
the available literature.
C. Plant Effects
Effective concentrations based on chlorophyl a
content and cell number for the freshwater alga, Selena-
2
-------
strum capricornutum, ranged from 35,600 to 90,300
while the marine alga, Skeletonema costatum, was more sensi-
tive, with effective concentrations ranging from 65,500
to 85,000 ug/1.
D. Residues
A bioconcentration of 117 was obtained for the
freshwater invertebrate, Daphnia magna.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria de-
rived by U.S. EPA (1979a) , which are summarized below, have
gone through the process of review; therefore, there is
a oossiriJiuV chac these criteria will be chanced.
;j * '
A. Human
Based on nno ^ £ ?- —c ~" lens's ob s e ^ v°d '•" chron1'0
feeding studies with rats or dogs, the U.S. EPA has calcu-
lated an... acceotaole daily intaks 'ADI* level of 438 mg/dav
. r
for DEP.
' /
• _')The recommended water quality criterion level
for protection of human health, is 50 nig/I -for DEP (U.S.
SPA, 1979a). -
B. Aquatic
Data are insufficient to draft criterion for the
protection of either freshwater or marine organisms (U.S.
EPA, 1979a).
-------
DIETHYL PHTHALATES
REFERENCES
Engelhardt, G. at al. 1975. The raicroDial metabolism of
di-n-butyl phthaiate and related dialkyl phthalates. Bull.
Environ. Contain. Toxicol. 13: 32.
Milkov, L.E., et al. 1975. Health status of workers ex-
posed to phthalata plasticizers in the manufacture of artifi-
cial leather and films based on PVC resins. Environ. Health
Perspect. Jan. 1975.
Rubin, R.J., et al. 1979. Ames mutagenic assay of a series
of phthalic acid esters: Positive response of the dimethyl
and diethyl esters in TA 100. Abstract. Soc. Toxicol. Annu.
Meet. March 11, 1979, New Orleans.
Singh. A. et al. 1972. Teratogenicity of phthaiate esters
in rats. Jour. Fharm. Sin. Gl, 51.
CJ.S'. SPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. Agency, Contract No. 68-01-4646.
U.S. EPA. 1979a. Phthaiate Esters: Ambient vvater Quality-
Criteria (Draft).
U.S. EPA. IS79b. Environmental Criteria and Assessment
Office. Hazard Profile: Phthala-e Esters (Draft).
-------
No. 86
DimethyInitrosaraine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
-10 If-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny 'to
ensure its technical accuracy.
-------
DIMETHYLNITROSAMINE
SUMMARY
Dimethylnitrosamine produces liver and kidney tumors
in rats. It is mutagenic in several assay systems. No
information specifically dealing with the teratogenicity,
chronic toxicity or other standard toxicity tests of dimethyl-
nitrosamine was available for review.
Hepatocellular carcinoma has been induced in rainbow
trout administered 200 to 800 pq dimethylnitrosamine in
their diet.
-------
DIMETHYLNITROSAMINE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Nitrosamines (U.S. EPA, 1979a).
Specific information on the properties, production,
and use of dimethylnitrosamine was not available. For general
information on dimethylnitrosamine, refer to the ECAO/EPA
Hazard Profile for Nitrosamines (U.S. EPA, 1979b).
Dimethylnitrosamine can exist for extended periods
of time in the aquatic environment (Tate and Alexander,
1975; .Fine, et al., 1977a).
II. EXPOSURE
A. Water
Dimethvlnitrcsa~ine has beer, detected at a concen-
tration of 2 to 4 ug/1 in wastewater samples from waste
treatment plants adjacent to. or receiving effluent from,
industries using nitrosamines or secondary amines in produc-
tion operations (Fine, et al., 1977b).
3. Food
Dimethyinitrosamine was found to oe present in
a variety of foods (including smoked, dried or salted fish,
cheese, salami, frankfurters, and cured meats) in the 1
to 10 u/kg range and occasionally at levels up to 100 ug/kg
(Montesano and Bartsch, 1976).
The U.S. EPA (1979a) has estimated the weighted
average bioconcentration factor for dimethylnitrosamine
for the edible portions of fish and shellfish consumed by
-1017
-------
Americans to be 0.06. This estimate is based on the n-octanol/
water partition coefficient of dimethylnitrosamine.
C. Inhalation
Dimethylnitrosamine has been detected in ambient
air samples collected near two chemical plants, one using
the amine as a raw material and the other discharging it
as an unwanted byproduct (Fine, et al., 1977a).
Tobacco smoke contains dimethylnitrosamine. The
intake of dimethylnitrosamine from smoking 20 cigarettes
per day has been estimated at approximately 2 ug/day (U.S.
EPA, 1979a) .
III. ?HA?J'!ACGKINETICS
A. Absorption
Pertinent data could r.ct be located in the avail-
able literature.
B. Distribution
Following intravenous injeccion into, rats, dimetnyi-
nitrosamine is rapidly and rather uniformly distributed
throughout the body (Magee, 1972) .
C. riecaboiism and ixcrecion
Ln vitro studies have demonstrated that the organs
in the rat with the. major capacity f-or metabolism of dimethyl-
nitrosamine are the liver and kidney (Montesano and Magee,
14
1974). After administration of C-labeled--dimethylnitro-
samine to rats or mice, about 60 percent of the isotope
appears as CO? within 12 hours, while 4 percent is excreted
-------
in the urine (Magee, et al., 1976). Dimethylnitrosamine
is excreted in the milk of female rats (Schoental, et al.,
1974) .
IV. EFFECTS
A. Carcinogenicity
Chronic feeding of dimethylnitrosamine at doses
of 50 mg/kg induces liver tumors in rats (Magee and Barnes,
1956; Rajewski, et al., 1966). Shorter, more acute expo-
sures to dimethylnitrosamine ranging from 100 to 200 mg/kg
produce kidney tumors in rats and liver tumors in hamsters
(Magee and Barnes, 1959; Tomatis and Cafis, 1967). A single
unspecified intraperitoneal dose given to newborn mice in-
duced hepatocellular carcinomas (Toth, et al., 1964).
3. Mutacenicity
Di.T.ethylnitrcsamine and diethylnitrosamine have
been reported to induce forward and reverse mutations in
;5. c yphimur ium, S. coli , iVeurospora c r a s s a and other organisms;
gene recombination and conversion in Saccharomyces carevisiae;
"recessive lethal mutation" in Drosophila; and chromosome
aberrations in mammalian ceils (Montesano ana Barcscn, 1976).
Nitrosamines must be metabolically activated to be mutagenic
in microbial assays (U.S. EPA, 1979a). Negative results
were obtained in the mouse dominant lethal test (U.S. EPA,
1979a).
C. Teratogenicicy and Other Reproductive Effects
Pertinent information could not be located in
the available literature on the teratogenicity and other
reproductive effects of dimethylnitrosamine.
-IOU-
-------
D. Chronic Toxicity
Pertinent information could not be located in
the available literature on the chronic activity of dimethyl-
nitrosamines.
E. Other Relevant Information
Aminoacetonitrile, which inhibits the metabolism
of dimethylnitrosamine, prevented the toxic and carcinogenic
effects of dimethylnitrosamine in rat livers (Magee, et
al., 1976).
Ferric oxide, cigarette smoke, volatile acids,
aldehydes, methyl nitrite, and benzo(a)pyrene have been
suggested .to act in a cocarcinogenic manner with dimethyi-
nitro-samine (Ster.back, et al., 1973; Magee, et al. , 1975).
". AQUATIC TOXICITY
Pertinent information about acute and chronic aquatic
~oxicin^' was not found in the 2v* ?.liable literature. -edition™
ally, no mention was made in any reports about plant effects
or residues.
One study reported that Shasta strain rainbow trout
(Salmo gairdneri), fed dimethylnitrosamine in their diet
for 52 weeks, developed a dose-response incidence of hepato-
cellular carcinoma during a range of exposures from 200
to 300 mg dimethylnitrosamine per kg body weight 52 to 78
weeks after dosing (Grieco, 1978).
VI. . EXISTING GUIDELINES AND STANDARDS
Neither the human health, nor aquatic criteria derived
by U.S. EPA (1979a), which are summarized below, have gone
-------
through the process of public review; therefore, there is
a possibility that these criteria may be changed.
A. Human
The U.S. SPA (1979a) has estimated that the water
concentrations of dimetnylnitrosamine corresponding co life-
time cancer risks for humans of 10~ , 10~°, or 10~ are
0.026 ug/1, 0.0026 ug/1, and 0.00026 pg/1, respectively.
3. Aquatic
Data are insufficient to draft freshwater marine
criteria for dimethylnitrosamine.
-------
DIMETHYLNITROSAMINE
REFERENCES
Fine, D.H., et al. 1977a. Human exposure to N-nitroso com-
pounds in the environment. In; H.H. Hiatt, et al., eds.
Origins of human cancer. Cold Spring Harbor Lab., Cold
Spring Harbor, New York.
Fine, D.H., et al. 1977b. Determination of dimethylnitrosa-
mine in air, water and soil by thermal energy analysis: mea-
surements in Baltimore, Md. Environ. Sci. Technol. 11:
581.
Grieco, M.P., et al. 1978. Carcinogenicity and acute toxic-
ity of dimethylnitrosamine in rainbow trout (Salmo gaird-
neri). Jour. Natl. Cancer Inst. 60: 1127.
Magee, P.N; 1972. Possible mechanisms of carcinogenesis and
mutagenesis by nitrosamines. In:- W. Nakahara, et al., eds.
Topics in chemical carcinogenesTs. University of Tokyo
Press, Tokyo.
Magee, P.N., and J.M. Barnes. 1-956 * The production of ma-
lignant primary hepatic tumors in the rat by feeding dimethyl-
nitrcsamine; Br. Jour. Cancer 10: 114.
Magee, P.M., and J.M. Barnes. 1959. The experimental pro-
duction of cumors in che rat by d iinethylni trosamine (M-nitro-
3Od ime thyiaiuine ) . Acta. Un. Int. Cancer 13: 187.
Magee, P.:;., et al. 1976. .l-J-N itroso cc.~pcur.ds and related
carcinogens. In: C.S.' Searle, ed. Chemical Carcinogens.
ACS Monograph Mo. 113.. Am. Chem. Soc. , Washington, D.C.
Montesano, R., and H. Bartscn. 1976. Mutagenic and carcino-
genic N-nitroso compounds: possible environmental hazards.
Mutat. Res. 32: 179.
Montesano, R., and P.N. Magee. 1974. Comparative metacolism
jLn v i tro of nitrcsamines in-various animal species including
man. In: R. Montesano, et.al., eds. Chemical carcinogenesis
essays. IARC Sci. Pub. No. 10. Int. Agency Res. Cancer,
Lyon, France.
Rajewsky, M.F., et al. 1966. Liver carcinogenesis by-di-
ethyinitrosamine in the rat. Science 152:, 83.
Schoental, R., et al. 1974. Carcinogens in milk: transfer
of ingested diethylnitrosamine into milk lactating rats. Br.
Jour. Cancer 30:'238.
-------
Stenback,, F., et al. 1973. Synergistic effect of ferric
oxide on dimethylnitrosamine carcinogenesis in the Syrian
golden hamster. Z. Krebsforsch. 79: 31.
Tate, R.L., and M. Alexander. 1976. Resistance of
nitrosamines to microbial attack. Jour. Environ. Qual. 5:
131.
Tomatis, L., and F. Cefis. 1967. The effects of multiple
and single administration of dimethylnitrosamine to hamsters.
Tumori 53: 447.
Toth, B., et al. 1964. Carcinogenesis study with dimethyl-
nitrosamine administered orally to adult and subcutaneously
to newborn BALBC mice. Cancer Res. 24: 2712.
U.S. EPA. 1979a. Nitrosamines: Ambient Water Quality Cri-
teria. (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment-Of-
fice. -. Mitrcsamines: Hazard Profile.
-------
No. 87
2,4-Dimethylphenol
Health and Environmental iffacts
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
2.4-OIMETHYLPHENOL
Summary
2,4-Oimethylphenol (2,4-OMP) is an intermediate in a number of indus-
trial and agricultural products. The main route of exposure for humans is
dermal with 2,4-OMP being readily absorbed through the skin.
Little data is available on the mammalian effects of 2,4-OMP. Tests on
mice conclude that the compound may be a promoting agent in carcinogenesis.
2,4-OMP inhibits vasoconstriction in isolated rat lungs; this ability may
cause adverse health effects in chronically exposed humans.
A reported 96-hour LC5Q value for fathead minnows is 16,750 ,ug/l;
chronic value using embryo-larval stages of the same -species is 1,100 ug/1.
Oaohnia maqna has an observed 48-hour LC5Q value, of 2,120 ,ug/l. In
limited testing, one aquatic alga ana auckweed are over 100 times less
sensitive than the Dapnnia- in acute exposures. The bicccncentration factor
for 2,4- dimethyIpnenoi is 150 for the oluegill. From haif-iife stuoies,
residues of the chemical are not a potential hazard for aquatic species.
-------
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for 2,4-Oimethylphenol (U.S. EpA, 1979).
2,4-Oirnethyipnenol (2,4-QMP) is derived from coal and petroleum sources
and cccurs naturally in some plants. 2,4-DMP (CgH10Q) is usually found
with the five other dimethylphenol and three methylphenol isomers. It has a
molecular weight of 122.17 and normally exists as a colorless crystalline
solid. 2,4-OMP has a melting point of 27 to 28°C, a boiling point of
210°C (at 760 mm Hg), a vapor pressure of 1 mm Hg at 52.8°C,. and a dens-
ity of 0.0965 g/ml at 20°C (U.S. EPA, 1979).
2 &—QMP is a \vesk acid (pk —10.6) 3nd is soluble in alkaline solu-
tions. It readily dissolves in organic -solvents and is slightly soluble in
water (Weast, 1976).
2,4-GMP is a chemical intermediate in the nianufsecure of a number of
industrial ana agricultural products, including phenolic antioxidants, dis-
infectants, solvents, Pharmaceuticals, insecticides, fungicides, plssti-
cizers, rubber chemicals, polyphenyiene oxide, wetting agents, and dye-
stuffs. It is also found in lubricants, gasolines, and cresylic acid (U.S.
EPA, 1979).
Very little information exists on the environmental persistence of 2,4-
DMP. Complete biodegradation of 2,4-OMP occurs in approximately two months
(U.S. EPA, 1979); however, no environmental conditions were described.
II. EXPOSURE
A. Water
U.S. EPA (1979) reported that no specific data are available on the
»
amounts of 2,4-OMP in drinking water. The concentrations of 2,4-OMP present
in drinking water vary depending on the amounts present in untreated water
-1017-
/
-------
and on the efficiency of water treatment systems in removing phenolic com-
pounds. In the U.S., the gross annual discharge of 2,4-OMP into waters was
estimated to be 100 tons in 1975 (Versar, 1975). Manufacturing was the lar-
gest source of the discharge. Lsachates from municipal and industrial
wastes also contain the compound (U.S. EDA, 1979).
Hoak (1957) determined that, at 30°C, the odor threshold for 2,4-
DMP was 55.5 pg/1.
B. Food
DMP's occur naturally in tea (Kaiser, 1967), tobacco (Baggett and
Morie, 1973; Spears, 1963), marijuana (Hoffmann, et al. 1975), and a conifer
(f-orncst3°v3 ^t 3^ ^ 977). The"**0 is no °viderice to sur*c°st tht^t
dimethylpnenols occur in many plants used for food; however, it may be
assumed that trace amounts are ingested (U.S. EPA, 1979).
The U.S. • E?A (1575). has estimated the weightea average oiocon-
centration factor for 2.4-OMP to be 340 for the acibis portions of fish anc
shellfish consumed by Americans. This estimate is basea on -ne measures
steady-state oicconcentration studies in the bluegill.
C. Inhalation'
2,4-Oimethyiphenol has been found in commercial degreasing agents
-(.NICSH, 1573), cresol vapors (Corcos, 1939), cigarette smoke condensates
(Baggett and Morie, 1973; Hoffmann and Wynder, 1963; Smith and Sullivan,
1964), marijuana cigarette smoke (Hoffmann, et al. 1975) and vapors from the
combustion and pyrolysis of building materials (Tsuchiya and Sumi, 1975).
Concentrations in smoke condensates from six different 'brands of American
cigarettes ranged from 12.7 to 20.8 mg/cigarette without filters and 4.4 to
*
9.1 mg/cigarette with filters (Hoffman and Wynder, 1963).
-------
There is no evidence in the available literature indicating that
humans are exposed to 2,4-OMP other than as components of complex mixtures.
Adverse health effects have been found in workers exposed to mixtures con-
taining amounts of 2,4-DMP; hcwever, the effects were not attributed to
dimethylphenol exposure per se (NIOSH, 1978).
0. Dermal
Absorption through the skin is thought to be the primary route of
human exposure to complex mixtures containing 2,4-OMP (U.S. EPA, 1979).
III. PHARMACOKINETICS
A. Absorption
2,4-CMP is readily absorbed through the skin (U.S. EPA, 1579). The
dermal. LDC(-. for molten 2,4-OMP is 1,040 mg/kg in the rat (Uzhdovini, et
al. 1974).
B. Distribution
U.S. EPA (1979) found no pertinent: cats on the distribution of 2,4-
OMP in humans or animals in the available literature. 2,6- or 3,4-CMP given
orally to rats for eight months caused damage to the liver, spleen, kidneys,
and heart (Maazik. 1963).
C. Metabolism
Urinary metabolites, resulting from oral administration of 850 mg
of 2,4-OMP to rabbits, were .primarily ether-soluble acid and ether glucuro-
nide, with lesser amounts of ethereal sulfate, ester glucuronide and free
non-acidic phenol (Bray, et al. 1950). Similar metabolism of the other
dimethylphenol positional isomers was reported.
0. Excretion
»
A study done on rabbits by Bray, et al. (1950) indicates rapid
metabolism and excretion of 2,4-OMP.
-------
IV. EFFECTS
A. Carcinogenic!ty
Epidemic-logic studies of workers exposed to 2,4-OMP were not loca-
ted in the available literature.
In a carcinogenic!ty bioassay, 26 female Sutter mice were dermally
exposed to 25 jul of 20 percent 2,4-OMP in benzene twice weeekly for 24
weeks. Twelve percent of the exposed mice developed carcinomas; however,
benzene was not evaluated by itself in this study (Boutwell and Bosch,
1959). In a related study, Boutwell and Bosch (1959) applied 25 ul of 20
percent 2,4-OMP in benzene to the skin of female Sutter mice twice a week
for 23 weeks following a single application, of a sub-carcinogenic cess (75
ug) of CM8A. Papillomas or .carcinomas developed in 18 percent of the mice,
indicating that 2,4-QMP may be a promoting agent for carcinogenesis.
Fractions of cigarette smoke condensate containing pnenol,' methyl-
phenols and 2,4-OMP have been shewn to promote'carcinogenesis in mouse skin
pioassays (Lazar, et al. 1^66; Sccx, et ai. 1971; Roe, et al. 1959).
3. Mutagenicity, Teratogenicity and Other Reproductive Effects
Pertinent data could - not be located in the available literature
regarding mutagenicity, teratogenicity and other reproductive effects.
C. .Chronic Toxicity
Pertinent information concerning the chronic effects of 2,4- DMP
was not located in the available literatureKU.S. EPA, 1979): however, data
was available on other positional isomers. Examination of rats treated
orally with 6 mg/kg of 2,6-dimethylphenol or 14 mg/kg of 3,4-cSimethylphencl
for eight months revealed fatty dystrophy and atrophy of the hepatic cel^s,
-------
hyaline-droplet dystrophy in the kidneys, proliferation of mycloid and
reticular cells, atrophy of the lymphoid follicles of the spleen, and paren-
chymatous dystrophy of the heart cells (Maazik, 1968).
0. Other Relevant Information
Tests on isolated rat lungs indicate that 2,4-OMP may inhibit vaso-
constriction, most likely due to its ability to block ATP (Lunde, et al.
1968). Because of 2,4-OMP's physiological activity, U.S. EPA (1979) reports
that chronic exposure to the compound may cause adverse health effects in
humans.
V. AQUATIC TOXICITY
Pertinent data could net be located in tha available literature re-
garding any saltwater species.
A. Acute Toxicity
A reported 96-hcur LC-n value for juvenile fathead minnows is
^-U
16,750 ,ug/l (U.S. EPA, 1579). For the freshwater inverteorate Oa'phnia
magna, the observed 43-hour -£cQ is 2,120 ;jg/l (U.S. EPA, 1979).
3. Chronic Toxicity
Based on an embryo-larval test with the fathead minnow, Pimephales
promelas, the derived chronic value is 1,100 ug/1 (U.S. EPA, 1978). No
chronic values are available for invertebrate species.
C. Plant Effects
Based on chlorosis effects, the reported LC-g for duckweed, Lemna
minor, is 292,800 jjg/1 for 2,4-dimethylphenol exposure (Blackman, et al.
1955).
0. Residues
»
A bioconcentration factor of 150 was obtained for the bluegill.
The biological half-life in the bluegill is less than one day, indicating
-------
that 2,4-dimethylphenol residues are probably not a potential hazard for
aquatic organisms (U.S. EPA, 1978).
VI. EXISTING GUIDELINES AND STANDARDS
Standards have not been promulgated for 2,4-DMP for any sector cf the
environment or workplace.
A. Human
The draft criterion for 2,4-dimethylphenol in water recommended by
the U.S. EPA (1979) is 15.5 jug/1 based upon the prevention of adverse
effects attributable to the organoleptic properties of 2,4-OMP.
8. Aquatic
For 2,4-dimethylphenoi, the draft criterion to protect freshwater
aquatic life is 38 jjg/1 as a 24-hour average; the concentration should not
exceed 86 jug/1 at any time. NO criterion exists for saltwater species (U.S.
EPA, 1579).
-------
2.4-OIMETHYLPHENOL
References
Baggett, M.S., and G.P. Morie. 1973. Quantitative determination of phenol
and alkylphenols in ciaarette smoke and their removal by various filters.
Tob. Sci.' 17: 30.
Blackman, E.G., et al. 1955. The physiological activity of substituted
phenols. I. Relationships between chemical structure and physiological
activity. Arch. Biochem. Biophys. 54: 45.
Bock, F.G., et al. 1971. Composition studies on tobacco. XLIV. Tumor-
promoting activity of subfractions of the weak acid fraction of cigarette
smoke condensate. Jour. Natl. Cancer Inst. 47: 427.
Boutwell, R.K., and O.K. Bosch. 1959. The tumor-producing action of phenol
and related compounds for mouse skin. Cancer Res. 19: 413.
Bray, H.G.. et al. 1950. Metabolism of derivatives of toluene. 5. The
fate of the xylends in the rabbit with further observations on the metab-
olism of the xylenes. 3iochem. Jour._ 47: 395.
Corccs, A. 1939. Contribution to the study of occupational poisoning ;by
cresois. Dissertation. Vigot Freres Editeurs. (Fre).
Gorncstaeva, !_.!., et al. 1977. Phar.cls frcm abies sibirica essentaial
oil. Khim. Pirir. Scedin: 1SS'3, 417-413.
Hcak, R.O. 1957. The causes cf tastes and odors in drinkinc water. F~c.
llth Ind. Waste Conf. Purdue Univ. Eng. Bull. 41: 229.
Hoffmann, D., et al. 1975. On the carcinogenicity of marijuana srncke.
Recent:Adv. Phytochem. 9: 63.
Hoffmann, D., and E.L. Wynder. 1563. Filtration of phenols from cigarette
s,Tioke. Jcur. Natl. Cancer Inst. 30: 67.
Kaiser, H.E. 1967. Cancer-promoting effects of phenols in tea. Cancer
20: 614.
Lazar, P., et al. 1966. Senzo(a)pyrene, content and carcinogenicity of
cigarette smoke condensate - results of short-term and long-term tests.
Jour. Natl. Cancer Inst. 37: 573.
Lunde, P.K., et al. 1968. The inhibitory effect of various phenols on
ATP-induced vasoconstriction in isolated perfused raobit lungs. Acta.
Physiol. Scand. 72: 331.
#
Maazik, I.K. 1968. Oimethylphenol (xylenol) isomers and their standard
contents in water bodies. Gig. Sanit. 9: 18.
-------
National Institute of Occupational Safety and Health. 1973. Occupational
exposure to cresol. OEW (NIOSH) Publ. No. 78-133. U.S. Dep. Health Edu.
Welfare, Pub. Health Ser., Center for Ois. Control.
Roe, F.J.C., et al. 1959. Incomplete carcinogens in cigarette smoke con-
densate: tumor-production by a phenolic fraction. Br. Jour. Cancer
13: 623.
Smith, G.A., and P.J. Sullivan. 1964. Determination of the steam-volatile
phenols present in cigarette-smoke condensate. Analyse 39: 312.
Spears, A.W. 1963. Quantitative determination of phenol in cigarette
smoke. Anal. Chem. 35: 320.
