HEALTH AND ENVIRONMENTAL
EFFECT PROFILES
APRIL 30, 1980
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFBICE OF SOLID WASTE
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BACKGROUND DOCUMENT
RESOURCE CONSERVATION AND RECOVERY ACT
SUBTITLE C - IDENTIFICATION AND LISTING OF HAZARDOUS WASTE
APPENDIX A - HEALTH _AND ENVIRONMENTAL EFFECT PROFILE-S
APRIL 30, 1980
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF SOLID WASTE
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Preface
These health and eavironmental effect profiles have
been compiled to support, the listing of approxaia tely 170
of the hazardous constituents identified on Appendix VIII
in the regulations (40 CFR, Part 261). These profiles are
also being used to support the listing of hazardous wastes
in Subpart D of Part 261, due to the presence in the
wastes, of these hazardous constituents. Many of these
profiles have been summarized from the water quality criteria
documents prepared in support of various programs under
the Clean Water Act. In each case, however, the document
is based on information and references available to the
Agency and which are referenced in each individual document.
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Table of Contents
Chemical Substance(Document Number) Page
Acetaldehyde(1) 1
Acetonitrile(2) 10
Acetophenone(3) 22
Acetyl Chloride(4) 29
Acrolein(5) 35
Acrylamide(Reserved) —
Acrylonltrile(7) 51
Aldrin(8) 65
Allyl Alcohol(9) 79
Antimony(10) 87
Arsenic(ll) 104
Asbestos(12) 125
Barium(13) 145
Benzal Chloride(14) 156
Benzene(lS) 163
Benzidine(16) 179
Benz(a)anthracene(17 ) 193
Benzo(b)fluoranthene(18) 205
Benzo(a)pyrene(19 ) 216
Benzotrichloride(20) 228
Benzyl Chloride(21) 235
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Chemical Substance(Document Number) Page
Beryllium(22) 247
Bis(2-chloroethoxy) Methane(23) . 263
Bis(2-chloroethyl) Ether(24) 269
Bis(2-chloroisopropyl) Echer(25) 280
Bis(chloromethyl) Ether(26) 288
'Bis(2-ethylhexyl) Phthalate( 2 7 ) 298
Bromoform(28) 312
Bromomethane(29) 322
4-Bromophenyl Phenyl Ether(30) 332
Cadmium(31) 339
Carbon Disulfide(32) 366
Carbon Tetrachloride (Tetrachloromethane)(33) 374
Chloral(34) 387
Chlordane(35) 400
Chlorinated Benzenes(36) 418
Chlorinated Ethanes(37) 435
Chlorinated Naphthalenes(38) 453
Chlorinated Phenols(39) 464
Chloroacetaldehyde(40) 486
Chloroalkyl Sthers(41) 497
Chlorobenzene(42) 510
p-Chloro-m-creso1(43) 520
Chloroethane(44) 526
Chloroethene(Vinyl Chloride)(45) 533
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Chemical Substaace(Document Number) Page
2-Chloroethyl Vinyl Ether(46) 550
Chloroform (Carbon Trichloromethane)(47) 558
Chloromethane(48) 574
2-Chloronaphthalene(49 ) 584
2-Chlorophenol(50) 595
Chromium(51) 607
Chrysene(52) 626
Cresote(53) 637
Cresols and Cresylic Acid(54) 653
Crotonaldehyde(55) 684
Cyanides(56) 694
Cyanogen Chloride(57) 707
DDD(58) 713
DDE(59) 724
DDT(60) 734
Dibromochloromethane(61) 751
Di-n-butyl Phthalate(62) 758
Dibenzo(a,h)anthracene(63 ) 767
l,2-Dichlorobenzene(64) 779
l,3-Dichlorobenzene(65) 790
1,4-Dichlorobenzene(66) 798
Dichlorobenzenes(67) 809
3,3'-Dichlorobenzidine(68) 823
l,l-Dichloroethane(69) . 836
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Chemical Substance(Document Number) Page
1,2-Dichloroethane(70) 843
1,1-Dichloroethylene(71) 855
trans-l,2-Dichloroethylene(72) 866
Dichloroethylenes(73) ' 874
Dichloromethane(74) 887
2,4-Dichlorophenol(75 ) 898
2,6-Dichlorophenol(76) 911
2,4-Dichlorophenoxyacetic Acid (2,4-D)(77) 918
1, 2-Dichloropr.opane(78) 935
Dichloropropanes/Dichloropropenes(79) 944
Dichloropropanol(80) 955
l,3-Dichloropropene(81) 962
Dieldrin(82) 970
0,0-Diethyl Dithiophosphoric Acid(83) 991
o , o-Diethyl-S-methyl Phosphorodithioate(84) 999
Diethyl Phthalate(85) 1006
Diniethylnitrosainine(86) 1014
2,4-Dimethylphenol(87) 1024
Dimethyl Phthalat e(88 ) 1035
Dinitrobenzenes(89) 1043
4,6-Dinitro-o-cresol(90) 1052
2,4-Dinicrophenol(91) 1060
Dinitrotoluene(92) 1070
2,4-Dinicrotoluene(93 ) .1083
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Chemical Substance(Document Number) Page
2,6-Dinitrotoluene(94) 1095
Di-n-octyl Phthalate(95) 1104
1,2-Diphenylhydrazine(96) 1111
Disulfoton(97) 1121
Endosulfan(98) 1132
Endrin(99) 1149
Epichlorohydrin (1-Chloro-2,3-epoxypropane)(100) 1167
Ethyl Methacrylate(101) 1181
Ferric Cyanide(102) 1189
Fluoranthene(103) 1195
Forraaldehyde(104) 1206
Formic Acid(105) ' 1221
Fumaronitrile(106) 1231
Halomethanes(107 ) 1237
Heptachlor(108) 1252
Heptachlor Epoxide(109) ' 1271
Hexachlorobeazene(110) 1283
Hexachlorobutadiene(111) 1297
Hexachlorocyclohexane(112) 1310
gamma-Hexachlorocyclohexane(113) 13 30
Hexachlorocyclopentadiene(114) 1349
Hexachloroethane(115) 1361
Hexachlorophene(116) 1369
Hydrofluoric Acid(117) '1378
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Chemical Substance(Document Number) Page
Hydrogen Sulfide(llS) ' 1390
Indeno (1,2,3-cd) Pyrene(119) 1400
Isobutyl Alcohol(120) 1410
Lead(121) 1415
Maleic Anhydride(122) . 1434
Malonotiitr tle( 123 ) 1441
Mercury(124) 1451
Methomyl(125) 1475
Methyl Alcohol(126) 1491
S,ST-methylene-o ,o ,o' ,o'-Tetraethyl Phosphorod!chioate(127 ) 1513
Methyl Lu.iyl Ketone(128) 1520
Methyl Isobutyl Ketone(129) 1526
Methyl Methacrylate(130) 1532
Naphthalene(131) 1543
1,4-Naphwhoquinone( 132) 1556
Nickel(n.p 1563
Nitrobenzene(134) 1579
4-Nitrophenol(135 ) 1591
Nitrophenols(136) 1600
Nitrosamines(137 ) 1616
N-Nitrosodiphenylamine( 138) 1633
N-Nitrosodi-n-propylamine(139) 1643
Paraldehyde(140) 1657
Pentachlorobenzene(141) 1666
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Chemical Substance(Document Number) Page
Pentachloronitrobenzene(142) 1675
Pentachlorophenol(143 ) 1690
Phenol(144) 1706
PhoraCe(145) 1722
Phthalate .Esters(146) 1737
Phthalic Anhydride( 147 ) 1753
2-Picoliae(148) 1760
Polynuclear Aromatic Hydrocarbons(PAHs)(149) 1769
Pyridine(150) 1791
Quinones(151) 1801
)
Resorcinol( 152) -' 1810
Selenium(153) 1821
Silver(154) 1833
TCDD(155) 1848
1,1,1,2-TetrachlJroethane(156) 1862
l,l,2,2-Tetrachl^roechane(157) 1872
Tetrachloroethylene(Perchloroethylene)(158) 1883
Thalliuin(159) 1897
Toluene(160) 1909
2 ,4-Toluenediatnine( 161) 1926
Toluene DiisocyanaCe(162) 1935
Toxaphene(163) 1949
1 ,1 ,l-Trichloroethane(164) 1970
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Chemical Substance(Document Number) Page
1 ,l,2-TrichloroetHane(165) 1981
Trichloroethylene(166) 1990
Trichlorofluoromethane and Dichlorodifluororaethane(167) 2003
2,4,6-Trichlorophenol(168) 2014
1,2,3-Trichloropropane(169) 2026
o ,o ,o-Triechyl PhosphoroChioate(170) 2033
Trinitrobenzene(171) 2040
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No. 1
Acetaldehyde
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.
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ACETALDEHYDE
Summary
An increased incidence of malignant neoplasms was reported in
workers in an aldehyde factory. Acetaldehyde was found in
concentration of 1 to 7 mg/m^ but there was no indication that
acetaldehyde was the causative factor for the cancers.
Equivacol results were obtained from a number of mutugenicity
as says.
I. INTRODUCTION
Acetaldehyde (CI^COH) is a clear, flammable liquid with a
pungent, fuity odor. It has the following physical/chemical
properties (Hawley, 1977; U.S. EPA, 1976a):
^5.0
Chemical Structure: CE-2 ~ C'CT
^H
CAS No.: 75-07-0
Molecular Formula: C2H40
Boiling Point: 20.2°C
Melting Point: -123.5°C
Vapor Pressure: 740 mm (20°C)
Density: 0.7834 at 18°C/4°C
Octanol/Water
Partition Coefficient: 0.43
Vapor Density: 1.52
»
Solubility: soluble in water and most
organic solvents
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A review of the production range (includes importation)
statistics for acetaldehyde (CAS No. 75-07-0) which was listed in
the initial TSCA Inventory (1977) has shown that between 1 billion
and 2 billion pounds of this chemical were produced/imported in
1977. *_/
Acetaldehyde is used mainly as a chemical intermediate in the
production of paraldehydes, acetic acid, acetic anhydride, and a
variety of other chemicals (Hawley, 1977).
II. EXPOSURE
The NIOSH National Occupational Hazard Survey estimates that
2,430 workers are exposed to acetaldehyde annually (1976).
A. Environmental Fate
The available data do not indicate a potential for persis-
tance and accumulation in the environment. While there is little
information on the environmental fate of acetaldehyde, the BOD/COD
of 0.72 confirms that acetaldehyde will readily biodegrade
(Verschueren, 1978) .
As to its fate in air, aldehydes are expected to photodisso-
ciate rapidly and competively .with their oxidation for a half-life
of 2 to 3 hours. Aldehydes do not persist in the atmosphere but
the fact that acetaldehyde is a component of vehicle exhaust may be
significant in its contribution to smog (U.S. EPA, I977b).
j^/ This production range information does not include any production/
importation data claimed as confidential by the person(s) report-
ing 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 Regulation (40 CFR 710).
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B. Bioconcentration
Acetaldehyde has an octanol/water partition coefficient
of 0.43 indicating that it is highly hydrophiiic and should not
accumulate (U.S. EPA, 1976).
C. Environmental Occurrence
Acetaldehyde is a normal intermediate product in the
respiration of higher plants; it occurs in traces in ripe fruits
and may form in alcoholic beverages after exposure to air. It has
been reported that acetaldehyde is found in leaf tobacco, ciga-
rette smoke, and automobile and diesel exhaust (U.S. EPA, 1977a).
Acetaldehyde has been reported in both finished drinking water
supplies and effluents from sewage treatment plants in several
locations throughout the U.S. (EPA, 1976b).
III. PHARMACOKINETICS
Acetaldehyde which is the first occurring metabolite of ethanol
in mammals is produced in the liver and is often found in various
tissues after the consumption of alcohol (Obe and Ristow, 1977).
It is an intermediate product in the metabolism of sugars in the
body and hence occurs in traces in blood (EPA, 1977b).
IV. HEALTH EFFECTS
A. Carcinogenicity
Watanabe and Sugimoto (1956) administered 0.5-5% acetalde-
hyde subcutaneously to rats for a period of 489 to 554 days. Four
of the 14 animals developed spindle cell carcinomas at the site of
inject ion.
•
An increased incidence of malignant neoplasms has been observed
in workers at an aldehyde factory who were exposed to acetaldehyde,
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butyraldehyde, crotonaldehyde, aldol, several alcohols, and longer
chain aldehydes. Acetaldehyde was found in concentrations of
1-7 mg/ra^. Of the 220 people employed in this factory, 150 has
been exposed for more than 20 years. During the period 1967 to
1972, tumors were observed in nine males (all of whom were smokers).
The tumor incidences observed in the workers exceeded incidences of
carcinomas of the oral cavity and bronchogenic lung cancer expected
in the general population and, for the age group 55-59 years, the
incidence of all cancers in chemical plant workers. There is no
indication that acetaldehyde was the causative factor in the excess
incidence of cancer (Bittersohl, 1974; Bittersohl, 1975).
Acetaldehyde has been found positive in a variety of mutagenicity
tests: siter chromatid exchange in cultured human lymphocytes and
a Chinese hamster (ovary) cell line (Ristow and Obe, 1978; Obe and
Ristow, 1977); S. typhimirium (Ames Test); (Pol A~) E. coli
(Rosenkranz, 1977); and WP2 uvrA trp~) E. coli (Veghelyi et al.,
1978). It has, however, also been reported negative by other
investigators: S. typhimurium, with and without activation (Cotruvo
et al., 1977; Commoner, 1976; Laumbach et al., 1977); Saccharomyces
cerevi siae test for recombination(Cotruvo et al., 1977); and
Bacillus subtilis repair essay (Laumbach et al., 1977). Thus, of
ten reports of in vitro tests for the mutagenicity of acetaldehyde,
5 were positive and 5 were negative. Acetaldehyde was also found
to cross-link isolated calf thymus DNA (Ristow and Obe, 1978).
C. Other Toxicity
»
1. Ac ut e
™" vo *
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A Cable summarizing the acute toxiclty of acetaldehyde
in rats and mice is found below:
Species Dose
rat I6,000ppm x 4 hrs.
rat 4,000ppm x 4 hrs.
rat 640 tug/kg
rat 20,000ppm x 30 min.
rat 1,930 mg/kg
mouse 560 aig/kg
mouse 1,232 mg/kg
Route
Result
Reference
ihl
ihl
s . c .
ihl
oral
s . c .
oral
lethal
lethal
LD50
LC50
LD50
LD50
LD50
Smyth, 1956
NIOSH, 1977
Skog, 1950
Skog, 1950
NIOSH, 1977
Skog, 1950
NIOSH, 1977
D. Other Relevant Data
Acetaldehyde is a mucous membrane irritant in humans
(Verschueren, 1978).
V. AQUATIC EFFECTS
A. Acute
The 24-hour median threshold limit (TLm) for acetaldehyde.
pinperch is 70 mg/1. The 96-hour TLm in sunfish is 53 mg/1
(Verschueren, 1978).
VI. EXISTING GUIDELINES
A. Humans
The American Conference of Governmental and Industrial
Hygienists (ACGIH) has adopted a Threshold Limit Value (TLV) of
100 ppra for acetaldehyde. The OSHA standard in air is a Time
Weighted Average (TWA) of 200 ppm.
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REFERENCES
ACGIH (1977). American Conference of Governmental and Industrial
Hygienists, Threshold Limit Values for Chemical Substances and
Physical Agents in the Workroom Environment, Cincinnati, Ohio.
Bittersohl, G. (1974). Epdemiological investigations on cancer
in workers exposed to aldol and other aliphatic aldehydes. Arch.
Geschwalstforsch. 43:172-176.
Bittersohl, G. (1975). Env. Qual. Safety. 4:285-238 (as cited
in NCI, 1978).
Commoner, B. (1976). Reliability of bacterial mutagenesis
techniques to distinguish carcinogenic and non-carcinogenic
chemicals. EPA-600/1-76-002.
Cotruvo, J.A. -£_t_ ^1_. , (1977). Investigation of tnutagenic effects
of products of ozonation reactions in water. Ann. N.Y. Acad.
Sci. 298:124-140.
Hawley, G.G. (1977). Condensed Chemical Pictionary, 9th edition.
Van Nostrand Reinhold Co.
Laumbach, A.D., e t al. (1977). Studies on the mutagenicity of
vinyl chloride metabolites and related chemicals. Prev. Select.
Cancer. (Proc. Int. Symp.) 1 :155-170.
NIOSH (1976). National Occupational Hazard Survey.
NIOSH (1977). Registry of Toxic Effects of Chemical Substances.
Obe, G., and H. Rlstow. (1977). Acetaldehyde, But Not Ethanol,
Induces Sister Chromatid Exchanges in Chinese Hamster Cells in
Vitro. Mutation Research. 56:211-213.
National Cancer Institute, Chemical Selection Working Group,
September 28, 1978.
OSHA (1976). Occupational Safety and Health Standards (29'CFR
1910), OSHA 2206.
Ristow, H., and G. Obe. (1978). Acetaldehyde Induces Cross-Links
in DNA and Causes Sister-Chromated Exchanges in Human Cells.
Mutation Research 58:115-119.
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Rosenkranz, H.S. (1977). Mutagenicity of halogenated alkanes and
their derivatives. Env. Hlth. Perspect. 21:79-84.
Skog, Z. (1950). A toxicological investigation of lower aliphatic
aldehydes I. Toxicity of formaldehyde, acetaldehyde, propionaldehyde,
and butyraldehyde; as well as of acrolein and crotonaldehyde.
Acta Pharmacol. 6:29-318.
Smyth, H.F. (1956). Am. Ind. Hyg. Assn. Quarterly, 17:144.
U.S. EPA (1976a). Preliminary Scoring of Selected Organic Air
Pollutants. EPA-450/3-77-008. PB 264-443.
U.S. EPA (1977a). Potential Industrial Carcinogens and Mutagens.
EPA-560/5-77-005.
U.S. EPA (1977b). Review of the Environmental Fate of Selected
Chemicals. EPA-560/5-77-003.
U.S. EPA (1979). Toxic Substances Control Act Chemical Substances
Inventory, Production Statistics for Chemicals on the Non-Confidential
Initial TSCA Inventory.
Veghelyl, P.V. et^ al. (1978). The fetal alcohol syndro,u_ / symptoms
and pathogenesis. Acta Pediatr. Acad. Sci. Hung. 19:171-189.
Verschueren, K. (1978). Handbook olc Environmental Data on Organic
Chemicals. Van Sostrand Reinhold Co., New York.
Watanabe, F. and S. Sugimoto (1956). Study on the careinogenicity
of aldehyde. 3rd Report. Four cases of sarcomas of ra'-s. appearing
in areas of repeated subcutaneous injections of acetaldtJyde.
Gann. 47:599-601.
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No. 2
Aceton!trlie
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.
-il-
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ACETONITRILE
SUMMARY
Depending on the amount absorbed, acetonitrile may cause
disorders in the central nervous system. Liver, kidneys, car-
diovascular system and gastrointestinal system, regardless of
the route of administration. These effects are attributed to
the metabolic release of cyanide from the acetonitrile mole-
cule, although the parent molecule itself may cause these ef-
fects.
This Hazard Assessment Profile was based largely on in-
formation obtained from NIOSH and its Criteria for a Recom-
mended Standard: Occupational Exposure to Nitriles, (NIOSH,
1978) .
The NIOSH 1972-1974 National Occupational Hazards Survey
estimates that about 26,000 workers are occupationa I ly ex-
posed to ni t r iles .
Major occupational exposures to nitrite occur by inhala-
tion of vapor or aerosols and by skin absorption. Adverse
effects of nitriles are also found from eye contact.
There is no available evidence to indicate that acetoni-
trile has mutagenic or carcinogenic activity. Two studies
have reported teratogenic effects in rats.
Unlike the immediate onset of cyanide toxicity, nitrile
poisoning displays a delayed onset of symptoms.
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I. INTRODUCTION
Ace tonitri le (CHjCN) is a mononitri I e and falls into
the saturated aliphatic class of nitrites. It is a colorless
liquid and has a vapor pressure of 73 mm Hg at 20' C. It has
a molecular weight of 41.05 and a specific gravity of 0.786
(NIOSH, 1978) .
When heated to decomposition, nitriles emit toxic fumes
containing cyanides (Sax, 1968).
Acetonitrile was introduced to the commerical market in
1952, and its industrial uses lie in the manufacture of plas-
tics, synthetic fibres, elastomers, and solvents. Acetoni-
trile is used as a solvent in the extractive distillation
.that ' separates olefins from diolefins, butadiene from buty-
lene, and isoprene from isopentane.
In 1964, 3.5 million pounds of acetonitrile were con-
sumed industrially.
" II. EXPOSURE
A. Water and Food
Pertinent data were not found in the available lit-
erature.
3. Inhalation
Acetonitrile can be readily absorbed from oral mu-
cosa (McKee, et at. 1962; Oalhamn, et at. 1968).
In the workplace, acute poisoning and death have
been reported following the inhalation of acetonitrile (Oe-
~ »
qui dt, et a I .. 1 974) .
Studies have demonstrated that acetonitrile is ab-
sorbed by lung tissue (Oequidt, et at. T974; Grabois, 1955;
Amdur, 1959).
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C. Dermal
Dermal exposures to ac et on.i t r i le have caused ad-
verse ' reactions including death in some cases (NIOSH, 1978).
Acetonitrile has been reported to have been absorb-
ed through the intact skin of rabbits, yielding a dermal
LDjg of 980 mg/kg (Pozzani, et al. 1959).
III. PHARMACOKINETICS
A. Absorption
Acetonitrile is a component of cigarette smoke and
is absorbed by the oral tissues (McKee, et al. 1962; Dalhamn,
et al. 1968) .
Humans have been shown to absorb acetonitrile di-
rectly through the skin and respiratory tract (Zeller, et al.
1969; Amdur, 1959; Dequidt, et al. 1974).
8. Distribution
Studies by McKee, et al. (1962) and Dalhamn, et al.
(1968) show that acetonitrile from cigarette smoking is re-
tained by the lungs.
Tissue distribution studies indicated that mononi-
triles (and acetonitrile, in particular) are distributed uni-
formly in the internal organs of humans and that cyanide me-
tabolites are found predominantly in the spleen, stomach and
skin, and to a lesser extent, in the liver, lungs, kidneys,
hearts, brain, muscle, intestines, and testes (Dequidt, et
al. 1974).
Haguenoer, et al. (1975) exposed three rats to '
2,800 or 25,000 ppm acetonitrile by inhalation. At 25,000
ppm, all three rats died after 30 minutes. Chemical analysis
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of the organs showed that the mean concentration of
acetonitrile in muscle was 136 ug/100 g of tissue and 2,438
ug/100 g of kidney tissue. High acetonitrile excretion or
possible renal blockage were postulated as the causes for the
high renal concentration.
Nitriles and their metabolic products have been de-
tected in urine, blood and tissues (WcKee, et al. 1962).
C. Metabolism
Since human and animal studies report symptoms
characteristics of cyanide poisoning, it is reasonable to
assume that a portion of the effects of exposure to acetoni-
trile is due to the release of the cyanide ion from the par-
ent compound (Zeller, et al. 196*9; Amdur, 1959; Pozzani,
1959).
After absorption, nitriles may be metabolized to an
alpha cyanohydrin or to inorganic cyanide, which is oxidized
to thiocyanate and is excreted in the urine. The C=N group
may be converted into a carboxylic acid derivative and ammon-
ia, or may be incorporated into cyanocobalamine. Ionic cya-
nide also reacts with carboxyl groups and with disulfides
(McKee, et a I. 1 962) .
Haguenoer, et al (1975) injected white male Wistar
rats with varying levels of acetonitrile ranging from 600
trig/kg to 2,340 mg/kg. A-t autopsy, the internal organs showed
that the combined hydrogen cyanide consisted essentially of
t h i ocy ana t es , cyanohydrins and cyanocoba I am i nes . '
0. Excretion
Acetonitrile is found in the morning urine of cigar
ette smokers. Concentrations of acetonitrile range from 2.2
-AT-
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of the organs showed that the mean concentration of
acetoni t ri le in muscle was 136 ^jg/100 g of tissue and 2,438
ug/100 g of kidney tissue. High acet on i t r i Le excretion or
possible renal blockage were postulated as the causes for the
high renal concentration.
Nitriles and their metabolic products have been de-
tected in urine, blood and tissues (tfcKee, et al. 1962).
C. Me tabo I i sm
Since human and animal studies report symptoms
characteristics of cyanide poisoning, it is reasonable to
assume that a portion of the effects of exposure to acetoni-
trile is due to the release of the cyanide ion from the pai —
ent compound (Zeller, et al. 1969; Amdur, 1959; Pozzani,
1959).
After absorption, nitriles may be metabolized to an
a I pha cy anohydr in or to inorganic cyanide, which is oxidized
to thiocyanate and is excreted in the urine. The C=N group
may be converted into a carboxylic acid derivative and ammon-
ia, or may be incorporated into cy anocoba lam i ne . Ionic cya-
nide also reacts with carboxyl groups and with disulfides
(McKee, et al. 1 962) .
Haguenoer, et al (1975) injected white male Wistar
rats with varying levels of acetonitrile ranging from 600
mg/kg to 2,340 mg/kg. At autopsy, the internal organs showed
that the combined hydrogen cyanide consisted essentially of
th i ocy anat es , cyanohydrins and cyanocoba L am i nes . .
0. Excretion
Acetonitrile is found in the morning urine of cigar
ette smokers. Concentrations of acetonitrile range from 2.2
- !<*-
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ug/100 ml urine for those smoking three cigarettes per day up
to 20 ,ug/lOO ml urine for heavy smokers (up to 2.5 packs per
day). The results showed that acetonitrile, once absorbed
into the body, can be excreted unchanged in the urine (McKee,
et al. 1962) .
Acetonitrile is also excreted unchanged in exhaled
air (Haguenoer, et al. 1975).
IV. EFFECTS
A. Careinogenicity
Dorigan, et al. (1976) failed to show significant
carcinogenic effects in a two-year exposure study conducted
with rats.
8. Mutagenicity
Pertinent data were not found in the available lit-
erature.
C. Te ratog en i c i t y
Intraperitonea I (i.p.) administration of acetoni-
trile to pregnant rats produced fetal malformations (Dorigan,
et al. 1976). Schmidt, et al. (1976) have determined skele-
tal abnormalities in rats following i.p. exposure to acetoni-
tri le.
D. Other Reproductive Effects
Pertinent data were not found in the available lit-
erature.
E. Ch roni c Toxicity
In an experiment to stimulate chronic occupational
exposure (seven hours per day, five days per week), 30 rats
were exposed to a concentration of 655 ppm acetonitrile for
- i -)-
-------
90 days. The rats exhibited bronchial inflammation, desqua-
matization and hypersecretion of mucus, and hepatic and renal
lesions. Monkeys exposed by the same regimen, but to 350 ppm
acetonitrile for 91 days, experienced bronchitis and moderate
hemorrhage of the superior and inferior sagi11a I sinuses of
the brain (Pozzani, et al. 1959).
Dogs exposed to acetonitrile at a concentration of
300 ppm for 91 days showed a reduction in body weight as well
as a reduction in hemoglobin and hematocrit values (Pozzani,,
et al. 1959).
Monkeys exposed to 660 ppm acetonitrile per day
showed poor coordination during the second week of exposure
and a monkey exposed to 330 ppm showed hyperexcitabi I ity
toward the end of the 13th week (Pozzani, et al. 1959).
The same -investigators'reported chronic LD^Q
values of 0.85 and 0.95 ml/kg for female rats which i.p. ad-
ministration of acetonitrile.
G. Other Relevant Information
Dogs exposed with lethal quantities of acetonitrile
(16,000 ppm for four hours) showed blood cyanide levels rang-
ing from 305-433 ug/100 ml of blood after three hours (Poz-
zani, et a 1. 1959).
V. AQUATIC TOXICITY
A. Acute
Observed 96-hour LC$Q values for the fathead
minnow (Pimephales prome las) are 1020 mg/l in hardwater aod
1000 ml/I in softwater (Bringmann, 1976). For bluegills,
(L epom i s macrochi rus) andguppies .(Lebist.es reticulatus), the
-------
respective 96-hour values in softwater are 1850 mg/l and 1650
mg/l (Jones, 1971; Henderson, e't at. 1960).
8. Chronic, Plant Effects, and Residue
Pertinent data were not found in the available lit-
erature.
C. Other .Re levant Information
Aceton i trr i le has been observed to damage the bron-
chial epithelium of fish (Belousov, 1969). This compound,
when added to the aqueous environment of roaches and fil-
berts, disrupted blood circulation and protein metabolism and
induced hyperemia, hemorrhages, and the appearance of small
granules in the heart, brain, liver, and gills of fish. The
hepatic glycogen level decreased sharply. CH^CN induced-
death apparently resulted from circulatory disturbances and
necrobiotic changes in the cerebral neurons (Be lousov, 1972).
Acetonitrile at a concentration of 100 mg/l inhib-
ited nitrification in saprophytic organisms (Chekhovskaya,
1966).
VI. EXISTING GUIDELINES
A. Human
A federal occupational standard exists for acetoni-
trile and is based on the TLV for workplace exposure pre-
viously adopted by American Conference of Governmental and
Industrial Hygienists. This TLV is 40 ppm (70 mg/m^) and
is an eight-hour TWA.
3 . Aquat i c
Pertinent data were not found in the available lit-
erature.
-------
REFERENCES
Amdur, M.L. 1959. Accidental group exposure to acetoni-
triLes - A clinical study. J. Occup. Med. 1: 627.
American Conference of Governmental Industrial Hygienists.
Threshold limit values for chemical substances and physical
agents in the workroom environment, with intended changes for
1979. Cincinnati, Ohio. 94 pp.
Belousov, Y.A. 1969. Effects of some chemical agents on the
histophysioLogicaI state of the bronchial epithelium. (Uch.
Zap. Yoroslav. Gos. Pedagog. Inst. USSR 62:126-129). Chem.
Abst. 97853c.
Belousov, Y.A. 1972. Morphological changes in some fish
organs during poisoning. Vlujanie Pestits. Oikikh Zhivotn.
41-45. Chem. Abst. 141567d, Vol. 80.
Sringmann, G. 1976. Vergleichende Vefunde der Schadwirkung
wassergefahrdender. Stoffee gezen Bakterien (Speudomomas
putida) und Blaualgen (Microcystis aeruginosa) nwfaLIwasser .
117-119.
Checkhovskaya, E.V., et al. 196~6. Data for experimental
studies of toxicity of waste waters from aery Ionitri le pro-
duction. (Vodosnabzh. Kanaliz. Gidrotekh. Sooruzh. Mezhved.
Resp. Nauch. USSR SB 1: 83-88). Chem. Abst. 88487k.
Oalhamn, T., et al. 1968. Mouth absorption of various com-
pounds in -cigarette smoke. Arch. Environ. Health 16: 831.
/
Dequidt, J., et al. 1974. Intoxication with acetonitrile
with a report on a fatal case. Eur. J. Toxicol. 7: 91.
Dirigan, et al. 1976. Preliminary sco.ring of selected
organic air pollutants. Environ. Prot. Agency, Contract No.
68-02-1495.
Grabois, B. 1955. Fatal exposure to methyl cyanide. NY
State Dep. Labor Div. Ind. Hyg. Won. Rev. 34: 1,7,8.
Haguenoer, J.M., et al. 1975. Experimental acetonitrile
intoxications - I. Acute intoxicatios by the intraperitoneal
route. Eur.J.Toxicol. 8:94.
Henderson, C., et al. 1960. The effect of some organic
cyanides (nitriles) on fish. Purdue Univ. Eng. Bull. Exp.
Ser. 106: 120.
Jones, H. 1971. Environmental control in the organic and*
petrochemical industries. Noyse Data Corp.
-20-
-------
McKee, H.C., et aL. 1962. Acetonitrile in body fluids re-
lated to smoking. Public Health Rep. 77: 553.
NIOSH. 1978. NIOSH Criteria for a Recommended Standard:
Occupational Exposure to Nitrites. U.S. OHEW, Cincinnati.
Pozzani, V.C., et at. 1959. An investigation of the mammal-
ian toxicity of acetonitri I e. J. Occup. Med. 1: 634.
Sax. N.I. 1968. Dangerous Properties of Industrial Materi-
als, 3rd ed. NY Van Nostrand Reinhold Co.
Schmidt, W., et aL. 1976. Formation of skeletal abnormali-
ties after treatment with aminoacetonitri le and cycy lophosph-
amide during rat fetogenesis. (Verh. Anat. 71:635-638 Ger.)
Chem. Abst. 1515w.
Sunderman, F.W., and J.F. Kincaid. 1953. Toxicity studies
of acetone cyanohydrin and ethylene cyanohydrin. Arch. Ind.
Hyg. Occup, Med. 8: 371.
Zeller, H.V., et aL. 1969. Toxicity of nitrites. Zentralbl
Arbirtsmed Arbeitsschutz. 19: 255.
-ai-
St
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No. 3
Acetophenone
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-22.-
-------
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.
-------
ACETOPHENONE
Summary
Acetophenone is present in various fossil fuel processes and products,
particularly coal and petroleum products. It is used as a flavoring agent
in products for human consumption and as an intermediate in organic
synthetic processes, particularly plastics manufacturing.
No data on the potential for carcinogenic, mutagenic, or teratogenic
effects or on the chronic toxicity of acetophenone were found in the
available literature.
There are no existing OSHA, NIOSH, or ACGIH standards or guidelines.
Acetophenone is a skin irritant and has been shown to cause 'severe eye irri-
tation in rabbits at microgram quantities. Acetophenone is highly toxic to
aquatic life
-------
I. INTRODUCTION
Acetophenone (1-phenylethanone, phenyl methyl ketone, acetyl-
benzene, benzoyl methide, hypnone, C^CQQ^; molecular weight 120.15)
is a liquid with a melting point of 20.5°C and is slightly soluble in
water. Acetophenone is used to impart a pleasant jasmine or orange-
blossom-like odor to perfumes, as a catalyst for the polymerization of ale-
fins, and in organic syntheses, especially as a photosynthesizer (Windholz,
1976). Additionally, it is used as a tobacco flavoring, as a solvent or
intermediate in the synthesis of Pharmaceuticals, and as a by-product of the
coal processing industry. Acetophenone is present in gasoline exhaust at
less than 0.1 to 0.4 ppm (Verschueren, 1977).
II. EXPOSURE
No data on levels of acetophenone in food or water or on other
.potential (inhalation or dermal) exposures were found in the readily avail-
able literature.
III. PHARMACOKINETICS
Information on the absorption, distribution, metabolism, or ex-
cretion of acetophenone was not found in the readily available literature,
despite the fact that it is used in pharmaceutical preparations and in
tobacco, perfume, and other products for human comsumption.
IV. EFFECTS
A. Carcinogenicity, Mutagenicity, Teratogenicity, and Chronic Toxicity
Readily available data are extremely limited. One paper suggests
the possible mutagenicity of acetophenone due to its ability to cause DNA
breakage in bacterial systems following ONA photosensitization (Rahn, et
al. 1974). Because of the particular sensitivity of the bacterial system
to DNA breakage, this information by itself is insufficient to establish
acetophenone as a mutagenic agent.
y
-2S--
-------
There is no additional data readily available on the potential for
carcinogenic, mutagenic, or teratogenic activity by acetophenone. No data
are available on chronic toxicity.
B. Acute Toxicity
Skin irritaion was observed in the rabbit at 10 mg/24 hrs. using
the draize procedure and at 515 mg when applied to the skin in the absence
of the absorbent gauze patch. Severe eye irritation was obtained in the
rabbit following application of 771 ug of acetophenene. The oral LD5Q in
rats was 900 mg acetophenone/kg, while the lethal dose following intra-
peritoneal injection in mice was 200 mg/kg (NIOSH, 1978). Acetophenone is a
hypnotic in high concentrations and was used as an anesthetic in the last
century before less toxic substances were found (Kirk and Othmer, 1963).
C. Other Relevant Information
Based upon the retention time in a gas chromatographic/mass spec-
trographic column, Veith and Austin (1976) suggest a potential for bio-
accumulation of acetophenone. There is no additional information available
to verify this situation, however.
Microbial metabolism of acetophenone as the sole source of carbon
and energy has been demonstrated in pure culture (Cripps, 1975).
V. AQUATIC TOXICITY
Based upon reported values in the literature, acetophenone has
been shown to be highly toxic to aquatic life, (U.S. EPA, 1979). LC5Q
values for fathead minnow are reported for the following time periods: 1
hour, greater than 200 mg/1; 24 hours, 200 mg/1; 48 hours, 163 mg/1; 72
hours, 158 mg/1; and 96 hours, 155 mg/1 (U.S. EPA, 1976).
Acetophenone has been reported to be a major constituent (36 per-
cent) of a weathered bunker fuel. This suggests that it may .be present in
large quantity following spills of some bunker fuels (Guard, et al. 1975).
-------
Bunker fuels are highly variable form refinery to refinery; thus, a blanket
statement as to percentage composition of acetophenone or other constituents
cannot be made.
VI. EXISTING GUIDELINES AND STANDARDS
There are no existing guidelines and standards from OSHA, NIOSH,
or ACGIH. Similarily, no ambient water quality standards for acetophenone
exist.
-27-
-------
REFERENCES
Cripps, R.E. 1975. The microbial metabolism of acetophenone: metabolism
of acetophenone and some chloroacetophenones by an Arthrobacter species.
Biochem. Jour. 152: 233.
Guard, H.E., et al. 1975. Identification and potential biological effects
of the major components in the seawater extract of a bunker fuel. Bull.
Environ. Contam. Toxicol. 14: 395.
Kirk, R.E. and D.F. Othmer. 1963. Kirk-Othmer. Encyclopedia of Chemical
Technology. 2nd ed. J. Wiley and Sons, Inc., New York.
National Institute for Occupational Safety and Health. 1978. Registry of
Toxic Effects of Chemical Substances. E. Fairchild (ed.). U.S. Department
of Health, Education, and Welfare. Cincinnati, Ohio.
Rahn, R.O., et al. 1974. Formation and chain breaks and thymine dimers in
ONA upon photosensitization at 313 nm with acetophenone, acetone, or benzo-
phenone. Photochem. Photobio. 19: 75.
U.S. EPA. 1976. Acute Toxicity of Selected Organic Compounds to Fathead
Minnows. EPA-600-3-76-097. U.S. EPA Environmental Research Lab., Duluth,
Minnesota.
U.S. EPA. 1979. Biological Screening of Complex Samples From In-
dustrial/Energy Processes. EPA-600-8-79-021. U.S. EPA, Research Triangle
Park, North Carolina.
Veith, G.O. and N.M. Austin. 1976. Detection and isolation of bioaccumu-
latable chemicals in complex effluents. In: L.H. Keith (ed.), Identifi-
cation and Analysis of Organic Pollutants in Water. Ann Arbor Science
Publishers, Inc., Ann Arbor, MI. p. 297.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chem-
icals. Van Nostrand Reinhold Company, New York.
Windholz, M. (ed.) 1976. Merck Index. 9th ed. Merck and Co., Rahway,
N.J.
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No. 4
Acetyl Chloride
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.
-30-
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ACETYL CHLORIDE
Summary
Acetyl chloride is an irritant and a corrosive. Cutaneous exposure
results in skin burns, while vapor exposure causes extreme irritation of the
eyes and mucous membranes. Inhalation of two ppm acetyl chloride has been
found irritating to humans. Death or permanent injury may result after
short exposures to small quantities of acetyl chloride. An aquatic toxicity
rating has been estimated to range from 10 to 100 ppm.
However, acetyl chloride reacts violently with water. Thus, its half-
life in ambient water should be short and exposure from water should be nil.
The degradation products should likewise pose no exposure problems if the pH
of the water remains stable.
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ACETYL CHLORIDE
I. INTRODUCTION
Acstyl chloride (ethanoyl chloride; CH^COCl; molecular weight, 78.50)
is a colorless, fuming liquid with a pungent odor, a boiling point of
51-52°C, and a melting point of -112°C (Windholz, 1976). It is used as
an acetylating agent in testing for cholesterol and in the qualitative
determination of water in organic liquids. It is miscible with benzene,
chloroform, ether or glacial acetic acid (Windholz, 1976). In the presence
of water or alcohol, however, acetyl chloride hydrolyzes violently to form
hydrogen chloride and acetic acid. Phosgene fumes, which are highly toxic,
are emitted when acetyl chloride is heated to decomposition (Sax, 1975).
The 1975 U.S. annual production of acetyl chloride was approximately
4.54 x 10 grams (SRI, 1976). During transportation, this chemical should
be stored in a cool, well-ventilated place, out of direct sunlight, and away
from areas of high fire hazard; it should periodically be inspected (Sax,
1975). Acetyl chloride must be protected from water (Windholz, 1976).
II. EXPOSURE
Acetyl chloride reacts violently with water (see above). Thus, its
half-life in ambient water should be short and exposure from water should be
nil. The degradation products should likewise pose no exposure problems if
the pH of the water remains stable. Internal exposure to acetyl chloride
will most likely occur through inhalation of the vapor, or, on rare occa-
sions, through ingestion. Skin absorption is very unlikely although severe
burns would be expected.
III. PHARMACOKINETICS
9
Pertinent data could not be located in the available literature.
-3.2-
-------
IV. EFFECTS
Acetyl chloride is an irritant and a corrosive. Cutaneous exposure
results in skin burns. Vapor exposure causes extreme irritation of the eyes
and mucous membranes (Windholz, 1976). Inhalation of 2 ppm acetyl chloride
was found irritating to humans (Handbook of Organic Industrial Solvents,
1961). Death or permanent injury may result after very short exposures to
small quantities of acetyl chloride (Sax, 1975).
Because the toxicity of acetyl chloride might be expected to pattern
that of its breakdown product hydrogen chloride (HCL), LC. value (the
lowest concentration of a substance in air which has been reported to cause
death in humans or animals) for HC1 might be indicative of its toxicity.
This value in humans is 1000 ppm for one minute (Mason, 1974).
Pertinent information could not be located in the available literature
regarding the carcinogenicity, mutagenicity, teratogenicity and chronic
toxicity of acetyl chloride.
V. AQUATIC TOXICITY
Acetyl chloride has been shown to be toxic to aquatic organisms in the
ranges of 10 to 100 ppm (Hann and Jensen, 1974). No other information has
been found in the literature.
VI. EXISTING GUIDELINES AND STANDARDS
NO standards for acetyl chloride have been reported. However, a
ceiling limit of 5 ppm has been reported for hydrogen chloride (the most
irratating hydrolysis product of acetyl chloride) in industrial exposures.
(Mason, 1974).
2"
-33-
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ACETYL CHLORIDE
REFERENCES
Handbook of Organic Industrial Solvents, 2nd ed. 1961. Cited in: Registry
of toxic effects of chemical substances. NIOSH (DHEW) Pub. No. 79-100, p. 4.
Hann, W. and P.A. Jensen. 1974. Water quality characteristics of hazardous
materials. Vol. 2. Texas A&M University.
Mason, R.V. 1974. Smoke and toxicity hazards in aircraft cabin furnish-
ings. Ann. Occup. Hyg. 17: 159.
Sax, N.I. 1975. Dangerous properties of industrial materials, 4th ed. Van
Nostfand Reinhold Co., New York, p. 355.
Stanford Research Institute. 1976. Chemical economics handbook.
Windholz, M. -(ed.) 1976. The Merck Index, 9th ed. Merck and Co., Inc.,
Rahway, N.J., p. 11.
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No. 5
Acrolein
/ 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.
-36,-
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ACROLEIN .
SUMMARY
Acrolein has not been shown to be a carcinogen or cocarcinogen in in-
halation experiments. Acrolein is mutagenic in some assay systems. Infor-
mation on teratogenicity is not available. The only reported chronic effect
of acrolein in humans is irritation of the mucous membranes. Chronic expo-
sure of Syrian golden hamsters to acrolein in the air caused reduced body.
weight, gains and inflammation and epithelial '• metaplasia in the nasal
cavity. In addition, females had decreased liver weight, increased lung
weight, and slight hematologic changes.
Acrolein has been demonstrated to be acutely toxic in freshwater organ-
isms at concentrations of 57 to 160 pg/1. A single marine fish tested was
somewhat more resistant with a 48-hour LC5Q of 240 jug/1. Toxicity to
marine invertebrates was comparable to that of freshwater organisms.
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ACROLEIN
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Acrolein (U.S. EPA, 1979).
Acrolein (2-propenal; CH-=CHCHO; molecular weight 56.07) is a flamm-
able liquid with a pungent odor. It has the following physical and chemical
properties (Weast, 1975; Standen, 1967):
Melting Point -86.95°C
Boiling Point Range 52.5 - 53.5°C
Vapor Pressure 215mm Hg..at 20°C
Solubility Water: 210.8 percent by weight
at 20°C
Density 0.8410 at 20°C
Production (Worldwide) 59 kilotons (Hess, et al. 1978)
Capacity (Worldwide) 102 kilotons/year
Capacity (United States) 47.6 kilotons/year
Acrolein is used as a biocide, crosslinking agent, and tissue fix-
ative. It is used as an intermediate throughout the chemical industry.
The fate of acrolein in water was observed in natural channel waters
(Bowmer. and Higgins, 1976). No equilibrium was reached between dissipating
acrolein and degradation products, with the dissipating reaction apparently
being continued to completion. Degradation and evaporation appear to be the
major pathways for loss, while a smaller amount is lost through absorption
and uptake in aquatic organisms and sediments (Bowmer and Sainty,. 1977;
Hopkins and Hattrup, 1974).
II. EXPOSURE
There is no available evidence that acrolein is a contaminant of pot-
able water or water supplies (U.S. EPA, 1979).
Acrolein is a common component of food. It is commonly geperated
during cooking or other processing, and is sometimes produced as an unwanted
-------
by-product in the fermentation of alcoholic beverages (Izard and Libermann,
1978; Kishi, et al. 1975; Hrdlicka and Xuca, 1965; Boyd, et al. 1965;
Rosenthaler and Vegezzi, 1955). However, the data are insufficient to
develop a conclusive measure of acrolein exposure from food processing or
cooking.
The-U.S. EPA (1979) has estimated the weighted average bioconcentration
factor for acrolein to be 790 for the edible portions of fish and shellfish
consumed by Americans. This estimate is based on measured steady-state bio-
concentration studies in bluegills.
Atmospheric acrolein is generated as a combustion product of fuels and
of cellulosic materials (e.g., wood and cigarettes), as an intermediate in
atmospheric oxidation of propylene, and as a component of the volatiles pro-
duced by heating organic substrates (U.S. EPA, 1979). Acrolein is present
in urban smog; average concentrations of 0.012 - 0.018 mg acrolein/m and
peak concentrations of 0.030 - 0.032 mg acrolein/m were noted in the air
of Los Angeles (Renzetti and Bryan, 1961; Altshuller and McPherson, 1963).
Diesel exhaust emissions contained 12.4 mg acrolein/m ; trace amounts of
acrolein were present in samples taken from an area of traffic; and no acro-
lein was detected in ambient air from an open field (sensitivity of measure-
ment was below one part per million) (Bellar and Sigsby, 1970). Acrolein
content of smoke from tobacco and marijuana cigarettes ranged from 85 to 145
ug/cigarette (Hoffman, et al. 1975; Horton and Guerin, 1974). Acrolein was
detected at levels of 2.5 - -30 mg/m at 15 cm above the surface of pota-
toes or onions cooking in edible oil (Kishi, et al. 1975).
-------
III. PHARMACOKINETICS
A. Absorption
Total respiratory tract retention of acrolein in anesthetized dogs
was 77 to 86 percent (Egle, 1972).
8. Distribution
Pertinent data were not found in the available literature.
C. Metabolism
Relatively little direct information is available on the metabolism
of acrolein. _In vitro, acrolein can serve as a substrate for alcohol dehy-
drogenases from human and horse liver (Pietruszko, et al. 1973). J.n_ vivo
studies in rats indicate that a portion of subcutaneously administered acro-
lein is converted to 3-hydroxylpropylmercapturic acid (Kaye and Young, 1972;
Kaye, 1973). Acrolein undergoes both spontaneous and enzymatically cata-
lyzed conjugation with glutathione (Boyland and Chasseaud, 1967; Esterbauer,
et al. 1975). The low pH's encountered in the upper portions of the gastro-
intestinal tract probably would rapidly convert acrolein to saturated alco-
hol compounds (primarily beta propionaldehyde) (U.S. EPA, 1979). As /several
of the toxic effects of acrolein are related to the high reactivity of the
carbon-carbon double bond, saturation of that bond should result in detoxi-
fication (U.S. EPA, 1979).
D. Excretion
In rats given single subcutaneous injections of acrolein, 10.5 per-
cent of the administered dose was recovered in the urine as 3-hydroxy-
propylmercapturic- acid after 24 hours (Kaye and Young, 1972; Kaye, 1973).
-wo-
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IV. EFFECTS
A. Carcinogenicity
One-year and lifespan inhalation studies with hamsters indicate
that acrolein is not a carcinogen or cocarcinogen (Feron and Kruysse, 1977;
National Cancer Institute, 1979).
B. Mutagenicity
Both positive and negative results have been obtained in muta-
genicity assays. Acrolein induced sex-linked mutations in Drosophila
melanoqaster (Rapoport, 1948) and was mutagenic for DMA polymerase-deficient
Escherichia coli (Bilimoria, 1975) and Salmonella typhimurium (Bignami, et
al. 1977). Mutagenic activity was not detected in the dominant lethal assay
in ICR/Ha Swiss mice (Epstein, et al. 1972) or in a strain of E. coli used
for detecting forward and reverse mutations (with or without microsomal
activation) (Ellenberger and Mohn, 1976; 1977). Acrolein was weakly muta-
genic for Saccharomyces cerevisiae (Izard, 1973).
C. Teratogenicity
Pertinent data were not found in the available literature.
C. Other Reproductive Effects
Exposure of male and female rats to 1.3 mg/m acrolein vapor for
26 days did not have a significant effect on the number of pregnant animals
or the number and mean weight of fetuses (Bouley, et al. 1976).
E. Chronic Effects
Little information is available on the chronic effects of acrolein
on humans. An abstract of a Russian study indicates that occupational expo-
sure to acrolein (0.8 to 8.2 mg/m ), methylmercaptan (0.003 to 5.6
•
mg/m ), methylmercaptopropionaldehyde (0.1 to 6.0 mg/m ), formaldehyde
(0.05 to 3.1 mg/m3), and acetaldehyde (0.48 to 22 mg/m3) is associated
-M)-
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with irritation of the mucous membranes. This effect is most frequent in
women working for less than one and greater than seven years (Kantemirova,
1975). Acrolein is known to produce irritation of the eyes and nose (Albin
1962; Pattle and Cullumbine, 1956; Sim and Rattle, 1957) and is thought to
be responsible, at least in part, for the irritant properties of
photochemical smog (Altshuller, 1978; Schuck and Renzetti, 1960) and
cigarette smoke (Weber-Tschopp, et al. 1976a; 1976b; 1977).
In the only published chronic toxicity study on acrolein in animals
(Feron and Kruysse, 1977), male and female Syrian golden hamsters were ex-
posed to acrolein at 9.2 mg/m in air, seven hours per day, five days per
week, for 52 weeks. During the first week only, animals evidenced signs of
eye irritation, salivated, had nasal discharge, and were very restless.
During the exposure period, both males and females had reduced body weight
gains compared to control groups. Survival rate was unaffected. Slight
hematological changes, increased hemoglobin content and packed cell volume,
decreases in liver weight (-16 percent), and increases in lung weights (+32
percent) occurred only in females. In both sexes, the only pathological
changes in the respiratory tract were inflammation and epithelial metaplasia
in the nasal cavity.
In a study of subacute oral exposure, acrolein was added to the
drinking water of male and female rats at 5 to 200 mg acrolein/1 for 90 days
(Newell, 1953). No hematologic, organ-weight, or pathologic changes could
be attributed to acrolein ingestion.
F. Other Relevant Information
Acrolein is highly reactive with thiol groups. Cysteine and other
f
compounds containing thiol groups antagonize the toxic effects of acrolein
-HZ-
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(Tillian, et al. 1976; Low, et al. 1977; Sprince, et al. 1973; Munsch, et
al. 1973;1974; Whitehouse and Beck, 1975). Ascorbic acid also antagonizes
the toxic effects of acrolein (Sprince, et al. 197S).
The effects of acrolein, on the adrenocortical response of rats
unlike those of DDT and parathion, are not inhibited by pretreatment with
phenobarbital and are only partially inhibited by dexamethason (Szot and
Murphy, 1970). Pretreatment of rats with acrolein significantly prolongs
hexobarbital and pentobarbital sleeping time (Jaeger and Murphy, 1973).
V. AQUATIC TOXICITY
A. Acute Toxicity
A relatively narrow range of acute toxicity to six species of
freshwater fish has been reported for acrolein (U.S. EPA, 1979). LCqQ
values ranged from 61 to 160 /ug/1 with fathead minnows, (Pimephales
promelas), being most sensitive and largemouth bass, (Microoterus
salmoides), the most resistant of the species tested. Results from 7 static
bioassays varying.from 24 to 96 hours in duration were reported. The fresh-
water invertebrate Daphnia magna was as sensitive to acrolein as freshwater
fish with 48-hour static LC,,, values of 59 and 80 jug/1 being reported in
two individual studies. The longnose killifish, (Fandulus similis), was the
only marine species tested for acute toxicity of acrolein; a 48-hour flow-
through LCcg of 150 /jg/1 was obtained. The eastern oyster, (Crassostrea
virginica), and adult brown shrimp, (Penacus aztecus), were the most sensi-
tive species tested an EC5n value of 55 pg/1 based on 50% decrease in
shell growth of oysters and an EC-n value of 100 based on loss of equi-
librium of brown shrimp (Butler, 1965). Adult barnacles were more resistant
»
in static assays with 48-hour LC50 values of 1,600 and 2,100 fig/1 being
reported.
-------
3. Chronic Toxicity
In a chronic life cycle test with the freshwater fathead minnow,
Pimephales promelas, survival of newly hatched second generation fry was
reduced significantly at 42 but not 11 ug/1, leading to a chronic value of
21.8 ug/1 (Macek, et al. 1976). A comparable value of 24 ug/1 was obtained
from reduced survival of three generations of Daphnia maqna. Chronic data
for marine organisms was not available.
C. Plant Effects
Pertinent data relating the phytotoxitity of freshwater marine
plants could not be located in the available literature.
D. Residues
A bioconcentfation factor of 344 was obtained for radio labeled
acrolein administered to bluegills, (Lepomis macrochivas). A biological
half-life greater than seven days was indicated (U.S. EPA. 1979).
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
Based on the use of subacute toxicological data for rats (no
observable effect level of 1.56 mg/kg body weight) and an uncertainty factor
of 1000, the U.S. EPA (1979) has derived a draft criterion of 6.50 ug/1 for
acrolein in ambient water. This draft criterion level corresponds to the
calculated (U.S. EPA, 1979) acceptable daily intake of 109 pg.
The ACGIH (1977) time-weighted average TLV for acrolein is 0.1 pom
(0.25 mq/m^}. The same value is recommended by OSHA (39 FR 23540). This
-------
standard was designed to "minimize, but not. entirely prevent, irritation to
all exposed individuals" (ACGIH, 1974).
The FDA permits acrolein as a slime-control substance in the manu-
facture of paper and paperboard for usage in food packaging (27 FR 46) and
in the treatment of food starch (28 FR 2676) at not more than 0.6 percent
acrolein.
B. Aquatic
The draft criterion for protecting freshwater organisms is 1.2 ug/1
as a 24-hour average not to exceed 2.7 ug/1. For marine life, the draft
criterion has been proposed as 0.88 ug/1, not to exceed 2.0 ug/1.
-------
ACROLEIN
REFERENCES
Albin, T. B. 1962. Page 234. _ln: C.W. Smith, ed. Handling
and toxicology, in acrolein. John Wiley and Sons, Inc.,
New York.
Altshuller, A. P. 1978. Assessment of the contribution
of chemical species to the eye irritation potential of photo-
chemical smog. Jour. Air Pollut. Control Assoc. 28: 594.
Altshuller, A. R. , and S. P. McPherson. 1963. Spectrophoto-
metric analysis of aldehydes in the Los Angeles atmosphere.
Jour. Air Pollut. Control Assoc. 13: 109.
American Conference of Governmental Industrial Hygienists.
1974. Documentation of the threshold limit value. 3rd ed.
American Conference of Governmental Industrial Hygienists.
1977. Threshold limit values for chemical substances in
workroom air.
Bellar, T. A., and J. E. Sigsby. 1970. Direct gas chromato-
graphic analysis of low molecular weight substituted organic
compounds in emissions. Environ. Sci. Technol. 4: 150.
Bignami, M. , et al. 1977. Relationship between chemical
structure and mutagenic activity in some pesticides: The
use of Salmonella typhimur ium and Aspergillus nidulans.