Tsuchiya, Y., and K. Sumi. 1975. Toxicity of decomposition products -
phenolic resin. Build. Res. Note-Natl. Res.'Counc. Can., Oiv. Build. Res.
106.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract NO. 68-01-4646. U.S. Environ. Prot.
Agency, Washington, O.C.
U.S. EPA. 1979. 2,4-Dimethylphenol: Ambient Water Quality Criteris
(Draft).
Uzhdovini, E.R., et al. 1974. Acute toxicity of lower phenols. Gig. fr.
Prof.. Zaboi. (2): 56.
Versar, Inc. 1975. Identification, of • organic ccmccuncs in effluents from
industrial sources. EPA-560/3-73-Q02. U.S. Environ. Prot. Agency.
'iVeast, R.C. 1976. Handbook of chemistry and physics. 57th ed. CRC Press,
Cleveland, Ohio.
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No. 88
Dlmethvl Phthalate
Health and Environnsr.-iai Effaces
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracv.
1036-
-------
DIMETHYL PHTHALATE
SUMMARY
Dimethyl phthalate has been shown to produce mutagenic
effects in the Ames Salmonella assay.
Administration of dimethyl phthalate to pregnant rats
by i.p. injection has been reported to produce teratogenic
effects in a single study. Other reproductive effects pro-
duced by dimethyl ph.thalate included impaired implantation
and parturition in rats following i.p. administration.
Chronic feeding studies in female rats have indicated
an effect of dimethyl phthalate on the kidneys. There is
no evidence to indicate that dimethyl phthalate has carcino-
genic effaces.
Amcnc the four aquatic species examined, freshwater
fish and invertebrates appeared to be more sensitive than
their marine counterparts. Acute toxicity values at concen-
trations .of 49,500 pg/1 were obtained for freshwater fish.
Criterion could not be drafted because of insufficient data
concerning the toxic effects of dimethyl phthalates to aquatic
organisms.
/ '/D37-
-------
DIMETHYL PHTHALATE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Phthalate Esters (U.S. EPA, 1979a).
Dimethyl 'phthalate (DMP) is a diescer of the ortho
form of benzene dicarboxylic acid. The compound has a mole-
cular weight of 194.18, specific gravity of 1.189, boiling
point of 232°C, and a solubility of 0.5 gms in 100 ml of
water (U.S. EPA, 1979a).
DMP is used as a plasticizer for cellulose ester plas-
tics and as an insect repellant.
•3
Currant Production: 4.9 x .10w tons/year. ":--'^ 1977 (U.S.
SPA, 1979a).
Phthalates have been detected in soil, air, and water
samples; in' animal and .human tissues; and in certain ve^eca-
tion. Evidence from in vitro studies indie?.t
-------
by use of plastic blood bags, tubing, and infusion devices
(mainly DEHP release). Relevant factors in the migration
of phthalate esters from packaging materials to food and
beverages are: temperature, surface area contact, lipoidial
nature of the food, and length of contact (U.S. EPA, 1979a).
Monitoring studies have indicated that most water phtha-
late concentrations are in the ppm range, or 1-2 pg/liter
(U.S. EPA, 1979a). Industrial air monitoring studies have
measured air levels of phthalates from 1.7 to 66 mg/m (Mil-
kov, et al. 1973). Information on levels of DMP in foods
is not available.
The U.S. EPA (1979s) has estimated the wei9hted avsrace
bioconcentration factor for BMP to be 130 for the edible
portions of fish and shellfish consumed, by Americans. This
estimate is based on the measured steady-state bioconcen-
tration studies in biuegills.
III. PEARMACOKINETICS
Specific information is not available on the absorp-
tion, distribution, metabolis:?., or excretion of DMP. The
reader is referred to a general coverage of phthalate metabo-
lism in the phthalate ester hazard profile (U.S. EPA, 1979b).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the avail-
able literature.
B. Mutagenicity
Dimethyl phthalate has been shown to produce muta-
genic effects in the Ames Salmonella assay (Rubin, et al.
1979) .
-------
C. Teratogenicity
Administration of DMP to pregnant rats by i.p.
injection has been reported to produce teratogenic effects
(Singh, et al. 1972). Intraperitoneal administration of
DM? to pregnant rats in another study did not result in
teratogenic effects (Peters and Cook, 1973).
D. D. Other Reproductive Effects
Adverse effects by DMP on implantation and parturi-
tion were reported by Peters and Cook (1973) following i.p.
administration of the compound to rats.
E. Chronic Toxicity
Two-year feeding studies with dietary DMP have
produced some kidney effects in female rats and minor growth
effects (Draize, et al. 1943).
'/. AQUATIC TOXICITY
A. Acute Toxicity
Two freshwater species were examined for acute
toxicity from dimethyl phthalate exposure. The 48-hour
static LC for the Cladoceran, Daphnia magna, was 33,000
ug/i (u.3. EPA, 1978). . The 96-hour static LC-~ value for
the bluegill, Lepomis macrochirus, was 49,500 pg/1. For
marine species, 96-hour static LC5Q values for the sheeps-
head minnow, Cyprinodon variegatus, .and mysid shrimp, Mysid-
opsis bahia, were 58,000 and 73,700 ^ig/1, respectively.
B. Chronic Toxicity
»
Pertinent information could not be located in
the available literature.
-sow
-------
C. Plant Effects
Effective concentration's based on chlorophyl a
content and cell number for the freshwater algae Selena-
strum capr icornutum and the marine algae Skeletonema costa-
tum ranged from 39/300 to 42,700 ug/1 and 25,100 to 29,300
ug/1, respectively.
D. Residues
A bioconcentration factor of 57 was obtained for
the freshwater bluegill, Lepomis macrochirus.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived
by U.S. SPA ( 1979a) . -..which are summarized below, have cone
through the process of puolic review; therefore, there is
a possibility that these criteria will be changed.
A. Human
3ased on "no effect'1 levels observed in chronic
\ '
feeding studies in rats and dogs, the U.S. EPA (1979a) has
calculated an accep. l>le daily intake (ADI) level of 700
mg/day for DMP.
.
protection of human health is 160 mg/liter for DMP (U.S.
EPA, 1979a) .
B. Aquatic
The data base for toxicity of dimethyl phthalate
was insufficient for drafting criterion for either fresh-
water or marine organisms (U.S. EPA, 1979a) .
-------
DIMETHYL PHTHALATES
REFERENCES
Draize, J.K., et al. 1948. Toxicological investigations
of compounds proposed for use as insect repellents. Jour.
Pharmacol. Exp. Ther. 93: 26.
Engelhardt, G., et al. 1975. The microbial metabolism
of di-n-butyl phthalate and related dialkyl phthalates.
Bull. Environ. Contam. Toxicol. 13: 342.
Milkov, L.S., et al. 1973. Health status of workers exposed
to phthalate plasticizers in the manufacture of artificial
leather and films based on PVC resins. Environ. Health
Perspect. Jan. 175.
Peters, J.W., and R.M. Cook. 1973. Effects of phthalate
esters on reproduction of rats. Environ. Health Pecspect.
Jan. 91.
Rubin, R.J., et al. 1979. Ar.as niutagenic assay of a series
of phthalic acid esters: positive response of the dimethyl
and diethyl esters in TA 100, Abstract:. Sec. Texicol. Anna.
Meet. New Orleans, March 11.
Singh, A., et ai. 1972. Teratccenicity cf phthalate escers
in rats. jour. Pharis. Sci. 61: 31.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts cf selected water pollutants. U.S. Environ..
?rot. Agency, Contract No. 68-01-4646.
U.S. SPA. 1979a. Phthalate Esters: Ambient Water Quality
Criteria (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment
Office. .Hazard'Profile: Phthalate Esters (Draft).
-JO ¥2-
-------
No. 89
Dinitrobenzenes
Haaith and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal . The information- contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
•ensure its technical accuracy.
-------
DINITROBENZENES
Summary
Du6 to th8 lack of . availsole infoTT'sticr' no assessment of the octsn—
tial of dinitrobenzenes to producs carcinogenic effects, mutsgenic effects,
teratogenic effects, or adverse reproductive effects can be made.
Oinitrobenzene is the most potent methemoglobin-forming agent of the
nitroaromatics and rapidly produces cyanosis in exposed populations.
•.
Fish have been acutely affected by exposure to non-specified isomers of
dinitrobenzene at concentrations ranging from 2,000 to 12,000 ug/1.
/ -j
-------
• DINITROBENZENE-
I. INTRODUCTION
This profile is based on the Investigation of Selected Potential
Environmental Contaminants: Nitroaromatics (U.S. EPA, 1976).
The dinitrobenzenes exist as the ortho, meta, or para isomers, depend-
ing on the position of the nitro group substitutents. Ortho-dinitrobenzene
(1,2-dinitrobenzene, M.W. 168.1) is a white, crystalline solid with a boil-
ing point of 319°C, a melting point of 11S°C, and a specific gravity of
1.57. Meta-dinitrobenzene (1,3-dinitrobenzene) is a yellow, crystalline
solid that melts at 39-90°C, boils at 300-303°C, . and has a density of
1.55. Para-dinitrobenzene (1,4-dinitrobenzene) is a white, crystalline
solid with a boiling point of 29S"C, a melting point of 173-174UC, and a
density of 1.63 (Windholz, 1976). The dinitrobenzenes have low aqueous
solubility and are soluble in alcohci.
The dinitrobenzenes. are- used in organic synthesis, the pr:cuccion of
dyes, and as a camphor substitute in.celluloid production.
The domestic production volume of meta-dinitrobenzene in 1572 was
approximately 6 x 103 tons (U.S. EPA, 1976).
Oinitrcbsnzanas are generally stable in neutral aqueous solutions; as
the medium becomes more, alkaline they ~ay undergo hydrolysis (Murto, 1966).
Para-dinitrobenzene will undergo photochemical reduction in isoproparol
under nitrogen,, but this reaction is quenched when the solvent is aerated
(Hashimoto and Kano, 1972).
Biodegradation . of dinitrobenzenes .has been reported for acclimated
microorganisms (Chambers, et al. 1963; Bringmann and Kuehn, 1959).
9
Based on the octanol/water partition coefficient, Neely et al. (1974)
have estimated a low bioconcentration potential for the dinitrobenzenes.
-------
II . EXPOSURE
Industrial dinitrobenzene poisoning reports have- shown that workers
will develop intense cyanosis with only slight exposure (U.S. EPA, 1976).
Exposure to sunlight or ingestion of alcohol may exacerbate the toxic
effects of dinitrobenzene exposure (U.S. EPA, 1976).
Monitoring- data on levels of dinitrobenzenes in water, air, or food
were not found in the available literature; human exposure from these
sources cannot be evaluated.
III. PHARMACOKINETICS
A. Absorption
Methe.T.oglcbin formation in v/crksrs exposed to dinitrobenzene indi-
cates that absorption of the compound by inhalation/dermal routes occurs.
Animal stuoies demonstrate tnat oinitrooenzene is absorbed following oral
B. Distribution
Pertinent information on Distribution of dinitrcbenzenss was not
found in the available literature.
C. Metabolism
Dinitrocsnzene undergoes both metabolic reduction ard oxidation .
.-•-linal studies indicate that the major reduction productions fallowing oral
dinitrobenzene administration were nitroaniline and phenylene diamine (35%
of the administered dose) (Parke, 1961). The major oxidative metabolites of
meta-dinitrobenzene were 2,4-diaminophenol (31% of initial dose) and
2-amino-A-nitrophenol (1455 of initial dose). The phenols are further con-
jugated as giucuronides or etheral sul fates (Parke, 1961).
-------
0. Excretion
Oral administration of radiolabelled meta-dinitrobenzene to
rabbits was followed by elimination of 65-93% of the -dose within two days.
Excretion was almost entirely via the urine; 1-5% of the administered label
was determined in the fecss (Parks, 1961).
IV. EFFECTS
A. Carcinogenicity
Information on the Carcinogenicity of the dinitrobenzenes was not
found in the available literature.
B. Mutagenicity
Information on the mutagenicity . of the dinitrobenzenes was not
found in the available literature. The oossible dinitrobenzene rnetsco'its
dinitropnenoi ~\u'.S. EPA, 1979), has been reported to induce chromatid breaks
ir, bone marrow ceils of injected'mice (Micra anc-Manna. 1971).
C. TeratoGsnicicy
Information on tne teratogenicity of the dinitrobenzenes was not
found in the .available literature. The oossible dinitrobenzene rnetaoolite,
dinitropnenoi ";>S. EPA, 1979), has produced developmental abnormalities in
the sea urchin (Hagstrom and Lonning, 1966). No effects were sesr, foilov/ing
i~jecti-n cr crai sc.T.ir.istraticn cf ciinitrophenoi to mice (Gibson, 1973).
0. Other Reproductive Effects
Pertinent information was not found in the available literature.
E. Chronic Toxicity
Dinitrobenzene is the most potent methemoglobin-forming agent of
the nitroaromatics. Poisoning symptoms in humans may be potentiated by
exposure to sunlight or ingestion of alcohol (U.S. EPA. 1976).
,/
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
McKee and Wolf (1963) have presented a brief synopsis of the
toxic effects of dinitrcbenzer.es to aquatic life. A study by LeClerc (1960)
reported lethal doses of non-specific isomers of dinitrobenzene for minnows
(unspecified) at concentrations of 10,000 to 12,000 ug/1 in distilled water
or 8,000 to 10,000 pg/1 in hard water. Meinck et al. (1956) reported lethal
concentration of•2,000 jug/1 for unspecified dinitrobenzenes for an unspeci-
».
fied fish species.
8. Chronic Toxicity
Pertinent data could not be found in ths available iitp^stu^s
regarding aquatic toxicity.
C. Plant Effects
Howard et ai. (i^7o) report that the sigae Chlorella sp. aisplayec
inhibited phciosynthetic activity upon exposure to m-dinitrocenzers at s
concentration of 1C" M.
VI. EXISTING GUIDELINES
The 8-hour time-weighted-average (TWA) occupational exposure limit for
dinitrobenzenes is 0.15 pprn(ACGIH, 1974).
A
-------
DINITROBENZENES
References
ACGIH. 1974. Committee on threshold - limit values: Documentation of the
threshold limit values for substances in the workroom air._ Cincinnati, Ohio.
Bringmann, G. and R. Kuehn. 1959. Water toxicity studies with protozoans
as test organisms. Gesundh.-Ing. 80: 239.
Chambers, C.W., et al. 1963. Degradation of aromatic compounds-by pheno-
ladopted bacteria. Jour. Water Pollut. Contr. Fedr. 35: 1517.
Gibson, J.E. 1973. Teratology studies in mice with 2-sec-Sutyl-4,- 6-dini-
trophenol (Dinoseb). Fd. Cosmet. Toxicol. 11: 31...
Hagstrom, 8.E. and S. Lonning. 1966. Analysis of the effect of -Dinitro-
phenol on cleavage and development of the sea urchin embryo. Protoplasma.
42(2-3): 246.
Hashimctc, S. and K. Xano. 1972. Photochemical reduction of nitrobenzene
and reduction intermediates. X. Photochemical reduction of the mono-
substit'Jtsd nitre-benzenes in 2-propanol. Bull. Chem. Soc. Jap. 45(2): 549.
Howard, P.M., et al. .1976. Investigation cf selected potential environ-
mental contaminants: Nitrcsrcmatics. Syracuse-, N.Y.: Syracuse Research
Corporation, TR 75-57'3.
LeClerc, E. I960. Self purification of streams and the relationship be-
tween chemical and biological tests. 2nd Symposium' on the Treatment of
Waste Waters. Peraamon Press, p. 232.
McKee, J.E. and H.W. Wolf. 1963. Water quality criteria. The Resource
Agency of California State Water Quality Control Board Publication No. 3-A.
Meinck., F., et al. 1956. Industrial waste water. 2nd ed. Gustav Fisher
Verlsg Stutgsrt, o. 536.
Micra, A.B. and G.K. Manna. 1971. Effect of some phenolic compounds on
chromosomes of bone marrow, cells on mice. Indian J. Med. Res. 59(9): 14^2.
Murto, J. 1966. Nucleophilic reactivity. Part 9. Kinetics .of the reac-
tions of hydroxide ion and water with picrylic compounds. Acta Chem.
Scand. 20: 310.
Neely, W.8., et al. 1974. Partition coefficient to measure bicconcsn-
tration potential of •organic chemicals in fish. Environ. Sci. Technol.
8: 1113.
»
Parke, D.W. 1961. Detoxication. LXXXV. The metabolism of m-dinitro-
benzene-C14 in the rabbit. Biochem. Jour. 78: 262.
-------
U.S. EPA. 1976. Investigation of selected potential environmental contam-
inants: Nitroaromatics.
U.S. EPA. 1979. Environmental Criteria and Assessment Office. 2,4-Oini-
trophenol: Hazard Profile (Draft).
Windhclz, M. (ed.) 1975. The Merck Index. 9th sd. Merck and Co., Inc.,
Rahway, N.J. p. 3269.
'I OS I-
-------
No. 90
4,6-Dinitro-o-cresol
Haaich and Environnantal Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-uracy.
-/QS3-
-------
4,6-DINITRO-O-CRESOL
SUMMARY
There is no available evidence to indicate that 4,6-
dinitro-ortho-cresol (DNOC) is carcinogenic.
This compound has produced some DNA damage in Profceus
mirabilis but failed to show mutagenic effects in the Ames
assay or in Jj. coli. Available information does not
indicate that DNOC produces teratogenic or adverse
reproductive effects.
Human exposure incidents have shown that DNOC produces
an increase in cataract formation.
-/05Y-
-------
4,6-DINITRO-G-CRESOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Nitrcphenols (U.S. EPA, 1979a).
Dinitrocrescls are compounds closely related to the di-
nitrophenols; they bear an additional 2-position methyl
group. The physical properties of 4,6-dinitro-ortho-cresol
(DNOC, M.W. 198.13) include a melting point of 35.8°C and a
solubility of 100 mg/1 in water at 20°C (U.S. EPA, 1979a).
Dinitro-ortho-cresol is used primarily as a blossom
thinning agent on fruit trees and as a fungicide, insecticide
and micicide on the fruit trees during the dormant season.
There is no record of current domestic manufacture of DNCC
(U.S. EPA, 19792). For additional information regarding the
nitrcphenols in general, the reader is referred to the Hazarc
Profile on Kitrophanols (U.S. EPA, 1979b).
II. EXPOSURE
The lack of monitoring data makes it difficult to assess
exposure from water, inhalation, and foods. DNOC has been
detected at 13 rr,g/l in effluents from chemical olants (U.S.
EPA, 1979a).
Exposure to DNOC appears to be primarily through occupa-
tional contact (chemical manufacture, pesticide application).
Contaminated water may result in isolated poisoning inci-
dents.
The U.S. EPA (1979a) has estimated a weighted average
biocon.centration factor for DNOC to be 7.5 for the edible
portions of fish and shellfish consumed by Americans. This
estimate is based on the octanol/water partition coefficient.
-------
III. PHARMACOKINETICS
A. Absorption
DNOC is readily absorbed through the skin, the res-
piratory tract, and the gastrointestinal tract (NIOSH,
1978).
B. Distribution
DNOC has been found in several body tissues; how-
ever, the compound may be bound to serum proteins, thus pro-
ducing non-specific organ distribution (U.S. EPA, 1979a).
C. tMetabolism
Animal studies on the metabolism of DNOC indicate
that like che nitrophenols, both conjugation of the compound
and reduction of the nitro groups to amino groups occurs.
The metabolism of CMOC to 4-amino-4-nitro-o-crasiol is a de-
toxification mechanism that is effective only when tcxic
doses of CNOC are administered (I*.3. EFA, 1979a) . The
metabolism of DNOC is very slow in man as compared to that
observed in.animal studies (King and Harvey, 1953).
D. Excretion
The experiments of Parker and coworkers (1951) in
several animal species indicates that DNOC is rapidly ex-
creted following injection; however, Harvey, et al. (1951)
have shown slow excretion of DNOC in volunteers given the
compound orally. As in metabolism, there is a substantial
difference in excretion patterns of humans vs. experimental
animals.
-------
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not located in the available
1iterature.
3. Mutagenicity
Adler, et al. (1976) have reported that DNOC shows
some evidence of producing CNA damage in Proteus mirabilis.
Testing of this compound in the Ames Salmonella system
(Anderson, et al., 1972) or in E. coli (Nagy, et al., 1975)
failed to show any mutagenic effects.
C. ^eratocjenicitv and Other Reproductive Effects
Pertinent data could rjot be located in the
available literature regarding teratogenicity and other
reproductive effects.
D. Chroni'c Tcxicity
Human use of DNOC as a dieting aid has produced
poisoning cases at accepted the'reputic dose levels, as well
as some cases of cataract development resulting, from
overdoses (NIOSH, 1978).
£. Other Relevant Information
DNOC is an uncoupler of oxidative phosphorylation,
an effect which accounts for its high acute toxicity in
mammals.
V. AQUATIC TOXICITY
Pertinent information could not be located in the
available literature.
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. An eight-hour TLV exposure limit of 0.2 mg/m^ has
been recommended for DNOC by the ACGIH (1971).
A preliminary draft water criterion for DNOC has
been established at 12.3 ug/1 by the U.S. EPA (iS79a). This
draft criterion has not gone through the process of ~public
review? therefore, there is a possibility that the criterion
may be changed.
B. Aquatic
Criteria for the protection of freshwater and
marine aquatic organisms were not drafted due to lack, of
toxicological evidence (U.S. EPA, 1979a) .
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. An eight-hour TLV exposure limit of 0.2 mg/m^ has
been recommended for DNOC by the ACGIH (1971).
A preliminary draft water criterion for DNOC has
been established at 12.3 ug/1 by the U.S. EPA (137Sa). This
draft criterion has not gone through the process of public
review; therefore, there is a possibility that the criterion
may be changed.
B. Aquatic
Criteria for the protection of freshwater and
marine aquatic organisms were not drafted due to lack of
toxicological evidence (U.S. SPA, I979a).
-------
No. 91
2,4-Dinitrophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-ID to -
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This, document has undergone scrutiny to
ensure its technical accuracy.
-------
2,4-DINITROPHENOL
Summary
There is no evidence to indicate that 2,4-dinitrophenol pos-
sesses carcinogenic activity.
Genetic toxicity testing has shown positive effects in mouse
bone marrow cells and in E_-_ coli. In vitro cell culture assays
failed to show the potential for mutagenic activity of 2,4-dinitro-
phenol as measured by unscheduled DNA synthesis.
Teratogenic effects have been observed in the chick embryo
following administration of 2,4-dinitrophenol. Studies in mammals
failed to show that the compound produced any taratcgenic effects.
At the levels of compound used in these mammalian studies, embryo-
toxic offsets were observed.
Human, use- of 2,4-dinitrophenol as a dieting aid has produced
some cases of agranuiocytosis, neuritis, functional heart damage,
and cacaract development.
For aquatic organisms LC^Q values ranged from 520 jag/1 for
the bluegill to 16,700 ug/1 for the fathead minnow.
-------
2,4-DINITROPHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Nitrophenols (U.S. EPA, 1979a).
The dinitrophenols are a family of compounds composed of the
isomers resulting from nitro-group substitution of phenol at vari-
ous positions. 2,4-Dinitropheriol has a molecular weight of 184.11,
a melting point of 114-115°C, a density of 1.683 g/ml and is sol-
uble in water at 0.79 g/1 (U.S. EPA, 1979a).
The dinitrophenols are used as chemical intermediates for
sulfur dyes, azo dyes, photochemicals, pest control agents, wood
preservatives, and explosives. (U.S. EPA, i979a) . The. 1963 pro-
duction of 2,4-dinitrophenol was 4.3 x Id44 tons/yr. (U.S. EPA/
1979a).
For additional information regarding the nitrophenols as
a class, the reader is referred to the Hazard Profile on Nitro-
phenois (1979b).
II. EXPOSURE
The lack of monitoring data for the nitrophenols makes it
difficuic to assess exposure from wacer, innaiacion, and roods.
Nitrophenols have been detected in effluents from chemical plants
(U.S. SPA, 1979a) . Dermal absorption of the dinitrophenols has
been reported (U.S. EPA, 1979a).
Exposure to nitrophenols appears to be primarily through
occupational contact (chemical plants, pesticide application) .
•
Contaminated water may contribute to isolated poisoning incidents.
The U.S. EPA (1979a) has estimated the weighted average biocon-
centration factor for 2,4-dinitrophenol to be 2.4 for the edible
-------
portions of fish and shellfish consumed by Americans. This esti-
mate was based on the octanol/water partition coefficients of
2,4-dinitrophenol.
III. PHARMOCOKINETICS
A. Absorption
The dinitrophenols are readily absorbed following oral,
inhalation, or dermal administration (U.S. EPA, 1979a).
3. Distribution
Dinitrophenol blood concentrations rise rapidly after
absorption, with little subsequent distribution or storage at tis-
sue sites (U.S. EPA, 1979a).
C. Metabolism
• Metabolism of the nitrophenols occurs through conjuga-
tion and reduction of nitre-groups to aminc-groups, or oxidation to
dihydric.-nitrochenols (U.S. EFA, I979a) .