Mutat. ReTI ?b :
Bilimoria, M. H. 1975. Detection of mutagenic activity
of chemicals and tobacco smoke in bacterial system. Mutat.
Res. 31: 328.
Bouley, G. , et al. 1976. Phenomena of adaptation in rats
continuously exposed to low concentrations of acrolein.
Ann. Occup. Hyg . 19: 27.
Bowmer, K. H. , and M. L. Higgins. 1976. Some aspects of
the persistence and fate of acrolein herbicide in water.
Arch. Environ'. Contain. Toxicol. 5: 87.
Bowmer, K. H., and G. R. Sainty. 1977. Management of aqua-
tic plants with acrolein. Jour. Aquatic Plant Manage. 15:
40.
Boyd , E. N., et al. 1965. Measurement of monocarbonyl classes
in cocoa beans and chocolate liquor with special reference
to flavor. Jour. Food Sci. 30: 854.
-1-1(0-
-------
Boyland, E., and L. F. Chasseaud. 1967. Enzyme-catalyzed
conjugations of glutathione with unsaturated compounds.
Biochem. Jour. 104: 95.
Butler, P. A. 1965. Commercial fisheries investigations.
Effects of pesticides on fish and wildlife, 1964 research
•findings Fish Wildl. Serv. U.S. Fish Wildl. Serv. Circ.
Egle, J. L., Jr. 1972.' Retention of inhaled formaldehyde,
propionaldenyde, and acrolein in the dog. Arch. Environ.
Health 25: 119.
Ellenberger, J., and G. R. Mohn. 1976. Comparative mutageni-
city testing of cyclophosphamide and some of its metabolites.
Mutat. Res. 38: 120.
Ellenberger, J., and G. R. Mohn. 1977. MUtagenic activity
of major mammalian metabolites of cyclophosphamide toward
several genes of Escherichia coli. Jour. Toxicol. Enviorn.
Health 3: 637.
Epstein, S. S., et al. 1972. Detection of chemical mutagens
by the dominant lethal assay in the mouse. Toxicol. Appl.
Pharmacol. 23: 288.
Esterbauer, H. , et al. 1975'. Reaction of glutathione with
conjugated carbonyls. Z. Naturforsch. C: Biosci. 30c:
466.
Feron, V. J., and A. Kruysse. 1977. Effects of exposure
to acrolein vapor in hamsters simultaneously treated with
benzo (a)pyrene or diethylnitrosamine. Jour. Toxicol. Environ,
Health 3: 379.
Hess, L. B. , et al. 1978. Acrolein and derivatives. In
Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed.
Interscience Publishers, New York.
Hoffman, D., et al. 1975. On the carcinogenicity of mari-
juana smoke. Recent Adv. Phytochem. 9: 63.
Hopkins, D. M., and A. R. Hattrup. 1974. Field evaluation
of a method to detect acrolein in.irrigation canals. U.S.
PB Rep. No. 234926/4GA. Natl. Tech. Inf. Serv.
Horton, A. D., and M. R. Guerin. 1974. Determination of
acetaldehydes and acrolein in the gas phase of cigarette
smoke using cryothermal gas chromatography. Tob. Sci. 18:
19-
Hrdlicka, J., and J. Kuca. 1965. The changes of carbonyl
comoounds in the heat-processing of meat. Poultry Sci.
44:27.
-------
Izard, C. 1973. Recherches sur les effets mutagenes de
I1 acroleine et des ses deux epoxydes: le glycidol et le
glycidal, sur Saecharomyces cerevisiae, C.R. Acad. Sci.
Ser. D. 276: 303T
Izard, C., and C. Libermann. 1978. Acrolein. Mutat. Res.
47: 115.
Jaeger, R. J., and S. D. Murphy. 1973. Alterations of
barbiturate action following 1,1-dichloroethylene, corti-
costerone, or acrolein. Arch. Int. Pharmacodyn. Ther. 205:
281.
Kantemirova, A. E. 1975. Illness with temporary work dis-
ability in workers engaged in acrolein and methylmercaptopro-
pionaldehyde (MMP) production. Tr. Volgogr. Cos. Med. Inst.
26: 79. Chem. Abst. 88: 109868g.
Kaye, C. M. 1973. Biosynthesis of mercapturic acids from
allyl alcohol, allyl esters, and acrolein. Biochem. Jour.
134: 1093.
Kaye, C. M. , and L. Young. 1972. Synthesis of mercapturic
acids from allyl compounds in the rat. Biochem. Jour. 127:
87.
Kishi, M., et al. 1975. Effects of inhalation of the vapor
from heated edible oil on the circulatory and respiratory
systems in rabbits. Shokuhin Eiseigaku Zasshi. 16: 318.
Low, E. S., et al. 1977. Correlated effects of cigarette
smoke components on alveolar macrophage adenosine triphos-
phatase activity and phagocytosis. Am. Rev. Respir. Dis.
115: 963.
Macek, K. J., et al. 1976. Toxicity of four pesticides
to water fleas and fathead minnows: Acute and chronic toxi-
city of acrolein, heptachlor, endosulfan, and tribluralin
to the water flea (Daphnia magna) and the fathead minnow
(Primephales prgmelas). EPA~5UU/3-76-099. U.S. Environ.
Prot. Agency.
Munsch,. N., et al. 1973. Effects of acrolein on DNA syn-
thesis in vitro. Fed. Eur. Biochem. Soc. Lett. 30: 286.
Munsch, N., et al. 1974. In vitro binding of tritium labeled
acrolein to regenerating rat liver DNA polymuase. -Experi-
mentia 30: 1234.
National Cancer Institute. 1979. Personal communication
from Sharon Feeney.
-Newell, G. W. 1958. .Acute and subacute toxicity of acro-
lein. Stanford Res. Ins. SRI Project No. 5-868-2. Summar-
ized in.Natl. Acad. Sci. 1977.
-------
Pattle, R. E., and H. Cullumbine. 1956. Toxicity of some
atmospheric pollutants. Brit. Med. Jour. 2: 913.
Pietruszko, R., et al. 1973. Comparison of substrate specifi-
city of alcohol dehydrogenases from human liver, horse liver,
and yeast towards saturated and 2-enoic alcohols and alde-
hydes. Arch. Biochem. Biophys. 159: 50.
Rapoport., I. A. 1948. Mutations under the influence of
unsaturated aldehydes. Dokl. Akad. Nauk. (U.S.S.R.), 61:
713. Summarized in Izard and Libermann, 1978.
Renzetti, N. A., and R. J. Bryan. 1961. Atmospheric samp-
ling for aldehydes and eye irritation in Los-Angeles smog
- I960. Jour. Air Pollut. Control Assoc. 11: 421.
Rosenthaler, L. , and G. Vegezzi. 1955. Acrolein in alco-
holic liquors. Z. Lebensm.-Untersuch. u. - Forsch. 102:
117.
Schuck, E. A., and N. A. Renzetti. 1960. Eye irritants
formed during photooxidation of hydro-carbons in the pre-
sence of oxides of nitrogen. Jour. Air Pollut. Control
Assoc. 10: 389.
Sim, V. M., and R. E. Pattle. 1957. Effect of possible
smog irritants on human subjects. Jour. Am. Med. Assoc.
165: 1908.
Sprince, H., et al. 1978. .Ascorbic-acid and cysteine pro-
tection against aldehyde toxicants of cigarette smoke.
Fed. Proc. 37: 247.
Standen, A., ed.. 1967. Kirk-Othmer Encyclopedia of Chemi-
cal Technology. Interscience Publishers, New York.
Szot, R. J., and S. D. Murphy. 1970. Phenobarbital and
dexamethasone inhibition of the adrenocortical response
of rats to toxic chemicals and other stresses. Toxicol.
Appl. Pharmacol. 17: 761.
Tillian, H. M., et al. 1976. Therapeutic effects of cys-
teine adducts of alpha, beta-unsaturated aldehydes on ehr-
lich ascites tumor of mice. Eur. Jour. Cancer 12: 989.
U.S. EPA. 1979. Ambient Water Quality Criteria: Acrolein.
(Draft)
Weast, R. C., ed. 1975. Handbook of chemistry and physics.
56th ed. CRC Press, Cleveland, Ohio. '
Weber-Tschopp, A., et al. 1976a. Air pollution and irri-
tation due to cigarette smoke. Soz.-Praeventivmed 21: 101.
-------
Weber-Tschopp, A., et al. 1976b. Objective and subjective
physiological effects of passive smoking. Int. Arch. Occup,
Environ. Health 37: 277.
Weber-Tschopp, A., et al. 1977. Experimental irritating
effects of acrolein on man. Int. Arch. Occup. Environ.
Health 40: 117.
Whitehouse, M. W., and F.W.J. Beck. 1975. Irritancy of
cyclophosphamide-derived aldehydes (acrolein, chloracetalde-
hyde) and their effect on lymphocyte distribution _in vivo;
Protective effect of thiols and bisulfite ions. Agents
Actions 5: 541.
-so-
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No. 7
Acrylonitrile
HealCh and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL-30, 1980
-SI-
-------
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 chenical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
acrylonitrile and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
ACRYLONITRILE
Summary
Acrylonitrile is the most extensively produced aliphatic nitrile and
ranks 45th on the list of high-volume chemicals produced in the U.S. Chron-
ic exposure to acrylonitrile produces mild liver damage and functional dis-
orders of the central nervous system, cardiovascular and hemopoietic sys-
tems. Acrylonitrile has shown mutagenic activity in Drosophila and bacter-
ia. This compound is teratogenic in rats whether exposure is by inhalation
or ingestion in drinking water. There are. both animal and epidemiologic
data to suggest "that acrylonitrile may be a human carcinogen.
The fathead minnow has an observed 96-hour LC5Q value ranging from
10,100 .to 18,100 ug/1 depending on test condition and a 30-day LC5Q value
of 2,600 ug/1. For the freshwater invertebrate, -Daohnia magna, a reported
48-hour LC=Q value is 7,550 jug/1 with no adverse effects to concentrations
as high as 3,600 ug/1 in a life cycle test. A saltwater fish has an observ-
ed 96-hour LC50 of 24,500 jug/1. A bluegill in a 28-day study bioconcen-
trated acrylonitrile 48-fold with a half-life of 4-7 days.
-------
ACRYLONITRILE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Acrylonitrile (U.S. EPA, 1979).
Acrylonitrile (OL=CHCN) is an explosive, flammable liquid having a
normal boiling point of 77°C and a vapor pressure of 30 mm Hg (20°C).
Currently, 1.6 billion pounds per year of acrylonitrile are manufactured in
the United States. The major use of acrylonitrile is in the manufacture of
copolymers for the production. of acrylic and modacrylic fibers. Acryloni-
trile has been used as a fumigant; however, all U.S. registrations for this
use were voluntarily withdrawn as of August 8, 1978 (U.S. EPA, 1979).
II. EXPOSURE
A. Water
While no data on monitoring of water supplies for the presence of
acrylonitrile were found in the literature, potential problems may exist.
Possible sources of acrylonitrile in the aqueous environment are: (a) dump-
ing of chemical wastes, (b) leaching of wastes from industrial landfills,
(c) leaching of monomers from polymeric acrylonitrile, and (d) precipitation
from rain. Acrylonitrile is short-lived in the aqueous environment; a 10
ppm solution was completely degraded after 6 days in Mississippi River water
(Midwest Research Institute, 1977).
B. Food
There is no data on the levels of acrylonitrile in food. However,
acrylonitrile may contaminate food by leaching of the monomer from polyacry-
lonitrile containers (National Resources Defense Council, 1976). The U.S.
EPA (1979) has estimated the weighted average bioconcentration factor' for
-------
acrylonitrile to be 110 for the edible portions of fish and shellfish con-
sumed by Americans. This estimate is based on steady-state bioconcentration
studies in bluegills.
C. Inhalation
NIOSH (1978) estimated that 125,000 workers are exposed to acrylo-
nitrile each year. Acrylonitrile may be liberated to the atmosphere via
industrial processes or by the burning of polyacrylonitrile fiber (Monsanto,
1973). Data could not be found in the available literature regarding the
concentrations of acrylonitrile in ambient air.
III. PHARMACOKINETICS
A. Absorption
When orally administered to rats, essentially all of the acryloni-
• trile is absorbed (Young, et al. 1977).
B. Distribution
In rabbits, after administration of a 30 mg/kg dose, acrylonitrile
rapidly disappeared from the blood; only 1 mg/kg .remained after 4 hours
(Hashimoto and Kanai, 1965). In rats the metabolites of acrylonitrile dis-
tributed to the stomach wall, erythrocytes, skin, and liver (Young, et al.
1977). .
C. Metabolism
Earlier reports (Giacosa, 1883; Meurice, 1900) indicated that most
aliphatic nitriles are metabolized to cyanide which is then detoxified to
thiccyanate.. A more recent report concluded that acrylonitrile exerts its
toxicity by the metabolic release of cyanide ion, and that the relative abi-
lity of various species to convert CN~ to SCN~ determined their suscep-
tibility -to the toxic action of acrylonitrile (Srieger, et al. 1952). Other
facts, however, suggest that acrylonitrile toxicity is due in part, to the
-------
acrylonitrile molecule itself or other unknown metabolite(s) rather than
just to the cyanide functional group (U.S. EPA, 1979). In a comprehensive
tracer study with rats Young, et al. (1977) found three uncharacterized
metabolites as well as CCL after acrylonitrile administration. Also, cya-
noethylated mercapturic acid conjugates have been detected after administra-
tion of acrylonitrile (U.S. EPA, 1979).
0. Excretion
Urinary excretion of thiocyanate after acrylonitrile administration
ranges from 4-33 percent of the administered dose --depending on the species
(U.S. EPA, 1979). Urinary excretion also depends on route of administration
(Gut, et al. 1975).
IV. EFFECTS
A. Carcinogenicity
In two studies rats received acrylonitrile in the drinking water at
concentrations of 0, 35, 100 and 300 mg/1, which is equivalent to daily dos-
ages of approximately 4, 10, 30 mg/kg body weight respectively, excess mam-
mary tumors and tumors of the ear canal and nervous system were noted (Nor-
ris, 1977; Quast, et al. 1977). Both the intermediate and the highest doses
produced increased tumor incidences. In rats administered acrylonitrile in
olive oil by stomach tube at 5 mg/kg body weight 3 times per week for 52
weeks, a slight enhancement of the incidence of mammary tumors, forestomach
papillomas and acanthomas, skin carcinomas, and encephalic tumors has been
reported (Maltoni, et al. 1977). Also, exposure of rats by inhalation (40,
20, 10, and 5 ppm for 4 hours daily, 5 times/week) for 52 weeks caused in-
creases in tumor incidence (Maltoni, et al. 1977). It should be pointed out
*
that possible impurities found in the acrylonitrile -used by various investi-
gators might determine the carcinogenic effect. The specific role of these
impurities has not yet been determined (U.S. EPA, 1979).
-57-
-------
Retrospective studies on workers in a textile fiber plant (O'Berg,
1977) and on workers in the polymerization recovery and'laboratory areas of
a 3.F. Goodrich plant (Monson, 1977) have shown higher than expected inci-
dences of cancers of all sites in workers exposed to acrylonitrile. The
greatest increase was noted with lung cancer. It should be noted that these
workers were exposed to other chemicals in their working environment.
8. Mutagenicity
Acrylonitrile is a weak mutagen in Drosophila melanogastar (Benes
and Sram, 1969); although toxicity limited this testing. Milvy and Wolff
(1977) reported mutagenic activity for acrylonitrile in Salmonella tvphimur-
iunv with a mammalian liver-activating system. In Escherichia coli mutagenic
activity was observed without an activating system (Venitt, et al. 1977).
C. Teratogenicity
. Studies in pregnant rats demonstrated that acrylonitrile adminis-
tered by gavage at 65 mg/kg/day caused fetal malformations (Murray, et al.
1976). These malformations included acaudea, short-tail, short trunk, miss^-
ing vertebrae, and right-sided aortic arch. ' In a subsequent study, Murray,
et al. (1978) concluded that in pregnant rats exposed to 0, 40, or 80 ppm of
acrylonitrile by inhalation, teratogenic effects in the offspring were seen
at 80 ppm but not -40 ppm. Significant maternal toxicity was found at both
80 and 40 ppm, as well as in the previous study at 65 mg/kg/day.
D. Other Reproductive Effects
Pregnant rats receiving 500 ppm acrylonitrile in their drinking
water showed reduced pup survival, possibly due to a maternal toxicity
(Bellies and Mueller, 1977).
-------
E. Chronic Toxicity
Knoblock, et al. (1972) observed a perceptible change in peripheral
blood pattern, functional disorders in the respiratory and cardiovascular
systems, and the excretory system, as well as signs of neuronal lesions in
the central nervous system of rats and rabbits breathing acrylonitrile (50
mg/m air) for 6 months. Babanov, et al. (1972) reported that inhalation
of acrylonitrile vapor (0.495" mg/m , 5 hours/day, 6 days/week) for 6
months resulted in central nervous system disorders, increased erythrocyte
count, and decreased leukocyte count in rats. Workers exposed for long per-
iods of time to acrylonitrile have subjective complaints including headache,
fatigue, nausea and weakness, as well as clinical symptoms of anemia, jaun-
dice, conjunctivitis and abnormal values of specific gravity of whole blood,
blood serum and cholinesterase values, urobilinogen, bilirubin, urinary pro-
tein and sugar (Sakarai and Kusimoto, 1972). In another study, functional
disorders of the central nervous system, cardiovascular and hemopoietic sys-
tems were noted (Shustov and Mavrina, 1975). Sakarai and Kasumoto (1972)
concluded that acrylonitrile exposures at levels of 5-20 ppm caused mild
liver injury and probably a cumulative general toxic effect.
F. Other Relevant Information
HCN and CO were-found to enhance acrylonitrile toxicity in experi-
mental animals (Yamamoto, 1976) as well as in workers engaged in acryloni-
trile production (Ostrovskaya, et al. 1976).
V. Aquatic Toxicity
A. Acute Toxicity
The 96-hour LC5Q values of fathead minnows (Pimeohales promelas)
were 10,100 and 18,100 pg/1 for flow-through and static tests, respectively,
and 14,300 and 18,100 ^ig/1 for hard (380 mg/1) and soft (29 mg/1) waters,
-------
respectively (Henderson, et al. 1961). A reported 48-hour LCcn for Oaph-
_3U
nia- magna is 7,550 jjg/1 (U.S. EPA, 1978). The saltwater pinfish (Lagodon
rhomboide_s). has an observed 96-hour LC5Q value of 24,500 ug/1 in a static
concentration unmeasured test (Daugherty and- Garrett, 1951).
3. Chronic Toxicity
Daphnia magna has been exposed for its life cycle and the results
indicate no adverse effects at concentrations as high as 3,600 pg/1 (U.S.
EPA, 1978). Henderson, et al. (1961) observed a 30-day LC50 value of
2,600 ug/1 with Pimephales promelas (.fathead minnows). No chronic test data
are available for saltwater species.
C. Plant 'Effects
Pertinent data could not be located in the available literature on
• i
the sensitivity of plants to acrylonitrile.
D. Residues
In the only reported study, the bluegjll (Lepomis rnacrochirus) was
exposed for 28 days and the determined whole body bioconcentration factor
was 48, with a half-life between 4-7 days (U.S. EPA, 1978). !
VI. EXISTING GUIDELINES AND STANDARDS -j '
Neither the human health nor the aguatic 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 American Conference of Governmental Industrial Hygienists
threshold limit value (TLV) (ACGIH, 1974) for acrylonitrile is 20 ppm. In
»
January, 1978, the Occupational-Safety and Health Administration (OSHA) an-
nounced an emergency temporary standard for acrylonitrile of 2 ppm averaged
-------
over an eight-hour period. Based on rat data (Morris, 1977; Quast, et al.
1977; Maltoni, et al. 1977), and using the "one-hit" model, the U.S. EPA
(1979) has estimated levels of acrylonitrile in ambient water which will re-
sult in specified risk levels of human cancer:
Exposure Assumptions Risk
(per day)
0
2 liters of drinking water
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish and
shellfish only.
Levels and . Corresponding Draft Criteria
io-7
0.008 x
10-4 ng/i
0.016 x
10-4 ng/1
10-6
0.08 x
10-4 ng/1
0.16 x
10-4 ng/1
10-5
0.3 x
10-4 ng/1
1.6 x
10-4 ng/1
B. Aquatic
For acrylonitrile, the draft criterion to protect freshwater aquat-
ic life is 130 ug/1 as a 24-hour average, and the concentration should not
exceed 300 ug/1 at any time. To protect saltwater species, the draft cri-
terion is 130 ug/1 as a 24-hour averagey with the concentration not to exceed
290/jg/1 at any time (U.S. EPA, 1979).
-------
ACRYLONITRILE
REFERENCES
Babanov, G.'P. , et al. 1972. Adaptation of an organism
to acylonitrile at a low concentration factor in an indus-
trial environment. Toksikol. Gig. Prod. Neftekhim. 45:
58.
Beliles, R.P., and S. Mueller. 1977. Three-generation
reproduction study of rats receiving acrylonitrile in drink-
ing water. Acrylonitrile progress report second generation.
Submitted by Litton Bionetics, Inc. to the Manufacturing
Chemists Association. LBI Project No. 2660. November, 1977.
Benes, V., and R. Sram. 1969. Mutagenic activity of some
pesticides in Drosophila melanogaster. Ind. Med. Surg.
38: 442. ' • '
Brieger, et al. 1952. Acrylonitrile: Spectrophotometric
determination, acute toxicity and mechanism of action.
Arch. Indust. Hyg. Occup. Med. 6: 128.
Daugherty, P.M., Jr., and J.T. Garrett. 1951. Toxicity
levels of hydrocyanic acid and some industrial by-products.
Tex. Jour. Sci. 3: 391.
Giacosa, P. 1883. Toxicity of aliphatic nitriles. Hoppe-
Seyle 2: 95.
Hashimoto, K., and R. Kanai. 1965. Toxicology of acrylo-
nitrile: metabolism, mode of action, and therapy. Ind. Health
3: 30.
Henderson, C.., et al. 1961. The effect of some organic
cyanides (nitriles) on fish. Eng. Bull. Ext. Ser. Purdue
Univ. No. 106: 130.
Knobloch, K., et al. 1972. Chronic toxicity of acryloni-
tr ile. Med. Pracy 23: 243.
Maltoni, C., et al. 1977. Carcinogenicity bioassays on
rats of acrylonitrile administered by inhalation and by
ingestion. La Medicina del Lavoro 68: 401.
Meurice, J. 1900. Intoxication and detoxification of dif-
ferent nitriles. Arch. Internat. de Pharmacodynamie et
de Therapie 7: 2.
Midwest Research Institute. 1977. Sampling and analysis
of. selected toxic substances. Section V. Sampling and
analysis protocol for acrylonitrile. Progress Report No.
13, Oct. 1-31, 1977. EPA*Contract No. 68-01-4115", MRI Pro-
ject No. 4280-C (3) .
-------
Milvy, P., and M. Wolff. 1977. Mutagenic studies with
acrylonitrile. Mutation Res. 43: 271.
Monsanto Company. July 19, 1973. Environmental Impact
of Nitrile Barrier Containers, LOPAC: A case study. Monsanto
Co. St. Louis, Missouri.
Monson, R.R. November 21, 1977. Mortality and Cancer Mo-
bidity among B.F. Goodrich White Male Union Members who
ever worked in Departments 5570 through 5579. Report to
B.F. Goodrich Company and to the United Rubber Workers.
Federal Register No. 43FR45762 (see OSHA Dockit H-108, ex-
hibits 67 and 163).
Murray, F.J., et al. 1976. Tertologic evaluation of acrylo-
nitrile monomer given to rats by gavage. Report from Toxi-
cology Research Lab., Dow Chem.
Murray, F.J., et al. 1978. Teratologic evaluation of in-
haled acrylonitrile monomer in rats. Report of the Toxi-
cology Research Laboratory, Dow Chemical U.S.A. Midland,
Michigan. May 31, 1978.
National Resources Defense Council. 1976. Pop bottles:
The plastic generation—a study of the environmental and
health problems of plastic beverage bottles, p. 33.
NIOSH. 1978. A Recommended Standard for Occupational Expo-
sure to Acrylonitrile. DHEW (NIOSH) Publication No. 78-116,
U.S. Government Printing Office.
Norris, J.M. 1977. Status report on two-year study incor-
porating acrylonitrile in the drinking water of rats. Health
Environ. Res. The Dow Chemical Company.
O'Berg, M. 1977. Epidemiologic studies of workers exposed
to acrylonitrile: Preliminary results. E.I. Du Pont de
Nemours & Company.
Ostrovskaya, R.S., et al. 1976. Health status of workers
currently engaged in production of acrylonitrile. Gig.
T. Prof. Zabol. 6: 8.
Quast, J.F., et al. 1977. Toxicity of drinking water con-
taining acrylonitrile in rats: Results after 12 months.
Toxicology Res. Lab., Health and Environmental Res. Dow
Chemical U.S.A.
Sakarai, H., and M. Kusimoto. 1972. Epidemiologic Study
of Health Impairment Among AN Workers. Rodo Kagaku,48:
273.
Shustov, V.Y., and E.A. Mavrina. 1975. Clinical picture
of chronic poisoning .in the production of nitron. Gig. Tr.
Prof. Zabol 3: 27.
-------
Threshold Limit Values. 1974. TLVs: Threshold Limit
Values for Chemical Substances and Physical Agents in the
Work Room Environment with Intended Changes for 1974. Am.
Conf. Govern. Ind. Hyg.
U.S. EPA. 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. 1979. Acrylonitrile: Ambient Water Quality
Criteria (Draft).
Venitt, S., et al. 1977. Mutagenicity of acrylonitrile
(cyanoethylane) in Escher ichia coli. Mutation Res. 45:
283.
Yamamoto, K. 1976. Acute combined effects of HCN and CO,
with the use of combustion products from PAN (polyacrylo-
nitrile)—gauze mixtures. Z. Rechtsmed. 78: 303.
Young, J.D.,4et al. 1977. The pharmacokinetic and metabolic
profile of C-acrylonitrile given to rats by three routes.
Report of the Toxicological Research Laboratory. Dow Chemi-
cal. Midland, Michigan.
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No. 8
Aldrin
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
aldrin and has found sufficient evidence to indicate that
this compound is carcinogenic.
-6.7-
-------
ALDRIN .
Summary
Aldrin is a man-made compound belonging to the group of cyclodiene in-
secticides. The chronic toxicity of low doses of aldrin include shortened
lifespan, liver changes, and teratogenic effects. The induction of hepato-
cellular carcinoma in both male and female mice from the administration of
aldrin leads to the conclusion that it is likely to be a human carcinogen.
Aldrin has not been found mutagenic in several test systems although it did
induce unscheduled DNA synthesis in human fibroblasts. The World Health
Organization acceptable daily intake level for aldrin is Q.I jjg/kg/day.
Aldrin is rapidly converted to dieldrin by a number of fresh and salt-
water species. The overall toxicity of aldrin is similar to dieldrin. The
96-hour LC50 values for freshwater fish vary from 2.2 to 37 pg/1 with in-
vertebrates being one order of magnitude less sensitive. Both, marine fish
and plants were susceptible to levels of aldrin corresponding to those of
freshwater fish.
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ALDRIN
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Aldrin and Dieldrin (U.S. EPA, I979a).
Aldrin is a white crystalline substance with a melting point of
104°C. It is soluble in .organic solvents. The chemical name for aldrin
is- 1,2,3,4,10,10-hexachloro-l, 4, 4a, 5,8,8a-hexahydro-l,4,:5,8-exo-dimethano-
naphthalene.. Aldrin is biologically altered in the environment to dieldrin,
a more stable and equally toxic form. For information concerning dieldrin
refer to the dieldrin hazard profile or the draft Ambient Water Quality Cri-
teria Document for Aldrin and Dieldrin (U.S. EPA, 1979a,b).
Aldrin was primarily used as a broad spectrum, insecticide until 1974
when the U.S. EPA restricted its use to termite control by direct soil in-
jection, and non-food seed and plant treatment (U.S.. EPA, 1979a). From 1966
to 1970 the use of aldrin in the United States dropped from 9.5 x 10 to
5.25 x 103 tons (U.S. EPA, 1979a). This decrease in use has been attri-
buted primarily to increased insect resistance to aldrin and to development
of substitute materials. Although the production of aldrin in the United
States is restricted, formulated products containing aldrin are imported
from Europe (U.S. EPA, 1979a).