D. Excretion
Experiments with several animal species indicate that
urinary clearance of dinitrophenols is rapid (Harvey, 1959).
VI. EFFECTS
A. Carcinogenicity
2,4-Dinitrophenol has been found not to promote skin
tumor formation in mice following DMBA initiation (Bautwell and
Bosch, 1959) .
B. Mutagenicity
Testing of 2,4-dinitrophenol has indicated mutagenic
»
effects in E. coli (Demerec, et al. 1951). ^n vitro assays of
unscheduled DNA synthesis (Friedman and Staub, 1976) and DNA
-------
damage induced during ceil culture (Swenberg, et al. 1976) failed
to show the potential for rnutagenic activity of this compound.
C. Teratogenicity
2,4-Dinitrophenol has been shown to produce development-
al aonormalities in the chick embryo (Bowman, 1967; Miyatmoto, et
al. 1975). No teratogenic effects were seen following intragastric
administration to rats (Wulff, et al. 1935) or intraperitoneal ad-
ministration to mice (Gibson, 1973).
D. Other Reproductive Effects
Feeding of 2,4-dinitrophenol to pregnant rats produced
an increase mortality in offspring (Wulff, et al., 1935); simi-
larly , intraperitoneal -administration of the compound to mice
induced embryotoxicity (Gibson, 1973). .The influence of this
compound .OP. maternal health niav have contributed to these affects.
E. Chronic Toxicity
Use of 2,4—dinitrophenol as a hurr.sr. dieting aid has pro-
duced some cases .of agranulocytosis, neuritis, functional heart
damage, and a large number of -patients suffering from cataracts
(Horner, 1342).
F. Other Relevant Information
2,4-Dinitrophenol is a classical uncoupler of oxidative
phosphorylation, an effect which accounts for its high acute
toxicity in mammals.
A synergistic action in producing ' teratogenic effects
in the developing chick embryo has been reported with a combina-
»
tion of 2,4-dinitrophenol and insulin (Landauer and Clark, 1964).
-------
V. AQUATIC TOXICITY
A. Acute
The bluegill (Lepomis macrochirus) was the most sensi-
tive aquatic organism tested, with an LC^Q of 620 pg/l in a static,
96-hour assay (U.S. EPA, 1978). Juvenile fathead minnows (Piine-
phales promelas) were more resistant in flow through tests, with
an LC5Q of 16,720 ug/1 (Phipps, et al. manuscript). The fresh-
water cladoceran (Daphnia magna) displayed a range of observed
LC5Q values of 4,090 to 4,710 ;ig/l (U.S. EPA, 1979a) . Acute
values for the marine sheepshead minnow (Cyprinodon variegatus)
are LC-- values ranging from. 5,500 to 29,400 pg/1 (Roser.thal
and Stelzer, 1970). The marine mysid shrimp (Mysidcpsis bahia)
had an LC5Q of 4,350 ug/1 (U.S. EPA, 1978). i
B. Chronic Toxicity
Pertinent. data . could • net be located, in- the available
literature.
p
Effective concentrations for freshwater plants ranged
from 1,472 ^pg/'l for ducKweed (Lemna minor) to 50,000 ,ug/l for
the alga- (Chlorella oyrenoidosa) (U.S. EPA, 1979a) . The marine
alga (Skeletonema costatum) was more resistant with a reported
96-hour EC5Q value based on cell numbers of 98,700 pg/1.
D. Residues
Based on the octanol/water partition coefficient, a bio-
concentration factor of 8.1 has been estimated for 2,4-dinitro-
phenol for aquatic organisms with a lipid content of 8 percent.
-------
V. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by U.S.
EPA (1979a) which are summarized below have undergone the process of
public review; therefore, there is a .possibility that these criter-
ia will be changed.
A. Human
The draft water criterion for dinitrophenols , based
on data describing .adverse effects, has been estimated by the
U.S. EPA (1979a) as 68.6 ug/1.
B. Aquatic
For protecting freshwater aquatic life, the draft cri-
terion is 79 ug/1 as a 24-hour avetage concentration noc to exceed
130 ug/1. The marine criterion has been proposed as 37 pg/I
as a 24-aour average .not to exceed 34 ug/1 at any time (U.S.
To protect saltwater life, the draft criterion is 37
ug/1 as a 24-hour average not to exceed 84 pg/1 at any time (U.S.
EPA, 197 9 a) .
'-1067-
-------
2,4-DINITROPHENOL
REFERENCES
Bautwell, R. , and D. Bosch. 1959. The tumor-promoting action
of ohenol and related compounds for mouse skin. Cancer Res.
19: "413.
Bowman, P. 1967. The effect of 2,4-dinitrophenol on the develop-
ment of early chick embryos. Jour. Embryol. Exp. Morphol. 17: 425.
Demerec, M., et al. 1951. A survey of chemicals for mutagenic ac-
tion on E. coli. Am. Natur. 85: 119.
Friedman, M.A., and J. Staub. 1976. Inhibition of mouse testicular
DNA synthesis by mutagens and carcinogens as a potential simple
mammalian assay for mutagenesis. tMutat. Res. 37: 67.
Gibson, J.E. 1973. Teratology studies in mice with 2-secbutyl-4,
5-dinitrop'nenol (dincseb) . Food Cosmet. Tcxicol. 11: 31.
Harvey, D.G. 1959. On the metabol-ism of some aromatic nitro com-
pounds oy different species of animal. Part III. The toxicity of
the dinitrophenols, with a note on the .effects of high environment'*-
al temperatures. Jour. Pharm. Pharmacoi. 11: 452.
Homer,. W.D. 1942. Dinitrophenol and its relation co formation of
cataracts. Arch. Cphthal. 27: 1097.
Landauer, W. , and E. Clark. 1964. iJncoupiers of oxidative phos-
phorylation and teratcgenic activity of insulin. Nature 204: 285.
Miyamoto, K., et ai. 1975. Deficient myelination by 2, 4-dinitro-
phenol administration in early stage of development. Teratology
12: 204.
phenols to the fathead minnow. (Manuscript).
Rosenthal, H. , and R. Stelzer. 1970. Wirkungen von 2,4-und 2,5-
dinitrophenol auf die Embryonalentwicklung des Herings Clupea
harengus. Mar. Biol. 5: 325*.
Swenberg, J.A., et al. 1976. In vitro DNA damage/akaline elution
assay for predicting carcinogenic potential., Biochem. Biophys.
Res. Ccmmun. 72: 732.
U.S. EPA. 1979a. Nitrophenols: Ambient water quality criteria.
(Draft).
U.S. EPA. 1979b. Nitrophenols: Hazard Profile. Environmental
Criteria and Assessment Office (Draft).
-------
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-4646.
Wulff, L.M.3., et al. 1935. Some effects of alpha- dinitrophenol
on pregnancy in the white rat. Proc. Soc. Exp. Biol. Med. 32: 678.
~/D £?~
-------
No. 92
Dinitrotoluene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-/D 70 -
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
DI'NITROTOLUENE
SUMMARY
Most of the information on the affects of dinitrotoluene
deals wich 2,4-dinitrocoiuene. 2,4-Dinitrotoluene induces
liver cancer and mammary tumors in mice and is mutagenic
in some assay systems. Information on teratogenicity was
not located in- the available literature. Chronic exposure
to 2,4-dinitrotoluene induces liver damage, jaundice, methemo-
globinemia and anemia in humans and animals.
Acute studies in freshwater fish and invertebrates
suggest that 2,3-dinitrotoluene is much more toxic than
2,4-dinitrotoluene.
-ib 73.
-------
DINITROTOLUENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Dinitrotoluene (U.S. SPA, 1979).
There are six isomers of dinitrotoluene (CK,C,H3 (N0~)~;
molecular weight 182.14), with the 2,4-isomer being the
most important commercially. 2,4-Dinitrotoluene has a melt-
ing point of 7i°C, a boiling point of 3GO°C with decomposi-
tion, and a solubility in water of 270 mg/1 at 22°C. It
is readily soluble in ether, ethanol, and carbon disulfide
(U.S. EPA. 1979). 2,6-Oinitrotoluene has a melting point
o
of 56 C and is soluble in alcohol. Production in 1975 was
.273 x 1C tons per year for the 2,4- and 2,6- isomers com-
Dinitrotoiuene is an incr.ecient of explosives fcr conurier-
„;_! ,_^_.:i.•;_.,.,., ,,__ - ~l „.:,,_ i _ 4. - u ;•!.•-, :_ i.i .. s
i^. anC -4_ — _ -.ij. _/ ^ —o, — _..-;.., ^^^-j. o _^_ ^ ^. j. i*a. ±. n -.nc ;.n.\»iu-aw-
iure of smokeless powder, an intermediate in the manufacture
of toluene diisocyanatas used ir. the production of urethane
polymers, and a raw material for che manufacture of dyestuffs.
Dinitrotolusnes are relatively stable at ambient tempera-
tures (U.S. EPA, 1979) .
II. EXPOSURE
A. Water
Data on concentration levels for Sinitrotoluene
were not available. Dinitrotoluene waste products are dumped
into surface water or sewage by industries that manufacture
dyes, isocyanates, polyurethanes and munitions (U.S. EPA,
1979) .
-JO 73
-------
B . Food
According to the U.S. EPA (1979), the likelihood
of dinitrotoluene existing in food is minimal since it is
not used as a pesticide or herbicide.
The U.S. EPA (1979) has estimated the weighted
average bioconcentration factor for 2 , 4-dinitrotoluene to
be 5.5 for the edible portions of fish and shellfish consumed
.by Americans. This estimate is based en the octanol/water
partition coefficient.
C. Inhalation
Exposure to dinitrotoluene by inhalation is most
likely to occur occupationaiiy (U.S. EPA, 1979) . ^- 'However ,
pertinent data could not be located in the available litera-
curs ~n atmospheric ccnc3~ tra~icr3 cf dini trctc-lusr.a an~,
thus, oossibls human exec-sure canncc be 35 tirr.Hisc .
""
A. Absorption
The absorption of ""C-labeled isomers -... dinitrotol-
uene after oral adrninistracion to rats was essentially com-
plete within 24 hours, with 50 to 90 percent of the dose
being absorbed. The 2,4- and 3,4-isomers were absorbed
to .a greater extent than the 3,5- and 2,5- isomers, which
in turn were absorbed to a greater extent than the 2,3-
and 2,6-isomers (Hodgson, et al. 1977). 2 ,'4-Dinitrotoluene
is known to be absorbed through the respiratory tract and
»
skin (U.S.. EPA, 1979).
-------
B. Distribution .
Tissue/plasma ratios of radioactivity after adminis-
14
tration of C-labeled dinitrotoluene to rats indicated
14
retention of C DMT in both the liver and kidneys but not
in other tissues (Hodgson, et al., 1977). A similar experi-
ment with tritium-labeled 2,4-dinitrotoluene ( H-2,4-DNT)
in the rat showed relatively high amounts of radioactivity
remaining in adipose tissue, skin, and liver seven days
after administration (Mori, et al., 1977).
C. Metabolism
No studies characterising the metabolism of dinitro-
toluene in mammals are available-. However, on the basis
of a comparison of the metabolism of 2,4-dinitrotoluene
and 2,4,o-trinitrotoluene in microbiai syscems, and the
:
-------
IV. EFFECTS
A. Carcinogenicity
2,4-Dinitrotoluene fed to rats and mice for two
years produced dose-related increases in fibrc-isas of the
skin in male rats and fibroadenomas of the mammary gland
in female rats. All of these were benign tumors. No statis-
tically significant increase in tumor incidence was noted
in mice (Natl. Cancer Inst., 1978).
In a second bioassay of rats and mice fed 2,4-
dinitrotoluene for two years, the findings in rats included
a significant increase of hepatoceiluiar carcinc-as and
neoplastic nodules in the livers.of females, a significant
increase of mammary gland tumors in females, and a suspicious
ir.craase or hapacoceliular carcinomas of the liv<=r in maj.es.
Male mice had a highly significant increase cf ,\i.cney tumors
{Lee, at al., 1973) .
3. Mutagenicity
2,4-Dihitrotoluene was mutagenic in the dominant
lethal assay and in Salmonella typhimurium strain TA1535
(Hodgson, et ai. 1976). Cultures of lymphocytes and kidney
cells derived from rats fed 2,4-dinitrotoluene had signifi-
cant increases in the frequency of chromatid gaps but not
in translocations or chromatid breaks (Hodgson, et al.,
1976).
The.mutagenic effects of products from ozonation
»
or chlorination of 2,4-dinitrotoluene and other dinitrotoluenes
•1676-
-------
were negative in one study (Simmon, et al., 1977), and,
for products of ozonation alone, were ambiguous in another
study (Cotruvd, et al., 1977).
C. Teratogenicity and other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
D. Chronic Toxicity
Chronic exposure to 2,4-dinitrotoluene may produce
liver damage, jaundice, methemoglobinemia and reversible
anemia with reticulocytosis in humans and animals (Linch,
1974; Key, et al. 1977; Proctor and Hughes, 1978; Kovalenko,
1973). •. •
E. Other Relevant Information
Animals were more resistant, to the toxic effects
of 2,4-dinitrotoluene administered in the diet when given
diets high in fat or-..protein (Clayton and Bauraann, 1944,
. ;) "
1948; Shils and Goldwater, 1953) or protein (Shils and Gold-
water, 1953) . •'.")
Alcohol has a synergistic effect on the toxicity
of 2,4-dinitrotoluene (Friedlander, 1900; McGee, et al.,
1942).
In subacute studies (13 weeks), 2,4- and 2,6-dini-
trotoluene caused methemoglobinemia, anemia with reticulocyto-
sis, gliosis and demyelination in the brain', and atrophy
with aspermatogenesis of the testes in several species (Ellis,
•
et al.,.1976).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Static assays with the freshwater bluegill (Lepomis
macrochirus) produced a 96-hour LC5Q value of 330 jag/1 for
2,3-dinitrotoluene (U.S. EPA, 1978), while the same assay
with the fathead minnow (Pimephales promelas) produced a
96-hour LC value of 31,0.00 }ig/l for 2,4-dinitrotoluene
(U.S. Army, 1976). The greater toxicity of 2,3-dinitrotoluene
when compared to that of 2,4-dinitrotoluene, was demonstrated
in 48-hour static assays with the freshwater cladoceran,
Daphnia magna, with LC5Q values of 660 pg/l(U.S. EPA,. 1978).
and 35,000 pg/1 (U.S. Army, 1976) being reported. A single
marine, fish, sheepshead minnow (Cyprinodon variegatus),
has been tested for adverse acute effects of 2,3-dinitro-
toluene. A 96-hour static assay LCeg value of 2,280 pg/1
was reported (U.S. EPA, 1978). For marine invertebrates
a 96-hour static LC5Q value of 590 pg/1 was obtained for
the mysid shrimp (Mysidopsis bahia) with 2,3-dinitrotoluene.
B. Chronic Toxicity
The sole chronic study examining the effects of
2,3-dinitrotoluene in an embryo-larval assay on the fathead
minnow produced a chronic value of 116 pg/1 based, on reduced
survival of these stages. No marine.chronic data were pre-
sented (U.S. EPA, 1979).
C. Plant Effects
i • *
Concentrations of 2,3-dinitrotoluene that caused
50 percent adverse effects in cell numbers or chlorophyll
-------
a in the freshwater algae, Selenastrum capricornutum, were
1,370 or 1,620 ug/1, respectively. These same effects mea-
sured in the marine algae, Skeletonema costatum, showed
it to be more sensitive. EC5Q values were 370 or 400 ug/1,
respectively.
D. Residues
A bioconcentration factor of 19 was obtained for
aquatic organisms having alipid content of 8 percent (U.S.
EPA, 1979).
VI. EXISTING STANDARDS AND GUIDELINES
Neither the human health nor aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gone
through the process of public review; therefore, there is
a possibility that these criteria may be changed.
A. Human
Based on the induction of fibroadenomas of the
mammary gland in female rats (Lee, et al., 1978), and using
the "one-hit" model, the U.S. EPA (1979) has estimated levels
of 2,4-dinitrotoluene in ambient water which will result
in specified risk levels of human cancer:
Exposure Assumptions Risk Levels and Corresponding Draft Criteri
(Per day>oi(T7 Iu^ 'IJT*
2 liters of drinking water and 7.4 ng/1 74.0 mg/1 740 ng/1
consumption of 18.7 grams fish
and shellfish.
Consumption of fish and shell- .156 ug/1 1.56 pg/1 15.6 jug/1
fish only.
-------
The American Conference of Governmental Industrial
Hygienists (1978) recommends a TLV-time weighted average
for 2,4-dinitrotoluene of 1.5 mg/m with a short term expo-
sure limit of 5 rag/m .
B. Aquatic
A criterion to protect freshwater life has been
drafted as 620 ug/1 for a 24-hour average not to exceed
1,400 ^ig/1 for 2.4-dinitrotoluene and 12 ug/1 not to exceed
27 ug/1 for 2,3-dinitrotoluene. For marine environments
a criterion has been drafted for 2,3-dinitrotoluene as a
4.4 ug/1 as a 24-hour average not to exceed 10 ^ig/1. Data
was insufficient to draft a criterion for 2,4-dinitrotoluene
for marine environments.
-------
OINITROTOLUENE
REFERENCES
American Conference of Governmental Industrial Hygienists. 1978. TLV's:
Threshold limit values for chemical substances and physical agents in the
workroom environment with intended changes for 1978.
Clayton, C.C. and C.A. Baumann. 1944. Some effects of diet on the resis-
tance of mice toward 2,4-dinitrotoluene. Arch. Biochem. 5: 115.
Clayton, C.C. and C.A. Baumann. 1948. Effect of fat and calories on the
resistance of mice to 2,4-dinitrotoluene. Arch. Biochem. 16: 415.
Cotruvo, J.A., et al. 1977. Investigation of mutagenic effects of products
of ozonation reactions in water. Ann. N.Y. Acad. Sci. 298: 124.
Ellis, H.V.,-III, et al. 1976. Subacute toxicity of 2,4-dinitrotoluene and
2,6-dinitrotoluene. Toxicol. Appl. Pharmacol. 37: 116. (Abstract from
15th Ann. Meet. Soc. Toxicol., March 14-18.)
Friedlander, A. 1900. On the clinical picture of poisoning with benzene
and toluene derivatives with special reference to the so-called anilinism.
Neurol. Centrlbl. 19: 155.
Hodgson, J.R., et al. 1976. Mutation studies on 2,4-dinitrotoluene.
Mutat. Res. 38: 387. (Abstract from the 7th Ann. Meet. Am. Environ. Muta-
gen. Soc., Atlanta, March 12-15.)
Key, M.M., et al. (eds.) 1977. Pages 278-279 In: Occupational diseases: A
guide to their recognition. U.S. Oept. Health Edu. Welfare. U.S. Govern-
ment Printing Office, Washington, O.C.
Kovalenko, I.I. 1973. Hemotoxicity of nitrotoluenes in relation to number
and positioning of nitro groups. Farmakol. Toxicol. (Kiev.) 8: 137.
Lee, C.C., et al. 1978. Mammalian toxicity of munition compounds. Phase
III: Effects of lifetime exposure. Part I: 2,4-dinitrotoluene. U.S. Army
Med. Res. Oev. Command. Contract No. OAMD-17-74-C-4073. Rep. NO. 7, Sep-
tember.
Linch, A.L. 1974. Biological monitoring for industrial exposure to cyano-
genic aromatic nitro and amino compounds. Am. Ind. Hyg. Assoc. Jour.
35: 426.
s
McGee, L.C., et al. 1942. Metabolic distrubances in workers exposed to
dinitrotoluene. Am. Jour. Dig. Dis. 9: 329.
»
Mori, M., et al. 1977. Studies on the metabolism and toxicity of dinitro-
toluenes — on excretion and distribution of tritium-labeled 2,4-dinitroto-
luene (^-2,4-ONT) in the rat. Radioisotopes 26: 780.
JDZI
-------
National Cancer Institute. ' 1978. Bioassay of 2,4-dinitrotoluene for possi-
ble carcinogenic!ty. Carcinogenesis Tech. Rep. Ser. No. 54. USDHEW (NIH)
Publ. No. 78-1360. U.S. Government Printing Office, Washington, D.C.
Proctor, N.H. and J.P. Hughes. 1978. Chemical hazards of the workplace.
J.B. Lippincott Co., Philadelphia/Toronto.
Shils, M.E. and L.J. Goldwater. 1953. Effect of diet on the susceptibility
of the rat to poisoning by 2,4-dinitrotoluene. Am. med. Assoc. Arch. Ind.
Hyg. Occup. Med. 8: 262.
Simmon, V.F., et al. 1977. Munitions wastewater treatments: does chlorina-
tion or ozonation of individual components produce microbial mutagens?
Toxicol. Appl. Pharmacol. 41: 197. (Abstract from the 16th Ann. Meet. Soc.
Toxicol., Toronto, Can., March 27-30.)
U.S. Army Research and Development Command. 1976. Toxicity of TNT waste-
water (pink water) to aquatic organisms. Final report, Contract DAMD17-75-
C-5056. Washington, D.C.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646.
U.S. EPA. 1979. Dinitrotoluene: Ambient Water Quality Criteria. (Draft) J
-------
No. 93
2,4-Dlnltrotoluene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of ts<= ^limitations of such sources, this short profile
may not ref j.. ,-t all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
2,4-dinitrotoluene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
2.4-OINITROTOLUENE
Summary
2,4-Qinitrotoluene induces liver cancer and mammary tumors in mice and
is mutagenic in some assay systems. Information on teratogenicity was not
located in the available literature. Chronic exposure to 2,4-dinitrotoluene
induces liver damage, jaundice, methemoglobinemia and anemia in humans and
animals.
Two acute studies, one on freshwater fish and the other on freshwater
invertebrates, provide the only data of 2,4-dinitrotoluene's adverse effects
on aquatic organisms. Acute LC5Q values were reported as 17,000 and
30,000 jjg/1. NO marine data are available.
-------
2,4-OINITROTOLUENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Oinitrotoluene (U.S. EPA, 1979a).
2,4-Oinitrotoluene (2,4-ONT) has a melting point of 71°C, a boiling
point of 300°C with decomposition, and a solubility in water of 270 mg/1
at 22°C. It is readily soluble in ether, ethanol, and carbon disulfide
(U.S. EPA, 1979a).
Production in 1975 was 273 x 10 tons/year for the 2,4- and
2,6-isomers combined (U.S. EPA, 1979a). 2,4-Oinitrotoluene is an ingredient
in explosives for commercial and military use, a chemical stabilizer in the
manufacture of smokeless powder, an intermediate in the manufacture . ' 'ol-
uene diisocyanates used in the production of urethane polymers, and a raw
material for the manufacture of dye-stuffs. Dinitrotoluenes are relatively
stable at ambient temperatures (U.S. EPA, 1979a). For additional infor-
mation regarding the dinitrotoluenes in general, the reader is refer- '\d to
the EPA/ECAO Hazard Profile on Dinitrotoluenes (U.S. EPA, 1979b).
II. EXPOSURE ''-J
A. water
Data on concentration levels of 2,4-ONT in water were not avail-
able. Dinitrotoluene waste products are dumped into surface water or sewage
by industries that manufacture dyes, isocyanates, polyurethanes and muni-
tions (U.S. EPA, 1979a).
B. Food
According to the U.S. EPA (1979a), the likelihood of 2,4-dinitro-
»
toluene existing in food is minimal since it is not used as a pesticide or
herbicide.
10*7-
-------
The U.S. EPA (1979a) has estimated the weighted average biocon-
centration factor for 2,4-dinitrotoluene to be 5.5 for edible portions of
fish and shellfish consumed by Americans. This estimate was based on the
octanol/water partition coefficient.
C. Inhalation
Exposure to dinitrotoluene by inhalation is most likely to occur
occupationally (U.S. EPA, 1979a). However, pertinent data could not be
located in the available literature on atmospheric concentrations of dini-
trotoluene; thus, possible human exposure cannot be estimated.
III. PHARMACOKINETICS
A. Absorption
The absorption of C-labeled isomers of dinitrotoluene after
oral administration to rats was essentially complete within 24 hours, with
60 to 90 percent of the dose being absorbed. The 2,4-and 3,4-isomers .were
absorbed to a greater extent than the 3,5- and 2,5-isomers, which in turn
were absorbed to a greater extent than the 2,3- and 2,6-isomers (Hodgson, et
al. 1977). From toxicity studies, 2,4-Oinitrotoluene is known to be ab-
sorbed through the respiratory tract and skin. (U.S. EPA, 1979a).
8. Distribution
Tissue/plasma . ratios of radioactivity after administration of
C-labeled . dinitrotoluene (DNT) to rats indicated retention of 14C
2,4-ONT in both liver and kidneys but not in other tissues (Hodgson, et al.
1977). A similar experiment with tritium-labeled 2,4-dinitrotoluene
( H-2,4-ONT) in the rat showed relatively high 'amounts of radioactivity
remaining in adipose tissue, skin, and liver seven days after administration
»
(Mori, et al. 1977).