II. EXPOSURE
A. Water
Aldrin has been applied to vast areas of agricultural 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 (U.S. EPA,
1979a). Levels of aldrin, ranging from 15 to 18 ng/1 or as high as 407 ng/1
-------
have been found in waters of the United States (U.S.. EPA, 1976; Leichten-
berg, et al. 1970). The half-life of aldrin in water one meter in depth has
been estimated to be 10.1 days (MacKay and Wolkoff, 1973).
8. Food
The estimated daily dietary intake of aldrin in 16 to 19 year old
males was estimated to be 0.001 mg in 1965 and only a trace amount in 1970
(Natl. Acad. Sci., 1975).
No direct measured bioconcentration factor for aldrin can be ob-
tained because it is rapidly converted to dieldrin by aquatic organisms
(U.S. EPA, 1979a). The U.S. EPA (1979a) has estimated the weighted average
bicconcentration factor of aldrin at 32. This estimate is based on the
octanol/water partition coefficient for aldrin.
C. Ini.. Jtion
Aldrin enters the air through various mechanisms such as spraying,
wind action, water evaporation, and adhesion to particles (U.S. EPA, 1979a).
Ambient air levels of 8 ng/m of aldrin have been reported (Stanley, et
al. 1971). y
D. Dermal,
. >
Dermal exposure to aldrin is limited to workers employed during
its manufacture and use as a pesticide. Wolfe, et al. (1972) reported that
exposure in workers is mainly through dermal absorption rather than inhala-
tion. The ban on the manufacture of aldrin in the United States has greatly
reduced the risk of exposure.
III. PHARMACOKINETICS
A. Absorption
«
Pertinent data could not be located in the available .literature
concerning the absorption of aldrin (U.S. EPA, 1979a).
-70-
-------
B. Distribution
The distribution of aldrin in humans or animals has not been ex-
tensively studied because aldrin is readily converted to dieldrin in vivo
via epoxidation (U.S. EPA, 1979a). For example, the blood plasma levels of
aldrin were lower than the corresponding blood plasma levels of dieldrin in
six workers just after chronic exposure to aldrin for five weeks (Mick, et
al. 1971).
C. Metabolism
The epoxidation of aldrin to dieldrin.. has been reported in many
organisms including man (U.S. EPA, 1979a). The reaction is NADPH-dependent
and the enzymes are heat-labile (Wong and Terriere, 1965). The metabolic
products of aldrin include dieldrin, as well as aldrin diol, and polar meta-
bolites excn ' iin the urine and feces (U.S. EPA, 1979a).
0. Excretion
Aldrin is excreted mainly in the feces and to some extent in the
urine in the form of several polar metabolites (U.S. EPA, 1979a). Ludwig,
et al. (1964v "'-reported nine times as much radioactivity in the feces as in
the urine of rats chronically administered C-aldrin. A saturation level
/
1
was reached in'these animals and concentrations of radioactivity in the body
decreased rapidly when feeding was terminated.
Specific values for the half-life of aldrin in humans were not
found in the available literature. However, in humans exposed to aldrin
and/or dieldrin the half-life of dieldrin in the blood was estimated to be
266 days (Jager, 1970). In another study with 12 volunteers ingesting vari-
ous doses of dieldrin, Hunter, et al. (1969) estimated the average dieldrin
half-life to be 369 days.
-71-
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IV. EFFECTS
A. Carcinogenicity
Aldrin has induced liver tumors in males and females in various
strains of mice according to reports of four separate feeding studies (Davis
and Fitzhugh, 1962; Davis, 1965; 43 FR 2450; Song and Harville, 1964). Ac-
cording to reports of five studies in two different strains of rats, aldrin
failed to induce a statistically significant carcinogenic response at all
but one site (Deicnmann, et al. 1967, 1970; Fitzhugh, et al. 1964; Cleve-
land, 1966; 43 FR 2450).
The only information concerning the carcinogenic potential of
aldrin in man is an occupational study by Versteeg and Jager (1973). The
workers had been employed in a plant producing aldrin and dieldrin with a
mean exposure time of 6.6 years. An average time of 7.4 years had elapsed
since the end of exposure. No permanent adverse effects including cancer
were observed.
B. Mutagenicity
Aldrin was found not to be mutagenic in two bacterial assays (S.
typhimurium and §_._ coli) with metabolic activation (Shirasu, et al. 1977).
Aldrin did, however, produce unscheduled DMA synthesis in human fibroblasts
with and without metabolic activation (Ahmed, et al. 1977).
C. Teratogenicity
Aldrin administered in single oral doses to pregnant hamsters
caused significant increases in hamster fetal death and increased 'fetal ano-
malies (i.e., open eye, webbed foot, cleft palate, and others). When a sim-
ilar study was done in mice at lower doses, teratogenic effects were also
•
observed, although these effects were less pronounced (Ottolenghi, et al.
1974).
it
-72-
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0. Other Reproductive Effects
Deichmann (1972) reported that aidrin and dieldrin (25 mg/kg diet)
fed to mice for six generations affected fertility, gestation, viability,
lactation and survival of the young.
E. Chronic Toxicity
The other effects produced by chronic administration of aldrin to
mice, rats, and dogs include shortened lifespan, increased liver to body
weight ratios, various changes in liver histology, and the induction of
hepatic enzymes (U.S. EPA, 1979a).
F. Other Relevant Information
Since aldrin and dieldrin are metabolized by way of mixed function
oxidase (MFO), any inducer or inhibitor of the MFO enzymes should affect the
metabolism of aldrin and dieldrin (U.S. EPA, 1979a).
When aldrin is administered with DOT, or after a plateau has been
reached in dogs with chronic DDT feeding, the retention of DDT by the blood
and fat increases considerably (Deichmann, et al. 1969). Clark and Krieger
(1976) found that tissue accumulation of C-aldrin was significantly in-
creased when an inhibitor of the epoxidation of aldrin to dieldrin was admi-
14
nistered prior to C-aldrin.
V. AQUATIC TOXICITY
A. Acute Toxicity
Aldrin is rapidly converted to dieldrin in the environment. How-
ever, a number of acute studies haved been done with aldrin, although the
test concentrations have not been measured after the bioassays. Reported
96-hour static LC5Q values are as follows: bluegill (Legomis macrochirus)
4.6 to 15 ;jg/l (Henderson, et al. 1959; Macek, et al. 1969); rainbow .trout
(Salmo qairdneri) 2.2 to 17.7 jug/1 (Macek, et al. 1969; Katz, 1961); and
-73-
-------
fathead minnows (Pimephales promelas) 32 and 37 jjg/1 (Henderson, et al.
1959). Acute toxicity varies greatly in freshwater invertebrates. In bio-
assays in which the aldrin concentrations were not measured, the observed
48-hour LC5Q value for Daphnia pulex was 28 ;jg/l (Sanders and Cope, 1966),
and the observed 96-hour LCcQ values ranged from 4,300 to 38,500 jug/1 for
scud, Gammarus spp. (Sanders, 1969, 1972; Gaufin, et al. 1965).
In flow-through exposures to aldrin, the 48 and 96-hour LC
values for six saltwater fish species ranged from 2.0 to 7.2 pg/1. Inverte-
brate LC50 values ranged from 0.37 to 33.0 jjg/1 (U:-S. EPA, 1979a).
B. Chronic Toxicity
NO entire cycle or embryo-larval tests have been reported for any
fresh or saltwater species (U.S. EPA, 1979a).
C. Plant Effects
An aldrin concentration of 10,000 jjg/1 reduced the population
growth in 12 days for water meal, Wolffia papulifera (Worthley and Schott,
1971). The productivity of a phytoplankton community was reduced 85 percent
after four hour exposure to 1,000 pg/1 aldrin (Butler, 1963).
D. Residues
No freshwater or saltwater residue studies have been reported for
aldrin (U.S. EPA, 1979a).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the 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 will be
changed.
-------
A.. Human
The current exposure level for aldrin set by the Occupational
Safety and Health Administration is a time-weighted average of 250 jjg/m^
for skin absorption (37 FR 22139). In 1969, the U.S. Public Health Service
Advisory Committee recommended that the drinking water standard for aldrin
be 17 yg/1 (Mrak, 1969). The U.N. Food and Agricultural Organization/World
Health Organization acceptable daily intake for aldrin is 0.1 pg/kg/day
(Mrak, 1969).
The carcinogenicity data of the National Cancer Institute (1976)
(43 FR 2450) were used to calculate the draft water quality criterion for
aldrin which keeps the lifetime cancer risk for humans below 10" . The
2
concentration for aldrin is 4.6 x 10 ng/1 (U.S. EPA, 1979a).
8. Aquatic
Draft criterion has not been proposed directly for aldrin because
of its rapid conversion to dieldrin (U.S. EPA, 1979a).
-73--
-------
ALDRIN
REFERENCES
Ahmed, F.E., et al. 1977. Pesticide-induced ONA damage and its repair in
cultured human cells. Mutat. Res. 42: 161.
Butler, P.A. 1963. Commercial fisheries investigations. In: Pesticide and
wildlife studies: A review of Fish and Wildlife Service investigations
during 1961 and 1962. U.S. Fish Wildl. Serv. Circ. 167: 11.
Clark, C.R and R.I. Krieger. 1976. Beta-diethylaminoethyldiphenyl-
propylacetate (SKF 525-A) enhancement of tissue accumulation of aldrin in
mice. Toxicol. Appl. Pharmacol. 38: 315.
Cleveland, F.P. 1966. A summary of work on aldrin and dieldrin toxicity at
the Kettering Laboratory. Arch. Environ. Health. ,13: 195.
Davis, K.J., 1965. Pathology report on mice for aldrin, dieldrin, hepta-
chlor, or heptachlor epoxide for two years. Internal Memorandum to Dr. A.J.
Lehman. U.S. Food 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. Toxicology of DDT and related chlorinated hydro-
carbon pesticides. Jour. Occup. Med. 14: 285.
Deichmann, W.B., et al. 1967. Synergism among oral carcinogens in the
simultaneous feeding of four tumorigens to rats. Toxicol. Appl. Pharmacol.
11: 88.
Deichmann, W.B., et al. 1969. Retention of dieldrin and DDT in the tissues
of dogs fed aldrin and DDT individually and as a micture. Toxicol. Appl.
Pharmacol. 14: 205.
Deichmann, W.8., et al. 1970.. Tumorigenicity of aldrin, dieldrin and en-
drin in the albino rat. Ind. Med. Surg. 39: 426.
Fitzhugh, O.G., et al. 1964. Chronic oral toxicity of aldrin and dieldrin
in rats and dogs. Food Cosmet. Toxicol. 2: 551.
Gaufin, A.R, et al. 1965. The toxicity of ten organic insecticides to var-
ious aquatic invertebrates. Water Sewage Works 12: 276.
Henderson, C., et al. 1959. Relative toxicity of ten chlorinated hydro-
carbon insecticides to four species of fish. Trans. Am. Fish. 'Soc. 88: 23.
Hunter, C.G., et al. 1969. Pharmacodynamics of Dieldrin (HEQD). Arch.
Environ. Health 18: 12.
Jager, K.W. 1970. Aldrin, dieldrin, endrin and telodrin: An epidemio-
logical and toxicological study of long-term occupational exposure.
Elsevier Publishino Co. Amsterdam.
-7
-------
Katz, M. 1961. Acute toxicity of some organic insecticides to three
species of salmonids and to the threespine stickleback. Trans. Am. Fish.
Soc. 90: 264.
Leichtenberg, J.J., et al. 1970. Pesticides in surface waters in the
United States - A five-year summary, 1964-1968. Pestic. Monitor. Jour.
4: 71.
Ludwig, G., et al. 1964. Excretion and distribution of aldrin-14C and
its metabolites after oral administration for a long period of time. Life
Sci. 3: 123.
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.
Mick, D.L., et al. 1971. Aldin and. dieldrin in human blood components.
Arch. Environ. Health 23: 177.
•Mrak, E.M. 1969. Report of the Secretary's commission on pesticides and
their relationship to environment health. U.S. Dept. Health, Edu. Welfare,
Washington, D.C.
National Academy of Sciences, National Research Council. 1975. Vol. 1 Pest
control: An assessment of present and alternative technologies. Contem-
porary pest control practices and prospects. Natl. Acad. Sci. Washington,
D.C.
Ottolenghi, A.D., et al. 1974. Teratogenic effects of aldrin, dieldrin and
endrin in hamsters and mice. Teratology 9: 11.
Sanders, H.O. 1969. Toxicity of pesticides to the crustacean, Gammarus
Lacustris. Bur. Sport Fish. Wildl. Tech. Pap. No. 25.
Sanders, H.O. 1972. Toxicity of some insecticides to four species of mala-
costracan crustaceans. Bur. Sport Fish. Wildl. Tech. Pap. No. 66.
Sanders, H.O. and O.B. Cope. 1966. Toxicities of several pesticides to two
species of cladocerans. Trans. Am. Fish. Soc. 95: 165.
Shirasu, Y., et al. 1977. .Mutagenicity screening on pesticides and modifi-
cation products: A basis of carcinogenicity evaluation. Page 267 _in H.H.
Hiatt, et al. (eds.). Origins of Human Cancer. Cold Spring Harbor Lab. New
York.
Song, J. and W.E. Harville. 1964. The carcinogenicity of aldrin and diel-
drin on mouse and rat liver. Fed. Proc. 23: 336.
-77-
-------
Stanley, C.W., et al. 1971. Measurement of atmospheric levels of pesti-
cides. Environ. Sci. Technol. 5: 430.
U.S. EPA. 1976. National interim primary drinking water regulations. U.S.
Environ. Prot. Agency. Publ. No. 570/9-76-003.
U.S. EPA. 1979a. Aldrin/Die'ldrin Ambient Water Quality Criteria Document.
Washington, O.C. (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Dieldrin:
Hazard Profile. (Draft).
Versteeg, J.P.J. and K.W. Jager. 1973. Long-term occupational exposure to
the insecticides aldrin, dieldrin, endrin, and telodrin, Br. Jour. Ind.
Med. 30: 201.
Wolfe, H.R., et al. 1972. Exposure of spraymen to pesticides. 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.
Worthley, E.G. and C.D. Schott. 1971. The comparative effects of CS and
various pollutants on freshwater phytoplankton colonies of Wolffia
papulifera Thompson. Dep. Army. Edgewood Arsenal Biomed. Lab. Task
IW662710-AD6302.
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Mo. 9
Allyl Alcohol
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.
-------
ALLYL ALCOHOL
Summary
Allyl alcohol is a severe irritant to the mucous membranes at high con-
centrations. Hepatotoxicity has been seen after oral and inhalation
exposures, however, results indicate that this effect may not be
.cumulative. Allyl alcohol is also absorbed percutaneously.
Information on the carcinogenic, mutagenic, teratogenic or other repro-
ductive effects of allyl alcohol was not found in the--available literature.
Data concerning the effects of allyl alcohol to aquatic organisms were
not found in the available literature.
-------
I. INTRODUCTION
This profile is based on computerized searches of Toxline, Siosis
and Chemical Abstracts, and a review of other available appropriate
information sources as available.
Allyl alcohol (molecular weight-58.08) is a limpid liquid with
pungent odor. It is soluble in water, alcohol and ether, has a melting
point of -50°c and a boiling point of 96-97°C (Sax, 1979).
The major uses of allyl alcohol are in the manufacture of allyl
compounds, war gas, resins, and plasticizers (Windholz, 1976). Sixty kt.
are used in this country per year, of which 50 kt. are used to manufacture
glycerol (Kirk and Othmer, 1963).
After several years of storage, allyl alcohol polymerizes into a
substance that is soluble in chloroform but not water. When treated with
ether this substance becomes brittle (Windholz, 1976).
II. EXPOSURE
Pertinent data were not found in the available literature on air
or water exposure.
Esters of allyl alcohol are used as food flavorings. Natural de-
rivatives of allyl alcohol are widely distributed in vegetable material
.(Lake, et al. 1978).
III. FHARMACOKINETICS
A. Absorption and Distribution
Pertinent data were not found in the available literature.
8. Metabolism
It has been suggested that allyl alcohol is completely metabolized
and that acrolein might be an intermediate metabolite (Browning, 1965). the
rate of metabolism in rats was found to be about 23 mg/kg/hr. during con-
stant intravenous infusion (Carpanini, et al. 1978).
-------
C. Excretion
Allyl alcohol was not found in the urine of animals that had been
dosed subcutaneously or intravenously with the compound (Browning, 1965).
Other pertinent data were not found in the available literature.
IV. EFFECTS
A. Carcinogenicity, Mutagenicity, Teratogenicity, and Reproductive
Effects
Information on the carcinogenic effects of allyl alcohol was not
found in the available literature.
B. Chronic Toxicity
Lake, et al. (1978) administered allyl alcohol to rats by gastric
intubation. The rats were dosed daily for 1, 10, or 28 days. Liver homo-
genates from treated animals were analyzed for enzyme activity. Adminis-
tration for one day produced marked periportal necrosis, but repeated ad-
ministration for 10 or 28 days did not seem to increase the damage.
Allyl alcohol administration in the drinking water at a dose of 72
mg/kg/day caused weight loss, transient pulmonary rales, crustiness of the
eyelids, and local areas of liver necrosis (Browning, 1965).
Rats exposed to 40, 60, or 100 ppm of allyl alcohol by inhalation
showed signs of acute mucous membrane irritation, such as gasping and nasal
discharge. At the 100 ppm dose, the animals died after 10 exposures
(Browning, 1965). No gross toxicity was seen at 5 or 10 ppm, 5 days a week
for 13 months in rats, rabbits, guinea pigs, and dogs. However, mild
reversible degenerative changes in the liver and kidney were seen at the
seven ppm dose. . A dose of 50 ppm was lethal to rats after 30 days
(Torkelson, et al. 1959).
-------
Carpanini, et al. (1978) gave rats doses of allyl alcohol 50, 100,
200, or 800 ppm im the drinking water for 15 weeks. Weight loss was seen in
males given 100, 200, or 800 ppm and females given 800 ppm. Food
consumption values were lower than the controls in males at 200 ppm and 800
ppm and females at 800 ppm. A dose-related decrease in water consumption
was seen in all treated animals. Minor changes were seen in the liver,
kidneys, and lungs of both treated and control groups upon histological
examination.
C. Acute Toxicity
Oral LD5Q'S of allyl alcohol have been found to be
64-100 mg/kg for rats, 96-139 mg/kg for mice, and 52-71 mg/kg for rabbits;
43 mg/kg was lethal to dogs. Intraperitoneal LD50's were 42 mg/kg for
rats and 60 mg/kg for mice. In rabbits an LD5Q of. 53-89 mg/kg was found
by percutan- eous absorption (Carpanini, et al. 1978). Inhalation of 1000
ppm was lethal to rabbits and monkeys after 3 to 4 hours. Erythema of the
conjunctiva and swelling of the cornea are seen in the eye after exposure to
allyl alcohol, however, no permanent damage was noted. Application to the
skin caused only mild erythema. Intravenous injection produced a drop in
blood pressure. Injection of 40- minims in a 20 percent saline solution
caused fluctuations in the blood .pressure, of rabbits resulting in violent
convulsions. Vomiting, diarrhea, convulsions, apathy, ataxia, lacrimation
and coma are seen after oral administration. Few cases of serious injury
due to inhalation have: been reported, however, because concentrations that
would cause severe damage in a short period of time are painful to the eyes
and nose. Five ppm are detectable by irritation and 2 ppm by odor
9
(Browning, 1965).
Moderate air contamination has been found to cause lacrimation,
pain around the eyes and blurred vision in man lasting up to 48 hours
(Carpanini, et al. 1978).
-------
D. Other Relevant Information
Allyl alcohol has an unusual effect on the central nervous system
of mice and rats. The effect is seen as apathy, unwillingness to move,
anxiety, and no interest in escaping. It is apparently different from nar-
cosis seen with other agents (Dunlap, et al. 1958).
V. AQUATIC TOXICITY
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES
The recommended maximum atmospheric concentration (8 hours) is 2
ppm (Indust. Hyg. Assoc., 1963).
-------
REFERENCES
Browning, E.G. 1965. Toxicity and Metabolism of Industrial Solvents.
Elsevier Publishing Co., Amsterdam, p. 739.
Carpanini, F.M.8., et al. 1978. Short-term toxicity of allyl alcohol in
rats. Toxicol. 9: 29.
Ounlap, M.K., et al. 1958. The toxicity of allyl alcohol. A.M.A. Archives
of Indust. Health. 18: 303.
Industrial Hygiene Association. 1963. Hygienic Guide Series: Allyl
Alcohol. Indust. Hyg. Assoc. Jour. 24: 636.
Lake, 3.G., et al. 1978. The effect of repeated administration on allyl
alcohol-induced hepatotoxicity in the rat. Biochem. Soc. Trans. 6: 145.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials. 5th ed.
Von Nostrand Reinhold Co., New York.
Torkelson, T.R., et al. 1959. Vapor toxicity of allyl alcohol as deter-
mined on laboratory animals. • Indust. Hyg. Assoc. Jour. 20: 224.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chem-
icals. Von Nostrand Reinhold Co., New York.
Windholz, M. (ed.) 1976. Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
-------
No. 10
Antimony
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
. WASHINGTON, D.C. 20460
APRIL 30, 1980
-<37-
-------
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.
-------
ANTIMONY
Summary
The adverse health effects most commonly associated with exposure to
antimony are pulmonary, cardiovascular, dermal, and certain effects on
reproduction, development, and longevity. Cardiovascular changes have
been well-established with exposure to antimony and probably represent
the most serious threat to human health. Antimony has not been assoc-
iated with carcinogenic effects. The lowest observed effect level for
antimony in the drinking water of rats was 5 ppm. A draft criterion of
145 jug/1 has been recommended for antimony in water based on an accep-
table daily intake of antimony from water, fish, and shellfish for man of
294 jug.
Antimony is highly toxic to aquatic organisms at a concentration
ranging from 19 mg/1 to 530 mg/1. Chronic values for antimony in fresh-
water organisms range from 0.8 mg/1 to 5.4 mg/1. ...
-------
ANTIMONY
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for Antimony (U.S. EPA, 1979). The health hazards of antimony
and its compounds have also been recently reviewed by the National Ins-
titute for Occupational Safety and Health (NIOSH, 1978).
Antimony (Sb; molecular weight 121.8) is a silvery, brittle, solid
belonging to group VB of the periodic table and lies between arsenic and
bismuth. It is classified as both a metal and a metalloid, and its prin^
cipal oxidation states are +3 and +5. Antimony has a boiling point
1366°C and a melting point of 636°C. Most inorganic compounds of an-
timony are either only slightly water soluble or decompose in aqueous
media.
Antimony reacts with both sulfur and chlorine to form the tri-a. J"
pentavalent sulfides and chlorides. Oxidation to antimony trioxida
(stibine), the major commercial oxide of antimony, is achieved under
controlled conditions.
Consumption of antimony in the United States is on the order of
40,000 metric tons per year (Callaway, 1969), of which half is obtained
from recycled scrap and the balance mainly imported. Use of antimony in
the United States is directed chiefly to the manufacture of ammunition,
storage batteries, matches and fireworks, and in the fire-proofing of
textiles.
-90-
-------
II. EXPOSURE
A. Water
Schroeder (1966) compiled data from surveys of municipal water
supplies in 94 cities and reported that levels averaged less than 0.2
pg/1 in finished water. In a related study, Schroeder and Kraemer (1974)
noted that tap water levels of antimony can be elevated in soft water
supplies due to leaching from plumbing.
8. Food
Because of the wide range of antimony levels in various types of
foods, it is not possible to accurately estimate an average dietary in-
take. Tanner and Friedman (1977) concluded that dietary intake of
antimony is negligible, based upon trace metal food monitoring data from
the U.S. Food and Drug Administration. However, in earlier studies, cal-
culated average dietary intakes were reported at 100 ug per day for man
(Schroeder, 1970) and in the range of 0.25 to 1.28 mg per day for insti-
tutionalized children (Murthy, et al. 1971). In one study on antimony
levels in Italian diets a mean daily value of several micrograms was re-
ported (Clemente, 1976).
C. Inhalation
Antimony is not- generally found in ambient air at measurable
concentrations. National Air Sampling Network data for 1966 showed pos-
sibly significant levels at only four urban stations (0.042 to 0.085
jug/m3) (Schroeder, 1970; Woolrich, 1973).
D. Other Routes
The total body burden of antimony arising from all environmental
media is apparently very small relative to other trace metals (i.e.,
•
lead, mercury, cadmium) in the environment. Clemente (1976) published
-------
limited data on fecal and urinary levels of antimony in selected Italian
populations and concluded that' daily intakes were less than 2.0 jjg/day.
In addition, data on the bioconcentration potential of antimony in fish
(U.S. EPA, 1978) indicate that no bioaccumulation is likely to occur.
The U.S. EPA (1979) has calculated the weighted average bioconcentration
factor (BCF) for antimony to be 1.4 for the edible portions of fish and
shellfish consumed by Americans. This estimate was based on 25-day bio-
concentration studies in bluegill.
Ill.PHARMACQKINETICS
Absorption of antimony in man and animals is mainly via the respir-
atory and gastro'-intestinal tracts. The extent of absorption is dependent
on factors such as solubility, particle size, and chemical forms
(Felicetti, et al. 1974a; 1974b). Absorption via the GI tract is of the
• order of several percent with antimony trioxide, a relatively insoluble
compound , and presumably would be much greater with soluble antimonials.
Blood is the main carrier for antimony, the extent of partition
between blood compartments depending on the valence state of the element
and the animal species studied (Felicetti, et al. 1974a). The rodent ex-
clusively tends to concentrate trivalent antimony for long periods in the
erythrocyte (Ojuric, et al. 1962). Whatever the species, it can gener-
ally be said that pentavalent antimony is borne by plasma and trivalent
antimony in the erythrocyte. Clearance of antimony from blood to tissues
is relatively rapid, and this is especially true in the case of paren-
teral administration and the use of pentavalent antimony (Casals, 1972;
Abdalla and Saif, 1962; El-Bassouri, et al. 1963).
The tissue distribution and subsequent excretion of antimony is a
function of the valence state.
-------
In animals, trivalent antimony aerosols lead to highest levels in the
lung, skeleton, liver, pelt, and thyroid while pentavalent aerosols show
a similar distribution, with the exception of slower uptake by the liver
(Fslicetti, et al. 1974a; 1974b; Thomas, et al. 1973).
Parenteral administration to animals shows trivalent antimony accumu-
lating in the liver and kidney as well as in pelt and thyroid (Molkhia
and Smith, 1969; Waitz, et al. 1965).
In man, non-occupational or non-therapeutic exposure shows very low
antimony levels in various tissues with little--evidence of accumulation
(Abdalla and Saif, 1962). Chemotherapeutic use leads to highest accumu-
lation in liver, thyroid, and heart for trivalent antimony.
The biological half-life of antimony in man and animals is a function
of route of exposure, chemical form, and oxidation state. The rat
appears to be unique in demonstrating a long biological half-time owing
to antimony accumulation in the erythrocyte. In other species, including
man, moderate half-times of the order of days have been demonstrated.
While most soft tissues do not appear to accumulate antimony, the skin
does show accumulation, perhaps because of its high content of sulfhydryl
groups. With respect to excretion, injection of trivalent antimony leads
mainly to urinary excretion in guinea pigs and dogs, and mainly fecal
clearance in hamsters, mice and rats.
. Pentavalent antimony is mainly excreted via the kidney in most
species owing to its higher levels in plasma.
Unexposed humans excrete less than 1.0 jug antimony daily via urine,
while occupational or clinical exposure may result in markedly increased
0
amounts.
-13-
-------
IV. EFFECTS
A. Carcinogenicity
Antimony has not been tested for carcinogenic activity using an
appropriately designed chronic bioassay protocol. However, Shroeder
(1970) indicated that the chronic administration of antimony at 5 ppm in
the drinking water of rats, had no apparent tumorigenic effect. However,
the shortened life span of treated animals (average 106 to 107 days less
than controls) limits the usefulness of these data. Similar results were
also observed in a study with mice chronically exposed to antimony at 5
ppm in the drinking water (Kanisawa and Schroeder, 1969).
A single epidemiologic investigation has been conducted into the
role of antimony in the development of occupational lung cancer (Oavies,
1973). This retrospective study, which was limited in scope, provided no
definitive information to support the passible role of antimony in lung
cancer development.
8. Mutagenicity
Antimony has not been tested for activity in standard muta-
genicity bioassays.
C. Teratogenicity
Little information is available concerning possible teratogenic
effects of antimony. In one study, Casals (1972) observed no effects,
i.e., no fetal abnormalities, following administration of a solution of
antimony dextran glycoside containing 125 or 250 mg Sb/kg to pregnant
rats on days 8 to 15 of gestation.
D. Other Reproductive Effects
»
Aiello (1955) observed a higher rate of premature deliveries*
among female workers engaged in antimony smelting and processing. In
-------
addition, dysmencrrhea was frequently reported among women workers.
Similarly, Belyaeva (1967) reported that a greater incidence of gyneco-
logical disorders was found among antimony smelter workers than in a con-
trol group (77.5 percent vs. 56 percent; significance unknown). Spon-
taneous late abortions occurred in 12 percent of the exposed females com-
pared to 4.1 percent among controls. Average urine levels of antimony
for exposed workers, however, were extremely high, ranging from 2.1 to
2.9 mg/100 ml. Antimony was also found in breast milk (3.3+ 2 mg/10),
placental tissue (3.2 to 12.6 mg/100 mg), amhiotic fluid (6.2 to 2.8
mg/100 mg), and umbilical cord blood (6.3 + 3 mg/100 ml).
In studies with, rats exposed either to antimony dust (50 mg/kg,
i.p.) or to antimony trioxide dust (250 mg/m , 4 hours per day for 1.5
to 2 months), Belyaeva (1967) reported increased reproductive failure,
fewer offspring, and damage to the reproductive tissues (ovary and
uterus).
E. Chronic Toxicity
The toxic effects of exposure to antimony have been repeatedly
observed in both humans and experimental rodents. Pulmonary, cardio-
vascular, dermal, and certain effects on reproduction, development, and
longevity are among the health effects most commonly associated with an-
timony exposure.
Cardiovascular changes have been well established following ex-
posure to antimony and probably represent the most serious human health
effects demonstrated thus far (U.S. EPA, 1979). Air concentrations of
-------
antimony trisulfide exceeding 3 mg/cu m were associated with the induc-
tion of altered 'ECG patterns and some deaths attributed to myocardial
damage among certain antimony workers (Brieger, et al. 1954). Also, in
parallel studies on animals, Srieger and coworkers (1954) observed ECG
alterations in rats and rabbits exposed to antimony in air at levels of
3.1 to 5.6 mg/m , 7 hours/day, 5 days/week for at least 6 weeks.
Gross and coworkers (1955) presented evidence for growth retardation
occurring when rats were chronically fed diets containing two percent
antimony trioxide. Other investigators (Schroeder, et al. 1970; Kanisawa
and Schroeder, 1969) reported that oral exposure to 5 ppm of antimony in
drinking water had no effect on the rate of growth of either rats or
mice. However, the 5 ppm exposure level was effective in producing
slight but significant lifespan shortening in both rats and mice, and
altered blood chemistries-in exposed rats. Therefore, the 5ppm exposure
level has been considered the "lowest observed effect level" in animals
that likely approximates the "no effect" level for antimony-induced ef-
fects on growth and longevity.
V. AQUATIC TOXICITY
A. Acute Toxicity
The data base for antimony and freshwater organisms is small and
indicates that plants may.be more sensitive than fish or invertebrate
species.
A 96-hour LC5Q of 22,000 /jg/1 was reported for antimony tri-
chloride with the fathead minnow, whereas the value for bluegills and
antimony trioxide is above 530,000 ug/1 (U.S. EPA, 1979). For Daphnia
magna a 48-hour LC5Q value of 19,000 jug/1 and a 64-hour EC5Q value of
19,800 pg/1 have been reported for antimony trichloride. Another 48-hour
-------
ECcn value for antimony trioxide and Daphnia magna has been reported to
be above 530,000 jug/1 (U.S. EPA, 1979).
B. Chronic Toxicity
No adverse effects on the fathead minnow were observed during an
embryo-larval test with antimony trioxide at the highest test concen-
tration of 7.5 pg/1 (U.S. EPA, 1978). However, a comparable test with
antimony trichloride produced limits of 1,100 and 2,300 jug/1 for a
chronic value of 800 pg/1. A life cycle test with Daphnia magna and an-
timony trichloride produced limits of 4,200 and.. 7,000 jug/1 for a chronic
value of 5,400/jg/l (U.S. EPA, 1979). Pertinent information could not be
located in the available literature regarding chronic effects of antimony
on saltwater organisms.
C. Plants Effects
The 96-hour ECcp values for chlorophyll a_ inhibition and re-
duction in cell number of the freshwater alga, Selenastrum capricornutum
are 610 and 630 pg/1, respectively. This indicates that aquatic plants
may be more sensitive than fish or invertebrate species (U.S. EPA,
1978). No inhibition of chlorophyll a reduction or in cell numbers of
the marine alga, Skeletonema costatum, were observed at concentrations as
high as 4,200 pg/1 (U.S. EPA, 1978).
0. Residues
There was no bioconcentration of antimony by the bluegill above
control concentrations during a 28 day exposure to antimony. No data
have been reported on bioconcentration of antimony in marine species.
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
X
-97-
-------
public review; therefore, there is a possibility that these criteria may
be changed.
A. Human
Existing .occupational standards for exposure to antimony are
reviewed in the recently released NIOSH criteria document,- Occupational
Exposure to Antimony (U.S. Department of Health, Education and Welfare,
1978). As stated in the NIOSH (1978) document, the American Conference
of Governmental Industrial Hygienists (ACGIH), in 1977, listed the TLV
for antimony as 0.5 mg/m along with a notice'-of intended change to a
proposed TLV of 2.0 mg/m3 for soluble antimony salts. The proposed TLV
was based mainly on the reports of Taylor (1966) and Cordasco (1974) on
accidental poisoning by antimony trichloride and pentachloride, respec-
tively. Proposed limits of 0.5 mg/m for handling and use of antimony
trioxide and 0.05 mg/m for antimony trioxide production were included
in the ACGIH (1977) notice of intended changes.
The Occupational Safety and-Health Administration earlier adopted the
1968 ACGIH TLV for antimony of 0.5 mg/m3 as the Federal standard (29
CFR 1910.1000). This limit is consistent with limits adopted by many
other countries as described in Occupational Exposure Limits for Airborne
Toxic Substances - A tabular Compilation of Values from Selected Coun-
tries, a publication released by the International Labour Office in
1977. The NIOSH (1978) document also presented table of exposure limits
.from several countries, reproduced here -as Table 1; the typical
standard adopted was 0.5 mg/m3.
-------
TABLE 1
HYGIENIC STANDARDS OF SEVERAL COUNTRIES FOR
ANTIMONY AND COMPOUNDS IN THE WORKING ENVIRONMENT
CountryStandardQualifications
(mg/m^)
:Finland;573Not stated
Federal Republic of Germany 0.5 8-hour TWA
Democratic Republic of Germany 0.5 Not stated
Rumania 0.5 Not stated
USSR 0.5 For antimony dust
0.3 For fluorides and
chlorides (tri-and
pentavalent); obli-
gatory control of HF
and HC1
1.0 For trivalent oxides
and sulfides
1.0 For pentavalent
oxides and sulfides
Sweden 0.5 Not stated
USA 0.5
8-hour TWA < '" \
Yugoslavia ' / Q.5 Not stated
Modified from Occupational Exposure Limits in Airborne ToxicSub-
stances, International Labour Office.
The 0.5 mg/m level was also recommended as the United States occupa-
tional exposure standard by the NIOSH (1978) criteria document, based
mainly on estimated no-effect If^Is for cardiotoxic and pulmonary ef-
fects.
Based upon the data presented in the Ambient Water Quality Criteria
Document for Antimony (U.S. EPA, 1979), a recommended draft criterion of
145 pg/1 has been established. This value is based upon an acceptable
daily intake for man of 294 ug, derived from experimental animal studies
in which 5 ppm of antimony produced a slight shortening of lifespan with
no other deserved effects. An uncertainty factor of 100 was used in ex-
trapolating from animal data to human health effects.
I*
-------
8. Aquatic
The draft criterion for Antimony to protect freshwater aquatic
life as derived using the Guidelines is 120 jjg/1 as a 24 hour average and
the concentration should not exceed 1,000 jug/1 at any time.
A saltwater criterion was not derived (U.S. EPA, 1979)
yf.
-/oo-
-------
ANTIMONY
REFERENCES
Abdalla, A., and M. Saif. 1962. Tracer studies with anti-
mony-124 in man. In; G.E.W. Walstenhalne and M. O'Conner,
eds., Bilharziasis. Little Brown and Co., Boston, p. 287.
Aiello, G. 1955. Pathology of antimony. Folia Med., Naples
38: 100.
American Conference of Governmental Industrial Hygienists.
1977. Threshold limit values for chemical substances in
workroom air.
Belyaeva, A.P. 1967. The effect of antimony on reproduc-
tion. Gig. Truda Prof. Zabol 11: 32.
Brieger, H., et al. 1954. Industrial antimony poisoning.
Ind. Med. Surg. 23: 521.
Callaway, H.M. 1969. Antimony. In: The Encyclopedia Britan-
nica. Ency. Brit., Inc., 2: 20. "Chicago.
Casals, J.B. 1972. Pharmacokinetic and toxicological studies
of antimony dextran glycoside (RL-712). Brit. Jour. Pharmac.
46: 281.
Clemente, G.F. 1976. Trace element pathways from environ-
ment to man. Jour. Radioanal. Chem. 32: 25.
Cordasco, E.M. 1974. Newer concepts in the management
of environmental pulmonary edema. Angiology 25: 590.
Davies, T.A.L. 1973. The health of workers engaged in
antimony oxide manufacture—a statement. London, Department
of Employment, Employment Medical Adivsory Service, p. 2.
Djuric, D. , et al. 1962. The distribution and excretion
of trivalent antimony in the rat following inhalation.
Arch. Gewerbepath. Gewerbehyg. 19: 529.
El-Bassouri, M. , et al. 1963. Treatment of active urinary
schistosomiasis in children with sodium antimony dimercapto
succinate by the slow method. Trans. Roy. Soc. Trop. Med.
Hyg. 57: 136.
Felicetti, S.W., et al. 1974a. Metabolism of two valence
states of inhaled antimony in hamsters. Amer. Ind. Hyg.
Assoc. Jour. 355: 292.
Felicetti, S.W., et al. 1974b. Retention of inhaled anti-
mony-124 in the beagle dog as a function of temperature
of aerosol formation. Health Phvs. 26: 525.
-------
Gross, et al. 1955. Toxicological study of calcium halo-
phasphate phosphors and antimony tribxide. In; Acute and
chronic toxicity and some pharmacological aspects. Arch.
Indust. Health 11: 473.
International Labour Office. 1977. Occupational exposure
limits for airborne toxic substance - a tabular compilation
of values from selected countries. Occupational Health
Series No. 37. United International Labour Office, Geneva.
p. 44.
Kanisawa, M. , and H.A. Schroeder. 1969. Life term studies
on the effect of trace elements of spontaneous tumors in
mice and rats. Cancer Res. 29: 892.
Molokhia, M.M., and H. Smith. 1969. Tissue distribution
of trivalent antimony in mice infected, with Schistosoma
Mansoni. Bull. WHO 40: 123.
Murthy, G.K., et al. 1971. Levels of antimony, cadmium,
chromium, cobalt, manganese and zinc in institutional total
diets. Environ. Sci. and Tech. 5: 436.
NIOSH. 1978. Criteria for a recommended standard: Occupa-
tional exposure to antimony. DHEW (NIOSH) G.P.O. No. 017-
033-00335-1.
Schroeder, H.A. 1966. Municipal drinking water and cardio-
vascular death rates. Jour. Amer. Med. Assoc. 195: 81.
Schroeder, H.A. 1970. A sensible look at air pollution
by metals. Arch. Environ. Health 21: 798.
Schroeder, H.A., and L.A. Kraemer. 1974. Cardiovascular
mortality, • municipal water and corrosion. Arch. Enviorn.
Health 28: 303.
Schroeder, H.A., et al. 1970. Zirconium, niabium, antimony
and lead in rats: Life term studies. Jour. Nutr. 100: 59.
Tanner, J.T., and M.H. Friedman. 1977. Neutron activation
analysis for trace elements in foods. Jour. Radioanal.
Chem. 37: 529.
Taylor, P.J. 1966. Acute intoxication from antimony tri-
chloride. Br. Jour. Ind. Med. 23: 313.
Thomas, R.G., et al. 1973. Retention patterns of antimony
in mice following inhalation of particles formed at different
temperatures. Proc. Soc. Exp. Biol. Med. 144(2): 544.
-------
U.S. EPA. 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. 1979. Antimony: Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.
Waitz, J.A., et al. 1965. Physiological disposition of
antimony after administration of "Sb-labeled tartar emetic
to rats, mice and monkeys and the effects of tris (p- amino
phenyl) carbonium pamoate on this distribution. Bull. WHO
33: 537.
Woolrich, P.P. 1973. Occurrence of trace metals in the
environment: an overview. Amer . Ind. Hvg. Assoc. Jour. 34:
217.
-------
No. 11
Arsenic
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-JOH-
-------
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. EPA's Carcinogen Assessment Group (GAG) has evaluated
arsenic and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
ARSENIC
SUMMARY
Epidemiological studies have shown increased death rates
from lung cancer in workers exposed to arsenic, probably
through inhalation. Other human studies have shown increased
skin cancers in non-occupationally exposed populations. In-
creased incidence of lymphomas and hemangioendotheliomas are
also occasionally reported.
Arsenicals have produced mutagenic effects in plants,
bacteria, in vitro leukocyte cultures, and in the lymphocytes
of exposed humans. The teratogenic effects of arsenicals
have been demonstrated in many animal species. An increased
frequency of abortions in pregnant women exposed to arsenic
has been reported in a single study (U.S. EPA, 1979).
The chronic toxic effects of arsenic involve skin hyper-
keratosis, liver damage, neurological disturbances (including
hearing loss), and a gangrenous condition of the extremities
(Blackfoot disease). An increased mortality from cardiovas-
cular disease resulting from chronic arsenic exposure has
been suggested in two studies.
The data base for the toxicity of arsenic to aquatic or-
ganisms is more complete for freshwater organisms, where con-
centrations as low as 128 y.g/1 have been acutely toxic to
freshwater fish. A single marine species produced an acute
value in excess of 8,000 ug/1- Based on one chronic life
cycle test using Daphnia magna, a chronic value for arsenic
was estimated at 853 ug/1.
-------
ARSENIC
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Arsenic (U.S. EPA, 1979).
Arsenic is a gray, crystalline metalloid with a molecu-
lar weight of 74.92, a density of 5,727, a melting point (at
28 atmospheres) of 817°C, and a boiling point (sublimates) of
613°C (Wea.st, 1975). Arsenic exists in a variety of valence
states; the most common forms include pentavalent (arsenate),
trivalent (arsenite), and -3 valency (arsine). Properties of
some inorganic arsenic compounds are shown in Table 1.
Conditions of low pH, low oxidation-reduction potential,
and low dissolved oxygen in water favor formation of the
lower valency states (arsenite and arsine); more basic, oxy-
genated waters favor the presence of arsenate. Inorganic
arsenic can be converted to organic alkyl-arsenic acids and
to methylated arsines under both aerobic and anaerobic condi-
tions (U.S. EPA, 1979).
Arsenic and its compounds are used in the manufacture of
glass, cloth, and electrical semiconductors, as fungicides
and wood preservatives, as growth stimulants for plants and
animals, and in veterinary applications (U.S. EPA, 1976).
Production is currently 1.8 x 10^ metric tons per year
(U.S. EPA, 1979).
Arsenic will persist in some form in the environment.
Inorganic arsenate is thermodynamically favored under normal
conditions over arsenite in water and is a more soluble form
(Ferguson and Gavis, 1972). Both arsenate and arsenite may
be precipitated from water by adsorption onto iron and alum-
-------
Table 1. Properties of Some Inorganic Arsenic Compounds
(Standen, 1967; U.S. EPA, 1976)
Compound
Formula
Water Solubility
Specific Properties
Arsenic trioxide
Arsenic pentoxide
Arsenic hydride
Arsenic(III) sulfide
Arsenic sulfide
Arsenic(V) sulfide
As2°3
As205
AsH-
AS4S4
As4S1Q
12 x 106 ug/1 @ 0°C
21 x 106 ug/1 § 25°C
2300 x 106 ug/1 @ 20°C
20 ml/100 g cold water
520 ug/1 e 18°C
Dissolves in water to form
arsenious acid (H-jAsOj:
K = 8 x 10-1° @ 25°C)
Dissolves in water to form
arsenic acid (H3As04:Ki = 2.5 10~4
K2 = 5.6 x 10~8;
K3 = 3 x 10~13)
This compound and its methyl
derivatives are considered to
be the most toxic.
Burns in air forming arsenic
trioxide and sulfur dioxide;
occurs naturally as orpiment.
Occurs naturally as realgar.
1400 ug/1 @ 0°C
-------
inum compounds (U.S. EPA, 1979). Methylated arsines appear
to be volatile and sparingly soluble. Waters, containing high
organic matter may bind arsenic compounds to colloidal humic
matter (U.S. EPA, 1979).
II. EXPOSURE
Arsenic appears to be ubiquitous in the environment.
The earth's crust contains an average arsenic concentration
of 5 mg/kg (U.S. EPA, 1976). The major sources of arsenic in
the environment are industrial, such as those in the smelting
of non-ferrous ores and in coal-fired power plants that uti-
lize fuel containing arsenic. Substantial arsenic contamina-
tion of water can occur from the improper use of arsenical
pesticides (U.S-. EPA, 1979).
Based on available monitoring data, the U.S. EPA (1979)
has estimated the uptake of arsenic by adult humans from air,
water, and food:
Source mg/day
Maximum Conditions Minimum Conditions
Atmosphere .125 .001
Water 4.9 0.002
Food 'Supply .9 .007
Total 5.925 .010
Contaminated well water, seafood, and air near smelting
plants all present sources of high potential arsenic intake.
The U.S. EPA (1979) has estimated the weighted average
bioconcentration factor (BCF) for arsenic to be 2.3 in the
edible portions of fish and shellfish consumed by Americans.
»
This estimate was based on bioconcentration studies in fresh-
water fish.
y.
-------
III. PHARMACOKINETICS
A. Absorption
The main routes by which arsenic can enter the body
are inhalation and ingestion. Particle size and solubility
greatly influence the biological fate of inhaled arsenic.
Falk and Kotin (1961) have reported that the optimal range of
particle size for deposition in the lower tracheobronchial
tree is 0.1 to 2 u- Larger particles are trapped by the
mucous membranes of the nose and throat and swallowed;
following this, the particles may be absorbed from the
gastrointestinal tract (U.S. EPA, 1979).
Human inhalation studies in terminal lung cancer
patients (Holland, et al. 1959) have indicated that 4.8 to
8.8 percent of inhaled arsenic-74 in cigarette smoke may be
absorbed. Radioactive arsenite inhaled in an aerosol solu-
tion by two patients showed 32 and 62 percent absorption, re-
spectively. Pinto, et al. (1976) studied arsenic excretion
in 24 workers exposed to the compound during copper smelting;
urinary arsenic levels were found to correlate significantly
with average airborne arsenic concentrations.
Water soluble arsenicals are readily absorbed through
the gastrointestinal tract. Studies with radioactive arse-
nate administered orally to rats have shown 70 to 90 percent
absorption from the gastrointestinal tract (Urakubo, et al.
1975; Dutkiewicz, 1977). Arsenic trioxide is only slightly
soluble in water and is not well absorbed. Theoretically,'
trivalent arsenicals should be less readily absorbed than
pentavalent forms due to reactivity with membrane components
-in' -
-------
and lower solubility (U.S. EPA, 1979). However, investiga-
tors have reported high absorption of trivalent arsenic from
the gastrointestinal tract in humans (Bettley and O'Shea,
1975; Crecelius, 1977).
The absorption of arsenicals following dermal expo-
sure has been described in rats (Dutkiewicz, 1977) and humans
(Robinson, 1975; Garb and Hine, 1977).
Arsenic has been detected in the tissues (Kadowaki,
1960) and cord blood of newborns (Kagey, et al. 1977), and
thus transfers across the placenta in humans.
B. Distribution
Injection of radiolabelled arsenite in terminally
ill patients produced widespread distribution of the compound
(WHO, 1973). Hunter, et al. (1942) studied the distribution
of radioactive arsenicals in humans following oral and paren-
teral administration and found arsenic in the liver, kidney,
lungs, spleen, and. skin during the first 24 hours after ad-
ministration. Levels of arsenic are maintained for long per-
iods in bone, hair and nails (Kadowaki, 1960; Liebscher and
Smith, 1968).
Tissue distribution of pentavalent arsenic has been
described in only a few animal studies; these studies indi-
cate only minor differences in distribution between trivalent
and pentavalent arsenicals (WHO,.1973).
-//a-
-------
C. Metabolism
Studies with brain tumor patients given injections
of trivalent arsenic indicate that about 60 percent of the
total urinary arsenic was in the pentavalent state the first
day after dosing (Mealey, et al. 1959). Braman and Foreback
(1973) have analyzed human urine samples and detected high
amounts of methylated forms (dimethyl arsenic acid and methyl
• arsenic acid). .Analysis of the urine of one patient who in-
gested arsenic-contaminated'wine indicated that 8 percent of
the initial dose was excreted as inorganic arsenic, 50 per-
cent was excreted as dimethyl arsenic acid, and 14 percent
was excreted as methyl arsenic acid (Crecelius, 1977).
The half-lives of inorganic and organic (methy-
lated) arsenicals in one patient have been reported as 10 and
30 hours, respectively (Crecelius, 1977).
D. Excretion
Arsenic is excreted primarily in the urine, with
small amounts removed in the feces and through normal hair
loss and skin shedding (U.S. EPA, 1979). Reports of minor
arsenic loss in sweat have also been made (Vellar, 1969).
Small amounts of radioactive arsenic (.003 to .35
percent) have been detected in expired air following adminis-
tration to rats (Dutkiewicz, 1977) and chickens (Overby and
Fredrickson, 1963).
IV. EFFECTS
A. Carcinogenicity *
Epidemiological studies have shown an increased
mortality rate from respiratory cancer in workers exposed to
-------
arsenic during smelting operations (Lee and Fraumani, 1969;
Pinto and Bennett, 1963; Snegireff and Lombard, 1951; Kurat-
sune, et al. 1974). - A retrospective study of Dow Chemical
employees indicated that workers exposed primarily to lead
arsenate and calcium arsenate showed increased death rates
from lung cancer and malignant neoplasms of the lymphatic and
hematopoietic systems (except leukemia) (Ott, et al. 1974).
A similar trend was noted in a study of retired
Allied Chemical workers (Baetjer, et al. 1975).
High rates of development of skin cancers have been
reported in several studies of populations exposed to high
concentrations of arsenic in drinking water (Geyer, 1898;
Bergogilio., 1964; Tseng, et al. 1968).
Hemangioendothelioma of the liver associated with
exposure to arsenicals through ingestion has been reported in
several case studies (Roth, 1957; Regelson, et al. 1968).
Extensive experiments in animal systems with arsen-
icals administered in. the diet or drinking water, or applied
topically or by intratracheal instillation failed to show
positive tumorigenic effects (U.S. EPA, 1979). However, two
recent reports have shown effects in animals. Schrauzer and
Ishmael (1974) indicated that feeding of sodium arsenite in
drinking water accelerated the rate of spontaneous mammary
tumor formation. Osswald and Goerttler (1971) found an
increase in leukemias and lymphomas in mice injected
repeatedly with sodium arsenate.
Animal studies on the skin tumor-promoting or co-
carcinogenic effects .of arsenicals have produced negative
results (Raposo, 1928; Baroni, et al. 1963; Bout-well, 1963).
-------
B. Mutagenicity
An increased incidence of chromosomal aberrations
has been found in persons exposed to arsenic occupationally
and medically (Petres, et al. 1970; Nordenson, et al. 1978;
Burgdorf, et al. 1977).
I_n vitro chromosomal changes following exposure to
arsenicals have been reported in root meristem cultures
(Levan, 1945) and in human leukocyte cultures (Petres and
Hundeiker, 1968; Petres, et al. 1970, 1972; Paton and
Allison, 1972).
Arsenate has been found to increase the frequency
of chromosome exchanges in Drosophila. Several organic ar-
senicals have a synergistic effect with ethylmethane sulfon-
ate in producing chromosome abnormalities in barley (Moutsh-
cen and Degraeve, 1965).-
Sodium arsenate, sodium arsenite, and arsenic tri-
chloride produced positive mutagenic effects in a recombinant
strain of Bacillus subtillus (Nishioka, 1975). Loforth and
Ames (1978) were unable to show mutagenic effects of trival-
ent and pentavelent arsenicals in the Ames Salmonella assay.
Arsenite exposure decreased the survival of _E. coli after UV
damage of cellular PNA (Rossman, et al. 1975).
-J/S-
-------
C. Teratogenicity
Nordstrom, et al. (1978) have reported an increase
in the frequency of spontaneous abortions in pregnant women
living in the vicinity of a copper smelting plant; the expo-
sure environment was complex, involving several heavy metals
and sulfur dioxide.
Sodium arsenate has been shown to induce teratogen-
ic effects in the chick embryo (Ridgway and Karnofsky, 1952),
in golden hamsters (Perm and Carpenter, 1968; Ferm, et al.
1971), in mice (Hood and Bishop, 1972), and rats (Beaudoin,
1974). Malformations noted included exencephaly, anenceph-
aly, renal agenesis, gonadal agenesis, eye defects, and rib
and genitourinary abnormalities. Sodium arsenite injected
intraperitoneally into mice produced a lower incidence of
malformations than an equivalent dose of sodium arsenate
(Hood and Bishop, 1972; Hood, et al. 1977). Thacker, et al.
(1977) has noted that a higher oral dose of sodium arsenate
is needed to produce teratogenic effects in mice, when com-
pared to intraperitoneal doses.
Feeding of three generations of mice with low doses
of sodium arsenite in the chow failed to produce teratogenic
effects, but did decrease litter size (Schroeder and Mitch-
ener, 1971).
D. Other Reproductive Effects
Pertinent information could not be located in the
available literature regarding other reproductive effects.
»
E. Chronic Toxicity
A variety of chronic effects of arsenic exposure
has been noted. This includes a characteristic nalmar-
-------
plantar hyperkeratosis and a gangrenous condition of the
hands and feet called Blackfoot disease (U.S. EPA, 1979).
Several clinical reports of liver damage in patients treated
with arsenical medication have been published (WHO, 1979).
An increased mortality from cardiovascular disease has been
noted in two epidemiological studies of smelter workers ex-
posed to high airborne arsenic (Lee and Fraumeni, 1969; U.S.
EPA, 1979). Neurological disturbances, including hearing
loss, .in workers exposed to arsenicals have been reported
(WHO, 1979).
Effects of arsenicals on the hematopoietic system
following chronic exposure have also been noted (WHO, 1979).
These include disturbed erythropoiesis and granulocytopenia,
which may lead to impaired resistance to viral infections.
V. AQUATIC TOXICITY
A. Acute Toxicity
Seven static and seven flow-through bioassays from
.48 to 96-hours in duration provide a range of LCcQ values
for freshwater fish of 290 to 150,000 u.g/1- Hughes and Davis
(1967) demonstrated the most sensitive species as being blue-
gill ~fingerlings , Lepomis macrochirus, while Sorenson (1976)
reports that the most resistant species was the green sun-
fish, Lepomis cyanellus. Both species were tested in static
tests. Sanders and Cope (1966) provided the data for fresh-
water invertebrates in static bioassays. The cladoceran,
Simocephalus serrulatus, was the most sensitive with an 48-
hour LC50 value of 812 ug/1/ while the stonefly, Ptaron-
arcys californica, was the most resistant species with an
-------
LCgo value of 22,040 ug/1- In marine, organisms, the chum
salmon, Onchorhynchus keta, had a 48-hour flow-through LC5Q
value of 3,331 ug/1 (Alderdice and Brett, 1957). Two marine
invertebrates were tested in 96 or 48-hour static-renewal or
static assays and produced the following LC5Q values: bay
scallop, Argopecten irradiana, with 3,490 ug/1; and the em-
bryos of the American oyster, Crassostrea virginica, with a
value of 4,330 ug/1.
B. Chronic Toxicity
One chronic life cycle freshwater test has provided
a chronic value of 853 ug/1 for arsenic to Daphnia magna.
Pertinent data could not be located in the available litera-
ture for the. chronic toxicity of arsenic to marine organisms.
C. Plant Effects
The lowest effective concentration recorded was 100
percent kill levels of 2,320 ug/1 for four species of fresh-
water algae.
D. Residues
Bioconcentration factors for five freshwater inver-
tebrate species and two fish species ranged from less than 1
to 17 (U.S. EPA, 1979) .