-------
C. Metabolism
No studies characterizing the metabolism of 2,4-dinitrotoluene in
mammals are available. However, on the basis of a comparison of the metab-
olism of 2,4-dinitrotoluene and 2,4,6-trinitrotoluene in microbial systems,
and the metabolism of 2,4,6-trinitrotoluene in mammals, the U.S. EPA (1979a)
speculated that the metabolites of 2,4-dinitrotoluene in mammals would be
either toxic and/or carcinogenic.
D. Excretion
14
In studies involving oral administration of C-dinitrotoluene or
3H-2,4-dinitrotoluene to rats (Hodgson, et al. 1977; Mori, et al, 1977),
elimination of radioactivity occurred mainly in urine and feces. NO radio-
activity was recovered in the expired air. About 46 percent of the admin-
istered dose in the latter study was excreted in the feces and urine during
the seven days following administration.
IV. EFFECTS
A. Carcinogenicity
2,4-Oinitrotoluene fed to rats and mice for two years produced
dose-related increases in fibromas of the skin in male rats and fibro-
adenomas of the mammary gland in female rats. These tumors were benign. No
statistically significant reponse was noted in mice (Natl. Cancer Inst.,
1978).
In a second bioassay of rats and mice fed 2,4-dinitrotoluene for
two years, the findings in rats included a significant increase of hepato-
cellular carcinomas and neoplastic nodules in the livers of females, a sig-
nificant increase of mammary gland tumors in females, and a suspicious in-
»
crease of hepatocellular carcinomas of the liver in males. Mice had a
highly significant increase of kidney tumors in males (Lee, et al. 1979).
-------
B. Mutagenicity
2,4-Oinitrotoluene was mutagenic in the dominant lethal assay and
in Salmonella tvphimurium strain T A 1535 (Hodgson, et al. 1976). Cultures
of lymphocytes and kidney cells derived from rats fed 2,4-dinitrotoluene had
significant increases in the frequency of chromatid gaps but not in trans-
locations or chromatid breaks (Hodgson, et al. 1976).
The mutagenic effects of products from ozonation or chlorination of
2,4-dinitrotoluene and other dinitrotoluenes were negative in one study
(Simmon, et al. 1977) and, of products from ozonation alone, were ambiguous
in another study (Cotruvo, et al. 1977).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature.
0. Chronic Toxicity i
Chronic exposure to 2,4-dinitrotoluene may produce liver damage,
jaundice, methemoglobinemia and reversible anemia with reticulocytosis in
humans and animals (Linch, 1974; Key, et al. 1977; Proctor and Hughes, 1978;
Kovalenko, 1973).
E. Other Relevant Information
Animals were more resistant to the toxic effects of 2,4-dinitro-
toluene administered in the diet when given diets high in fat (Clayton and
Baumann, 1944, 1948; Shils and Goldwater, 1953) or protein (Shils and
Goldwater, 1953).
Alcohol has a synergistic effect on the toxicity of 2,4-dinitrotoluene
(Friedlander, 1900; McGee, et al. 1942).
-------
In subacute studies (13 weeks) of several species, 1,2,4-dinitrotoluene
caused methemoglobinemia, anemia with reliculocytasis, gliosis, and demyeli-
nation in the brain, and atrophy with aspermatogenesis of the testes (Ellis
et al., 1976).
V. AQUATIC TOXICITY
A. Acute Toxicity
The only toxicity data available for the effects of 2,4-dinitro-
toluene in aquatic animals are from a single freshwater fish and inverte-
brate species (U.S. Army, 1976). A 96-hour static LC-Q value for the fat-
head minnow (Pimephales promelas) was reported as 31,000 ug/1 and a 48-hour
static LC50 value for the cladoceran, Daphnia maqna, was reported as
35,000pg/l.
a. Chronic Toxicity and Plant Effects
Pertinent data could not be located in the available literature.
C. Residues
A bioconcentration factor of 19 was obtained for 2,4-dinitrotoluene.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria may be changed.
A. Human
Based on the induction of fibroadenomas of the mammary gland in
female rats (Lee, et al. 1978), and using the "one-hit" model, the U.S. EPA
(1979a) has estimated levels of 2,4-dinitrotoluene' in ambient water which
will result in specified risk levels of human cancer:
-------
Exposure Assumptions Risk Levels and Corresponding Critgria
(per day)
0 10~7 10-6 io-5
Consumption of 2 liters of drink- 7.4 ng/1 74.0 ng/1 740 ng/1
ing water and 18.7 grams fish and
shellfish.
Consumption of fish and shellfish .156 pg/1 1.56 jug/1 15.6yug/l
only .
The American Conference of Governmental Industrial Hygienists
(1978) recommends a TLV-time-weighted average for 2,4-dinitrotoluene of 1.5
mg/m with a short term exposure limit of 5 mg/m .
3. Aquatic
A criterion has been drafted for protecting freshwater life from
the toxic effects of 2,4-dinitrotoluene. A 24-hour average concentration of
620 /jg/1, not to exceed 1,400 jag/1, has been proposed. Data are insuffi-
cient for drafting a marine criterion.
-------
2,4-DINITROTOLUENE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1978. TLV'sR: Threshold limit values for chemical
substances and physical agents in the workroom environment
with intended changes for 1978.
Clayton, C.C., and C.A. Baumann. 1944. Some effects of diet
on the resistance of mice toward 2,4-dinitrotoluene. Arch.
Biochem. 5: 115.
Clayton, C.C., and C.A. Baumann. 1948. Effect of fat and
calories on the resistance of mice to 2,4-dinitrotoluene.
Arch. Biochem. 16: 415.
Cotruvo,, J.A., et al. 1977. Investigation of mutagenic
effects of products of ozonation reactions in water. Ann.
N.Y. Acad. Sci. 298: 124.
Friedlander, A. 1900. On the clinical picture of poisoning
with benzene and toluene derivatives with special reference
to the so-called anilinism. Neurol. Centrlbl. 19: 155.
Hodgson, J.R., et al. 1976. Mutation studies on 2,4-dini-
trotoluene. Mutat. Res. 38: 387. (Abstract from the 7th
Annu. Meet. Am. Environ. Mutagen Soc., Atlanta, March 12-15).
Hodgson, J.R.,'et al. 1977. Comparative absorption, distri-
bution, excretion, and metabolism of 2,4,6-trinitroluene
(INT) and isomers of dinitrotoluene (DNT) in rats. Fed.
Proc. 36: 996.
Key, M.M., et al. (eds.) 1977. Pages 278-279 In:
Occupational diseases: A guide to their recognition. U.S.
Dept. Health, Edu. Welfare. U.S. Government Printing Office,
Washington, D.C.
Kovalenko, I.I. 1973. Hemotoxicity of nitrotoluene in rela-
tion to number and positioning of nitro groups. Farmakol.
Toxicol. (Kiev.) 8: 137.
Lee, C.C., et al. 1978. Mammalian toxicity of munition com-
pounds. Phase III: Effects of life-time exposure. Part I:
2,4-Dinitrotolune. U.S. Army Med. Res. Dev. Command. Con-
tract No. DAMD-17-74-C-4073. Rep. No. 7, September.
'/O 93 ~
-------
Linch, A.L. 1974. Biological monitoring for industrial ex-
posure to cyanogenic aromatic nitro and amino compounds. Am.
Ind. Hyg. Assoc. Jour. 35: 426.
McGee, L.C., et al. 1942. Metabolic disturbances in workers
exposed to dinitrotoluene. Am. Jour. Dig. Dis. 9: 329.
Mori, M., et al. 1977. Studies on the metabolism and toxic-
ity of dinitrotoluenes — on excretion and distribution of
tritium-labelled 2,4-dinitrotoluene (3H-2,4-DNT) in the
rat. Radioisotopes 26: 780. . .
National Cancer Institute. 1978. Bioassay of 2,4-dinitro-
toluene for possible carcinogenicity. Carcinogenesis Tech.
Rep. Ser. No. 54. U.S. DREW (NIH) Publ. No. 78-1360. U.S.
Government Printing Office, Washington, D.C.
Proctor, N.H., and J.P. Hughes. 1978. Chemical hazards of
the workplace. J.B. Lippincott Co., Philadelphia/Toronto.
Shils, M.E., and L.J. Goldwater. 1953. Effect of diet on
the susceptibility of the rat to poisoning by 2,4-dinitro-
toluene. Am. Med. Assoc. Arch. Ind. Hyg. Occup. Med. 8:
262.
Simmon, V.F., et al. 1977. Munitions wastewater treatments:
dose chlorination or ozonation of individual components pro-
duce microbial mutagens? Toxicol. Appl. Pharmacol. 41: 197.
(Abstract from the 16th Annu. Meet. Soc. Toxicol., Toronto,
Can., March 27-30).
U.S. Army Research and Development Command. 1976. Toxicity
of TNT wastewater (pink water) to aquatic organisms. Final
Report, Contract DAMD 17-75-C-5056. Washington, D.C.
U.S. EPA. 1979a. Dinitrotoluene: Ambient Water Quality Cri-
teria. (Draft).
U.S. EPA. 1979b. Dinitrotoluene: Hazard Profile. Environ-
mental Criteria and Assessment Office.
-------
No. 94
2,6-Dinltrotoluene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-/096-
-------
2,6-Dinitrotoluene
SUMMARY
2,6-Dinitrotoluene is known to cause methemoglobinemia in
cats, dogs, rats, and mice. When administered orally to these
animals for a maximum of thirteen weeks, the major effects seen
in addition to the blood effects were depressed spermatogenesis,
degeneration of the liver, bile duct hyperplasia, incoordination
and rigid paralysis of the hind legs, and kidney degeneration.
Positive results were obtained with mutagenicity testing in
a number of Salmonella typhimurium strains.
2,6-DNT has been found in tap water in the United States.
The nitro groups on the aromatic ring retard degeneration so
there is a potential for it to accumulate in the aquatic environ-
ment .
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Dinitrotoluene (U.S. EPA, 1979b) and a U.S. EPA
report entitled "Investigation of Selected Potential Environ-
mental Contaminants: Nitroaromatics" (1976).
2,6-Dinitrotoluene (2,6-DNT; CyHgNjO^ molecular weight
182.14) is a solid at room temperature. It is in the shape of
rhombic needles and is soluble in ethanol. Its melting point is
9
66"C and its density is 1.28 at lll'C (Weast, 1975).
A review of the production range (includes importation)
statistics for 2,6-dinitrotoluene (CAS. No. 606-20-2) which is
-------
listed in the initial TSCA Inventory (1979a) has shown that
between 50,000,000 and 100,000,000 pounds of this chemical were
produced/imported in 1977.—/
Mixtures of the dinitrotoluene isomers are intermediates- in
the manufacture of toluene diisocyanates, toluene diamines and
trinitrotoluene (Wiseman, 1972). Dinitrotoluene (both 2,4- and
2,6-) is an ingredient in explosives for commercial and military
use and is also used as a chemical stabilizer in the manufacture
of smokeless powder (U.S. EPA, 1979b).
II. EXPOSURE
. A. Environmental Fate
Based on the photodecomposition of trinitrotoluene (TNT)
described by Burlinson ^et^ _al_. (1973), 2,6-dinitrotoluene would be
expected to react photochemically. Decomposition of 65% of the
TNT had occurred when the decomposition products were examined.
2,6-Dinitrotoluene would be expected to biodegrade to a
limited extent. The nitro groups retard biodegradation and
studies with soil microflora have shown that mono- and di-
substituted nitrobenzenes persist for more than 64 days
(Alexander and Lustigmann, 1966), McCormick et al. (1976) and
Bringmann and Kuehn (1971) reported microbial degradation of
2,6-DNT by anaerobic and aerobic bacteria, respectively.
—1 This production range information does not include any .
production/importation data claimed as confidential by the
person(s) reporting for the TSCA inventory, nor does it
include any information which would compromise Confidential
Business Information. The data submitted for the TSCA
Inventory, including production range information, are subject
to the limitations contained in the Inventory Reporting
-------
B. Bioconcentration
In general nitroaromatic compounds do not have high biocon-
centration potential based on calculations using their octanol-
water partition coefficients. They are not expected to
biomagnify based on their water solubility (U.S. EPA, 1976).
C. Environmental Occurrence
2,6-Dinitrotoluene has been identified in tap water in the
United States (Kopfler and Melton, 1975). Its environmental con-
tamination would come almost exclusively from the chemical plants
where it is produced. It was detected in the water effluent from
a TNT plant in Radford, Virginia at concentrations of 3.39 to
56.3 ppm. It was also found in the raw waste of a DNT plant at
150 ppm. The raw effluent contained 0.68 ppm and the pond efflu-
ent 0.02 ppm (U.S. EPA, 1976).
III. PHARMACOKINETICS
2,6-Dinitrotoluene can enter the body through inhalation of
vapors or dust particles, ingestion of contaminated food, and
absorption through the skin (EPA, 1979b) . Hodgson _et_ _al_. (1977)
1 A
traced the pathway of *• C labeled di- and tri-substituted nitro-
toluenes after oral administration of the compounds to rats. All
of the compounds were well absorbed with 60 to 90% absorption
after 24 hours. The radiolabel was found in the liver, kidneys
and blood but not in other organs; none was found in the expired
air indicating that the aromatic ring was not broken down through
»
metabolism of the compounds. Most of the labeled compounds were
Regulations (40 CFR 710).
2
-/or?-
-------
eliminated in the urine as metabolites; biliary excretion was
also an important elimination pathway.
IV. HEALTH EFFECTS
A. Carcinogenicity
No carcinogenicity testing of 2,6-DNT has been reported in
the literature. The National Cancer Institute conducted a bio-
assay to determine the carcinogenicity of 2,4-DNT by administer-
ing it to rats and mice in their diet. 2,4-DNT induced benign
tumors in male and female rats, however, the benign tumors were
not considered a sufficient basis for establishing carcinogen-
icity. The assay produced no evidence of carcinogenicity of the
compound in mice (NCI, 1978).
B. Mutagenicity
Simmon et^ al_. (1977) tested 2,6-dinitrotoluene for
mutagenicity in Salmonella typhimurium. Positive results were
obtained with strains TA1537, TA1538, TA98, and TA100, but not
TA1535. These results were obtained without metabolic activa-
tion.
C. Other Toxicity
1. Chronic
The subchronic toxicity of 2,6-dinitrotoluene was determined
by oral administration to dogs, rats, and mice for about 13
weeks. The primary effects were on red blood cells, the nervous
system, and the testes. Both dogs and rats had decreased mu'scu-
lar coordination primarily in the hind legs, rigidity in exten-
sion of the hind legs, decreased appetite, and weight loss. The
-------
mice experienced only the decreased appetite and weight loss.
All of the animals had methemoglobinemia, and anemia with reticu-
locytosis. The tissue lesions seen were extramedullary hemato-
poeisis in the spleen and liver, gliosis and demyelination in the
brain, and atrophy with aspermatogenesis in the testes (Ellis et
al., 1976). Methemoglobinemia was also found in cats adminis-
tered 2,6-DNT (U.S. EPA, 1979b).
2. Acute
Oral LD50's have been reported for rats and mice. They are
180 mg/kg and 1,000 mg/kg respectively (Vernot et al., 1977). A
mixture of 2,4-DNT and 2,6-DNT was applied to the skin of rabbits
in a series of 10 doses over a two week period and no cumulative
toxicity was found (U.S. EPA, 1976).
VI. EXISTING GUIDELINES
The OSHA standard for 2,6-DNT in air is a time-weighted
average of 1.5 mg/m3 (39 PR 23540).
-------
BIBLIOGRAPHY
Alexander, M. and B.K. Lustigmann. Effect of chemical structure
on raicrobial degradation of substituted benzenes. J. Agr. Food.
Chem. 14(4), 410-41, 1966. (As cited in U.S. EPA, 1976).
Bringmann, G. and R. Kuehn. Biological decomposition of nitro-
toluenes and nitrobenzenes by Azotobacter Agilis. Gesundh.-Ing.,
92(9), 273-276, 1971. (As cited in U.S. EPA, 1976).
Burlinson, N.E. et al. Photochemistry of TNT: investigation of
the "pink water" problem. U.S. NTIS AD 769-670, 1973. (As cited
in U.S. EPA, 1976).
Ellis, H.V. , III e_t_ _al_. Subacute toxicity of 2,4-dinitrotoluene
and 2,6-dinitrotoluene. Toxicol. Appl. Pharm. 37, 116, 1976.
Hodgson, J.R. _e_t^ _al_. Comparative absorption, distribution,
excretion, and metabolism of 2,4,6-trinitrotoluene (TNT) and
isomers of dinitrotoluene (DNT) in rats. Fed. Proc. 36, 996,
1977.
Kopfler, F.C. and R.G. Melton. 1977. Human exposure to water
pollutants. In Advances in Environmental Science and Technology,
Vol. 8. Fate of Pollutants in the Air and Water Environments.
Part 2. Chemical and Biological Fate of Pollutants in the
Environment. Symposium at the 165th National American Chemical
Society Meeting in the Environmental Chemistry Division. Phila-
delphia, PA. April 1975. John Wiley and Sons, Inc., New York.
McCormick, N.G. et al. Microbial transformation of 2,4,6-trini-
trotoluene and other nitroaromatic compounds. Appl. Environ.
Microbiol. 31(6), 949-958, 1976.
National Cancer Institute. Bioassay of 2,4-dinitrotoluene for
possible carcinogenicity. PB-280-990, 1978.
National Institute of Occupational Safety and Health. Registry
of Toxic Effects of Chemical Substances, 1978.
Simmon, V.F. _et_ _al_. Mutagenic activity of chemicals identified
in drinking water. Dev. Toxicol. Environ. Sci. 2, 249-258, 1977.
U.S. EPA. Investigation of Selected Potential Environmental
Contaminants: Nitroaromatics. PB-275-078, 1-976.
U.S. EPA. Toxic Substances Control Act Chemical Substance
Inventory, Production Statistics for Chemicals on the Non-Confi-
dential Initial TSCA Inventory, 1979a.
U.S. EPA. Ambient Water Quality Criteria: Dinitrotoluene.
PB-296-794, 1979b. .
-------
Varnot, E.H. £t_ ^1_. Acute toxicity and' skin corrosion data for
some organic and inorganic compounds and aqueous solutions.
Toxicol. Appl. Pharmacol. 42(2), 417-424, 1977.
Weast, R.C., ed. 1978. CRC Handbook of Chemistry and Physics.
CRC Press, Inc., Cleveland, Ohio.
Wiseman, P. 1972. An Introduction to Industrial Organic
Chemistry. Interscience Publishers, John-Wiley and Sons, Inc.,
New York.
y
-------
No. 95
Di-n-octyl Phthalate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-not-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
•110*-
-------
DI-n-OCTYL PHTHALATE
Summary
Di-n-octyl phthalate has produced teratogenic effects following
i.p. injection, of pregnant rats. This same study has also indicated
some increased resorptions and fetal toxicity.
Evidence is not available indicating mutagenic or carcinogenic
effects of di-n-octyl phthalate.
Data pertaining to the aquatic toxicity of di-n-octyl phthalate
is not available.
-no *-
-------
DI-n-OCTYL PHTHALATE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Phthalate Esters (U.S. EPA, 1979a).
Di-n-octyl phthalate (DOP) is a diester of the ortho form of
benzene dicarboxylic acid. The compound has a molecular weight of
391.0, specific gravity of 0.978, boiling point of 220°C at 5 mm Hg,
and is insoluble in water.
DOP is used as a plasticizer in the production of certain plastics.
Current Production: 5.8 x 1fl3 tons/year in 1977 (U.S. EPA, 1979a).
Phthalates have been detected in soil, air, and water samples; in
animal and human tissues, and in certain vegetation. Evidence from in
vitro studies indicates that certain bacterial flora may be capable of
metabolizing DOP to the monoester form (Engelhardt, st al. 1975). For
additional information regarding the phthalate esters in general, the
reader is referred to the EPA/ECAO Hazard Profile on Phthalate Esters
"(U.S. EPA 1979b).
II. EXPOSURE
Phthalate esters appear in all areas of the environment. Environmental
release of phthalates may occur through leaching of the compound from
plastics, volatilization from plastics, or the incineration of plastic
items. Sources of human exposure to phthalates include contaminated
foods and fish, dermal application, and parenteral administration by
use of plastic blood bags, tubings, and infusion devices (mainly DEHP
release). Relevant factors in the migration of phthalate esters from
»
packaging materials to food and beverages are: temperature, surface
area contact, lipoidal nature of the food, and length of contact (U.S.
EPA, 1979a).
-1/6 >'
-------
Monitoring studies have indicated that most water phthalate concentrations
are in the ppm range, or 1-2 jug/liter (U.S. EPA, 1979a). Industrial
air monitoring studies have measured air levels of phthalates from 1.7
to 56 mg/m3 (Milkov, et al. 1973).
Information on levels of OOP in foods is not available. Bio-
concentration factor is not available for DOP.
III. PHARMACOKINETICS
Specific information could not be located on the absorption,
distribution, metabolism, or excretion of DOP. The reader is referred
to 'a general coverage of phthalate metabolism (U.S. EPA, 1979b).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature. ^
B. Mutagenicity
Pertinent data could not be located in the available literature.
C. Teratogenicity
Administration of DOP to pregnant rats by i.p. injection has
been reported to produce some teratogenic effects, although less so
than several other phthalates tested (Singh, et al. 1972).
D. Other Reproductive Effects
An increased incidence of resorption and fetal toxicity was
produced following i.p. injection of pregnant rats with DOP (Singh, et
al. 1972).
E. Chronic Toxicity
•
Pertinent data could not be located in the available literature.
-//of-
-------
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by O.S.
EPA (1979a), which are summarized below, have gone through the process
of public review; therefore, there is a possibility that these criteria
will be changed.
A. Human
Pertinent data concerning the acceptable daily intake
(ADI) level in humans of DOP could not be located in the available
literature.
Recommended water quality criterion level for protection
of human health is not available for DOP.
B. Aquatic
Pertinent data is not available pertaining to the aquatic
toxicity of di-n-octyl phthalate; therefore, no criterion could be
drafted.
-110?-
-------
DI-N-OCTYL PHTHALATE
. REFERENCES
Engelhardt, G., et al. 1975. The microbial metabolism of di-n-butyl phtha-
late and related dialkyl phthalates. Bull. Environ. Contam. Toxicol.
13: 342.
Milkov, L.E., et al. 1973. Health status of workers exposed to phthalate
plasticizers in the manufacture of artificial leather and films based on PVC
resins. Environ. Health Perspect. (Jan.): 175.
Singh, A.R., et al. 1972. Teratogenicity of phthalate esters in rats.
Jour. Pharm. Sci. 61: 51.
U.S. EPA. 1979a. Phthalate Esters: Ambient Water Quality Criteria. (Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Phthalate
Esters: Hazard Profile. (Draft)
-mo-
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No. 96
1,2-Diphenylhydrazine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (GAG) has evaluated
1,2-diphenylhydrazine and has found sufficient evidence to
indicate that this compound is carcinogenic.
-1)13-
-------
1,2-DIPHENYLHYDRAZINE
Summary
The adverse effects of exposure to 1,2-diphenylhydrazine in-
clude damage to both the kidney and liver. Acute LD,-Q values have
ranged from 300 to 960 mg/kg in experimentally dosed rats. No data
concerning the absorption, distribution, or excretion of the 1,2-
diphenylhydrazine have been generated. Benzidine has been identi-
fied as a metabolite in urine of rats exposed to the chemical.
Diphenylhydrazine is carcinogenic in both sexes of rats and in fe-
male mice.
The only aquatic toxicity data for diphenylhydrazine are for
freshwater organisms. Acute toxicity levels of 270 and 4,100 ug/1,
were reported for bluegill and Daphnia magna^ respectively, and a
single chronic value of 251 ^ig/1 was reported for Daphnia magna.
-------
1,2-DIPHENYLHYDRAZINE
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality
Criteria Document for Diphenylhydrazine.
Diphenylhydrazine (DPH) has a molecular weight of 184.24, a
melting point of 131°C and a boiling point of 220°C. DPH is slight-
ly soluble in water and is very soluble in benzene, ether and
alcohol.
The symmetrical isomer of diphenylhydrazine, 1,2-diphenyl-
hydrazine is used in the synthesis of benzidine for use in dyes,
and in the synthesis of phenylbutazone, an anti-arthritic drug.
The reported commercial production of more than 1000 pounds
annually, as of 1977, is most Irkely an underestimation of the
total amount of diphenylhydrazine available. Diphenylhydrazine i*s
produced in several synthetic processes as an intermediate and a
contaminant, but there is no way of estimating these substantial
quantities.
II. EXPOSURE
A. Water
The highest reported concentration of 1,2-diphenylhydra-
zine in drinking water is one ug/1 (U.S. EPA, 1975).
B. Pood
The U.S. EPA (1979).has estimated the weighted average
bioconcentration factor for diphenylhydrazine to be 29 for the
*•
edible portions of fish and shellfish consumed by Americans. This
estimate is based on the octanol/water partition coefficient of
diphenylhydrazine.
-------
C. Inhalation
Pertinent data could not be located in the available
literature.
III. PHARMACOKINETICS
Pertinent information could not be located in the available
literature regarding absorption, distribution and excretion.
A. Metabolism
Various metabolites, including the known carcinogen ben-
zidine, have been identified in the urine of rats. 1,2-Diphenylhy-
drazine was administered orally (200,400 rag/kg), intraperitoneally
(200 mg/kg), intratracheally (5,10 mg/kg) and intravenously (4,8
mg/kg). The metabolites detected were not dependent upon the base
or route of administration (Williams, 1959). 4
IV. EFFECTS
A. Carcinogenicity
Diphenylhydrazine has been identified as producing
significant increases in hepatocellular carcinoma at 5 ug/kg/day
and 18.8 pg/kg/day in both sexes of rats; Zymbal's gland squamous-
cell tumors in male rats at 18.8 jjg/kg/day; neoplastic liver
nodules in female rates at 7.5 jag/kg/day; and hepatocellular
carcinomas in female mice at 3.75 pg/kg/day (NCI, 1978). Diphenyl-
hydrazine was not carcinogenic in male mice.
B. Mutagenicity
No microbial mutagenetic assays with'or without metabolic
activation have been conducted on diphenylhydrazine. An intraperi-
»
toneal dose of 100 mg/kg had an inhibitory effect on the incorpora-
tion of (JH)-thymidine into testicular DNA of experimental mice
(Sieler, 1977).
-------
C. Teratogenicity
Pertinent information could not be located in the avail-
able literature.
D. Toxicity
One study reported an LDcQ of 959 mg/kg for male rats ad-
ministered DPH as a five percent solution. In the Registry of
Toxic Effects of Chemical Substances, the oral LD,-Q is listed as
301 mg/kg. Neoplasms resulted in rats after 52 weeks with a total
dose of 16 g/kg DPH administered subcutaneously . In 2 mice
studies, neoplasms resulted after 25 weeks with topical application
of 5280 mg/kg and after 38 weeks with subcutaneous injection of
8400 mg/kg DPH. Liver and kidney damage have been implicated in
the adverse effects of diphenylhydrazine chronically administered
to rats. No experimental or epidemiological studies have been con-
ducted on the effects of diphenylhydrazine in humans.
V. AQUATIC TOXICITY
A. Acute
Ninety-six-hour LC5Q values for freshwater organisms
have been reported as 270 jjg/1 for the bluegill, Lepomis macro-
chirus, and the 48-hour kCcn for the cladoceran, Daphnia magna,
is 4,100 pg/1 (U.S. EPA, 1978). No toxicity data for marine
.animals could be located in the available literature.
B. Chronic
A chronic value of 251 /ig/1 has be'en obtained for the
freshwater cladoceran, Daphnia Magna (U.S. EPA, 1978). No chronic
•
tests of diphenylhydrazine are available for marine organisms.
-I//7
-------
C. Plants
Pertinent data could not be located in the available
literature.
D. Residues
Based on the octanol/water partition coefficient of 870
for 1,2-diphenylhydrazine, a bioconcentration factor of 100 has
been estimated for aquatic organisms with a lipid content of 8 per-
cent.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by
.U.S. EPA (1979), which are summarized below have gone through
the process of public review; therefore, there is a possibility
that these criteria may be changed.
A. Humans
No standards were found for humans exposed.to diphenylhy-
drazine in occupational or ambient settings.
Recommended draft criteria for the protection. of human
health are as follows:
Exposure Assumptions Risk Levels and Corresponding Criteria
0 1£~7 ICT6 1£~5
2 liters of drinking water 0 4 ng/1 40 ng/1 400 ng/1
and consumption of 18.7
grams fish and shellfish. (2)
Consumption of fish and O .019 pg/1 0;'19 jag 1.9
shellfish only.
-------
B. Aquatic
Criterion to protect freshwater aquatic life from toxic
effects of diphenylhydrazine have been drafted as a 24-hour aver-
age concentration of 17 ug/1 and not to exceed 38 pg/1 at any
time.
-------
DIPHENYLHYDRAZINE
REFERENCES
NCI Publication NO. (NIH) 78-1342. 1978. Bioassay of hydrazoben-
zene for possible carcinogenicity.
Sieler, J.P. 1977. Inhibition of testicular DNA synthesis by
chemical mutagens and carcinogens. Preliminary results in the
validation of a novel short term test. Mutat. Res. 46: 305.
U.S. EPA. 1975. Primary assessment of suspected carcinogens
in drinking water. Report to Congress.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-4646.
U.S. EPA. 1979. Diphenylhydrazine: Ambient Water Quality Cri-
teria. (Draft).
Williams, R. 1959. Detoxication Mechanisms. New York: John
Wiley and Sons. p. 480.
-------
No. 97
Disulfoton
He& ) and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
-------
DISULFOTQN
Summary
Oisulfoton is a highly toxic organophosphorous insecticide used on many
agricultural crops. The human oral I_DLQ is estimated at 5 mg/kg boay
weight. Exposure results in central, nervous system toxicity. The LD5Q
for several animal species ranges from 3.2 to 6 mg/kg. Carcinogenic, muta-
genic, and teratogenic studies were not found in the available literature.
The occupational threshold limit value for disulfoton is 10 ug/m^. Allow-
able residue tolerances for agricultural commodities range from 0.3 to 11.0
ppm.
Although disulfoton is considered toxic to aquatic organisms, specific
studies on aquatic toxicity were not located in the available literature.
X
-------
I. INTRODUCTION
Disulfoton is a -highly toxic organophosphorous insecticide used in
agriculture to control mainly sucking insects such as aphids and plantfeed-
ing mites. Small amounts are used on home plants and. gardens in the form of
dry granules with low content of active ingredient (U.S. EPA, 1974). Disul-
foton was introduced in 1956 by Bayer Leverkusen (Martin and Worthing,
1974), and today it is produced by only one U.S. manufacturer, Mobay Chemi-
cal Corporation, at its Chemogro Agricultural Division in Kansas City, Mis-
souri (Stanford Research Institute (SRI), 1977). An estimated 4500 tonnes
were produced in 1974 (SRI, 1977). Disulfoton is made by interaction of
0,0-diethyl hydrogen phosphorodithioate and 2-(2-ethylthio)ethylchloride
(Martin and Worthing, 1974). Oisulfoton is slightly soluble in water and
readily soluble in most organics. Its overall degradation constant is
0.02/day. Disulfoton has a bioconcentration factor of 1.91 and an octanol/
water partition coefficient of 1.0 (see Table 1).
II. EXPOSURE
A. Water
Disulfoton concentrations are highest during the production pro-
cess. Concentrated liquid wastes are barged to sea (150-200 mi; 240-320
km), and sludge wastes are disposed in landfills.
Agricultural application rates normally range from 0.25 to 1.0
Ib/acre (0.28-1.1 kg/ha); to a maximum of 5.0 Ib/acre (5.5 kg/ha) for some
uses. Target crops include small grains, sorgum, corn, cotton, other field
crops; some.vegetable, fruit and nut crops; ornamentals (Fairchild, 1977).
Disulfoton is considered stable in groundwater. Less than 10 per-
cent is estimated to decompose in five days (equivalent to 50-250 mi; 80-400
'// 2 J-
-------
TABLE 1. PHYSICAL AND CHEMICAL PROPERTIES OF OISULFOTON
Synonyms: 0,0-Oiethyl S-(2-(ethylthio)ethyl) phosphorodithioate;
0,0-Oiethyl S-(2-(ethylthio)ethyl) dithiophosphate; Thiodemeton;
Frumin; Glebofos; Ethylthiometon B; VUAgT 1964; Di-Syston G;
Disipton; ENJ-23437; Ethyl thiometon; VUAgT 1-4; Bay 19639; M 74
[pesticide]; Ekatin TO; CAS Reg. No. 298-04-4; M 74 (VAN); Bayer
19639; Di-Syston; Dithiodemeton; Dithiosystox; Solvirex; Frumin
AL; Frumin G
Structural Formula:
Molecular Weight: 274.4
Description: Colorless oil; technical product is a dark yellowish oil;
readily soluble in most organics
Specific Gravity and/or Density: d^ = 1.144
Melting and/or Boiling Points: bp 62OQ at 0.01 mm Hg
Stability: Relatively stable to hydrolysis at pH below 8
Overall degradation rate constant (0.02/day)
Solubility (water): 25 ppm at room temp.
sediment . .5
H20 ' 1
Vapor Pressure: 1.8 x 10-4 mm Hg at 20°C
Bioconcentration Factor (BCF) and/or
Octanol/water partition coefficient .(Kow): «0w = 1-91
BCF = 1.0
Source: Martin and Worthing, 1974; FairchiJrd, 1977; Windholz, 1976;
U.S. EPA, 1980; Berg, et al. 1977.
-------
km) in a river environment. Decomposition in a lake environment is estimat-
.ad to be near 90 percent in one year (U.S. EPA 1980).
8. Food
In a study by Van Dyk and Krause (1978), disulfoton was applied as
a granular formulation at 2 g/m length in rows during cabbage planting (5
percent active ingredients, rows one meter apart, plants 0.5 meters apart).
The disulfoton sulphone concentration reached a maximum in 18 to 32 days and
decreased to between 0.3 and 6.4 mg/kg 52 riays after application. The cab-
bage residue of disulfoton at harvest time was below the maximum limit of
0.5 mg/kg.
Disulfoton applied at about 1.5 kg/10 cm-ha (hectare slice) per-
sisted for the first week, and residue levels declined slowly the following
week. After one month, only 20 percent of the amount applied was found.
Disulfoton was not found to translocate into edible parts of lettuce,
onions, and carrots (less than 5 ppb), but was present at about 20 ppb in
the root system of lettuce (Belanger and Hamilton, 1979).
C. Inhalation and Dermal
Data are not available indicating the number of people subject to
inhalation or dermal exposure to disulfoton. The primary human exposure
would appear to occur during production and application. The U.S. EPA
(1976). listed the frequency of illness, by occupational groups caused by
exposure to organophosphorous pesticides. In 1157 reported cases, most ill-
nesses occurred among ground applicators (229) and mixer/loaders (142); the
lack of or refusal to use safety equipment, was a major factor of this con-
tamination. Other groups affected were gardeners (101), field workers ex-
posed to pesticide residues (117), nursery and greenhouse workers (75), soil
»
fumigators in agriculture (29), equipment cleaners and mechanics (28), trac-
-------
tor drivers and irrigators (23), workers exposed to pesticide drift (22),
pilots (crop dusters) (17), and flaggers for aerial application (6). Most
illnesses were a result of carelessness, lack of knowledge of the hazards,
and/or lack of safety equipment, under dry, hot conditions, workers tended
not to wear protective clothing. Such conditions also tended to increase
pesticide levels and dust on the crops.
III. PHARMACOKINETICS
A. Absorption, Distribution, and Excretion
Pertinent data could not be located in the available literature.
B. Metabolism
Disulfpton is metabolized in plants to sulfoxide and sulfone and
the corresponding derivatives of the phosphorothioate and demeton-S. This
is also the probable route in animals (Martin and Worthing, 1974; Menzie
1974; Fairchild, 1977).
IV. EFFECTS
A. Carcinogenic!ty, Mutagenicity and Teratogenicity
Pertinent data could not be located in the available literature.
8. Chronic Toxicity and Other Relevant Information
Disulfoton is highly toxic to all terrestrial and aquatic fauna.
Human oral LDLo is estimated to be 5 mg disulfoton per kilogram body
weight (5 mg/kg). The symptoms produced by sublethal doses are typical of
central and peripheral nervous-system toxicity (Gleason, et al. 1969). The
reported LD5Q concentrations for other species are summarized below (Fair-
child, 1977).
-------
Species Exposure Route LD5Q (mg/}
-------
Both tests were conducted at 25°C. The corresponding value for bluegilis
is estimated to be 0.07 mg/1 (McKee and Wolf, 1963).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The occupational threshold limit value for air has been estab-
lished as 100 jug/m3. Established residue tolerance for crops range from
0.3 to 12.0 ppm; 0.75 ppm for most (Fairchild, 1977).
8. Aquatic
Pertinent data could not be located in the available literature.
1)30
-------
REFERENCES
Belanger, A. and H.A. Hamilton. 1979. Determination of disulfoton and per-
methrin residues in an organic soil and their translocation into lettuce,
onion and carrot. Jour. Environ. Sci. Health. B14: 213.
Berg, G.L., et al. (ed.) 1977. Farm Chemicals Handbook. Meister Publish-
ing Company, Willoughby, Ohio.
Fairchild, E.J., (ed.) 1977. Agricultural chemicals and pesticides: A
subfile of the NIOSH registry of toxic effects of chemical substances, U.S.
Dept. of HEW, July.
Gleason, M.N., et al. 1969. Clinical Toxicology of Commercial Products.
Acute Poisoning, 3rd ed.
Gopal, P.K. and S.P. Ahuja. 1979. Lipid and growth changes in organs of
chicks Gallus domesticus during acute and chronic toxicity with disystbn and
folithion.
Holt, T.M. and R.K. Hawkins. 1978. Rat hippocompel norepinephrine re., ,,Ase
to cholinesterase inhibition. Res. Commun. Chem. Pathol. Pharmacol 20: 239.
Martin and Worthing, (ed.) 1974. Pesticide Manual, 4th ed. p. 225
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria. 2nd ed. Cali-
fornia State Water Quality Control Board. Publication 3-A.
Menzie, C.M. 1974. Metabolism of Pesticides: An Update. U.S. Dept. ^ Ythe
Interior Special Scientific Report — Wildlife No. 184, Washington, D.C."
Stanford Research Institute. 1977. Directory of Chemical Producers. Jnlo
Park, California.
Tiwari, J.K., et al. 1977. Effects of insecticides on microbial flora of
groundnut field soil. Ind. Jour. Micro. 17: 208.
U.S. EPA. 1974. Production, Distribution, Use, and Environmental Impact
Potential of Selected Pesticides. .Report No. EPA 540/1-74-001. U.S. Envi-
ronmental Protection Agency, Office of Water and Hazardous Materials, Office
of Pesticide Programs.
U.S. EPA. 1976. Organophosphate Exposure from Agricultural Usage, EPA 6007
1-76-025.
U.S. EPA. 1980. Aquatic Fate and Transport Estimates for Hazardous Chemi-
cal Exposure Assessments. Environmental Research Laboratory, Athens', Geor-
gia-
Van Dyk, L.P. and M. Krause 1978. Persistence and efficacy of disulfoton
on Cabbages. Phytophylactica 10: 53.
Windholz, M., (ed.) 1976. The Merck Index, 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
7/3 A
-------
No. 98
Endosulfan
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
ENDOSULFAN
Summary
Endosulfan is an insecticide and is a member of the organochlorocyclo-
diene insecticides. Endosulfan does not appear to be carcinogenic, mutagen-
ic or teratogenic. In humans, chronic toxic effects have not been observed
when endosulfan has been properly handled occupationally. Chronic feeding
of endosulfan to rats and mice produced kidney damage, parathyroid hyperpla-
sia, testicular atrophy, hydropic change of the liver, and lowered survival.
Oral administration of endosulfan to pregnant rats increased fetal mortality
and resorpticns. Sterility can be induced in embryos in sprayed bird eggs.
At very high levels of acute exposure, endosulfan is toxic to the central
nervous system. The U.S. EPA has calculated an ADI of 0.28 mg based on a
NOAEL of 0.4 mg/kg for mice in a chronic feeding study. The ADI established
by the Food and Agricultural Organization (1975) and World Health Organiza-
tion is 0.0075 mg/kg.
Ninety-six hour LC5Q values ranged from 0.3 to 11.0 jug/1 for five
freshwater fish; from 0.09 to 0.6 ;jg/l for five saltwater fish in 48- or 96-
hour tests; from 0.04 to 380 jug/1 (EC50 and LC5n) for seven saltwater
invertebrate species; and from 62 to 166 pg/1 for Daphnia magna (48-hour
LCcg). In the only chronic aquatic study involving endosulfan, no adverse
effects on fathead minnows were observed at 0.20 jug/1.
•1131-
-------
I. INTRODUCTION
Entiosulfan (6,7,3,9,10,10-hexachloro-l,5,5a,6,9,9a-hexahydro-6,9-
methano-2,4,3-benzodioxathiepin-3-oxide; C^ClgHgO-jS; molecular
weight 406.95) is a light to dark brown crystalline solid with a terpene-
like odor. Endosulfan is a broad spectrum insecticide of the group of poly-
cyclic chlorinated hydrocarbons called cyclodiene insecticides. It also has
uses as an acaricite. It has a vapor pressure of 9 x 10" mm Hg at 80
degrees centigrade. It exhibits a solubility in water of 60 to 150 jug/1 and
is readily soluble in organic solvents (U.S. EPA, 1979). The trade names of
endosulfan include Beosit, Chlorithiepin, Cyclodan, Insectophene , Kop-Thio-
dan, Malix, Thifor, Thisnuml, Thioden, and Thionex (Berg, 1976).
Technical grade endosulfan has a purity of 95 percent and is composed
of a mixture of two stereoisomers referred to as alpha-endosulfan and beta-
endosulfan or I and II. These isomers are present in- a ratio of 70 parts
alpha-endosulfan to 30 parts beta-endosulfan. Impurities consist mainly of
the degradation products and may not exceed 2 percent endosulfandiol and 1
percent endosulfan ether (U.S. EPA, 1979).
Production: three million pounds, in 1974 (U.S. EPA, 1979).
Endosulfan is presently on the Environmental Protection Agency's re-
stricted list. However, significant commercial use for insect control on
vegetables, fruits, and tobacco continues (U.S. EPA, 1979).
Endosulfan is stable to sunlight but is susceptible to oxidation and
the formation of endosulfan sulfate in the presence of growing vegetation
s
(Cassil and Drumrcbnd, 1965). Endosulfan is readily adsorbed and absorbed by
sediments (U.S. EPA, 1979). It is metabolically converted by microorgan-
isms, plants, and animals to endosulfan sulfate, endosulfandiol, endosulfan
ether, endosulfan hydroxyether and endosulfan lactone (Martens, 1976; Chopra
-1/3
-------
and Mahfouz, 1977; Gorbach, et al. 1968; Miles and Moy, 1979). The end-pro-
duct, endosulfan lactone, disappears quickly once formed. Accumulation of
endosulfan sulfate may be favored in acidic soils (Miles and Moy, 1979).
II. EXPOSURE
A. Water
Endosulfan has been detected in water samples from some of the
streams, rivers, and lakes in the United States and Canada and in Ontario
municipal water supplies. The maximum concentration of endosulfan monitored
in municipal water was 0.083 ^ig/1, which was found in Ontario municipal
water samples but 68 jug/1 has been measured in irrigation run-off (U.S. EPA,
1979). Endosulfan contamination of water results from agricultural runoff,
industrial effluents, and spills. One serious accidental industrial dis-
charge in Germany in 1969 caused a massive fishkill in the Rhine River.
Most of the river water samples contained less than 500 ng/1 endosulfan.
Residues in run-off water from sprayed fields can be as high as 220 jug/1
(U.S. EPA, 1979).
B. Food
An average daily intake (ADI) less than or equal to 0.001 mg of
endosulfan and endosulfan sulfate was estimated for 1965-1970 from the mar-
ket basket study of the FDA (Duggan and Corneliussen, 1972). The U.S. EPA
(1979) has estimated the weighted average bioconcentration factor for endo-
sulfan to be 28 .for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on measured steady-state bioconcentration
studies with mussels. The processing of leafy vegetables causes endosulfan
residues to decline from 11 jug/kg to 6 pg/kg (Corneliussen, 1970).
7
-------
C. Inhalation
In 1970, air samples from 16 states showed an average level of 13.0
ng/m alpha-endosulfan and 0.2 ng/m beta-endosulfan. None of the air
samples collected in 1971 or 1972 contained detectable levels of either iso-
mer (Lee, 1976). Endosulfan residues (endosulfan and endosulfan sulfate)
have been detected in most types of U.S. tobacco products in recent years
(U.S. EPA, 1979). Average residue levels range from 0.12 rag/kg to 0.83
mg/kg for 1971-1973 (Domanski, et al. 1973,1974; Oorough and Gibson, 1972).
The extent to which endosulfan residues in tobacco products contribute to
human exposure is not known. Spray operators can be exposed up to 50
Lig/hour of endosulfan .from a usual application of a 0.08 percent spray
(Wolfe, et al. 1972). Non-target deposition on untreated plants after
spraying may lead to residues of up to 679 ;jg/kg (Keil, 1972).
0. Dermal
Wolfe, et al. (1972) estimated that sprayers applying a 0.08 per-
cent aqueous solution are exposed dermally to 0.6 to 98.3 mg/hour. Endosul-
fan can persist on the hands for 1 to 112 days after exposure (Kazen, et al.
1974).
III. PHARMACOKINETICS
A. Absorption
Undiluted endosulfan is slowly and incompletely absorbed from the
mammalian gastointestinal tract, whereas endosulfan dissolved in cottonseed
oil is readily though not completely absorbed (Boyd and Oobos, 1969; Maier-
-•
Bode, 1968). The beta-isomer is more readily absorbed than the alphaisomer.
Alcohols, oils, and emulsifiers accelerate the absorption of endosulfan by
the skin (Maier-Sode, 1968). Inhalation is not considered to be an impor-
tant route.of absorption for endosulfan except in spray operators (U.S. EPA,
1979).
-------
8. Distribution
After ingestion by experimental animals, endosulfan is first dis-
tributed to the liver and then to the other organs of the body and the- re-
mainder of the gastrointestinal tract (Boyd and Dobos, 1969; Maier-Sode,
1968). In cats, endosulfan levels peaked in brain, liver, spinal cord and
plasma, with the brain and liver retaining the highest concentrations after
administration of a 3 mg/kg dose (Khanna, et al. 1979).
In mice, 24 hours after oral administration of C-endosulfan,
residues were detected in fat, liver, kidney, brain, and blood (Deema, et
al. 1966).
Data from autopsies of three suicides show levels of endosulfan in
brain which were much lower than those in liver and kidney, which in turn,
were lower than levels in blood (Coutselinis, et al. 1978). Data from an-
other suicide indicate higher levels of endosulfan in liver and kidneys than
in blood (Demeter, et al. 1977).
Ci Metabolism
Endosulfan sulfate is the metabolite most commonly present in tis-
sues, feces, and milk of mammals after administration of endosulfan (Whit-
acre, 1970; Demma, et al. 1966; FMC, 1963). The largest amounts of endosul-
fan sulfate are found in small intestine and visceral fat with only traces
in skeletal muscle and kidney (Deema, et al. 1966). Endosulfan sulfate has
been detected in the brains of two humans who committed suicide by ingesting
endosulfan (Demeter and Heyndrickx, 1978), but not in the brains of mice
given nonfatal doses of endosulfan. However, it has been detected in liver,
visceral fat and small intestines of mice (Deema, et al. 1966). Other meta-
bolites of endosulfan are endosulfan lactone, endosulfandiol, endosulfan hy-
droxyether, and endosulfan ether (Knowles, 1974; Menzie, 1974). These meta-
bolites have also been found in microorganisms and plants (U.S. EPA, 1979).
-------
D. Excretion
The principal route of excretion for endosulfan and endosulfan sul-
fate is in the feces (U.S. EPA, 1979). Other metabolites are also excreted
in the feces and to a small extent in the urine, the metabolites in the lat-
ter being mainly in the form of endosulfan alcohol (U.S. EPA, 1979). In
studies with sheep receiving a single oral dose of radiolabeled endosulfan,
92 percent of the dose was eliminated in 22 days. The organ with the high-
est concentration of radiolabeled endosulfan after 40 days was the liver.
Major metabolites did not persist in the fat or in the organs (Gorbach, et
al. 1968). After a single oral dose, the half-life of radiolabeled endosul-
fan in the feces and urine of sheep was approximately two days (Kloss, et
al. 1966). Following 14 days of dietary exposure of female rats, the half-
life of endosulfan residues was approximately seven days (Dorough, et al. .-
1978).
IV. EFFECTS
A. Carcinogenicity
In bioassays on both mice and rats, orally administered endosulfan
was not carcinogenic even though doses were high enough to produce symptoms
of toxicity (Kotin, et al. 1968; Innes, et al. 1969; Weisburger, et al.
1978).
8. Mutagenicity
Data from assays with Salmonella typhimurium (with and without mi-
crosomal activation) (Oorough, et al. 1978), Saccharomyces cerevisiae, Esch-
*
ericia coli, and Serratia marcescens (Fahrig, 1974) indicate that endosulfan
is not mutagenic.
•11.31-
-------
C. Teratogenicity
Endosulfan did not produce teratogenic effects in rats (Gupta,
1978).