VI. EXISTING GUIDELINES AND STANDARDS
A. . Hunan
Criteria for organic and inorganic arsenicals have
been derived. However, due to public comment questioning bhe
relevancy and accuracy of the studies used in the development
of these criteria, further review is necessary before, final
reccnmendat ion .
-JI9-
-------
The OSHA. tine-weighted a-verage exposure criterion
-3
for arsenic is 10 ug/n-5.
B. Aquatic
For arsenic, the draft criterion for freshwater or-
ganisms is 57 ug/1, not to exceed 130 ug/1- For marine or-
ganisms, the draft criterion is 29 ug/1, not to exceed 67
ug/1 (U.S. EPA,1579).
-------
ARSENIC
REFERENCES
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arsenite to young chum salmon. Prog. Rep. Pacific Coast Stat.
Fish. Res. Board Can. 108: 27.
• Baetjer, A.M., et al. 1975. Cancer and occupational exposure
to inorganic arsenic. Page 393 in Abstracts. 18th Int. Cong.
Occup. Health Brighton, England, September 14-19.
Baroni, C., et al. 1963. Carcinogenesis tests of two inor-
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Beaudoin, A.R. 1974. Teratogenicity of sodium arsenate in
rats. Teratology 10: 153.
Bergoglio, R.M. 1964. Mortalidad por cancer en zonas de
aguas arsenicales de la Provincia de Cordoba,. Republica Argen-
tina. Prensa Med. Argent. 51: 994.
• Bettley, F., and .J. O'Shea. 1975. The absorption of arsenic
and its relation to carcinoma. Brit. Jour. Dermatol. 92:
563.
Boutwell, R. 1963. A carcinogenicity evaluation of potassium
arsenite and arsenilic acid. Jour. Agric. Food Chem. 11:
381.
Braman, R.S., and C.C. Foreback. 1973. Methylated forms of
arsenic in the environment. Science 182: 1247.
Burgdorf, W., et al. 1977. Elevated sister chromatic ex-
change rate in lymphocytes of subjects treated with arsenic.
Hum. Genet. 36: 69.
• Crecelius, E.A. 1977. Changes in the chemical speciation of
arsenic following ingestion by man. Environ. Health Perspect.
19: 147.
. Dutkiewicz, T. 1977. Experimental studies on arsenic absorp-
tion routes in rats. Environ. Health Perspect. 19: 173.
Falk, H.L., and P. Kotin. 1961. An assessment of factors
concerned, with the carcinogenic properties of air pollutants.
Natl. Cancer Inst. Mon. 9: 81.
Ferguson, J.F., and J. Gavis. 1972. A review of the arsenic
cycle in natural waters. Water Res. 6: 1259.
-------
Ferm, V.H., and S.J. Carpenter. 1968. Malformation induced
by sodium arsenate. Jour. Reprod. Fertil. 17: 199.
Ferm, V.H., et al. 1971. The teratogenic profile of sodium
arsenate in the golden hamster. Arch. Environ. Health 22:
557.
Garb, L.G., and C.H. Hine. 1977. Arsenical neuropathy: Res-
idual effects following acute industrial exposure. Jour.
Occup. Med. 19: 567.
Geyer, L. 1898. Uber die chronischen Hautveranderungen beim
Arsenicismus und Betrachtungen uber die Massenerkrankungen in
Reichenstein in Schlesien. Arch. Derm. Syphilol. 43: 221.
Holland, R.H., et al. 1959. A study of inhaled arsenic-74 in
man. Cancer Res. 19: 1154.
Hood, R.D., and S.L. Bishop. 1972. Teratogenic effects of
sodium arsenate in mice. Arch. Environ. Health 24: 62.
Hood, R.D./.et al. 1977. Effects in the mouse and rats of
prenatal exposure to arsenic. Environ. Health Perspect. 19:
219.
Hunter, F.T., et al. 1942. Radioactive tracer studies on
arsenic injected as potassium arsenite. jour. Pharmacol. Exp.
Ther. 76: 207.
Hughes, J.S., and J.T. Davis. 1967. Effects of selected
herbicides on bluegill sunfish. Pages 480-482. In Proc. 18th
Ann. Conf., S.E. Assoc. Game Fish Comm., October T8, 19, 20
and 21, 1964. Clearwater, Fla. Columbia, S.C.: S.E. Assoc.
Game Fish Comm.
Kadowaki, K. 1960. Studies on the arsenic contents in organ-
tissues of the normal Japanese. Osaka City Med. Jour. 9:
2083.
Kagey, B., et al. 1977. Arsenic levels in maternal-fetal
tissue sets. Trace Subst. Environ. Health 11: 252.
Kuratsune, M., et al. 1974. Occupational lung cancer among
copper smelters. Int. Jour. Cancer 13: 552.
Lee, A.M., and J.F. Fraumeni, Jr. 1969. Arsenic and respira-
tory cancer in man: An occupational study. Jour. Natl. Can-
cer Inst. 42: 1045.
Levan, A. 1945. Cytological reactions induced by inorganic
salt solutions. Nature 156: 751.
-------
Liebscher, K., and H. Smith. 1968. Essential and nonessen-
tial trace elements. -A method of determining whether an ele-
ment is essential or nonessential in human tissue. Arch.
Environ. Health 17: 881.
Lofroth, G., and B. Ames. 1978. Mutagenicity of inorganic
compounds in Salmonella typhimurium; arsenic, chromium, and
selenium. Mutat. Res. 53: 65.
Mealey, J., Jr., et al. 1959. Radioarsenic in plasma,
urine, normal tissues, and intracranial neoplasms. Arch.
Neurol. Psychiatry 81: 310.
Moutshcen, J., and N. Degraeve. 1965. Influence of thiol—
nhibiting substances on the effects of ethyl methane sulphon-
ate (EMS) on chromosomes. Experientia 21: 200.
Nishioka, H. 1975. Mutagenic activities''of metal compounds"
in bacteria. Mutat. Res. 31: 185.
Nordenson, I., et al. 1978. Occupational and environmental
risks in and around a smelter in northern Sweden. II. Chro-
mosomal aberrations in workers exposed to arsenic. Hereditas
88: 47.
Nordstrom, S., et al. 1978. Occupational and environmental
risks in and around a smelter in northern Sweden. III. Fre-
quencies of spontaneous abortion. Hereditas 88: 51.
Osswald, H., and Kl. Goerttler. 1971. Laukosen bei der Maus
nach diaplacentarer und postnataler Arsenik-Applikation.
Dtsch. Gesmte Path. 55: 289.
Ott, M.G., et al. 1974. Respiratory cancer and occupational
exposure to arsenicals. Arch. Environ. Health 29: 250.
Overby, L.R., and R.L. Fredrickson. 1963. Metabolic stabil-
ity of radioactive arsanilic acid in chickens. Jour. Agric.
Food Chem. 11: 378..
Paton, G.R., and A.C. Allison. 1972. Chromosome damage in
human cell cultures induced by metal salts. Mutat. Res. 16:
332.
Petres, J., and M. Hundeiker. 1968. "Chromosomenpulverisa-
tion" nach Arseneinwirkung auf Zelljulturen in vitro. Arch.
Klin. Exp. Dermatol. 231: 366.
Petres, J., et al. 1970. Chromosomenaberrationen an mensch-
lichen Lymphozyten bei chronischen Arsenchaden. Dtsh. Med.
Wochenschr. 95: 79.
»
Petres, J., et al. 1972. Zum Einfluss anorganischen-Arsens
auf die DNS-Synthese menschlicher Lymphocyten in vitro. Arch
Derm. Forsch. 242: 343.
-------
Pinto, S.S., and B.M. Bennett. 1963. Effect of arsenic tri-
oxide exposure on mortality. Arch. Environ. Health 7: 583.
• Pinto, S.S., et al. 1976. Mortality experience of arsenic
exposed workers. Unpubl.
Raposo, L. 1929. Le cancer a 1'arsenie. C.P. Soc. Biol.
(Paris) 98: 86.
Regelson, W., et al. 1968. Hemangioendothelial sarcoma of
liver from chronic arsenic intoxication by Fowler's solution.
Cancer 21: 514.
Ridgway, L.P., and D.A. Karnovsky. 1952. The effects of
metals on the chick embryo: Toxicity and production of abnor-
malities in development. Annu. N.Y. Acad. Sci. 55: 203.
Robinson, T. 1975. Arsenical polyneuropathy due to caustic
arsenical paste. Brit. Med. Jour. 3: 139.
Rossman, T.', et al. 1975. Effects of sodium arsenite on the
survival of UV-irradated Escherichia coli: Inhibition of a
rec A dependent function. Mutat. Res. 30: 157.
Roth, F. 1957. The sequelae of chronic arsenic poisoning in
Moselle vintners. German Med. Monthly 2: 172.
Sanders, H.O., and O.B. Cope. 1966. Toxicities of several
pesticides to two species of cladocerans. Trans. Am. Fish.
Soc. 95: 165.
. Schrauzer, G., and D. Ishmael. 1974. Effects of selenium
and of arsenic on the genesis of spontaneous mammary tumors
in inbred C^H mice. Ann. Clin. Lab. Sci. 4: 441.
Schroeder, H.A., and M. Mitchener. 1971. Toxic effects of
trace elements on the reproduction of mice and rats. Arch.
Environ. Health 23: 102.
Snegireff, L.S., and O.M. Lombard. 1951. Arsenic and can-
cer. Observation in the metallurgical industrv. AMA Arch.
Ind. Hyg. 4: 199.
Sorenson, E.M.B. 1976. Toxicity and accumulation of arsenic
in green sunfish, Lepomis cyanellus, exposed to arsenate in
water. Bull. Environ. Contam. Toxicol. 15: 756.
Sram, R., and V. Bencko. 1974. A contribution to the evalu-
ation of the genetic risk of exposure to arsenic. Cesk Hyg.
19: 308.
Standen, A. (ed.) 1967. Kirk-Othmer encyclopedia of chemi-
cal technology. Interscience Publishers, Mew York.
-------
Thacker, G., et al. 1977. Effects of administration routes
on arsenate teratogenesis in mice. Teratology 15: 30.
Tseng, W.P., et al. 1968. Prevalence of.skin cancer in an
endemic area of chronic arsenicism in Taiwan. Jour. Natl.
Cancer Inst. 40: 453.
U.S. EPA. 1976. Arsenic and its compounds. EPA 560/6-76-
016. U.S. Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1979. Arsenic: Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.
Urakubo, G. , et al. 1975. Studies in the fate of poisonous
metals in experimental animals (V). Body retention and ex-
cretion of arsenic. Jour. Food Hyg. Soc. Jpn. 16: 34.
Vellar, 0. 1969. Nutrient lopes through sweating. Thesis,
Universitetsforlaget, Oslo, Norway.
Weast, R.C. (ed.) 1975. Handbook of chemistry and physics.
56th ed. CRC Press, Cleveland, Ohio.
WHO. 1973. Environmental Health Criteria: Arsenic. World
Health Organization. Geneva.
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No. 12
Asbestos
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 thr '
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 (GAG) has evaluated
asbestos and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
ASBESTOS
Summary
Numerous studies indicate that asbestos fibers introduced into the
pleura, peritoneum, and trachea of rodents have induced malignant tumors.
The strongest evidence for the carcinogenicity of ingested asbestos is pro-
vided by epidemiology of human populations occupationally exposed to high
concentrations of airborne asbestos dust. Inhalation exposure to asbestos
dust is accompanied by ingestion because a high percentage of the inhaled
fibers are removed from the lung by mucociliary action and subsequently
swallowed. -Peritoneal mesothelioma, often in great excess, and modest ex-
cesses of stomach esophagus, colonrectal, and kidney cancer have been linked
to occupational exposure to asbestos.
Pertinent data on the acute or.chronic effects of asbestos to aquatic
organisms were not-found in the available literature.
-------
ASBESTOS
I. INTRODUCTION
This profile is based primarily upon the Ambient Water Quality Criteria
Document for Asbestos (U.S. EPA, 1979). In addition, valuable information
Is available from recent reviews by the International Agency for Research on
Cancer (IARC, 1977) and the National Institute for Occupational Safety and
Health (NIOSH, 1977).
Asbestos is a broad term applied to numerous fibrous mineral silicates
composed of silicon, oxygen, hydrogen, and metal cations such as sodium,
magnesium, calcium, or iron. There are two major groups of asbestos, ser-
pentine (chrysotile or "white asbestos") and amphibole. Although chrysotile
is considered to be a distinct mineral, there are five fibrous amphiboles:
actinolite, amosite ("brown asbestos"), anthophyllite, crocidolite ("blue
asbestos"), and tremolite.. The chemical composition of different asbestos
fibers varies widely, and typical formulas are presented in Table 1. Some
typical physical properties of three different mineral forms of asbestos are
presented in Table 2.
TABLE 1
TYPICAL FORMULAS FOR ASBESTOS FIBERS
1. Serpentines chrysotile
2. Amphiboles amosite
crocidolite Na/2(Mg,Fe)5S
anthophyllite
tremolite
actinolite
-------
TABLE 2 .
TYPICAL PHYSICAL PROPERTIES OF CHRYSOTILE (WHITE ASBESTOS),
CROCIDOLITE (BLUE ASBESTOS), AND AMOSITE
Units
Approximate
diameter of micron
smallest fibers
Specific
gravity
Average
tensile Ib./inch2
strength
Modulus of Ib./inch2
elasticity
Chrysotile
(white asbestos)
0.01
2.55
3.5 x 105
23.5 x 10^
Crocidolite - Amosite
(blue asbestos)
0.08 0.1
3.37 3.45
5 x 1Q.5 1.75 x 1Q5
27.0 x 106 23.5 x 10<$
Asbestos minerals, despite a relatively high fusion temperature, are
completely decomposed at temperatures of 1,000°C. Both the dehydroxyla-
tion temperature and decomposition temperature increase with increased MgO
content among the various amphibole species (Spell and Leineweber, 1969).
The solubility product constants for various chrysotile fibers range
IV 1 7
from 1.0 x 10 to 3 x 10" . Most materials have a negative surface
charge in aqueous systems. However, since chrysotile has a positive ( + )
charge, it will attract, or be 'attracted to, most dispersed materials. The
highly reactive surface of asbestos causes many surface reactions which are
intermediate between, simple -• absorption and a true chemical reaction. The
absorption of various materials on the surface of chrysotile supports the
premise that the polar surface of chrysotile has a.-greater affinity for
polar molecules, (e.g., H20, NH^) than for non-polar molecules (Speil and
Leineweber, 1969).
~J30-
-------
Of all the asbestos minerals, chrysotils is the most susceptible to
acid attack. It is almost completely destroyed within one hour in 1 N HCL
at 95°C. Amphibols fibers are much more resistant to mineral acids
(Lindell, 1972).
The resistance of the asbestos fibers to attack by reagents other than
acid is excellent up to temperatures of approximately 100°C with rapid
deterioration observed at higher temperatures. Chrysotile is completely de-
composed in concentrated KOH at 200°C. In general, organic acids have a
tendency to react slowly with chrysotile (Speil and Leineweber, 1969).
Chrysotile is the major type of asbestos used in the manufacture of as-
bestos products. These products include asbestos cement pipe, flooring pro-
ducts, paper products (e.g., padding), friction materials (e.g., brake lin-
ings and clutch facings), roofing products, and coating and patching com-
pounds. In 1975, the total consumption of asbestos in the U.S. was 550,900
thousand metric tons (U.S. EPA, 1979).
Of the 243,527 metric tons of asbestos discharged to the environment,
98.3 percent was discharged to land, 1.5 percent to air, and 0.2 percent to
water (U.S. EPA, 1979). Solid waste disposal by consumers was the single
largest contribution to total discharges. Although no process water is used
in dry mining of asbestos ore, there is the potential for runoff from asbes-
tos waste tailings, wet mining, and iron ore mining. Mining operations can
also contribute substantially to asbestos concentrations in water by air and
solid waste contamination. In addition to mining and industrial discharges
of asbestos, asbestos fibers, which are believed to be the result of rock
outcroppings, are found in rivers and streams.
-------
II. EXPOSURE
A. Water
Asbestos is commonly found in domestic water supplies. Of 775 re-
cent samples analyzed by electron microscopy under the auspices of the U.S.
EPA, 50 percent showed detectable levels of asbestos, usually of the chryso-
tile variety (Millette, 1979). Nicholson and Pundsack (1973) measured aver-
age asbestos levels of 0.3-1.5 pg/1 in drinking water from two Eastern
United States river systems. Levels of 2.0 to 172.7 x 10° fibers/1 have
been reported in Canadian tap water, the highest levels being found in un-
filtered tap water near a mining area (Cunningham and Pontefract, 1971). In
.other studies of Canadian drinking water levels of 0.1 to 4 x 10 fibers/1
have been reported (Kay, 1973). The U.S. EPA (1979) has concluded • that
about 95 percent of water consumers in the United States are exposed to as-
bestos • fiber concentrations of less than 10 fibers/1. The mass concen-
trations of chrysotile asbestos in the water of cities with less than 106
fibers/1 are likely to be less than 0.01 jug/1, corresponding. to an adult
daily intake of less than 0.02 ug. Pertinent data on the ability of aquatic
organisms to bioconcentrate asbestos from water were not located in .the
available literature.
B. Food
There are scant data on the contribution of food products to popu-
lation asbestos exposure. However, asbestos fibers and talc, which some-
times contains asbestos as an impurity, may be used in the manufacture of
certain processed foods such as sugar, coated rice, vegetable oil and lard
(IARC, 1977). Cunningham and Pontefract (1971) reported that certain beers
*
and wines could contain asbestos fibers at levels similar to those found in
drinking water systems (10 to 107 fibers/1).
-------
C. Inhalation
Asbestos is present in virtually all metropolitan areas. Concen-
trations of asbestos in urban atmosphere are usually less than 10 ng/m"*,
but may reach 100 ng/m-5 (Nicholson; et al. 1971; Nicholson and Pundesack,
1973; Sebastien, et al. 1976; IARC, 1977). Construction sites and buildings
fireproofed with loose asbestos material showed the most significant contam-
ination with individual measurements as high as 800 ng/m (Nicholson, et
al. 1975).
III. PHARMACOKINETICS
There are contradictory data concerning whether ingested asbestos
fibers are capable of passage across the gastrointestinal mucosa (Gross, et
al. 1974; Cooper and Cooper, 1978; Cunningham and Pontefract, 1973;
Cunningham, et al. 1977). Most ingested asbestos particles are excreted in
the feces (Cunningham, et al. 1976). However, at least one recent study
(Cook and Olson, 1979) indicates that ingestion of drinking water containing
amphibole fibers may result in the appearance of these fibers in the urine,
thus providing evidence for passage of asbestos across the human gastro-
intestinal tract.
Ingestion of asbestos fibers is accompanied by swallowing of many
fibers cleared from the respiratory tract by mucociliary action. More than
half the asbestos inhaled will likely be swallowed (U.S. EPA, 1979). The
deposition of asbestos fibers in the lung is a function of their diameter
rather than length, as about 50 percent of particles with a mass median dia-
meter of less than 0.1 urn will be deposited on nonciliated pulmonary sur-
faces. Deposition on nasal and pharyngeal surfaces becomes important as
»
mass median diameter approaches 1 jum and rises rapidly to become the domi-
nant deposition site for airborne particles 10 urn in diameter or greater
-/33-
-------
(Brain and Volberg, 1974). Portions of inhaled asbestos fibers which are
not cleared by microciliary action may remain trapped in the lung for de-
cades (Pooley, 1973; Langer, 1973). However, the chrysotile content of the
lung does not build up as significantly as that of the amphiboles for simi-
lar exposure circumstances (Wagner, et al. 1974).
IV. EFFECTS .
A. 'Carcinogenic.! ty
All commercial forms of asbestos have demonstrated carcinogenic
activity in mice, rats, hamsters, and rabbits. 'Intraperitoneal injection of
various asbestos fibers has produced mesotheliomas in rats and mice (Maltoni
and Annoscia, 1974; Pott and Friedrichs, 1972; Pott, et al. 1976). In rats,
chronic inhalation of various types of asbestos have produced lung carcino-
mas and mesotheliomas (Reeves, et al. 1971, 1974; Gross, et al. 1967;
Wagner, et al. 1974; Davis, et al. 1978). Intrapleural injection of asbes-
tos fibers has produced- mesotheliomas in rats, hamsters, and rabbits (Donna,
1970; Reeves, et al. 1971; Stanton and Wrench, 1972; Stanton, 1973; Wagner,
et al. 1973, 1977; Smith and Hubert, 1974). The oral administration of as-
bestos filter material reportedly caused malignancies in rats (Gibel, et al.
1976) although other feeding studies have produced equivocal results.
Occupational 'exposure to chrysotile, amosite, anthophyllite, and
mixed, fibers containing crocidolite has resulted in high incidences of human
lung cancers (Selikoff, et al. 1979; Seidman, et al. 1979; Enterline and
Henderson, 1973; :Henderson and Enterline, 1979; IARC, 1977).. Occupational
exposure to crocidolite, amosite, and chrysotile have also been associated
with a large incidence of pleural and peritoneal mesatheliomas. An excess
»
of gastrointestinal cancers has been associated in some studies with expo-
sure to amosite, chrysotile, or mixed fibers containing crocidolite (Seli
-------
koff, 1976; Selikoff, et al. 1979; Elmes -and Simpson, 1971; Henderson and
Enterline, 1979; Nicholson, et al. 1979; Seidman, et al. 1979; Newhouse and
Berry, 1979; McDonald and Liddell, 1979; Kogan, et al. 1972).
In the general environment, mesotheliomas have occurred in persons
living near asbestos factories and crocidolite mines and in the household
contacts of asbestos workers (Wagner, et al. 1960; Newhouse and Thomson,
1965). In addition, several studies have implicated asbestos in drinking
water with the development of cancer of the lung and digestive tract cancers
(Mason, et al. 1974; Levy, et al. 1976; Cooper,'' et al. 1978, 1979). There
is convincing evidence to support the contention that asbestos exposure and
cigarette smoking act synergistically to produce dramatic increases in lung
cancer over that from exposure to either agent alone (Selikoff, et al. 1968;
)
Berry, et al. 1972).
In a study by Hammond, et al. (1979) involving 17,800 insulation
workers, the death rate for non-smokers was 5.17 times that of a non-smoking
control population. The death rate was 53.24 times that of the non-smoking
r
control population or 4.90 times' the death rate for a comparable group of
non-exposed smokers. Cancers ") the larynx, pharynx and buccal cavity in
insulators were also found to be associated with cigarette smoking, together-
with some non-malignant asbestos effects such as fibrosis and deaths due to
asbestosis.
B. Mutagenicity
In cultured Chinese hamster cells, chrysotile and crocidolite have
produced genetic damage and morphologic transformation (Sincock and
Seabright, 1975; Sincock, 1977). On the other hand, chrysotile, amosite,
and anthophyllite showed no mutagenic activity toward tester strains of §_._
coli or S_._ tyohifnurium (Chamberlain and Tarmy, 1977).
/
-------
C. Teratogenicity
Pertinent data on the possible teratogenic effects of asbestos were
not located in the available literature, although transplacental passage of
asbestos fibers has been reported (Cunningham and Pontefract, 1971, 1573).
D. Other Reproductive Effects
It is not known whether asbestos exposure .may impair fertility or
interfere with reproductive success (U.S. EPA, 1979).
E. Chronic Toxicity
The chronic ingestion of chrysotile by'-rats (0.5 mg or 50 mg daily
for 14 months) produced no effects on the esophagus, stomach, or cecum tis-
sue, but histological changes were seen in the ileum, particularly of the
villi (Jacobs, et al. 1978).
The long-term L ' ^ase entity, asbestosis, results from the inhala-
tion of asbestos fibers and is a chronic, progressive pneumoconiosis. It is
characterized by fibrosis of the lung parenchyma and produces shortness of
breath as the primary symptom. Asbestos has accounted for numerous cases of
occupational disablement "Curing life as well as a considerable number of
deaths among worker groups. _ In groups exposed at lower concentrations such
"i
.f
as the families of workers, there is less incapacitation and although asbes-
tosis can occur,.deaths have not been reported (Anderson, et al. 1976).
Extrapulmonary chronic effects reported include "asbestos corns"
from the penetration of asbestos fibers into the skin. No chronic nonmalig-
nant. gastrointestinal effects have been reported.
V. AQUATIC TOXICITY
Pertinent data concerning the effects of asbestos to either fresh-
water or marine organisms were not located in the available literature.
-------
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 Occupational Safety and Health Administration (OSHA)
standard for an 8-hour time-weighted average (TWA) occupational exposure to
asbestos is 2 fibers longer than 5 microns in length per milliliter of air
(2f/ml or 2,000,000 f/m3). Peak exposures of up to 10 f/ml are permitted
for no more than 10 minutes (Fed. Reg., 1972). This standard has been in
effect since July 1, 1976, when it replaced an earlier one of 5 f/ml (TWA).
Great Britain also has a value of 2 f/ml as the accepted level, below which
no controls are required (BOHS, 1968). The British standard, in fact,
served as a guide for the OSHA standard (NIOSH, 1972).
The British standard was developed specifically to prevent asbes-
tosis among working populations; data were felt to be lacking that would
allow for determination of a standard for cancer (BOHS, 1968). Unfor-
tunately, among occupational groups, cancer is the primary cause of excess
death for workers (see "Carcinogenicity" section) with three-fourths or more
of asbestos-related deaths caused from malignancy. This fact has led OSHA
to propose a lower TWA standard of 0.5 f/ml (500,000 f/m3) (Fed. Reg.,
1975). The National Institute for Occupational Safety and Health (NIOSH),
in their criteria document for the hearings on a new standard, have proposed
a value of 0.1 f/ml (NIOSH, 1977). In the discussion of the NIOSH proposal,
it was stated that the value was selected on the basis of the sensitivity of
t
analytical techniques using optical microscopy and that 0.1 f/ml may not
neces
-/27-
-------
sarily protect against cancer. Recognition that no information exists that
would define a threshold for asbestos carcinogenesis was also contained in
the preamble of the OSHA proposal. The existing standard•in Great Britain.
has been questioned by Peto (1978), who estimates that asbestos disease may
cause the death of 10 percent of workers exposed at 2 f/ml for a working
lifetime.
The existing federal standard for asbestos emissions into the en-
vironment prohibits "visible emissions" (U.S. EPA, 1975). No numerical
value was specified because of difficulty in monitoring ambient air asbestos
concentrations in the ambient air or in stack emissions. Some local govern-
ment agencies, however, may have numerical standards (e.g., New York, 27
ng/m ).
NO standards for asbestos in foods or beverages exist even though
the use of filtration of such products through asbestos filters has been a
common practice in past years. Asbestos filtration, however, is prohibited
or limited for human drugs (U.S. FDA, 1976).
The draft recommended water quality criterion for asbestos par-
ticles (U.S. EPA, 1979) is derived from the substantial data which exists
for the increased incidence of peritoneal mesothelioma and gastrointestinal
tract cancer in humans exposed occupationally to asbestos. This derivation
assumes that much or all of this increased disease incidence is caused by
fibers ingested following clearance from the respiratory tract. Several
studies allow the association of approximate airborne fiber concentrations
to which individuals were exposed with observed excess peritoneal and gas-
trointestinal cancer. All of the inhaled asbestos is assumed to be even-
tually cleared from the respiratory tract and ingested.
-------
The draft criterion calculated to-keep the individual lifetime can-
cer risk below 10~:>, is 300,000 fibers of all sizes/liter. The corres-
ponding mass concentration for chrysotile asbestos is approximately 0.05
ug/1. This criterion has not yet gone through the process of public review;
therefore, there is a possibility that the criterion may be changed.
8. Aquatic
Because no data are available on the aquatic toxicity of asbestos,
the U.S. EPA (1979) derived no aquatic criteria.
- /39-
-------
ASBESTOS
REFERENCES
Anderson, H.A., et al. i97o. Household-contact asbestos neo-
plastic risk. Ann. N.Y. Acad. Sci. 271: 311.
Berry, G., et al. 1972. Combined effect of asoestos exposure
and smoking on mortality from lung cancer in factory workers.
Lancet 2: 476.
Brain, J.D., and P.A. Volberg. 1974. Models of lung retention
based on ICRP task group report. Arch. Environ. Health 28: 1.
British Occupational Hygiene Society. 1968. Hygiene standard
for chrysotile asbestos dust. Ann. Occup. Hyg. 11: 47.
Chamberlain, M. and E.M. Tarmy. 1977. Asbestos ana glass fibres
in bacterial mutation tests. Mutat. Res. 43: 159.