0. Other Reproductive Effects
In rats, endosulfan produced dose-related increases in maternal
toxicity and. caused increases in fetal mortality and. resorptions (Gupta,
1978). Doses of 100 mg/kg reduce hatchability of fertile white leghorn
chicken eggs by 54 percent, but this was dependent on carrier (Dunachie and
Fletcher, 1969). Alterations in the gonads of the embryos within sprayed
hens' eggs were noted and the progeny of hens and quails, Coturnix Coturnix
japonica, were sterile (U.S. EPA, 1979).
E. Chronic Toxicity
In the NCI bioassays (Xotin, et al. 1968; Weisberger, et-al. 1978) ^
.endosulfan was toxic to the kidneys of rats of both sexes, and to the kid-
neys of male mice. Other signs of toxicity were parathyroid hyperplasia,
testicular atrophy in male rats, and high early death rates in male mice.
In a two-year feeding study with rats. (Hazelton Laboratories,
1959), endosulfan at 10 mg/kg diet reduced testis weight in males and low-
ered survival in females; at 100 mg/kg diet, renal tubular damage and some
hydropic changes in the liver were induced.
In humans, there has been an absence of toxic effects with proper
handling of endosulfan in the occupational setting (Hoechst, 1966).
F. Other Relevant Information
The acute toxicity of endosulfan sulfate is -'about the same as that
of endosulfan. The I_D5Q for technical endosulfan in rats is -— 22 to 46
mg/kg and 6.9 to 7.5 mg/kg in mice (Gupta, 1976). Reagent grade a- and J3-
endosulfan are less toxic to rats (76 and 240 mg/kg, respectively; Hoechst,
-------
1967). The inhalation 4-hour LC5Q values for rats have been reported as
350 and 80 ug/1 for males and females, respectively (Ely, et al. 1967).
Acute toxicities of other metabolites (endosulfan lactone, endosulfandiol,
endosulfan hydroxyether and endosulfan ether) are less than that of the
parent compound (Dorough, et al. 1978).
At very high levels of acute exposure, endosulfan is toxic to the
central nervous system (U.S. EPA, 1979). Endosulfan is a convulsant and
causes fainting, tremors, mental confusion, irritability, difficulty in uri-
nation, loss of memory and impairment of visual-motor coordination. Acute
intoxification can be relieved by diazepam but chronic effects are manifest-
ed in central nervous system disorders (Aleksandrowicz, 1979).
There appear to be sex differences (see previous Chronic Toxicity
section) and species differences in sensitivity to endosulfan. Of the spe- ."
pies tested with endosulfan, cattle are the most sensitive to the neurotoxic
effects of endosulfan and appear to be closer in sensitivity to humans.
Dermal toxicity of endosulfan-sprayed cattle is also high. Typical symptoms
are listlessness, blind staggers, restlessness, hyperexcitability, muscular
spasms, goose-stepping and convulsions (U.S. EPA, 1979).
Endosulfan is a nonspecific inducer of drug metabolizing enzymes
(Agarwal, et al. 1978). Protein deficient rats are somewhat more suscepti-
ble to the toxic effects of endosulfan than controls (Boyd and Oobos, 1969;
Boyd, et al. 1970).
V. AQUATIC TOXICITY
A. Acute Toxicity
Ninety-six hour LC5Q values, using technical grade endosulfan,
for five species of freshwater fish range from 0.3 jjg/1 for the rainbow
trout, Salmo gairdneri, (Macek, et al. 1969) to 11.0 ug/1 for carp finger-
-------
lings, Cyprlnus carpio (Macek, et al. 1969; Schoettger, 1970; Ludemann and
Neumann, 1960; Pickering and Henderson, 1966). Among freshwater inverte-
brates, Daphnia maqna is reported to have 48-hour LC5Q values ranging from
62 to 166 ug/1 (Macek, et al. 1976; Schoettger, 1970), with three other in-
vertebrates yielding 96-hour LC5Q values of 2.3 (Sanders and Cope, 1968)
to 107 jjg/1 (Sanders, 1969; Schoettger, 1970). Levels of 400 and 800 ng/1
of technical endosulfan damaged the kidney, liver, stomach and intestine of
Gymonocorymbus ternetzi . The 96-hour LC5Q value was 1.6 ;jg/l (Amminikutty
and Rege, 1977,1978).
Of the five saltwater fish species tested, the reported 48- or 96-
hour LC5Q values ranged from 0.09 (Schimmel, et al. 1977) to 0.6 jjg/1
(Butler, 1963,1964; Kom and Earnest, 1974; Schimmel, et al. 1977). The
: " j
most sensitive species was the spot (Leiostomus xanthurus ) .
The seven saltwater invertebrate species tested showed a wide range
of sensitivity to endosulfan. The range of EC5Q and LC50 values is from
0.04 (Schimmel, et al. 1977) to 380 jug/1 with the most sensitive species be-
ing the pink shrimp (Penaeus duorarum) .
8. Chronic Toxj "ty
.Macek, et al. (1976) provided the only aquatic chronic study in-
volving endosulfan. .No adverse effects on fathead minnow, Pimephales prome-
las, parents or offspring were observed at 0.20 Jug/1. Gymonocorymbus ter-
netzi chronically exposed to 400 and 530 ng/1 for 16 weeks evinced necrosis
of intestinal mucosa cells, ruptured hepatic cells and destruction of pan-
creatic islet cells (Amminikutty and Rege, 1977,1978).
C. Plant Effects
»
Little data is available concerning the effects of endosulfan on
aquatic micro/macrophy tes . Growth of Chlorella vulqaris was inhibited
>2000jug/l (Knauf and Schulze, 1973).
-//*-
-------
D. Residues
Schimmel, et al. (1977) studied the uptake, depuration, and metabo-
lism of endosulfan by the striped mullet, Mugil ceohalus. When the concen-
trations of endosulfans I and II and endosulfan sulfate were combined to
determine the bioconcentration factor (BCF), an average whole-body BCF of
1,597 was obtained. Nearly all the endosulfan was in the form of the sul-
fate. Even though the duration of the study was 28 days, this investigator
questioned whether a steady-state condition was reached. Complete depura-
tion occurred in just two days in an endosulfan-free environment. Residues
in pond sediments may be as high as 50 pg/kg 8-endosulfan and 70 ;jg/kg of
endosulfan sulfate 280 days after insecticidal endosulfan application (FMC,
1971).
Dislodgable residues on cotton foliage in Arizona declined to 10
percent and one-third for the low-melting and high-melting isomers, respec-
tively, 24 hours after application of 1.1 kg/ha endosulfan. However, though
residues had declined to 4 percent and 11 percent respectively, 4 days after
application endosulfan sulfate residues on the leaves increased markedly to
0.14 jjg/cm2 (Estesen, 1979).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic, criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
The U.S. EPA (1979) has recommended a draft criterion for endosul-
fan in ambient water of 0.1 mg/1 based on an ADI of 0.28 ing/day. This ADI
was calculated from a NOAEL of 0.4 mg/kg obtained for mice in a chronic
feeding study (Weisburger, et al. 1978) and an uncertainty factor of 100.
-///.?-
-------
The American Conference of Governmental Industrial Hygienists
(ACGIH, 1977) TLV time weighted average for endosulfan is 0.1 mg/m . The
tentative value for the TLV short-term exposure limit (15 minutes) is 0.3
mg/m"5.
The ADI for endosulfan established by the Food and Agricultural
Organization and the World Health Organization is 7.5 ug/kg (FAQ, 1975).
8. Aquatic
For endosulfan, the draft criterion to protect freshwater aquatic
life is 0.042 ug/1 in. a 24-hour average and not to exceed 0.49 /jg/1 at .any
time. Saltwater criteria cannot be developed because of insufficient data
(U.S. EPA, 1979).
-1111-
-------
ENDOSULFAN
REFERENCES
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agents.in the workroom environment with intended changes for 1977. 1977 TLV
Ariborne Contaminants Committee, American Conference of Government Indus-
trial Hygienists, Cincinnati, Ohio.
Agarwal, O.K., et al. 1978. Effect of endosulfan on drug metabolizing en-
zymes and lipid peroxidation in rat. Jour. Environ. Sci. Health C13: 49.
Aleksandrowicz, O.R. 1979. Endosulfan poisoning and chronic brain syn-
drome. Arch. Toxicol. 43: 65.
Amminikutty, C.K. and M.S. Rege. 1977. Effects of acute and chronic ex-
posure to pesticides, Thioden 35 E.G. and Aoallol "3" on the liver of widow
tetra (Gymonocorymbus ternetzi). Boulenger-Indiana Jour. Exp. Biol. 15: 97.
Amminikutty, C.K. and M.S. Rege. 1978. Acute and chronic effect of Thioden
35 E.G. and Aoallol "3" on kidney, stomach and intestine of the widow tetra
(Gymonocorymbus ternetzi). Boulenger-IndiaRa Jour. Exp. Biol. 16: 202.
Berg, H. 1976. Farm chemicals handbook. Meister Publishing Co.,
Willoughby, Ohio.
Boyd, E.M. and I. Dobos. 1969. Protein deficiency and tolerated oral doses
of endosulfan. Arch. Int. Pharmacodyn. 178: 152.
Boyd, E.M., et al. 1970. Endosulfan toxicity and dietary protein. Arch.
Environ. Health. 21: 15.
Butler, P.A. 1963. Commercial fisheries investigations, pesticide-wildlife
studies. A review of Fish and Wildlife Service Investigations during 1961
and 1962. U.S. Dept. Inter. Fish Wildl. Circ. 167: 11.
Butler, P.A. 1964. Pesticide-wildlife studies, 1963. A review of Fish and
Wildlife Service Investigations during the calendar year. U.S. Oept. Inter.
Fish Wildl. Circ. 199: 5.
Cassil, C.C. and P.E. Orummond. 1965. A plant surface oxidation product of
endosulfan.. Jour. Econ. Entomol.- 58: 356.
Chopra, N. and A. Mahfouz. 1977. Metabolism of endosulfan I, endosulfan
II, and endosulfan sulfate in tobacco leaf. Jour. Agric.' Food Chem. 25: 32.
Gorneliussen, P.E. 1970. Residues in food and feed: pesticide residues in
total diet samples (V). Pestic. Monit. Jour. 4: 89.
Coutselinis, A., et al. 1978. Concentration levels of endosulfan in bio-
logical material (report of three cases). Forensic Sci. 11: 75.
-------
Oeema, P., et al. 1966. Metabolism, storage, and excretion of
sulfan in the mouse. Jour. Econ. Entomol. 59: 546.
Oemeter, J. and A. Heyndrickx. 1978. Two lethal endosulfan poisonings in
man. Jour. Anal. Toxicol. 2: 68.
Demeter, J., et al. 1977. Toxicological analysis in a case of endosulfan
suicide. Bull. Environ. Contain. Toxicol. 18: 110.
Oomanski, J.J., et al. 1973. Insecticide residues on 1971 U.S. tobacoo
products. Tobacco Sci. 17: 80.
Oomanski, J.J., et al. 1974. Insecticide residues on 1973 U.S. tobacco
products. Tobacco Sci. 18: 111.
Dorough, H.w. and J.R. Givson. 1972. .Chlorinated insecticide residues in
cigarettes purchases in 1970-72. Environ. Entomol. 1: 739.
Dorough, H.W., et al. 1978. Fate of endosulfan in rats and toxicological
considerations of apolar metabolites. Pestic. Biochem. Physiol. 8: 241.
Ouggan, R..E. and P.E. Corneliussen. 1972. Dietary intake of pesticide
chemicals in the United States (III), June 1968 to April 1970. Pestic.
Monit. Jour. 5: 331.
Dunachie, J.F. and W.W. Fletcher. 1966. Effect of some insecticides on the
hatching rate of hens' eggs. Nature 212: 1062.
Ely, T.S., et al. 1967. Convulsions in Thiodan workers: a preliminary
report. Jour. Occup. Med. 9: 36.
Estesen, B.J., et al. 1979. Dislodgable insecticide residues on cotton
foliage: Permethrin, Curocron, Fenvalarate, Sulprotos, Decis and Endosulfan.
Bull. Environ. Contam. Toxicol. 22: 245.
Fahrig, R. 1974. comparative mutagenicity studies with pesticides. Int.
Agency Res. Cancer Sci. Publ. 10: 161.
FAO. 1975. Pesticide residues in food: report of the 1974 Joint Meeting of
the FAO Working Party of Experts on Pesticide Residues and the WHO Expert
Committee on Pesticide Residues. Agricultural Studies NO. 97, Food and
Agriculture Organization of the United States, Rome.
FMC Corp. 1963. Unpublished laboratory report of Niagara Chemical Divi-
sion, FMC Corporation, Middleport, New York. In: Maier-Bode, 1968.
FMC Corp. 1971. Project 015: Determination of endosulfan I, endosulfan II
and endosulfan sulfate residues in soil, pond, mud and water. Unpublished
report. Niagara Chemical Division, FMC Corp., Richmond, Cal. In: Natl.
Res. Council, Canada, 1975.
Gorbach, S.G., et al. 1968. Metabolism of endosulfan in milk sheep. Jour.
Agric. Food Chem. 16: 950.
-i in-
-------
Gupta, P.X. 1976. Endosulfan-induced neurotoxicity in rats and mice.
Bull. Environ. Contam. Toxicol. 15: 708.
Gupta, P.K. 1978. Distribution of endosulfan in plasma and brain after re-
peated oral administration to rats. Toxicology 9: 371.
Hazleton Laboratories. 1959. Unpublished report, May 22. Falls Church,
Virginia. In: ACGIH, 1971.
Hoechst. 1966. Unpublished report of Farbwerke Hoechst A.G., Frankfurt,
West Germany. In: Maier-8ode, 1968. . ....
Hoechst. 1967. Oral LD5Q values for white rats. Unpublished report of
Farbwerke Hoechst A.G., Frankfurtr, West Germany. Cited in Demeter and
Heyndrickx, 1978. Jour. Anal. Toxicol. 2: 68.
Innes, J.R.M., et al. 1969. bioassay of pesticides and industrial chem-
icals for tumorigenicity in mice: a preliminary note. Jour. Natl. Cancer
Inst. 42: 1101.
Kazen, C., et al. 1976. Persistence of pesticides on the hands of some
occupationally exposed people. Arch. Environ, health 29: 315.
Keil, J.E., et al. 1972. Decay of parathion and endosulfan residues on
field-treated tobacco, South Carolina, 1971. Pestic. Monit. Jour. 6: 73.
Khanna, R.N., et al. 1979. Distribution of endosulfan in cat brain. Bull.
Environ. Contam. Toxicol. 22: 72.
Kloss, G., et al. 1966. Versuche an Schaffen mit cl^-markierten Thiodan.
Unpublished. In: Maier-Bode, 1968.
Knaut, W. and C.F. Schulze. 1973. New findings on the toxicity of endo-
sulfan and its metabolites to aquatic organisms. Meded. Fac. Landlouwwey.
Kijksuniv. Gent. 38: 717.
Knowles, C.O. 1974. Detoxification of acaricides by animals. Pages 155-
176 In; M.A. Kahn and J.P. Sederka, Jr., eds. Survival in toxic environ-
ments. Academic Press, New York.
Korn, S., and R. Earnest. 1974. Acute toxicity of 20 insecticides to
striped bass Morone saxatilis. Calif. Fish Game 69: 128.
Kotin, P., et al. 1968. Evaluation of carcinogenic, teratogenic and muta-
genic activites of selected pesticides and industrial chemicals. Pages 64,
69 In: Vol. 1: carcinogenic study. Bionetics Research Laboratories report
to Natl. Cancer Inst. NTIS-PB-223-159.
Lee, R.L., Jr. 1976. Air pollution from pesticides and agricultural pro-
cess. CRC Press, Inc., Cleveland, Ohio.
Ludemann, 0. and H. Neumann. 1960. Versuche uber die akute toxische
Wirkung neuzeitlicher Kontaktinsektizide auf einsommerige Karfen (Cyprinum
caroio L.) Z. Angew. Zool. 47: 11.
-If1/7-
-------
Macek, K.J., et al. 1969. The effects of temperature on the susceptibility
of bluegills and rainbow trout to selected pesticides. Bull. Environ.
Contam. Toxicol. 4: 174.
Macek, K.J., et al. 1976. Toxicity of four pesticides to water fleas and
fathead minnows. EPA-600/3-76-099. U.S. Environ. Prot. Agency.
Maier-Sode, H. 1968. Properties, effect, residues and analytics of the
insecticide endosulfan (review). Residue Rev. 22: 2.
Martens, R. 1976. Degradation of (8,9,-C-14) endosulfan by soil micro-
organisms. Appl. Environ. Microbiol. 31: 853.
Menzie, C.M. 1974. Metabolism of pesticides: an update. Special scien-
tific report. Fish and Wildlife Service, Wildlife 184. U.S. Department of
Interior, Washington, D.C.
Miles, J.R.W. and P. Moy. 1979. Degradation of endosulfan and its metab-
olites' by a mixed-culture of soil microorganisms. Bull. Environ. Contam.
Toxicol. 23: 13.
Pickering, Q.H. and C. Henderson. 1966. The acute toxicity of some pesti-
cides to fish. Ohio Jour. Sci. 66: 508.
Sanders, H.O. 1969. Toxicity of pesticides to the crustacean Gammarus
lacustris. U.S. Bur. Sport Fish Wildl. Tech. Pap. 25.
Sanders, .H.O. and O.B. Cope. 1968. The relative toxicities of several
pesticides to naiads of three species of stoneflies. Limnol. Oceanogr.
. 13: 112.
Schimmel, S.C., et al. 1977. Acute toxicity to and bioconcentration of
endosulfan by estuarine animals. Aquatic toxicology and hazard evaluation.
ASTM STP 634, AM. Soc. Test. Mat.
Schoettger, R.A. 1970. Fish-pesticide research laboratory, progress in
sport fishery research. U.S. Dept. Inter. Bur. sport Fish Wildl. Resour.
Publ. 106.
U.S. EPA. 1979. Endrin: Ambient Water Quality Criteria. (Draft)
Weisburger, J.H., et al. 1978. Bioassay of endosulfan for possible car-
cinogenicity. National Cancer Institute Division of Cancer Cause and
Prevention, National Institutes of Health, Public Health Service, U.S.
Department of Health, Education and Welfare, Bethesda, Maryland, Pub.
78-1312. Report by Hazleton Laboratories to NCI, NCI-CG-TR-62. 54 pp.
Whitacre, D.M. 1970. Endosulfan metabolism in temperature-stressed rats.
Diss. Abstr. Int. 30: 44358.
Wolfe, H.R., et al. 1972. Exposure of spraymen to pesticides. Arch.
Environ. Health 25: 29.
-------
No. 99
Endrln
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal . The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
EN DRIM
SUMMARY
Endrin does not appear to be carcinogenic. Endrin is
teratogenic and embroytoxic in high doses and produces gross
chromosomal abnormalities when administered intratesticu-
larly. Chronic administration of endrin causes damage to the
liver, lung, kidney, and heart of experimental animals. No
information about chronic effects in humans is available.
The ADI established by the Food and Agricultural Organization
and World Health Organization is 0.002 mg/kg.
Endrin has proven to be extremely toxic to aquatic orga-
nisms. In general, marine fish are more sensitive to endrin
with an arithmetic mean LCgg value of 0.73 ug/1/' than
freshwater fish with an arithmetic mean LCgg value of
4.42 ug/1. Invertebrate species tend to be more resistant
than fish with arithmetic mean LCjQ values of 3.80 and
58.91 ug/1 for marine and freshwater invertebrates, respec-
tively .
'1151-
-------
ENDRIN
I. INTRODUCTION
Endrin (molecular weight 374) is a broad spectrum insec-
ticide of the group of polycyclic chlorinated cyclediene hy- .
drocarbons of which the insecticides aldrin and dieldrin are
also members. Endrin is isomeric with dieldrin and is used
as a rodenticide and ovicide. The endrin sold in the U.S. is
a technical grade product containing not less than 95 percent
active ingredient. The solubility of endrin in water at 25°C
is about 200 ug/1 (U.S. EPA, 1979). Its vapor pressure is 2
x 10~7 mm Hg at 25°C (Martin, 1971).
Endrin is used primarily as an insecticide and also as a
rodenticide and avicide. Over the past several years, endrin
utilization has been increasingly restricted (U.S. EPA, 1979.
Endrin production in 1978 was approximately 400,00.0 pounds
(U.S. EPA, 1978). Endrin persists in the soil (U.S. EPA,
1979).
II. EXPOSURE
A. Water
Occasionally, groundwater may contain more than 0.1
ug/1. Levels as high as 3 ug/1 have been correlated with
precipitation and run off following endrin applications (U.S.
EPA, 1978).
Concentrations of endrin in finished drinking water
have been decreasing. In a study of ten municipal water
»
treatment plants on the Mississippi or Missouri Rivers, the
number of finished water samples containing concentrations of
endrin exceeding 0.1 y.g/1 decreased from ten percent in 1964-
-------
1965 to zero in 1966-1967 (Schafer, et al., 1969). The high-
est concentration of endrin in drinking water in New Orleans,
Louisiana measured by the O.S. EPA in 1974 was 4 ng/1 (U.S.
EPA, 1974).
B. Food
The general population is rarely exposed to endrin
through the diet. In the market basket study by the FDA, the
total average daily intake from food ranged from approximate-
ly 0.009 ugAg body weight in 1965 to 0.0005 ugAg body
weight in 1970 (Duggan and Lipscomb, 1969; Duggan and Corne-
liussen, 1972).
The U.S. EPA (1979) has estimated the weighted av-
erage bioconcentration factor of endrin at 1,900 for the edi-
ble portions of fish and shellfish consumed by Americans.
This estimate is based on measured steady-state bioconcentra-
tion studies in six species (both freshwater and saltwater).
C. Inhalation
Exposure of the general population to endrin via
the air decreased from a maximum level of 25.6 ug/^3 in
1971 to a maximum level of 0.5 ug/m3 in 1975 (U.S. EPA,
1979).
Tobacco products are contaminated with endrin resi-
dues. Average endrin. residues for various types of tobacco
,•
products have been reported in the range of 0.05 ug/9 to 0.2
ug/g (Bowery, et al., 1959; Domanski and Guthrie, 1974).
Inhalation exposure of users and manufacturers of
endrin sprays may be around 10 ug/hour (Wolfe, et al. 1967)
but use of dusts can produce levels as high as 0.41 mg/hour
(Wolfe, et al. 1963).
-------
D. Dermal
Dermal exposure of spray operators .can range up to
3 mg/body/hour even for operators wearing standard protective
clothing (Wolfe, et al. 1963, 1967). The spraying of dusts
can lead to exposures of up to 19 mg/hour (Wolfe, et al.
1963).
III. PHARMACOKINETICS
A. Absorption
Endrin is known to be absorbed through the skin,
lungs, and gut, but data on the rates of absorption are not
available (U.S. EPA, 1979).
B. Distribution
Endrin is not stored in human tissues in signifi-
cant quantities. Residues were not detected in plasma, adi-
pose tissue, or urine of workers exposed to endrin (Hayes and
Curley, 1968). Measurable levels of endrin have not been de-
tected in human subcutaneous fat or blood, even in persons
living in areas where endrin is used extensively (U.S. EPA,
1979). Endrin residues have been detected in the body tis-
sues of humans only immediately after an acute exposure (U.S.
EPA, 1979; Coble, et al. 1967).
In a 128 day study, dogs were fed 0.1 mg/endrin/kg
body weight/day. . Concentrations of endrin in the tissues at
the end of the experiment were as follows: adipose tissue,
0.3 to 0.8 ug/g; heart, pancreas, and muscle, 0.3 ug/1;
»
liver, kidney and lungs, 0.077 to 0.085 ug/g; blood, 0.002 to
0.008 ug/g (Richardson, et al., 1967). In a six month.feed-
ing study with dogs at endrin levels of 4 to 8 ppm in the
-IISV-
7
-------
diet, concentrations of endrin were 1 ug/g in fat, 1 ug/g in
liver, and 0.5 ug/g in kidney (Treon, et al. ,_ 1955) .
C. Metabolism
In rats, endrin is readily metabolized in the liver
and excreted as hydrophilic metabolites including hydroxyen-
drins, and 12-ketoendrin (also known as 9-ketoendrin). Hy-
droxyendrins and especially 12-ketoendrin have been reported
to be more acutely toxic to mammals than the parent compound
(Bedford, et al., 1975; Hutson, et al., 19.75). The 12-keto-
endrin is also more persistent in tissues. Female rats me-
tabolize endrin more slowly than males (Jager, 1970).
D. Excretion
Endrin is one of the least persistent chlorinated
hydrocarbon pesticides (U.S. EPA, 1979). Body content of en-
drin declines fairly rapidly after a single dose or when a
continuous feeding experiment is terminated (Brooks, 1969).
In rats, endrin and its metabolites are primarily excreted
with the feces (Cole, et al., 1968; Jager, 1970). The major
metabolite in rats is anti-12-hydroxyendrin which is excreted
in bile as the glucuronide. 12-Ketoendrin was observed as a
urinary metabolite in male rats; the major urinary metabolite
in female rats is anti-12-hydroxyendrin-O-sulfate (Hutson, et
al. , 1975).
In rabbits, excretion is primarily., urinary. In fe-
males, endrin excretion also occurs through the milk. Al-
though endrin is rapidly eliminated from the body, some of
its metabolites nay persist for longer periods of time (U.S.
EPA, 1979) .
-------
IV. EFFECTS
A. Carcinogenicity
In lifetime feeding studies with Osborne-Mendel
rats, endrin was neither tumorigenic nor carcinogenic (Deich-
mann, et al., 1970; Deichmann and MacDonald, 1971; Deichmann,
1972). A recent NCI bioassay concluded that endrin was not
carcinogenic for Osborne-Mendel rats or for B6C3F1 mice
(DHEW, 1979). However, a different conclusion has been
reached by Reuber (1979) based only on one study (National
Cancer Institute, 1977), compared with eight other inconclu-
sive or unsatisfactory studies.
B. Mutagenicity
Endrin (1 mg/kg) administered intratesticularly
caused chromosomal aberrations in germinal tissues of rats,
including stickiness, bizarre configurations, and abnormal
disjunction (Dikshith and Datta, 1972, 1973).
C. Teratogenicity
An increased incidence of club foot was found in
fetuses of mice that had been treated with endrin (0.58 mg/
kg) before becoming pregnant (Nodu, et al., 1972).
Treatment of pregnant hamsters with endrin (5 mg/
kg) produced the following congenital abnormalities: open
eye, webbed foot, cleft palate, fused ribs, and meningoen-
*
cephalocele (Ottolenghi, et al.., 1974; Chernoff, et al.,
1979). Treatment of pregnant mice with endrin (2-5 mg/kg)
produced open eye and cleft palate in the offspring (Otto-
lenghi, et al., 1974). Single doses which produced terato-
-------
genie effects in hamsters and mice were one-half the LDcg
in each species (Ottolenghi, et al., 1974).
D. Other Reproductive Effects
Endrin given to hamsters during gestation produced
behavioral effects in both dams and offspring (Gray, et al.,
1979). In another study endrin produced a high incidence of
fetal death and growth,, retard at ion (Ottolenghi, et al.,
1974).
E. Chronic Toxicity
Manmals appeared to be sensitive to the toxic ef-
fects of endrin at low levels in their diet. Significant
mortality occurred in deer mice fed endrin at 2 mg/kg/day in
the diet (Morris, 19^>\ The mice exhibited symptoms of CNS
toxicity including convulsions. Lifetime feeding of endrin
to rats at 12 mg/kg/day in the diet decreased viability and
produced moderate increases in congestion and focal hemor-
rhages of the lung; slight enlargment, congestion and mott-
y
ling of the liver, and slight enlargement, discoloration or
congestion of the kic. ..eys (Deichmann, et al. , 1970). After
19 months on diets containing 3 mg/kg/day endrin, dogs had
significantly enlarged kidneys and hearts (Treon, et al.,
1955) .
Chronic administration of relatively small doses of
endrin to monkeys produced a characteristic change in the
electroencephalogram (EEC); at higher doses, electrographic
seizures developed. EEC and behavior were still abnormal
three weeks after termination of endrin administration; sei-
-------
zures recurred under stress conditions months after termina-
tion of endrin administration (Revin, 1968). :
F. Other Relevant Information
Endrin is more toxic, in both acute and chronic
studies, than other cyclodiene insecticides (U.S. EPA,
1979).
Female rats metabolize and eliminate endrin more
slowly than males (Jager, 1970) and are more sensitive to en-
drin toxicity (U.S. EPA, 1979). Dogs and ..monkeys are more
susceptible to endrin toxicity than other species (U.S. EPA,
1979).
Endrin,•given in equitoxic doses with delnav, DDT,
or parathion gave lower than expected LD$Q values, sug-
gestive of antagonism. Endrin given in equitoxic doses with
aldrin (a closely related compound) or chlordane gave higher
than expected LD5Q values suggestive of synergism (Kep-
linger and Deichmann, 1967). Humans poisoned acutely exhibit
convulsions, vomiting, abdominal pain, nausea, dizziness,
mental confusion, muscle twitching and headache. Such symp-
toms have been elicited by doses as low as 0.2 mg/kg body
weight. Any deaths have usually occurred through respiratory
failure (Brooks, 1974).
V. . AQUATIC TOXICITY
A. Acute
The toxic effects of endrin have been extensively
studied in freshwater fish. LCgg values for static
bioassays ranged from 0.046 ug/1 for carp fry (Cyprinus
carpio) fry to 140.00 ug/1 for adult carp (lyatomi, et al.,
-------
1958). Excluding the results of age factor differences for
this species, adjusted static LC5Q values ranged from
0.27 ug/1 for large mouth bass (Microptecus salmoides)
(Fabacler, 1976) to 8.25 ug/1 for the bluegill (Lepomis
macrochirus) (Katz and Chadwick, 1961). The LC50 values
for flow-through assays were 0.27 ug/1 for the bluntnose
minnow (Pimeplales notatus) to 2.00 ug/1 for the bluegill
(U.S. EPA, 1979). Twenty-five LC50 values for 17 species
of freshwater invertebrates were reported,'' and ranged from
0.25 ug/1 for stoneflies (Pteronarcys californica) to 500.0
ug/1 for the snail, (Physa gyrina) (U.S. EPA, 1979).
For marine fish, LC^Q values ranged from 0.005
ug/1 for the Atlantic silversides (Menidia menidia) (Eisler,
1970) to 3.1 ug/1 for the northern puffer (Sphaeroides macu-
latus). A total of 17 species were tested in 33 bioassays.
The most sensitive marine invertebrate tested was the pink
shrimp, (Penaeus duordrum) with an LCgg value of 0.037
ug/1, while the blue crab (Callinectes sapidus) was the most
resistant, with an LC5Q of 25 ug/1.
B. Chronic
Freshwater fish chronic values of 0.187 ug/1 and
0.257 ug/1 were reported for fathead minnows (Pimephales
promelas) (Jarvinen and Tyo, .1978) and flagfish (Jordanella
floridae) Hermanutz, 1978), respectively, in life cycle
toxicity tests. No freshwater invertebrate species have been
chronically examined. The marine fish, the sheepshead minrfow
(Cyprinodon variegatus) has provided a chronic value of 0.19
ug/1 from embryolarval tests (Hansen, et al., 1977). The
-/AT?
-------
grass shrimp (Palaemonetes pugio) must be exposed to less
than a chronic concentration of 0.038 ug/1 for reproductive
success of this marine invertebrate species (TylerShroeder,
in press).
C. Plants
Toxic effects were elicited at concentrations for
freshwater algae ranging from 475 ug/1 for Anacystis nidu-
laras (Batterton, 1971) to >20,000 ug/1 for Scenedesmus quad-
ricauda and Oedogonium sp. Marine: algae a-ppeared more sensi-
tive with effective concentration ranging from 0.2 ug/1 for
the algae, Agmenellum quadruplicatum (Batterton, 1978), to
1,000 ug/1 for the algae Dunaliella tertiotecta (U.S. EPA,
1979).
D. Residues
Bioconcentration factors ranged from 140 to 222 in
four species of freshwater algae. Bioconcentration factors
ranging from 1,640 for the channel catfish Ictalurus puncta-
tus (Argyle, et al. 1973) to 13,000 for the flagfish Jordan-
ella floridae (Hermanutz, 1978) have been obtained. Among
four marine species, bioconcentration factors ranging from
1,000 to 2,780 were observed for invertebrates and from 1,450
to 6,400 for marine fish. Residues as high as 0.5 ppm have
been found in- the mosquito fish, Gambus ia affinis (Finley, et
-•
al. 1970) and fish frequently have contained levels above 0.3
ppm (Jackson, 1976).
VI. EXISTING GUIDELINES AND STANDARDS
Both the human health and aquatic criteria derived by
U.S. EPA (1979), which are summarized below, have not gone
-------
through the process of public review;, therefore, there is a
possibility that" these criteria may be changed.
A. Human
The U.S. EPA (1979) has calculated an ADI for en-
drin of 70 ug from a MOAEL of 0.1 rag/kg for dogs in a 128 day
feeding study and an uncertainity factor of 100. The U.S.
EPA (1979) -draft criterion of 1 ug/1 for endrin in ambient
water is based on the 1 ug/1 maximum allowable concentration
for endrin in drinking water proposed by the Public Health
Service in 1965 (Schafer, et al., 1969) and on the calcula-
tions by EPA. Human exposure is assumed to come from drink-
ing water and fish products only.
A maximum acceptable level of 0.002 mg/kg body
weight/day (ADI) was established by the Food and Agricultural
Organization (1973) and the World Health Organization.
A time weighted average TLV for endrin of 100
ug/m^ has been established by OSHA (U.S. Code of Federal
Regulations, 1972) and ACGIH (Yobs, et al., 1972).
The U.S. EPA (40 CFR Part 129.102) has promulgated
a toxic pollutant effluent standard for endrin of 1.5 ug/1
per average working day calculated over a period of one
month, not to exceed 7.5 ug/1 in any sample representing one
working-day's effluent. In add ition,. discharge is not to ex-
ceed 0.0006 kg per 1,000 kg of production.
-------
B. Aquatic
The draft criterion for the protection of fresh-
water aquatic life is 0.0020 ug/1 as a 24 hour average con-
centration not to exceed 0.10 ug/1. For marine, organisms,
the draft criterion is 0.0047 ug/1 as a 24 hour average not
to exceed 0.031 ug/1.
-------
ENDRIN
REFERENCES
Argyle, R.L., et al. 1973. Endrin uptake and release by
fingerling channel catfish, Ictaluras punctatus. Jour.
Fish Res. Board Can. 30: 1743"! "
Batterton, J.C., et al. 1971. Growth response of bluegreen
algae to aldrin, dieldrin, endrin and their metabolites.
Bull. Environ. Contain. Toxicol. 6: 589.
Bedford, C.T., et al. 1975. The acute toxicity of endrin
and its metabolites to rats. Toxicol. Appl. Pharmacol.
33: 115.
Bowery, T.G., et al. 1959. Insecticide residues on tobacco.
Jour. Agric. Food Chem. 7: 693.
Brooks, G.T. 1969. The metabolism of diene-organochlorine
(cyclodiene) insecticides. Residue Rev. 28: 81.
Brooks, G.T. 1974. Chlorinatedlnsecticides. Vol. II.
Biological and environmental aspects. CRC Press, Cleveland,
Ohio.
Chernoff, N., et al. 1979. Perinatal toxicity of endrin
in rodents. I. Fetotoxic effects of prenatal exposure in
hamsters. Manuscript submitted to Toxicol. Appl. Pharmacol.
and the U.S. Environ. Prot. Agency.
Colde, Y., et al. 1967. Acute endrin poisoning. Jour.
Amer. Med. Assoc. 203.: 489.
Cole, J.F., et al. 1968. Endrin and dieldrin: A comparison
of hepatic excretion rates in the rat. (Abstr.) Toxicol.
Appl. Pharmacol. 12: 298.
Deichmann, W.B. 1972. Toxicology of DDT and related chlorin-
ated hydrocarbon pesticides. Jour. Occup. Med. 14: 285.
Deichmann, W.B., and W.E. MacDonald. 1971. Organochlorine
pesticides and human health. Food Cosmet. Toxicol. 9:
91.
Deichmann, W.B., et al. 1970. Tumorigenicity of aldrin,
dieldrin, and endrin in the albino rat. Ind_ Med. Srug.
39: 37.
Dikshith, T.S.S., and K.K. Datta. 1972. Effect of intra-
testicular injection of lindane and endrine on the testes
of rats. Acta Pharmacol. Toxicol. 31: 1.
-J/63
-------
Dikshith, T.S.S., and K.K. Datta. 1973. Endrin induced
cytological changes in albino rats. Bull. Environ. Cotam.
Toxicol. 9: 65.
Domanski, J.J., and F.E. Guthrie. 1974. Pesticide residues
in 1972 cigars. Bull. Environ. Contain. Toxicol. 11: 312.
Duggan, R.E., and G.Q. Lipscomb. 1969. Dietary intake
of pesticide chemicals in the United States (II), June 1966-
April 1968. Pestic. Monitor. Jour. 2: 153.
Duggan, R.E., and P.E. Corneliussen. 1972. Dietary intake
of pesticide chemicals in the United States (III) , June
1968-April 1970. Pestic. Monitor. Jour. 5: 331.
Eisler, R. 1970. Acute toxicities of organochlorine and
organophosphorous insecticides to estuarine fishes. Tech.
Pap. 46. Bur. Sport Fish. Wildl. U.S. Dep. Inter.
Fabacher, D.L. 1976. Toxicity of endrin and an endrinmethyl
parathion formulation to largemouth bass fingerlings. Bull-
Environ. Contam. Toxicol. 16: 376.
Finley, M.T., et al. 1970. Possible selective mechanisms
in the development of insecticide resistant fish. Pest.
Monit. Jour. 3: 212.
Gray, L..E. , et al. 1979. The effects of endrin administra-
tion during gestation on the behavior of the golden hamster.
Abstracts from the 18th Ann. Meet. Soc. of Tox. New Orleans
p. A-200.
Hansen, D.J., et. al. 1977. Endrin: Effects on the entire
lifecycle .of saltwater fish, Cyprinodon variegatus. Jour.
Toxicol. Environ. Health 3: T2TT
Hayes, W.J., and A. Curley. 1968. Storage and excretion
of dieldrin and related compounds. Arch. Environ. Health
16: 155. •
Hermanutz, R.O. 1978. Endrin and malathion toxicity to
flagfish (Jordanella floridae). Arch. Enviorn. Contam.
Toxicol. 1: 159.
Hutson, D.H., et: al. 1975. Detoxification and bioactiva-
tion of endrin in the rat. Xenobiotica 11: 697.
lyatomi-, K.T., et al. 1958. Toxicity of endrin to fish.
Prog. Fish.-Cult. 20: 155.
Jackson, G.A. 1976. Biologic half-life of endrin in chan-'
nel catfish tissues. Bull. Environ. Contam. Toxicol. 16:
505.
-------
Jager, K.W. 1970. Aldrin, dieldrin, endrin, and telodrin.
Elsevier Publishing Co., Amsterdam.
Jarvinen, A.W., and R.M. Tyo. 1978.
minnows of endrin in food and water.
Toxicol. 7: 409.
Toxicity to fathead
Arch. Environ. Contam.
Katz, M., and G.G. Chadwick. 1961. Toxicity of endrin
to some Pacific Northwest fishes. Trans. Am. Fish. Soc.
90: 394.
Keplinger, M.L., and W.B. Deichmann. 1967. Acute toxicity
of combinations of pesticides. Toxicol. Aopl. Pharmacol.
10: 586.
Martin, H. 1971.
Prot. Council.
Pesticide manual, 2nd ed. Brit. Crop
Morris, R.D. 1968. Effects of endrin feeding on survival
and reproduction in the deer mouse, Peromyscus maniculatus,
Can. Jour. Zool. 46: 951.
National Cancer Institute. 1977. Bioassay of endrin for
possible carcinogenicity. NCI Technical Report Series,
No. 25.
National Cancer Institute. 1979. Bioassay of endrin for
possible carcinogenicity. HEW Pub. No. (NIH) 79-812. U.S.
Dept. of Health, Education and Welfare, Bethesda, Md.
Nodu, et. al. 1972. Influence of pesticides on embryos.
On the influence of organochloric pesticides (in Japanese)
Oyo Yakuri 6: 673.
Ottolenghi, A.D., et al. 1974. Teratogenic effects of
aldrin, dieldrin, and endrin in hamsters and mice. Terato-
logy 9: 11.
Reuber, M.D. 1979.
Environ. 12: 101.
Carcinogenicity of endrin. Sci. Tot.
Revin, A.M. 1968. Effects of chronic endrin administration
on brain electrical activity in the squirrel monkey. Fed.
Prac. 27: 597.
Richardson, L.A., et al. 1967. Relationship of dietary
intake to concentration of dieldrin and endrin in dogs.
Bull. Environ. Contam. Toxicol. 2: 207.
Schafer, M.L., et al. 1969. Pesticides in drinking water
- waters from the Mississippi and Missouri Rivers. Environ*.
Sci. Technol. 3: 1261.
-/I if'
-------
Treon, J.F., et al. 1955. Toxicity of endrin for labora-
tory animals. Agric. Food Chem. 3: 842.
Tyler-Schroeder, D.B. Use of grass shrimp, Palaemonetes
pugio, in a life-cycle toxicity test. In Proceedings of
Symposium on Aquatic Toxicology and Hazard Evaluation.
L.L. Marking and R.A. Kimerle, eds. Am. Soc. Testing and
Materials (ASTM), October 31-November 1, 1977. (In press).
U.S. EPA. 1974. Draft analytical report—New Orleans area
water supply study. Lower Mississippi River facility, Sur-
veillance and Analysis Division, Revion VI, Dallas. Texas.
U.S. EPA. 1978. Endrin-Position Document 2/3. Special
Pesticide Review Division. Office of Pesticide Programs,
Washington, D.C.
\
U.S. EPA. 1979. Endrin: Ambient Water Quality Criteria.
(Draft).
Wolfe, H.R.,- et al. 1963. Health hazards of the pesticides
endrin and dieldrin. Arch. Enviorn. Health 6: 458.
Wolfe, H.R., et al. 1967. Exposure of workers to pesti-
cides. Arch. Environ. Health 14: 622.
Yobs, A.R., et al. 1972. Levels of selected pesticides
in ambient air of the United States. Presented at the National
American Chemical Society—Symposium of Pesticides in Air.
Boston, Maine.
-------
No. 100
Epichlorohydrin (l-chloro-2,3-epoxypropane)
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including ; "' ) the
adverse health and environmental impacts presented by' the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
epichlorohydrin and has found sufficient evidence to in-
dicate that this compound is carcinogenic.
-III?-
-------
l-CHLDRO-2,3-EPOXYPROPANE
(Epichlorohydrin)
Summary
The adverse health effects associated with exposure to epichlorohydrin
are extreme irritation to the eyes, skin, and respiratory tract. Inhalation
of vapor and percutaneous absorption of the liquid are the normal human
routes of entry. Exposure to epichlorohydrin usually results from occupa-
tional contact with the chemical, especially in glycerol and epoxy resin op-
erations. Pulmonary effects have been well documented. Recent studies have
demonstrated epichlorohydrin to be a potent carcinogen to nasal tissue in
experimental animals. Cytogenic studies both in vitro and in vivo in humans
and experimental animals have indicated epichlorohydrin to be an active
clastogenic agent. No data on the concentration of epichlorohydrin in drink-
ing water or foods have been reported. Studies on the effects of epichloro-
hydrin to aquatic organisms could not be .located in the available literature.
-1170-
-------
I. INTRODUCTION
This profile is based primarily on a comprehensive review compiled by
Santodonato, et al. (1979). The health hazards of epichlorohydrin have also
been reviewed by the National Institute for Occupational Safety and Health
(NIOSH, 1976) and the Syracuse Research Corporation (SRC, 1979).
Epichlorohydrin (CHJDCHCHJ]!; molecular weight 92.53) is a color-
less liquid at room temperature with a distinctive chloroform-type odor.
The boiling point of epichlorohydrin is 116.4°C, and its vapor pressure is
20 mm Hg at 29°C. These factors contribute to the rapid evaporation of
the chemical upon release into the environment.
Epichlorohydrin is a reactive molecule forming covalent bonds with bio-
logical macromolecules. It tends to react more readily with polarized
groups, such as sulfhydryl groups.
The total U.S. production for epichlorohydrin was estimated at 345 mil-
lion pounds in 1973 (Oesterhof, 1975), with 160 million pounds used as feed-
stock for the manufacture of glycerine and 180 million pounds used in the
production of epoxy resins. Production levels for the year 1977 have been
estimated at 400 million pounds.
II. EXPOSURE
A. Water
No ambient monitoring data on epichlorohydrin are available from
which reliable conclusions on the potential exposure from drinking water may
be made. However, if a major release of epichlorohydrin were realized, the
chemical is stable enough to be transported significant distances. The rate
of evaporative loss would give an estimated half-life of about two days for
epichlorohydrin in surface waters (to a depth of 1m). The only reported
contamination of a public water supply resulted from a tank car derailment
-//7/-
-------
and subsequent spillage of 20,000 gallons (197,000 pounds) of epichlorohy-
drin at Point Pleasant, West Virginia on January 23, 1978. Wells at the
depth of 25 feet were heavily contaminated. More specific information is
not yet available.
B. Food
Epichlorohydrin is used as a cross-link in molecular sieve resins,
which are, in turn, used in the treatment of foods (21 CFR 173.40). Food
starch may be etherified with epichlorohydrin, not to exceed 0
alone or in combination with propylene oxide, acetic anhyd cc
anhydride (21 CFR 172.892). No data concerning concentrations of epichloro-
hydrin in foodstuffs has been generated.
C. Inhalation
Numerous environmental sources of .epichlorohydrin have been identi-
fied (SRC, 1979). Epichlorohydrin is released into the atmosphere through
waste ventilation processes from a number of industrial operations which re-
sult in, volatilization of the chemical. No quantitative monitoring informa-
tion is available on ambient epichlorohydrin concentrations. High concen-
trations have been observed in the immediate vicinity of a factory discharg-
ing epichlorohydrin into the atmosphere , but these were quickly despersed,
with no detection of the chemical at distances greater than 600 M (Fomin,
1966) .
III. PHARMACOKINETICS
A. Absorption
Absorption of epichlorohydrin in man and animals occurs via the
s
respiratory and gastointestinal tracts, and by percutaneous absorption (U.S.
EPA, 1979). Blood samples obtained from rats after 6 hours exposure to
(1ZlC) epichlorohydrin at doses of 1 and 100 ppm in air -revealed 0.46^0.19
and 27.8+4.7 jug epichlorohydrin per ml of plasma, respectively. The rates
-II73--
-------
epichlorohydrin per ml of plasma, respectively. The rates of uptake at
these exposure levels were determined as 15.48 and 1394 ug per hour, and the
dose received was 0.37 and 33.0 mg/kg (Smith, et al. 1979).
B. Distribution
The distribution of radioactivity in various tissues of rats fed
(^C)-epichlorohydrin has been examined (Weigel, et al. 1978). The chemi-
cal was rapidly absorbed with tissue saturation occurring within two hours
in males and four hours in females. The kidney and liver accumulated the
greatest amounts of radioactivity. Major routes af excretion were in the
urine (38 to 40 percent), expired air (18 to 20 percent), and the feces (4
percent). The appearance of large amounts of ^4C02 in expired air sug-
gests a rapid and extensive metabolism of (^4C)-epichlorohydrin in rats.
C. Metabolism
Limited data concerning mammalian metabolism of epichlorohydrin
suggest in_ vivo hydrolysis of the compound, yielding alpha-chlorohydrin
(Jones, et al. 1969). Upon exposure to radioactively-labeled epichlorohy-
drin a .small percentage of the radioactivity was expired as intact epi-
chlorohydrin, while a large percentage of the radioactivity was excreted as
C02, indicating a rapid and extensive metabolism of the (^C)epi-
chlorohydrin. Metabolites in the urine have been obtained by these re-
searchers, but the final analysis as to the identity of the compounds is not
yet complete. Van Ouuren (1977) has suggested a metabolite pathway of epi-
chlorohydrin to include glycidol, glycidaldehyde and epoxy-propionic acid.
D. Excretion
The percentages of total radioactivity recovered in the urine and
expired air as 14C02 were 46 percent and 33 percent in the 1 ppm group,
and 54 percent and 25 percent in the 100 ppm group, respectively. Rats
-// 73 -
3
-------
orally treated with 100 mg/kg excreted 51 percent of the administered epi-
chlorohydrin in the urine and 38 percent in expired air, while 7 to 10 per-
cent remained in the body 72 hours after exposure. Tissue accumulation of
radioactivity was highest in kidneys and liver.
IV. EFFECTS
A. Carcinogenicity
Epichlorohydrin appears to have low carcinogenic activity following
dermal application. In two studies, epichlorohydrin applied topically to
shaved backs of rats or mice did not induce any significant occurrence of
skin tumors (Weil, 1964; Van Duuren, et al. 1974). However, subcutaneous
injection of epichlorohydrin at levels as low as 0.5 mg have resulted in the
induction of tumors at the injection site.
Extensive inhalation studies have recently identified epichlorohy-
drin as a potent nasal carcinogen in rats.' At concentrations of 100 ppm,
significant increases in the occurrence of squamous cell carcinomas of the
nasal turbinates have been observed. Such tumors have been reported in
lifetime exposure studies at 30 ppm but not at 10 ppm (Nelson, 1977, 1978).
Several recent epidemiological studies have suggested the risk of
cancer as a result of occupational epichlorohydrin exposure. Both respira-
tory cancers and leukemia are in excess among some exposed worker popula-
tions,, but this increase was not shown to be statistically significant
(Enterline and Henderson, 1978; Enterline, 1979). The data suggest a laten-
cy period of roughly 15 years before the onset of carcinogenic symptoms. A
second survey has.failed to substantiate these findings (Shellenberger, et
al. 1979). However, this survey used a younger study population with less
exposure to epichlorohydrin.