Cook, P.M. and G.F. Olson. 197y. Ingested mineral fibers: Elimi-
nation in human urine. Science 204: 195.
Cooper, R.C. and W.C. Cooper. 1978. Public health aspects of
asbestos fibers in drinking water. Jour. Am. Water Works Assoc.
72: 338.
Cooper, R.C., et al. 1978. Asbestos in domestic water supplies
for five California counties. Prog^ rep. for period April 25,
1977 to June 30, 1978. EPA Contract No. R804366-02.
Cooper, R.C., et al. 1979. Asbestos in domestic water supplies
for five California counties. Part II EHS Puol. No. 79-1, School
of Public Health, Univ. Calif. Berkeley. pp. 247.
Cunningham, H.M. and R.D. Pontefract. 1971. Asoestos fioers
in- beverages and drinking water. Nature (Lond.) 232: 332.
Cunningnam, H.M. and R.D. Pontefract. 1973. Asbestos fibers
in beverages, drinking water and tissues: their passage through
the intestinal wall and movement through the body. Jour. Assoc.
Off. Analyt. Chem. 56: 97o.
Cunningham, H.M., et al. 1976. Quantitative relationship of
fecal asbestos to asbestos exposure. Jour. Toxicol. Environ.
Health 1: 377.
Cunningham, H.M., et al. 1977. Chronic effects of ingescea
asbestos in rats. Arch. Environ. Contam. Toxicol. 6: 507. '
Davis, J.M.G., et al. 1978. Mass and number of fioers in tne
pathogenesis of asbestos-related lung disease in rats. Br. Jour.
Can. 37: o7j.
-I'-SO-
-------
Donna, A. 1970. Tumori sperimentali da amiano di crisotilo,
crocidolite e amosite in ratto Sprague-Dawley. Med. Lavoro.
61: 1.
Elmes, P.C. ana M.J.C. Simpson. 1971. Insulation workers in
Belfast. III. Mortality 1940-66. Br. Jour. Ind. Med. 23: 226.
Enterline, P.E. ana V. Hencerson. 1973. Type of asbestos ana
respiratory cancer in the asbestos industry. Arch. Environ.
Health. 27: 312.
Federal Register. 1972. Standard for exposure to asbestos dust.
Title 29, Chap. XVII, Part 1910-Occupational Safety and Health
Standards. June 7, Washington, D.C. 37: 11318.
Federal Register. 1975. Occupational exposure to asbestos;
notice of proposed rulemaking. Oct. 9, Washington, D.C. 49: 197.
Gibel, W., et al. 1976. Tierexperimentelle untersuchungen uber
eine kanzerogene wirkung von asbestfiltermaterial nach oraler
aufnahme. Arch. Geschwulstforsch. 46: 437.
Gross, P., et al. 1967. Experimental asbestosis: The develop-
ment of lung cancer in rats with pulmonary deposits of chrysotile
asbestos dust. Arch. Environ. Health 15: 343.
Gross, P., et al. 1974. Ingested mineral fibres. Do they pene-
trate tissue or cause cancer? Arch. Environ. Health 29: 341.
Hammond, E.G., et al. 1979. Cigarette smoking and mortality
among U.S. asbestos insulation workers. Ann. N.Y. Acaa. Sci.
(In press).
Henderson, V.I. and P.E. Enterline. 1979. Asbestos exposure
factors associated with excess cancer and respiratory disease
mortality. Ann. N.Y. Acad. Sci. (In press).
IARC Monographs on the Evaluation of Carcinogenic Risk of Chemi-
cals to Man. 1977. AsDestps. Vol. 14.
Jacobs, R. , et al. 1978. Light and electron microscope studies
of the rat digestive tract following prolonged and short-term
ingestion of chrysotile asbestos. Br. Jour. Exp. Path. 59: 443.
Kay, G. 1973. Ontario intensifies search for asbestos in drinking
water. Water Pollut. Control 9: 33.
Kogan, F.M., et al. 1972. The cancer mortality rate among workers
of asbestos industry of the Urals. Gig. i Sanit. 37: 29.
Langer, A.M., et al. 1973. Identification of asbestos in human
tissues. Jour. Occup. Med i5: 287.
-------
Levy, B.S., et al. 1976. Investigating possible effects of
asbestos in city water: Surveillance 'of gastrointestinal cancer
incidence in Duluth, Minn. Am. Jour. Epidemiol. 103: 362.
Lindell, K.V. 1972. Biological
Agency Res. Cancer, Lyon, France.
effects of asbestos.
Int
Maltoni, C. and C. Annoscia. 1974. Mesotheliomas in rats following
the intraperitoneal injection of crocidolite. In: W. Davis and
C. Maltoni, eds. Advances in tumour prevention, detection ana
characterization. Vol. 1. Characterization of human tumours.
Excerpta Medica,. Amsterdam.
Mason, T.J., et al. 1974. Asbestos-like fibers in Duluth water
supply. Relation to cancer mortality. Jour. Am. Med. Assoc.
228: 1019.
McDonald, J.C. and D.K. Liddell. 1979.
miners and millers exposed to chrysotile.
(In press).
Mortality in Canadian
Ann. N.Y. Acad. Sci.
Millette, J.
cation).
1979. Health Effects Res. Lab. (Personal communi-
National Institute of Occupational Safety and Health. 1972.
.Criteria for a recommended standard...Occupational exposure to
asbestos. DHEW (NIOSH) Pb. No. 72-10267.
Natioal Institute of Occupational Safety and Health. 1977.
Revised recommended asbestos standard. DHEW (NIOSH) Pub. No.
77-169.
Newhouse, M.L. and G. Berry. . 1979
long-term asbestos workers in the
Acaa. Sci. (In press).
Patterns of disease among
United Kingdom. Ann. N.Y.
Newhouse, M.L.
and peritoneum
Br. Jour. Ina.
and H. Thomson. 1965. Mesothelioma of pleura
following exposure to asbestos in the London area.
Med. 22: 261.
Nicholson, W.J. 1971.
Final report, Contract
Admin.
Measurement
CPA 70-92.
of asbestos
Natl. Air
in amoient air.
Pollut. Control
Nicholson, .W.J. and F.L. Pundsack. 1973. Asbestos in the envi-
ronment. Page 126 i_n P. Bogovski, et al. eds. Biological effects
of asoestos. IARC Sci. Publ. No. 8. Int. Agency Res. Cancer,
Lyon, France.
Nicholson, W.J., et al. 1971.
York City. Page 136 iri H.M. England
Second Clean Air Cong. Acaaemic
Asoestos air pollution
and w.T. Barry, eds.
Press, New York.
in New
Proc.
Nicholson, v^.J., et al. 1975.
air in puolic buildings. Final
L7.3. Environ. Prot. Agency.
Asbestos contamination of the
report, Contract No. 63-02-13^0.
-> HI-
-------
Nicholson, w.J., et al. 1979. Mortality experience of asbestos
factory workers: Effect of differing intensities of asbestos
exposure. Environ. Res. (In press).
?eto, J. 1973. The hygiene standard for asbestos. Lancet 3062: 484.
Pooley, F.D. 1973. Mesothelioma in relation to exposure. Page
222 i_n P. Bogovski, et al. eds. Biological effects of asbestos.
IARC Sci. Pubi. No. 8. Int. Agency Res. Cancer, Lyon, France.
Pott, F. and K.H. Friedrichs. 1972. Tumoren der ratte nach
i.p.-injektion faserformiger staube. Naturwissenschaften. 59: 318.
Pott, F., et al. 1976. Ergebnisse aus tierversuchen zur kanzero-
genen wirkung faserformiger staube und ihre deutung im hinolick
auf die tumorentstehung beim raenschen. Zbl. Bakt. Hyg., I Abt.
orig. B. 162: 467.
Reeves, A.L., et al. 1971. Experimental asbestos carcinogenesis.
Environ. Res. 4: 496.
Reeves, A.L., et al. 1974. Inhalation carcinogenesis from various
forms of asbestos. Environ. Res. 8: 178.
Sebastien, P., et al. 1976. Les pollutions atmospheriques urbanies
par 1'asbeste. Rev. franc. Mai. resp. 4: 51.
Seidman, H., et al. 1979. Long-term observation following short-
term employment in an amosite asbestos factory. Ann. N.Y. Acad.
Sci. (In press) .
Selikoff, I.J. 1976. Lung cancer and mesothelioma during prospec-
tive surveillance of 1249 asbestos insulation workers, 1963-1974.
Ann. N.Y. Acad. Sci. 271: 448.
Selikoff, I.J., et al. 1968. Asbestos exposure, smoking and
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workers in the United States and Canada, 1943-1977. Ann. N.Y.
Acad. Sci. (In press).
Sincock, A.M. 1977. In vitro chromosomal effects of asoestos
and other materials. In Origins of human cancer. Cold Spring
Harbour, 1976.
Sincock, A.M. and M. Seabright. 1975. Induction of chromosome
changes in Chinese hamster cells by exposure to asbestos fibers.
Nature (Lond.) 257: 5o.
Smith, w.E. ana D.D. Hubert. i974. The intrapleural route as
a means for estimating carcinogenicity. Pages y2-101 in E.'Karbe
and J.F. Park, eds. Experimental lung cancer. Springer-Verlag,
Berlin. 92-101.
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Speil, S. and J.P. Leineweber. 1969. Asoestos minerals in modern
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Stanton, M.F. 1973. Some etiological considerations of fibre
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Stanton, M.F. and C. Wrench. 1972. Mechanisms of mesothelioma
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U.S. EPA. 1976. Quarterly report of the Environmental Research
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Environmental Protection Agency, Washington/ D.C.
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No. 13
Barium
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
- I VS~-
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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.
-------
3ARIUM
SUMMARY
Water-soluble barium compounds are highly toxic to man. Fish and lower
species of marine organisms have been shown to bioaccumulate barium. The con-
centration of barium in sea water ranges around 20 ug/L, while that of drinking
water averages about 6 ug/L.
Soluble barium salts have a high acute toxicity. Small amounts of barium
can accumulate in the skeleton of humans and animals. Barium salts are strong
muscle stimulants: acute intoxication generally results in uncontrolled
contractions followed by partial or complete paralysis. Cardiac disturbances
including arrythmias can also occur. Barium dusts are irritant to nose,
throat and eyes. Baritosis (pneumoconiosis) occurs following chronic
inhalation of (fine) barium dusts. Barium sulfate used in barium enemas,
swallows and artificial orthopedic bones can result in tissue injury following
solubiliaation of the barium sulfate and/or soluble impurities. Potassium
acts as an antagonist for barium induced cellular disturbances. The TWA
for exposure to soluble barium compounds is 0.5 mg/m .
I. INTRODUCTION . -
Barium (Ba; atomic weight 137.34) is a yellowish-white metal of the alkaline
earth group. It is relatively soft and ductile and may be worked readily.
Barium has a melting point of 729 C and a boiling point of 1640 C; its density
is 3.51 g/cm3 (Kunesh 1978).
Barium characteristically forms divalent compounds. At room temperature,
it combines readily and exothermically with oxygen and the halogens. It reacts
vigorously with water to form barium hydroxide, Ba(OH)_ (Kunesh 1978).
Barium occurs in nature chiefly as barite, crude BaSO,, and as witherite,
a form of BaCO,, both of which are highly insoluble salts. Only barite is
mined in this country (Kirkpatrick 1978).
A review of the production range (includes importation) statistics for
barium (CAS. No. 7440-39-3) which are listed in the Initial TSCA Inventory,
(U.S. EPA 1979) has shown that between 100,000 and 900,000 pounds of this
chemical were produced/imported in 1977*. ,
*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 Regulations (40 CFR 710).
-------
C. Environmental Occurrence
The flow of barium in the United States has been traced for the year 1969,
during which time consumption of barium totaled 1.87 billion pounds. It was
estimated that 30.8 million pounds of barium were emitted to the atmosphere.
Nearly 18 percent of the emissions resulted from the processing of barite, more
than 28 percent from chemical production, 26 percent from the combustion of
coal, and 23 percent from the manufacture of miscellaneous end products
(U.S. EPA 1972). • '.
The concentration of. barium in sea water is generally accepted as about
20 ug/L, with lower concentrations in the surface waters than at greater depths.
Barium ions are generally removed from solution quite rapidly by adsorption,
sedimentation and precipitation (U.S. EPA 1973). Concentrations of barium in
this country's drinking water supplies generally range from less than 0.6 ug/L
to about 10 ug/L, although a few midwestern and western states have had upper
limits of 100 to 300 ug/L (U.S. EPA 1976).
Due to the common use of barite as a weighting agent in drilling muds,
the resultant contamination of sediments near drilling sites was studied. The
average content of barium in benthic sediments from the Southern California Bight
was 637 parts per million (ppm), with a range from 43 to 1899 ppm. This area
includes active drilling sites where barium contamination is expected. The
concentration values were compared with the average 879 ppm barium found in
mainland intertidal sediments and the 388 ppm determined in the channel island
intertidal sediments. The lower barium content of the island sediments was
attributed to the volcanic soil of the islands; however, the higher barium
concentration of the mainland could not be traced to either natural or anthro-
pogenic origin. Due to variations in soil sources it is questionable whether
barium concentrations determined elsewhere could be used as reference values for
this study (Chow 1978).
In two studies correlating trace metal concentrations in the environment
with that in scalp hair of the inhabitants, barium was measured in the house
dust collected in four communities. Geometric mean values of barium determined
in house dust samples from the New York City area were as follows: 65.2 ug Ba/g
dust in Riverhead, 137.6 ug/g in Queens, and 312.4 ug/g in the Bronx (USEPA, 1978b)
The geometric mean value for barium measured in house dust in Ridgewood, New
Jersey was 330.0 ug/g (U.S. EPA 1978c).
-------
Barium and its compounds are used industrially as weighting agents in
oil and gas well drilling muds; as coloring agents in glass, ceramics, paint,
and pigments; as filler in rubber; and as antismoking agents in diesel
fuel (U.S. EPA 1972; NAPCA 1969). In medicine, barium sulfate is used as
an x-ray contrast medium because of its extreme insolubility and its ability to
absorb x-rays (Kirkpatrick 1978; U.S. EPA 1978a>.
II. EXPOSURE
A. Environmental Fate
Due to the high reactivity of barium, it is not found in its elemental
state in the environment. In sea water, the naturally present sulfate and
carbonate tend to precipitate any water-soluble barium components. Thus, the
sediment usually has a higher concentration of barium than its corresponding
water source (Guthrie 1979).
B. Bioconcentration
Due to the toxicity of soluble barium salts to man, the bioaccumulation
of the element has been a concern. Barium can be concentrated in goldfish by
a factor of 150. Concentration factors for barium listed in one study are
17,000 in phytoplankton, 900 in zooplankton, and 8 in fish muscle (U.S. EPA 1973).
Thus, ingestion of fish by man can be a source of barium exposure.
Another study conducted on various species of marine organisms produced the
following results (Guthrie 1979): Barnacles bioaccumulated about
five times greater concentration of barium than was in the water, while oysters
and clams contained concentrations of the element similar to that present in
the water. Crabs and polychaetes were also analyzed for barium and were found
to contain a significantly smaller quantity than that present in the sediment
on which they dwell. However, no significant differences were noted between
the concentration of barium in the two organisms and the concentrations in
the water column.
In man, studies-have been conducted to determine a correlation between barium
in the environment, measured as house dust, and the concentration of barium found
in scalp hair of the inhabitants. A significant positive correlation.has been
determined between the geometric mean concentrations of the element in house dust
and hair. Other covariants of significant value measured in the studies were sex,
hair length, and, in children less than 16 years old, age (U.S. EPA 1978b; U.S.
EPA 1978c).
-------
III. PHARMACOKINETICS
Soluble barium is retained by muscle tissue for about 30 hours, after
which the amount of retained barium decreases slowly (NAPCA 1969). Small
amounts of barium.become irreversibly deposited in the skeleton. However,
the acceptance level is limited, as quantitative analysis of human bone
reveals no accumulation of barium from birth to death. . Barium levels
averaged 7 ug/g ashed bone. Very little barium is retained by the liver,
kidneys, or spleen, and practically none by the brain, heart, or hair.
Transient high concentrations are seen in the liver with lesser amounts in
lung and spleen following acute experimental dosing.
Barium administered orally or intraperitoneally as Bad to weanling
male rats at doses of 1, 5, 25, or 125 mg/kg was taken up rapidly by the
soft tissues (30 mins), showed slow uptake by the skeleton (2 hrs) and was
excreted primarily in the feces (Clary and Tardiff, 1974) . No retention
data wera reported.
Pulmonary clearance rates of inhaled radioactive Ba salts ranged from
-l-_i_
several hours for the soluble BaCl to hundreds of days for Ba in fused
clay . Large amounts of barium were excreted in the feces; a lesser amount
was excreted in the urine. Although BaSO, is "insoluble" in water, 50% of
133
BaSO, dissolved in a simulated biological fluid within 2-3 days, indicating
that solubilization is relatively rapid.
IV. HEALTH EFFECTS
A. Carcinogenicity
Bronchogenic carcinoma developed in rats injected with radioactive S
(unspecified dose) labelled barium sulfate (Patty 1963). BaSO, powder (particle
size undefined) injected intrapleurally in female and male mice produced a
mesothelioma in only 1. out of 30 animals. No other pathological lesions were
investigated or reported. Saline controls (32) resulted in no mesotheliomas.
Barium sulfate had an oncogenic potency similar to that of glass powder and
aluminum oxide. It therefore appears likely that the observed tumor was due
•
to foreign-body-oncogenesis (Wagner).
-ISO -
-------
B. Acute and Chronic Toxicity
The soluble salts of barium are highly toxic when ingested,. Barium chloride
and barium carbonate, two of the soluble compounds, have been reported to
cause toxic symptoms of a severe but usually nonfatal degree. Seven grams of
barium chloride (^;4.5 g Ba) taken orally produced severe abdominal pain and
near-collapse, but not death (NAPCA 1969). However, Patty (1963) indicates
800 to 900 mg of barium chloride (550-600 mg Ba) to be a fatal human dose.
Few cases of industrial poisoning from soluble barium salts have been reported.
Most of these have been cases of accidental ingestion (NAPCA 1969) .
Ingested soluble barium compounds produce a strong stimulating effect on
all muscles of the body. The effect on the heart muscle is manifested by
irregular contractions followed by arrest of systolic action. Gastrointes-
tinal effects include vomiting and .diarrhea. Central nervous system effects
observed include violent tonic and clonic spasms followed in some cases by
paralysis (NAPCA 1969).
Death resulting from barium exposure may occur in a few hours or a few
days, depending on the dose and solubility of the barium compound. A death
attributed to barium oxide poisoning has been reported. However, the usual
effect of exposure to dusts and fumes of barium oxide, barium sulfide, and
bariua carbonate is irritation of eyes, nose, throat and the skin (NAPCA 1969).
Some of the BaSO, used in orthopedic bone cements has been shown to escape
into surrounding tissues (Rae 1977) . Mouse peritoneal macrophages exposed to
barium sulfate (10 particles .of unspecified size/macrophage) for periods up
to 144 hours showed a marked cytoplasciic vacuolization. Following cessation
of exposure only partial recovery occurred. No cell membrane damage was
observed (Rae 1977). The use of barium sulfate in barium swallows and
enemas \resuited in severe toxic "affects on rupture of the intestinal tract :
(Gardiner and Miller 1973, Bayer et al. 1974).
Inhalation of barium compounds is known to cause a benign respiratory
affliction (pneumoconiosis) called baritosis, which has been reported in
i workers exposed to finely divided barium sulfate in Italy, in barite miners
in the United States, Germany, and Czechoslovakia, and among workers exposed
to barium oxide. Generally, baritosis produces no symptoms of emphysema or
bronchitis, and lung function tests show no respiratory incapacity, although
some afflicted workers complain of dyspnea upon exertion. In the majority
of cases nodulation disappears if exposure to the barium compound is stopped
(NAPCA 1969). Aspirated 3aSO, can result in granulomas of the lung and other
sites in man (Patty 1963).
-------
Suicidal ingestion of a facial depilatory containing 15.3 g of BaS
resulted In paralysis of head, neck, arms, and trunk as well as respiratory
paralysis. Therapy with MgSO,, saline and potassium resulted in recovery
within 24 hours (Gould et al. 1973).
Acute oral toxicity values for barium carbonate were: mouse LD = 200 mg/
kg; rat LD = 50-200 mg/kg, LD5Q = 1480 + 340 mg/kg; rabbit LD = 170-300 mg/kg.
For barium chloride oral toxicity values were: mouse LD = 7-14 mg/kg; rat
LD = 355-533 mg/kg; rabbit LD = 170 mg/kg; dog LD = 90 mg/kg. For barium
flouride the acute oral LD for guinea pigs was 350 mg/kg (NAPCA 1969).
C. Other Relevant Information
Potassium acts as an in vitro antagonist of barium. Cardiac effects
such as arrythmias exerted by barium are also reversed rapidly by potassium.
Barium induces hypokalemia apparently by promoting a shift of potassium
from plasma into cells. The prolongation of action-potentials and depolariza-
tion of smooth and skeletal muscle by barium are thought to be due to
barium induced decreases in potassium conductance. In addition,, barium can
replace sodium to produce and/or prolong action potentials and can also
substitute for calcium in neurosecretory processes as described below (Peach 1975)
Barium chloride has been shown to cause arterial contractions in
_4
in vitro preparations of human digital arteries at concentrations of 10 to
10~ M (Jauernig and Moulds 1978). This activity was approximately 40 to 50
_2
fold more than that of potassium chloride. At Bad- concentrations above 10 M
contractions developed very slowly. The action of BaCl_ was inhibited by
^ _2
veraparmil, a calcium antagonist, at BaCl_ contractions below 10 M.
-------
V. AQUATIC TOXICITY
According to an EPA report, experimental data indicate that in fresh
and marine waters, the soluble barium concentration would need to exceed
50 mg/L before toxicity to aquatic life would be expected (U.S. EPA 1976).
Furthermore, in most natural waters, sufficient sulfate or carbonate is present
to precipitate barium in the water to a virtually insoluble, non-toxic
compound.
Soluble barium salts, however, are quite toxic. It has been reported
that 10 to 15 mg/L of barium chloride (9.9 mg/L Ba) was lethal to an aquatic
plant and two species of snails (species and origin unspecified). Bioassay
with this same barium salt showed the LC for Coho Salmon to be 158 mg/L
(104 mg/L Ba) (U.S. EPA 1973).
VI. GUIDELINES
A. Hunan Health
The OSHA Time Weighted Average for exposure to barium (soluble compound)
is 0.5 mg/m3 (29 CFR 1910:1000).
B. Aquatic
There is no established criterion for barium in the aquatic environment.
The U.S. EPA (1973) suggests, however, that concentrations of barium equal
to or exceeding 1.0 mg/L constitute a hazard in the marine environment, and
levels less than 0.5 mg/L present minimal risk of deleterious effects.
-------
References
X-
Bayer HP, Buhler F and Ostenneyer J, 1974. On the distribution of interstitial
and parenteral administered barium sulfate in the organism. Z. Rechtsmedizin
74: 207-215 (1974). (Ger.)
Chow T, Earl J, Reeds J, Hansen N, and Orphan V, 1978. Barium content of marine
sediments near drilling sites: A potent pollutant indicator. Marine Pollution
Bulletin. 9:97-99.
Clary JJ, and Tardiff RG, 1974. The absorption, distribution and excretion of
orally administered 133-BaCl- in weanling male rats. Toxicol. Appl. Pharmacol.
27:139.
Gardiner H and Miller RE, 1973. Barium peritonities. Am. J. Surgery 125:350-352.
Gould DB, Sorrell MB and Lupariello AD. 1973. Barium sulfide poisoning. Arch.
Jut. Med. 132:891-894.
Guthrie RK, Ernst M, Cherry D, Murray H, 1979. Bioraagnification of heavy metals
by organisms in a marine microcosm. Bull. Environm. Contain. Toxicol. 21:53-61.
Jauernig RA and Moulds RFW. 1978. A human arterial preparation for studying the
effects of vasoactive- agents. Circ. Res. 42:363-368.
Kirkpatrick T. 1978. Barium Compounds In Kirk-Othmer's Encyclopedia of
Chemical Technology, 3rd.edition. John Wiley and Sons, Inc. New York. 3:463-479.
Kunesh CJ. 1978. Barium In Kirk-Othmer's Encyclopedia of Chemical Technology,
3rd edition. John Wiley and Sons, Inc. New York. 3:458-^63.
NAPCA. 1969. Air Pollution Aspects of Barium and Its Compounds. National
Air Pollution Control Administration. PB 188 083.
Patty FA, Ed. 1963. Industrial Hygiene and Toxicology. Vol II. Toxicology.
2nd Edition. Interscience Publishers, New York; pp. 998-1002.
Peach MJ. 1975. Cations: Calcium, Magnesium, Barium, Lithium and Ammonium.
In: The Pharmaceutical Basis of Therapeutics. Goodman LS and Gilman A, Eds.
MacMillan Publishing Co., Inc. New York, pp. 791.
Rae.T, 1977. Tolerance of mouse macrophages in vitro to barium sulfate used in
orthopedic bone cement. Biomed. Mater. Res. 11:839-846.
U.S. Dept. of Labor. General Industry Standards Table Z-l. 29 CFR 1910:1000.
U.S. EPA 1972. National Inventory of Sources and Emissions - Barium, Baron,
Copper, Selenium, and Zinc 1969-Barium Section I. PB 210 676.
»
U.S. EPA 1973. Water Quality Criteria 1972. EPA-R-373-033.
-------
U.S. 1976. Quality Criteria for Water. EPA-440/9-76-023.
U.S. EPA 1978a. Source Assessment: Major Barium Chemicals. EPA-600/2-78-
0046. PB 280 756.
U.S. EPA. 1978b. Human Scalp Hair: An Environmental Exposure Index for Trace
Elements. I. Fifteen Trace Elements in New York, N.Y. (1971-1972). EPA-600/1-
78-037a. PB 284 434.
U.S. EPA. 1978c. Human Scalp Hair: An Environmental Exposure Index for Trace
Elements. II. Seventeen Trace Elements in Four New Jersey Communities (1972).
EPA-600/l-78-037b. PB 294 435.
U.S. EPA 1979. Toxic Substances Control Act Chemical Substance Inventory,
Production Statistics for Chemicals on the Non-Confidential Initial TSCA Inventory.
Wagner JC, Berry C, and Timbrell V. 1973. Mesotheliomas in rats after inocula-
tion with asbestos and other materials. Br. J. Cancer 28:173-185.
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No. 14
. Benzal Chloride
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-I St.-
-------
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.
-------
BENZAL CHLORIDE
Summary
Benzal chloride has been reported to induce papillomas, carcinomas, and
leukemia in mice. Details of this work were not available for assessment.
Mutagenic effects of benzal chloride exposure have been reported in
Salmonella, Bacillus, and §_._ coli.
There is no available information on the teratogenic or adverse repro-
ductive effects of the compound.
-------
I. INTRODUCTION
Benzal chloride, CAS registry number 98-87-3, is a fuming, highly re-
fractive, colorless liquid. It is made by free radical chlorinatioh of
toluene and has the following physical and chemical properties (Windholz,
1976; Verschueren, 1977):
Formula: C7H6C12
Molecular Weight: 161.03
Melting Point: -16°c
Boiling Point: 207°C
Density: 1.25614
. Vapor Pressure: 0.3 torr ® 20°C
Solubility: alcohol, ether
insoluble in water
Benzal chloride is used almost exclusively for the manufacture of ben-
zaldehyde. It can also be used to prepare cinnamic acid and benzoyl chlor-
ide (Sidi, 1971).
II. EXPOSURE
A. Water
Benzal chloride is converted to benzaldehyde and hydrochloric acid
on contact with water (Sidi, 1971).
B. Food
Pertinent data could not be located in the available literature.
C. Inhalation
It is likely that the only source of benzal chloride in the air is
production facilities. The compound will hydrolyze in moist air to give
benzaldehyde and hydrochloric acid. Inhaled benzal chloride will probably
produce effects similar to those of inhaled hydrogen chloride.
D. Dermal
Benzal chloride is irritating to the skin (Sidi, 1971).
-------
III. PHARMACOKINETICS
Pertinent data on the pharmacokinetics of benzal chloride could not be
located in the available literature.
IV. EFFECTS
A. Carcinogenicity
In a study of Matsushito, .et al. (1975) benzal chloride, along
with several other compounds, was found to induce carcinomas, leukemia, and
papillomas in mice. The details of the study were not available, but benzal
chloride was shown to possess a longer latency period than benzotrichloride
before the onset of harmful effects.