-I Hi
-------
B. Mutagenicity
Epichlorohydrin has been shown to cause reverse mutations in sev-
eral organisms (SRC, 1979).
Cytogenetic studies with experimental animals have revealed in-
creased aberrations in animals treated with epichlorohydrin. Both mice and
rats have displayed dose-dependent increases in abnormal chromosome morpho-
logy at exposure levels ranging from 1 to 50 mg/kg (Santodonato, et al.
1979).
In humans, the clastogenic properties of epichlorohydrin have been
reported in workers occupationally exposed to the chemical and in cultured
"normal" lymphocytes exposed to epichlorohydrin (SRC, 1979). Cytogenetic
evaluation of exposed workers has shown an increase of somatic cell chromo-
some aberrations associated with concentrations ranging from 0.5 to 5.0 ppm
(2.0 to 20 mg/irP) (SRC, 1979). Such chromosomal damage appears to be re-
versible once exposure to the chemical ceases.
C. Teratogenicity
Pregnant rats and rabbits exposed to 2.5 to 25 ppm epichlorohydrin
during days 6 to 15 or days 6 to 18 of 'gestation showed a mild teratogenic
response (John, et al. 1979). However examinations of all fetal tissue have
not been completed. The incidence of resorbed fetuses was not altered by
exposure to epichlorohydrin at the doses employed.
0. Other Reproductive Effects
The antifeftility properties of epichlorohydrin have been examined
by several investigators. Administration of 15 mg/kg/day of epichlorohydrin
for 12 days resulted in reduced fertility of male rats (Halen, 1970). Five
repeated doses of 20 mg/kg were more effective in rendering male rats infer-
tile than was one 100 mg/kg dose or five 50 mg/kg doses (Cooper, et al.
v/zr-
-------
1974). The suggested mode of action of epichlorohydrin is via the in vivo
hydrolysis of the compound which produces alpha-chlorohydrin. Altered re-
productive function has been reported for workers occupationally exposed to
epichlorohydrin at concentrations less than 5 ppm.
E. Chronic Effects
Two species of rats and one specie of mice (both sexes) were ex-
posed to 5 to 50 ppm epichlorohydrin for six hours per day, five days per
week for a total of 65 exposures. All species and sexes displayed inflamma-
tory and degenerative changes in nasal tissue, moderate to severe tubular
nephrosis, and gross liver pathology at 50 ppm exposure (Quast, et al.
1979a). The same research group has also examined the effect of 100 ppm
exposure for 12 consecutive days. The toxicity to nasal tissues was similar
(Quast, et al. 1979b).
Altered blood parameters (e.g. increased neutrophilic megamyelo-
cytes, decreased hemoglobin, hematocrit, and erythrocytes) have been ob-
served in .rats exposed to 0.00955 to 0.04774 ml epichlorohydrin per kg body
weight administered intraperitoneally.(Lawrence, et al. 1972).' Lesions of
the lungs and reduced weight gains were also observed.
Toxicity studies with various animal species have established that epi-
chlorohydrin is moderately, toxic by systemic absorption (Lawrence, et al.
1972). Acute oral LD5Q values in experimental animals have ranged from
155 to 238 mg/kg for the mouse and from 90 to 260 mg/kg in the rat. Inhala-
50 values range from 366 to 633 ppm in rats, ts 800 ppm in mice
(SRC, 1979). Single subcutaneous injections of epichlorohydrin in rats at
doses of 150 or 180 mg/kg have resulted in severe injury to the kidney
(Rotara and Pallade, 1966).
-------
Accidental human exposures have been reviewed (NIOSH, 1976; Santo-
donato, et al. 1979). Direct exposure to apichlorohydrin vapor results in
severe irritation of the eyes and respiratory membranes, followed by nausea,
vomiting, headache, dyspnea, and altered liver function. A significant de-
crease was reported in pulmonary function among workers exposed to epichlor-
ohydrin in an epoxy-resin manufacturing process. Workers were simultaneous-
ly exposed to dimethyl amino propylamine.
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Existing occupational standards for exposure to epichlorohydrin are re-
viewed in the NIOSH (1976) criteria document. The NIOSH recommended envi-
ronmental exposure limit is a 2 mg/irP 10-hour time-weighted average and a
19 mg/m3 15-minute ceiling concentration. The current Occupational Safety
and Health Administration standard is an 8-hour time-weighted average con-
centration of 5 ppm (20 mg/nv5).
-1/77-
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l-CHLORO-2,3-EPOXYPROPAME(EPICHLOROHYDRIN)
REFERENCES "
Cooper, E.R.A., et al. 1974. Effects of alhpa-chlorohydrin
and related compounds on the reproduction and fertility of
the male rat. Jour. Reprod. Fert. 38: 379.
Enterline, P.E. 1979. Mortality experience of workers ex-
posed to epichlorohydrin. In press: Jour. Occup. Med.
Enterline, P.E., and V.L. Henderson. 1978. Communication to
Medical Director of the Shell Oil Company: Preliminary find-
ing of the updated mortality study among v/orkers exposed to •
epichlorohydrin. Letter dated July 31, 1978. Distributed to
Document Control Office, Office of Toxic Substances (WH-557)
U.S. Environ. Prot. Agency.
Fomin, A.P. 1966. Biological effects of epichlorohydrin and
its hygienic significance as an atmospheric pollutant. Gig.
Sanit. 31: 7.
Halen, J.D. 1970. Post-testicular antifertility effects of
epichlorohydrin and 2,3-epoxypropanol. Nature 226: 87.
John, J.A., et a^.< 1979. Epichlorohydrin-subchronic
studies. IV. Interim results of a study of the effects of
maternally inhaled epichlorohydrin on rats' and rabbits' em-
bryonal and fetal development. Jan. 12, 1979. Unpublished
report from Dow Chemical Co. Freeport, TX.
Jones, A.R., et al. 1969. Anti-fertility effects and metab-
olism of of alp1"-1.- and epichlorohydrin in the rat. Nature
24: 83. •>'
Lawrence, W.H., ^-t/al. 1972. Toxicity profile of epichloro-
hydrin. Jour. Paarm. Sci. 61: 1712.
Nelson, N. 1977. Communication to the regulatory agencies
of preliminary findings of a carcinogenic effect in the nasal
cavity of rats exposed to epichlorohydrin. New York Univer-
sity Medical Center. Letter dated March 28, 1977.
Nelson, N. 1978. Updated communication to the regulatory
agencies of preliminary findings of a carcinogenic effect in
the nasal cavity of rats exposed to epichlorohydrin. New
York University Medical Center. Letter dated June 23, 1978.
NIOSH. 1976. NIOSH criteria for a recommended standard:
Occupational exposure to epichlorohydrin. U.S. DHEW. Na-
tional Institute for Occupational Safety and Health.
-------
Oesterhof, D. 1975. Epichlorohydrin-. Chemical Economics
Handbook. 642.302/A-642.3022. Stanford Research Corp.,
Menlo Park, Calif.
Quast, J.F., et al. 1979a. Epichlorohydrin - subchronic
studies. I. A 90-day inhalation study in laboratory rodents.
Jan. 12, 1979. Unpublished report from Dow Chemical Co.
(Freeport, TX).
Quast, J.F., et al. 1979b. Epichlorohydrin - subchronic
studies. II. A 12-day study in laboratory rodents. Jan. 12,
1979. Unpublished report from Dow Chemical Co. Freeport,
TX.
Rotara, G., and S. Pallade. 1966. Experimental studies of
histopathblogical features in acute epichlorohydrin
(l-chloro-2,3-epoxypropane) toxicity. Mortal Norm. Patol.
11: 155.
Santodonato, J., et al. 1979. Investigation of selected
potential environmental contaminants: Epichlorohydrin and
epibromohydrin. Syracuse Research Corp. Prepared for Office
of Toxic Substances, U.S. EPA.
Shellenberger, R.J., et al. 1979. An evaluation of the
mortality experience of employees with potential exposure to
epichlorohydrin. Departments of Industrial Medicine, Health
and Environmental Research and Environmental Health. Dow
Chemical Co. Freeport, TX.
Smith, F.A., et al. 1979. Pharmacokinetics of epichlorohy-
drin (EPI) administered to rats by gavage or inhalation.
Toxicology Research Laboratory, Health and Environmental
.Science. Dow Chemical Co., Midland, MI. Sponsored by the
Manufacturing Chemists Association. First Report.
Syracuse Research Corporation. 1979. Review and evaluation
of recent scientific literature relevant to an occupational
standard for epichlorohydrin: Report prepared by Syracuse
Research Corporation for NIOSH..
Van Duuren, B.L. 1977. Chemical structure, reactivity, and
carcinogenicity of halohydrocarbons. Environ. Health Persp.
21: 17.
Van Duuren, B.L., et al. 1974. Carcinogenic action of alky-
lating agents. Jour. Natl. Cancer Inst. 53: 695.
Weigel, W.W., et al. 1978. Tissue distribution and excre-
tion of (^-4c)-epichlorohydrin in male and female rats.
Res. Comm. Chem. Pathol. Pharmacol. 20: 275.
•mi-
-------
Weil, C.S. 1964. Experimental carcinogenicity and acute
toxicity of representative epoxides. Amer. Ind. Hyg. Jour,
24: 305.
-------
No. 101
Ethyl Methacrylate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
ETHYL METHACRYLATE
Summary
Information on the carcinogenic and mutagenic effects of ethyl methac-
rylate was not found in the available literature. Ethyl methacrylate has,
however, been shown to cause teratogenic effects in rats.
Chronic occupational exposure to ethyl methacrylate has not been re-
ported in the available literature.
Data concerning the effects of ethyl methacrylate on aquatic organisms
were not found in the available literature.
-------
ETHYL METHAGRYLATE
I. INTRODUCTION
Ethyl methacrylate (molecular weight 114. 15) is the ethyl ester of
methacry lie acid. It is a crystalline solid that melts at less than 75°C,
has a boiling point of 117°C, a density of 0.9135, and an index of refrac-
tion of 1.4147. It is insoluble in water at 25°C and is infinitely solu-
ble in alcohol and ether (Weast, 1975). It possesses a characteristic un-
pleasant odor (Austian, 1975).
Widely known as "Plexiglass" (in the polymer- form), ethyl methacrylate
is used to make polymers, which in turn are used for building, automotive,
aerospace, and furniture industries. It is also used by dentists as dental
plates, artificial teeth, and orthopedic cement (Austian, 1975).
II. • EXPOSURE
Ethyl methacrylate is used in large quantities and therefore has poten-
tial for industrial release and environmental contamination. Ethyl methac-
rylate in the polymerized form is not toxic; however, chemicals used to pro-
duce ethyl methacrylate are extremely toxic. No monitoring data are avail-
able to indicate ambient air or water levels of the compound.
Human exposure to ethyl methacrylate from foods cannot be assessed due
to a lack of monitoring data.
Bioaccumulation data on ethyl methacrylate were not found in the avail-
able literature.
III. PHARMACOKINETICS
Specific information on the metabolism, distribution, absorption, or
elimination of ethyl methacrylate was not found in the available literature.
y
-------
No evidence has been found of the presence of ethyl methacrylate in the
human urine. Therefore, it is hypothesized that it is rapidly metabolized
and undergoes complete oxidation (Austian, 1975).
IV. EFFECTS
A. Carcinogenic!ty and Mutagenicity
Information on the carcinogenic and mutagenic effects of ethyl
methacrylate was not found in the available literature.
B. Teratogenicity
Ethyl methacrylate is teratogenic in rats. Female rats were given
intraperitoneal injections of 0.12 rug/kg, 0.24 mg/kg, and 0.41 mg/kg, on
days 5, 10, and 15 of gestation. These doses were 10, 20, and 33 percent,
respectively, of the acute intraperitoneal LD^Q dose. Animals were sacri-
ficed one day before parturition (day 20).
Deleterious effects were observed in the developing embryo and fetus.
Effects were compound and generally dose-related. A 0.1223 ml/kg injected
dose resulted in unspecified gross abnormalities and skeletal abnormalities
in 6.3 percent and 5.0 percent of the test animals, respectively, when com-
pared to the untreated controls. A dose of 0.476 ml/kg resulted in gross
abnormalities in 15.7 percent of the treated animals and skeletal abnor-
malities in 11.7 percent of the treated animals (Singh, et al. 1972).
C. Other Reproductive Effects and Chronic Toxicity
Information on other reproductive effects and chronic toxicity of
ethyl methacrylate was not found in the available literature.
D. Acute Toxicity
Lower molecular weight acrylic monomers such as ethyl methacrylate
cause systemic toxic effects. Its administration results in an immediate
-//
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increase in respiration rate, followed by a decrease after 15-40 minutes. A
prompt fall in blood pressure also occurs, followed by recovery in 4-5
minutes. As the animal approaches death, respiration becomes labored and
irregularj lacrimation may occur, defecation and urination increase, and
finally reflex activity ceases, and the animal lapses into a coma and dies
(Austian, 1975).
Acrylic monomers are irritants to the skin and mucous membranes.
When placed in the eyes of animals, they elicit a very severe response and,
if not washed out, can cause permanent damage (Austian, 1975).
As early as 1941, Oeichmann demonstrated that injection of 0.03
cc/kg body weight ethyl methacrylate caused a prompt and sudden fall in
blood pessure, while respiration was stimulated immediately and remained at
this level for 30 minutes. The final lethal dose (0.90-.12 cc/kg) brought
about respiratory failure, although the hearts of these animals were still
beating (Deichmann, 1941).
Work by Mir, et al. (1974) demonstrated that respiratory system
effects alone may not kill the animal, but that cardiac effects may also
contribute to the cause of death (Austian, 1975). Twelve methacrylate
esters and methacrylic acid were tested on isolated perfused rabbit heart.
Concentrations as low as 1 part in 100,000 (v/v) produced significant ef-
fects. The effects were divided into three groups according to the rever-
sibility of the heart response. Ethyl methacrylate was placed in "Group 1",
in which the. heart response is irreversible at all concentrations
(1:100,000; 1:10,000; 1:1,000). Five percent (v/v-) caused a 41.2 percent
decrease in the heart rate of isolated rabbit heart. The same concentration
»
reduced heart contraction by 64 percent and coronary flow by 61.5 percent
(Austian, 1975).
-------
The findings of Oeichmann (1941) that ethyl methacrylate affects
blood pressure and respiration is substantiated by studies of Austian
(1975). Response following administration of ethyl methacrylate was charac-
terized by a biphenic response, an abrupt fall in blood pressure followed by
a more sustained rise. Austian (1975) also found that the respiration rate
is increased, the duration of effect being approximately 20 minutes, after
which time the respiration rate returned to normal.
In the available literature LD5Q values were found for only rab-
bit and rat; these were established by Oeichmanrr- in 1941. The oral value
for the rat is 15,000 mg/kg, as opposed to 3,654-5,481 mg/kg for the rab-
bit. Inhalation values for the rat have been reported to be 3,300 ppm for 8
hours (Patty, 1962). . Deichmann also established a skin toxicity LD5_ for
rabbit which was greater than 10 ml/kg. This was substantiated by another
test which showed that moderate skin irritation (in rabbits) does result
from ethyl methacrylate exposure (Patty, 1962).
VI. EXISTING GUIDELINES AND STANDARDS
Information on existing guidelines and standards was not found in the
available literature.
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ETHYL METHACRYLATE
References
Austian, J. 1975. Structure-toxicity relationships of acrylic monomers.
Environ. Health Perspect. 19: 141.
Deichmann, W. 1941. Toxicity of methyl, ethyl, and n-butyl methacrylate.
Jour. Ind. Hyg. Toxicol. 23: 343.
Mir, G., et al. .1974. Journal of toxicological and pharmacological actions
of methacrylate monomers. III. Effects on respiratory and cardiovascular
functions of anesthetized dogs. Jour. Pharm. Sci. 63: 376.
Patty, F.A. 1962. Industrial Hygiene and Toxicology, Vol. II. Inter-
science Publishers, New York.
Singh, A.R., et al. 1972. Embryo-fetal toxicity and teratogenic effects of
a group of methacrylate esters in rats. Tox. Appl. Pharm. 22: 314.
Weast, R. C. 1975. Handbook of Chemistry and Physics. 56th ed. CRC
Press, Cleveland, Ohio.
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No. 102
Ferric Cyanide
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-fife-
-------
FERRIC CYANIDE
I. INTRODUCTION
Ferric cyanide is a misnomer and is not listed as a specific compound
in the comprehensive compendia of inorganic compounds (Weast, 1978). There
are, however, a class of compounds known as "iron cyanide blues" consisting
of various salts where the anions are the ferricyanide, [FeCCN)^]3-, or
the ferrocyanide, CFe(CN)6]4-, ar,d the cations are either Fe(III) or
Fe(II) and sometimes mixtures of Fe(II) and potassium (Kirk and Othmer,
1967). The empirical formula of the misnamed ferric cyanide, Fe(CN),
corresponds actually to one of the ferricyanide compounds, the ferric ferri-
cyanide with the actual formula Fe[Fe(CN)6]j also known as -Berlin green.
The acid from which these salts are derived is called ferricyanic acid,
H3[Fe(CN)g] (also known as hexacyanoferric acid), molecular weight
214.98, exists as green-blue deliquescent needles, decomposes upon heating,
and is soluble in water and alcohol. .In this EPA/ECAO Hazard Profile only
ferric ferricyanide, Fe[Fe(CN)6]) and ferric ferrocyanide,
F'e4[Fe(CN)g]j, are considered; other ferrocyanide compounds are re-
ported in a separate EPA/ECAO Hazard Profile (U.S. EPA, 1980).
These compounds are colored pigments, insoluble in water or weak acids,
although they can form colloidal dispersions in aqueous media. These pig-
ments are generally used in paint, printing inks, carbon paper inks, cray-
ons, linoleum, paper pulp, writing inks and laundry blues. These compounds
are sensitive to alkaline decomposition (Kirk and Othmer, 1967).
II. EXPOSURE
Exposure to these compounds may occur occupationally or through inges-
tion of processed food or contaminated water. However, the extent of food
or water contamination from these compounds has not been described in the
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available literature. Prussian blue, potassium ferric hexacyanoferrate
(II), has been reported as an antidote against thallium toxicity. When
administered at a dose of 10 g twice daily by duodenal intubation, it pre-
vents the intestinal reabsorption of thallium (Dreisbach, 1977).
III. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available literature.
B. Metabolism
There is no apparent metabolic alteration, of these compounds. As
for the other ferrocyanide and ferricyanide salts, these compounds are not
cyanogenic (Gosselin, et al. 1976).
C. Excretion
No information is available for ferric hexacyanoferrates (II) or
(III), but information is available for other related ferrocyanide and fer-
ricyanide salts (U.S. EPA, 1980; Gosselin, et al. 1976) which seems to be
rapidly excreted in urine apparently without metabolic alteration.
IV. EFFECTS
A. Carcinogenicity, Mutagenicity, Teratogenicity, Chronic Toxicity,
and Other Reproductive Effects
Pertinent data could not be located in the available literature.
B. Acute Toxicity
No adequate toxicity data are available. All ferrocyanide and
ferricyanide salts are reported as possibly moderately toxic (from 0.5 to
5.0 mg/kg as a probable lethal dose in humans) (Gosselin, et al. 1976).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature regard-
ing the aquatic toxicity of ferric cyanide.
-------
VI. EXISTING GUIDELINES AND STANDARDS
Pertinent data could not be located in the available literature.
-// ?3 ~
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REFERENCES
Oreisbach, R.H. 1977. Handbook of Poisoning, 9th edition. Lange Medical
Publications, Los Altos, CA.
Gosselin, R.E., et al. 1976. Clincial Toxicology of Commercial Products,
4th edition. Williams and Wilkins, Baltimore, Maryland.
Kirk,R.E. and O.F. Othmer. 1967. Kirk-dthmer Encyclopedia of Chemical
Technology, II edition, Vol. 12. Interscience Publishers, div. John Wiley
and Sons, Inc., New York.
U.S. EPA. 1980. Environmental Criteria and Assessment Office. Ferrocya-
nide: Hazard Profile. (Draft)
Weast, R.C. 1978. Handbook of Chemistry and Physics, 58th ed. The Chemi-
cal Rubber Company, Cleveland, Ohio.
•lilt-
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No. 103
Fluoranthene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION A<2NCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-im-
-------
FLUORANTHENE
SUMMARY
No direct carcinogenic effects have been produced by
fluoranthene after administration to mice. The compound
has also failed to show activity as a tumor initiator or
promoter. However, it has shown cocarcinogenic effects
on the skin of mice when combined with benzo(a)pyrene, in-
creasing tumor incidence and decreasing tumor latency.
Fluoranthene has not shown mutagenic, teratogenic or
adverse reproductive effects.
Daphnia magna appears to have low sensitivity to fluoran-
thene with a reported 48-hour EC5Q of 325,000 pg/1. The
bluegill, however, is considerably more sensitive with an
observed 96-hour LC5Q value of 3,980. The 96-hour LC50
for mysid shrimp is 16 ug/1,. and a reported chronic value
is 16 ug/1. Observed 96-hour ECcn values based on cell
numbers for fresh and saltwater algae are over 45,000 ug/1.
-II97-
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FLUORANTHENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Fluoranthene (U.S. EPA, 1979).
Fluoranthene (1,2-benzacenapthene, M.W. 202) is a poly-
nuclear aromatic hydrocarbon of molecular formula c]_5Hig •
Its physical properties, include: melting point, 111°C; boil-
ing point, 375°C; water solubility, 265 ^yg/1 (U.S. EPA,
1978) .
Fluoranthene is chemically stable, but may be removed
from water by biodegradation processes (U.S. EPA, 1979).
The compound is relatively insoluble in aqueous systems.
Fluoranthene may be adsorbed and concentrated on a variety
of particulate matter. Micelle formation through the action
of organic solvents or detergents may occur. (U.S. EPA,
1979).
Flouranthene is produced from the pyrolytic processing
of coal and petroleum and may result from natural biosyn-
thesis (U.S. EPA, 1979).
II. EXPOSURE
Fluoranthene is ubiquitous in the environment; it has
been monitored in food, water, air, and in cigarette smoke
(U.S. EPA, 1979). Sources of contamination include indus-
trial effluents and emissions, sewage, soil infiltration,
and road runoff (U.S. EPA, 1979). Monitoring of drinking
»
water has shown an average fluoranthene concentration of
27.5 ng/1 in positive samples (Basu, et al. 1978). Food
-------
levels of the compound are in the ppb range, and will in-
crease in smoked or cooked foods (pyrolysis of fats) (U.S.
EPA, 1979). Borneff (1977) has estimated that dietary in-
take of fluoranthene occurs mainly from fruits, vegetables,
and bread.
An estimated daily exposure to fluoranthene has been
prepared by EPA (1979):
Source Estimated Exposure
^•^MBM^Vl^MMMI ^^Ma^H^MB«i^H^MMVB^lMiaM^WWMMBm^^Hn« f
Water 0.017 pg/day
Food 1.6 - 16 pg/day
Air 0.040 - 0.080 pg/day
Based on the octanol/water partition coefficient, the
U.S. EPA (1979) has estimated weighted average bioconcen-
tration. factor of 890 for fluoranthene for the edible por-
tion of fish and shellfish consumed by Americans.
III. PHAJRMACOKINETICS
A. Absorption
Based on animal toxicity data (Smythe, et al.
1962), fluoranthene seems well absorbed following oral or
dermal administration. The related polynuclear aromatic
hydrocarbon (PAH), benzo(a)pyrene, is readily absorbed across
the lungs (Vainio, et al. 1976).
.*
B. Distribution
Pertinent information could not be located in
»
the available literature. Experiments with benzo(a)pyrene
indicate localization in a wide variety of body tissues,
primarily in body fats (U.S. EPA, 1979).
-------
C. Metabolism
Pertinent information could not be located in
the available literature. 3y analogy with other PAH com-
pounds, fluoranthene may be expected to undergo metabolism
by. the mixed function oxidase enzyme complex. Transforma-
tion products produced by this action include ring hydroxy-
lated products (following epoxide intermediate formation)
and conjugated forms of these hydroxylated products (U.S.
EPA, 1979).
D. Excretion
Pertinent information could not be located in
the a ^)lable literature. Experiments with PAH compounds
indicate excretion through the hepatobiliary system and the
feces; urinary excretion varies with the degree of formation
of conjugated metabolites (U.S. EPA, 1979).
IV. . £. "j-ECTS
A. .t Carcinogenicity
•' .">
Testing of fluoranthene in a marine carcinogenesis
bioassay failed to show tumor production following dermal
or subcutaneous administration of fluoranthene (Barry, et
al., 1935).
Skin testing of fluoranthene as a tumor promoter
or initiator in mice has also failed to show activity of
the compound (Hoffman, et al. , 1972; Van Duuren and Gold-
schmidt, 1976).
Fluoranthene has been demonstrated to have car-
cinogenic activity (Hoffmann and Wynder, 1963; Van Duuren
X
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