B. Mutagenicity
Yasuo, et al. (1978) tested the mutagenicity of several compounds
including benzal chloride in microbial assay systems which include the rec-
assay using Bacillus subtilis, the reversion, assay using E_._ coli, and the
Ames assay using Salmonella typhimurium, with or without metabolic activa-
tion. Benzal chloride was positive in the rec-assay without activation and
in the reversion assays using S._ typhimurium and §_._ coli with metabolic
activation.
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Pertinent data could not be located in the available literature.
D. Acute Toxicity
The oral L-D5gis for mj_ce ancj rats exposed to benzal chloride are
2,462 mg/kg and 3,249 mg/kg, respectively (NIOSH, 1978).
V. AQUATIC TOXICITY
Pertinent aquatic toxicity data could not be located in the available
literature.
-------
VI. EXISTING GUIDELINES AND STANDARDS
There are no existing guidelines or standards for exposure to benzal
chloride.
-16,1 -
-------
REFERENCES
Matsushito, H., et al. 1975. Carcinogenicities of the related compounds in
benzoyl chloride production. 49th Annual Meeting Japan Ind. Hyg. Soc., Sap-
pro, Japan, p. 252.
National Institute for Occupational Safety and Health. 1978. Registry of
Toxic Effects.of Chemical Substances. NIOSH, DHEW Publ. No. 79-100.
Sidi, H. 1971. Benzyl Chloride, Benzal Chloride and Benzotrichloride. In;
Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed. Vol. 5, John Wiley
and Sons, New York. p. 281.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Co., New York. p. 127.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed., Merck and Co., Inc.,
Rahway, New Jersey.
Yasuo, K., et al. 1978. Mutagenicity of benzotrichloride and related com-
pounds. Mutation Research 58: 143.
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tfo. 15
Benzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20A60
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. EPA's Carcinogen Assessment Group (CAG) has evaluated
benzene and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
BENZENE -
Summary
Benzene is a widely used chemical. Chronic exposure to it causes
hematological abnormalities. Benzene is not mutagenic to bacteria, but
recent evidence shows it to be carcinogenic in animals. Also, benzene has
been shown to be leukemogenic in humans. There is suggestive evidence that
benzene may be teratogenic and may cause reduced fertility.
Benzene has been shown to be acutely toxic 'to aquatic organisms over a
concentration range of 5,800 to 495,000 /jg/1. The marine fish striped bass
was the most sensitive species tested.
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BENZENE .
I. INTRODUCTION
This profile is based on the draft Ambient Water Quality Criteria Docu-
ment for Benzene (U.S. EPA, 1979).
Benzene (Benzol CgH^; molecular weight 78.1) is a volatile, color-
less, liquid hydrocarbon produced principally from coal tar distillation,
from petroleum by catalytic reforming of light naphthas, and in coal pro-
cessing and coal coking operations (Weast, 1972; Ayers and Muder, 1964; U.S.
EPA, 1976a). Benzene has a boiling point of -30.1°C, a melting point of
5.5°C, a water solubility of 1,780 mg/1 at 25°C, and a density of
0.87865 g/ml at.20°C. The broad utility spectrum of benzene includes its
use as: an intermediate for synthesis in the chemical and pharmaceutical
industries, a thinner for lacquer, a degreasing and cleaning agent, a sol-
vent in- the rubber industry, an antiknock fuel additive, a general solvent
in laboratories and in the preparation and use of inks in the graphic arts
industries.
Current production of benzene in the U.S. is over 4 million metric tons
annually, and its use is expected to increase when additional production
facilities become available (Fick, 1976).
II. EXPOSURE
A. Water
A report by the National Cancer Institute (1977) noted benzene
levels of 0.1 to 0.3 ppb in four U.S. city drinking water supplies. One
measurement from a groundwater well in Jacksonville, Florida showed levels
higher than 100 ppb. One possible source of benzene in the aquatic snviron-
ment is from cyclings betv/een the atmosphere and water (U.S. EPA, 1976b).
Concentrations of benzene upstream and downstream from five benzene
-------
production or consumption plants ranged from less than 1.0 to 13.0 ppb, with
an average of 4.0 ppb (U.S. EPA, 1977a).
B. Food
Benzene has been detected in various food categories: fruits,
nuts, vegetables, dairy products, meat, fish, poultry, eggs, and several
beverages' (Natl. Cancer -Inst., 1977). NCI estimated that an individual
might ingest as much as 250 ug/day from these foods. The U.S. EPA (1979)
has estimated the weighted average bioconcentration factor of benzene for
the edible portion of fish and shellfish consumed by Americans to be 6.9.
This estimate is based on the octanol/water partition coefficient of benzene.
C. Inhalation
The respiratory route is the major source of human exposure to ben-
zene, and much of this exposure is by way of gasoline vapors and automotive
emissions. American gasolines contain an average of 0.8 percent benzene (by
weight) (Goldstein, 1977a), and automotive exhausts contain an average of 4
percent benzene (by weight) (Howard and Durkin, 1974). Concentrations of
benzene in the ambient air of gas stations have been found to be 0.3 to 2.4
ppm (Natl. Acad. Sci/Natl. Res. Council, 1977). Lonneman and coworkers
(1968) measured an average concentration of 0.015 ppm in Los Angeles air
with a maximum of 0.057 ppm. The rural background level for benzene has
been reported as 0.017 ppb (Cleland and Kingsbury,-1977).
III. PHARMACOKINETICS
A. Absorption
The respiratory absorption of benzene by humans has been measured
several times and found to be 40 to 50 percent retained on exposures, to 110
ppm or less (Srbova, et al. 1950; Teisinger, at al. 1952; Hunter and Blair,
1972; Nomiyama and Nomiyama, 1974). Absorption was slightly less efficient,
-------
23 to 34 percent, on exposure to 6,000 ppm (Duvoir, et al. 1946).
Oeichmann, et al. (1963) demonstrated that rats exposed to benzene (44 to 47
ppm) for long periods of time maintained blood benzene levels of approxi-
mately 4.25 mg/1.
3. Distribution
Free benzene accumulates in lipid tissue such as fat and bone
marrow, and benzene metabolites accumulate in liver tissue and bone marrow
(U.S. EPA, 1977b).
C. Metabolism
Benzene is metabolized by the mixed-function oxidase system to pro-
duce the highly reactive arene oxide (Rusch, et al. 1977). Arene oxide can
spontaneously rearrange to form phenol, undergo enzymatic hydration followed
by dehydrogenation to form catechol or a glutathione derivative, or bind
covalently with cellular macromolecules. Evidence has accumulated that a
metabolite of benzene is responsible for benzene toxicity, in light of the
fact that a protection from benzene toxicity is afforded by inhibitors of
benzene metabolism (Nomiyama, 1964; Andrews, et al. 1977). The specific
metabolite that produces benzene toxicity has not yet been identified, but
likely candidates are benzene oxide, catechol, and hydroquinone, or the cor-
responding semiquinones (U.S. EPA, 1977b).
0. Excretion
Phenol measurement (free plus combined) of the urine of human vol-
unteers indicated that 50 to 87 percent of the retained benzene was excreted
as phenol (Hunter and Blair, 1972). The highest concentration of phenol was
found in the urine within about 3 hours from termination of exposure.
Elimination via the lungs was no more than 12 percent of the retained dose.
-------
IV. EFFECTS
A. Carcinogenicity
On subcutaneous, dermal, oral, and inhalation exposure of rats and
mice to benzene, animal experiments have failed to support the view that
benzene is leukemogenic (U.S. EPA, 1979). Recent evidence suggests, how-
ever, that benzene is an animal carcinogen (Maltoni and Scarnato, 1979).
The evidence that benzene is a leukemogen for man is convincing and has re-
cently been reviewed by the Natl. Acad. Sci./Natl. Res. Coun. (1976), Natl.
Inst. Occup. Safety and Health (1977), and U.s; EPA (1977b). Vigliani and
Saita (1964) calculated a 20-fold higher risk of acute leukemia in workers
in northern Italy exposed to benzene. In some studies of acute leukemia
where benzene exposure levels have been reported, the concentrations have
generally been above 100 ppm (Aksoy, et al. 1972, 1974a,b, 1976a,b; Vigliani
and Fourni, 1976; Vigliani and Saita, 1964; Kinoshita, et al. 1965; Sellyei
and Kelemen, 1971). However, other studies have shown an .association of
leukemic evidence to benzene levels less than 100 ppm (Infante et al., 1977;
Ott et al., 1978).
B. Mutagenicity
Benzene has not shown mutagenic activity in the
Salmonella/microsome in vitro bioassay (Lyon, 1975; Shahin, 1977; Simmon, et
al. 1977).
C. Teratogenicity
With -rats exposed to 100 to 2,200 ppm benzene during days 6 to 15
of gestation some skeletal deformities were- observed in their offspring
(Amer. Pet. Inst., 1978). Pregnant mice given single subcutaneous injec-
»
tions of benzene - (3 ml/kg) on days 11 to 15 of gestation produced fetuses
-no-
-------
with cleft palates, agnathia, and microagnathia, when delivered by caesarean
section on day 19 (Watanabe and Yashida, 1970).
D. Other Reproductive Effects
Gofmekler (1963) found complete absence of pregnancy in female rats
exposed continuously to 209.7 ppm benzene for 10 to 15 days prior to impreg-
nation. One of ten rats exposed to 19.8 ppm exhibited resorption of em-
bryos. The number of offspring per female exhibited an inverse relationship
to benzene exposure levels from 0.3 to 209.7 ppm.
E. Chronic Toxicity
In humans, pancytopenia (reduction of blood erythrocytes, leuko-
cytes, and platelets) has clearly been related to chronic benzene exposure
(Browning, 1965; Goldstein, ' }77b; Intl. Labour Off., 1968; Snyder and
Kocsis, 1975). Also, impairment of the immunological system has been re-
ported with chronic benzene exposure (Lange, et al. 1973a; Smolik, et al.
1973). Wolf, et al. (1956) reported that the no-effect level for blood
changes in rats, guinea pigs, '\anti rabbits was below 88 ppm in the air when
the animals were exposed for 7 hours per day for up to 269 days.
3
F. Other Relevant Information
In rabbits and rats injected subcutaneously with 0.2 mg/kg/day ben-
zene, the frequency of bone marrow mitosis with chromosomal aberrations in-
creased from 5.9 percent to 57.8 percent after an average of 18 weeks
(Kissling and Speck, 1971; Dobrokhotov, 1972). In patients with benzene
induced aplastic anemia, lymphocyte chromosome damage, i.e., abnormal
karyo-type and deletion of chromosomal material, has been found (Pollini and
Colombi, 1964).
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V. AQUATIC TOXICITY
A. Acute
Acute toxicity values for freshwater fish are represented by
96-hour static LC5Q values of 20,000 to 22,490 ug/1 for the bluegill,
Lepomis macrochirus, to 386,000 pg/l for the mosquitofish, Gambusia affinis,
with goldfish, Carassius auratus, fathead minnows, Pimephales promelas, and
guppies, Poecilia reticulatius, being somewhat more resistant than the blue-
gill (U.S. EPA, 1979). Only one study was available for the acute effects
of benzene to freshwater invertebrates. A 48'-hour static LC5Q value of
203,000 pg/1 was obtained for the cladoceran Daphnia manna. LC5Q values
for marine fish were reported as 5,800 and 10,900 jug/1 for striped bass,
Morone saxatilis, and 20,000 to 25,000 jjg/1 for Pacific herring, Cluoea
'• )
pallasi, and anchovy, Engrauils mordax, larvae. Marine invertebrates were
much more resistant with LC50 values of 27,000, 108,000, and 450,000 /jg/1
reported for grass shrimp, Palaemonetes pugio, dungeness crab, Cancer
maqister, and the copepod, Tiqricopus californicus, respectively (U.S. EPA,
1979). ••>'
8. Chronic Toxicity ••, '
The only chronic toxicity test conducted on an aquatic species .was
performed on the freshwater cladoceran, Daphnia maqna. There were no ob-
served effects to these organisms at concentrations as high as 98,000 ug/1.
Pertinent information of the chronic effects of benzene on marine fish and
invertebrates could not be located in the available literature.
C. Plant Effects
A concentration of 525,000 jug/1 was responsible for a 50 percent
reduction in cell numbers at 48-hours for the freshwater algae, Chlorella
vulqaris, while marine plants were reported as having growth inhibition at
-------
concentrations ranging from 20,000 to • 100,000 yug/l for the diatom,
Skeletonema costatum, with the dinoflagellate, Arnphidinium carterae, and the
algae, Cricosphaera carterae, being intermediate in sensitivity with effec-
tive concentrations of 50,000 jug/1.
0. Residues
A bioconcentration factor of 24 was obtained for organisms with a
lipid content of 8 percent.
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 will be
changed.
A. Human
Existing air standards for occupational exposure to benzene include
10 pom, an emergency temporary level of 1 ppm by the U.S. Occupational
Safety and Health Administration (Natl. Inst. Occup. Safety Health, 1974,
1977), and 25 ppm by the American Conference of Governmental Industrial
Hygienists (ACGIH, 1971). Based on human epidemiology data, and using a.
modified "one-hit" model, the EPA (1979) has estimated levels of benzene in
ambient water which will result in specified risk levels of human cancer:
Exposure Assumptions Risk Levels and Corresponding Draft Criteria
(per day)
0 10-7 10-6 iQ-5
2 liters of drinking water 0 0.15 jjg/1 1.5 jug/1 15 jug/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and 0 2.5 jug/1 25 pg/1 250 ;ug/l
shellfish only.
-------
8. Aquatic
Criterion for the protection of freshwater organisms have been
drafted at 3,100 ug/1 as a 24-hour average concentration not to exceed 7,000
/jg/1. For marine organisms criterion have been drafted as a 24-hour average
concentration of 920 jjg/1 not to exceed 2,100 jug/1.
-J7H-
-------
BENZENE
REFERENCES
ACGIH. 1971. Threshold limit values. American Conference of Governmental
Industrial Hygienists. Cincinnati, Ohio.
Aksoy, M., et al. 1972. Acute leukemia due to chronic exposure to benzene.
Am. Jour. Med. 52: 160.
Aksoy, M., et al. 1974a. Acute leukemia in two generations following
chronic exposure to benzene. Hum. Hered. 24: 70.
Aksoy, M., et al. 1974b. Leukemia in shoe workers exposed chronically to
benzene. Blood 44: 837.
Aksoy, M., et al. 1976a. Combination of genetic factors and chronic expo-
sure to benzene in the aetiology of leukemia. Hum. Hered. 26: 149.
Aksoy, M., et al. 1976b. Types of leukemia in chronic benzene poisoning.
A study in thirty-four patients. Acta Haematologica 55: 65.
American Petroleum Institute. 1979. Table 6 in Submission to Environ.
Health Comm. of the Sci. Advis. Board, U.S. Environ. Prot. Agency. Jan. 13,
1978.
Andrews, L.S., et al. 1977. Biochem. Jour. 26: 293.
Ayers, G.W., and R.E. Muder: 1964. Kirk-Othmer encyclopedia of chemical
technology. 2nd ed. John Wiley and Sons, Inc., New York.
Browning, E. 1965. Benzene. In: Toxicity and metabolism of industrial
solvents. Elsevier Publishing Co., Amsterdam.
Cleland, J.G., and G.L. Kingsbury. 1977. Multimedia environmental goals
for environmental assessment. EPA 600/7-77-136. U.S. Environ. Prot.
Agency, Washington, D.C.
Deichmann, W.B., et al. 1963. The hemopoietic tissue toxicity of benzene
vapors. Toxicol. Appl. Pharmacol. 5: 201.
Dobrokhotov, V.B. 1972. The mutagenic influence of benzene and toluene
under experimental conditions. Gig. Sanit. 37: 36.
Duvoir, M.R., et al. 1946. The significance of benzene in the bone marrow
in the course of benzene blood diseases. Arch. Mai. Prof. 7: 77.
Fick, J.E. 1976.. To 1985: U.S. benzene supply/demand. Hydrocarbon Pro-
cessing. 55: 127. '
Gofmekler, V.A. 1968. Effect in embryonic development of benzene and for-
maldehyde. Hyg. Sanit. 33: 327.
-------
Goldstein, B.O. 1977a. Introduction (Benzene toxicity: Critical review).
Jour. Toxicol. Environ. Health Suppl. 2: 1.
Goldstein, G.D. 1977b. Hematotoxicity in humans. Jour. Toxicol. Environ.
Health Suppl. 2: 69.
Howard, P.M., and P.R. Durkin. 1974. Sources of contamination, ambient
levels, and fate of benzene in the environment. EPA 560/5-75-005. U.S.
Environ. Prot. Agency, Washington, D.C.
Hunter, C.G., and 0. Blair. 1972. Benzene: Pharmakokinetic studies in
man. Ann. Occup. Hyg. 15: 193.
Infante, P.I., et al. 1977. Leukemia in benzene workers. Lancet. 2: 76.
International Labour Office. 1968. Benzene: Uses, toxic effects, substi-
tutes. Occup. Safety Health Ser., Geneva.
Kinoshita, Y., et al; 1965. A case of myelogenous leukemia. Jour. Japan
Haematol. Soc. 1965: 85.
Kissling, M., and 8. Speck. 1971. Chromosomal aberrations in experimental
benzene intoxication. Helv. Med. Acta. 36: 59.
Lange, A., et al. 1973. Serum immunoglobulin levels in workers exposed to
benzene,, toluene and xylene. Int. Arch. Arbeitsmed. 31: 37.
Lonneman, W.A., et al. 1968. Aromatic hydrocarbons in the atmosphere of
the Los Angeles basin. Environ. Sci. Technol. 2: 1017.
Lyon, J.P. 1975. Mutagenicity studies with benzene. Ph.D. thesis.
University of California.
Maltoni, C. and C. Scarnato. 1979. LaMedicina del Lavoro. 70(5): 352.
National Academy of Sciences/National Research Council. 1976. Health ef-
fects of benzene: A review. Natl. Acad. Sci., Washington, D.C.
National Academy of Sciences/National Research Council. 1977. Drinking
water and health. Natl. Acad. Sci., Washington, D.C.
National Cancer Institute. 1977. On occurrence, metabolism, and toxicity
including reported carcinogenicity of benzene. Summary rep. Washington,
D.C.
National Institute of Occupational Safety and Health. 1974. Criteria for a
recommended standard. Occupational exposure to benzene. U.S. Dep. Health
Edu. Welfare, Washington, D.C.
*
National Institute of Occupational Safety and Health. 1977. Revised recom-
mendation for an occupational exposure standard for benzene. U.S. Dept.
Health Edu. Welfare, Washington, D.C.
-------
Nomiyama, K. 1964. Experimental studies on benzene poisoning. Bull. Tokyo
Med. Dental Univ. 11: 297.
Nomiyama, K., and H. Nomiyama. 1974a. Respiratory retention, uptake and
excretion of organic solvents in man. Int. Arch. A.rbertsmed. 32: 75.
Ott, M.G., et al. 1978. Mortality among individuals occupationally exposed
to benzene. Arch. Environ. Health. 33: 3.
Pollini, G., and R. Colombi. 1964. Lymphocyte chromosome damage in benzene
blood dyscrasia. Med. Lav. 55: 641.
Rusch, G.M., et al. 1977. Benzene metabolism. Jour. Toxicol. Environ.
Health Suppl, 2: 23.
Sellyei, M., and E. Kelemen. 1971. Chromosome study in a case of granu-
locytic leukemia with "Pelgerisation1 7 years 'after benzene pancytopenia.
Eur. Jour. Cancer 7: 83.
Shahin, M.Mi 1977. Unpublished results. The University of Alberta,
Canada. Cited in Mutat. Res. 47: 75.
Simmon, V.F.,.et al. 1977. Mutagenic activity of chemicals identified in
drinking water. 2nd Int. Conf. Environ. Mutagens, Edinburgh, Scotland,
July, 1977.
Smolik, R., et al. 1973. Serum complement level in workers exposed to ben-
zene, toluene and xylene. Int. Arch. Arbeitsmed. 31: 243.
Snyder, R., and J.J. Kocsis. 1975. Current concepts of chronic benzene
toxicity. CRC Crit. Rev. Toxicol. 3: 265.
Srbova, J., et al. 1950. Absorption and elimination of inhaled benzene in
man. Arch. Ind. Hyg. 2: 1.
Teisinger, J., et al. 1952. The metabolism of benzene in man. Procovni
Lekarstvi 4: 175.
U.S. EPA. 1976a. Health effects of benzene: A review. U.S. Environ. Prot.
Agency, Washington, D.C.
U.S. EPA. 1976b. Air pollution assessment of benzene. Contract No. EPA
68-02-1495. Mitre Corp.
U.S. EPA. 1977a. Sampling in vicinity of benzene production and consump-
tion facilities. Preliminary report to Off. Tox. Subst. Battelle-Columbus
Laboratories.
U.S. EPA. 1977b. Benzsne health effects assessment. U.S. Environ,. Prot.
Agency, Washington, D.C.
U.S. EPA. 1978. Environmental sources of benzene exposure: source contri-
bution factors. Contract No. 68-01-4635, Mitre Corp.
-J77-
-------
U.S. EPA. 1979. Benzene: Ambient Water Quality Criteria. (Draft).
Vigliani, E.G., and A. Forni. 1976. Benzene and leukemia. Environ. Res.
11: 122.
Vigliani, E.G., and- G. Saita. -1964. Benzene and leukemia. New England
Jour. Med. 271: 372.
Watanabe, G.I., and S. Yoshida. 1970. The teratogenic effects of benzene
in pregnant mice. Act. Med. Biol. 19: 285.
Weast, R.C. 1972. Handbook, of chemistry and physics. The Chemical Rubber
Co., Cleveland, Ohio.
Wolf, M.A., et al. 1956. Toxicological studies of certain alkylated ben-
zenes and benzene. Arch. Ind. Health 14: 387.
- IT3-
-------
No. 16
Benzldlne
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
benzidine and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
BENZIDINE
Summary
Benzidine is a known carcinogen and has been linked to an in-
creased incidence of bladder cancer in humans and to cancers and
tumors in experimental animals. Benzidine is mutagenic in the Ames
assay and gives positive results in a test measuring DNA synthesis
inhibition in KeLa cells.
Pertinent data could not be located in--the available litera-
ture concerning the toxic effects of benzidine to aquatic organ-
isms.
-------
BENZIDINE
I. INTRODUCTION
Benzidine (4,4'-diaminobiphenyl) is an aromatic amine with
a molecular weight of 184.24. It exists at environmental tempera-
ture as a grayish-yellow, white, or reddish-gray crystalline
powder. Its melting point is 128°C, and its boiling point is
400°C. Benzidine's amino groups have pKa values of 4.66 and
3.57 (Weast, 1972). Two and one-half liter's of cold water will
dissolve 1 g of benzidine, and its solubility increases as water
temperatures rise. Dissolution into organic solvents greatly
increases solubility. Benzidine is easily converted to and from
its salt. Diazotization reactions involving benzidine will result
in colored compounds which are used as dyes in industry (U.S.
EPA, 1979).
II. EXPOSURE
A. Water
Residential water supplies could be contaminated with
benzidine and its derivatives if the industrial effluent contain-
ing these chemicals were discharged into water-supplies, however,
to date U.S. EPA (1979) finds no reports of such contamination.
B. Food
While food may become contaminated with benzidine due to
poor industrial hygiene, U.S. EPA (1979) reports that the ingestion
of contaminated food is not a real contribution to benzidine toxi-
•
city.
-------
The U.S. EPA (1979) has estimated a weighted average
bioconcentration factor (BCF) of 50 for benzidine, on octanol/water
partition coefficients and other factors.
C. Inhalation
Due to poor industrial hygiene and the use of open sys-
tems in the early days of the chemical and dye industries, inhala-
tion was formerly a principal route of entry for benzidine and its
derivatives into the body. At present workers wear respirators and
protective clothing to avoid exposure when cleaning equipment
(Haley, 1975).
D. Dermal
Skin absorption is the most important route for entry of
benzidine into the body. Intact skin is easily-penetra*"-") by the
powdery benzidine base and is.penetrated less readily by 3,3'-di-
methoxybenzidine and 3 ,3'-dichlorobenzidine. High environmental
air temperatures and'humidity increase skin absorption of benzi-
dine, 3 , 3 ' -dimethoxybenzidine, 3 , 3 '-dichlorobenzidine, /'"id 3,3'-
dimethylbenzidine (U.S. EPA, 1979).
III. PHARMACOKINETICS -J
A. Absorption and Distribution
Benzidine is rapidly absorbed into the bodies of intra-
veneously injected rats, with maximum concentrations of free
and bound benzidine occurring at two and three hours, respectively.
The highest concentration of benzidine was found in the blood
followed by the liver, kidney, spleen, heart, and lung (Soloimskaya,
1968). Four hours after rats received intraperitoneal injections
#
of 100 rag benzidine/kg, high concentrations of the compound were
found in the stomach, stomach contents, and small intestine;
-------
12 hours after administration, benzidine was found in the small
intestine and its contents. Benzidine levels in the liver, the
target organ for toxicity in the rat, remained relatively high
and constant throughout the 12-hour period. The conjugated material,
indicative of the presence of metabolites, was high in urine
and tissues at 12 hours (Baker and Deighton, 1953) . In rats
given 20 mg of 3,3'-dimethylbenzidine subcutaneously once a week
. for eight weeks, amines were concentrated in the Zymbal's gland,
followed by the kidney, omentum, spleen, -and liver (Pliss and
Zabezhinsky, 1970).
B. Metabolism and Excretion
The urine of humans exposed to benzidine contained a num-
ber of metabolites: N-hydroxyacetylamino benzidine, 3-hydroxyben-
zidine, 4-amino-4-oxybiphenyl, and mono- and diacetylbenzidine
(Engelbertz and Babel, 1953; Troll, et al. 1963; Sciarini and
Meigs, 1961; Vigliani and Barsotti, 1962). Benzidine metabolites
in other species generally .differ considerably from those in
humans, although 3-hydroxybenzidine and its conjugation products
are common to both animals and humans (Haley, 1975).
The half-life of benzidine in blood was 68 hours for
the rat and 88 hours for the dog. Rats, dogs, and monkeys ex-
creted 97, 96, and 83 percent, respectively, within one week
of an 0.2 mg/kg dose of benzidine. The respective excretion
rates for 3,3'-dichlorobenzidine were 98, 97, 88.5 percent.
Dogs and monkeys excreted free benzidine in the urine and dichloro-
benzidine in the bile while rats excreted both compounds * via
the bile (Kellner, et al. 1973).
-------
Workers exposed to benzidine, who perspire freely and
have wet skin, contain a higher concentration of benzidine in the
urine (U.S. EPA, 1979). -
IV. EFFECTS
A. Carcinogenicity
Benzidine is a proven human carcinogen. Its primary site
of tumor induction is the urinary bladder (U.S. EPA, 1979).
Workers exposed to benzidine have a carcinogenicity risk
14 times higher than that of the unexposed population (Case, et al.
1954). The incidence of bladder tumors in humans resulting from
occupational exposures to aromatic amines (benzidine) was first re-
searched in Germany in 1895. In the United States, the first cases
of this condition were diagnosed in 1931 and reported in 1934.
A number of studies document the high incidence of blad-
der tumors in workers exposed to benzidine and other aromatic
amines (Gehrman, 1936; Case, et al. 1954; Scott, 1952; Deichmann
and Gerarde, .1969; Hamblin, 1963; Rye, et al. 1970; Int. Agency
Res. Cancer, 1972; Riches, 1972; Sax, 1975; Zavon, et al. 1973;
Mancuso and El-Attar, 1966, 1967; Kuzelova, et al. 1969; Billiard-
Duchesne, 1960; Vigliani and Barsotti, 1962; Forni, et al. 1972;
Tsuchiya, et al. 1975; Goldwater, et al. 1965). Initial exposure
concentration, exposure duration, and years of survival following
exposure as well as work habits and personal hygiene are involved
in the development of carcinomas where benzidine appears to be im-
plicated (Rye, et al. 1970).
Benzidine has also produced carcinogenic effects or
tumors in the mouse (hepatoma, lymphoma), the rat (hepatoma,
-------
carcinoma of the Zymbal's gland, adenocarcinoma, sarcoma, mammary
gland carcinoma), -the hamster (hepatoma, liver carcinoma, chol-
angioma), the rabbit (bladder tumor, gall bladder tumor) and
the dog (bladder tumor) (Haley, 1975).
At present, there is no evidence indicating that 3,3'-di-
methylbenzidine, 3,3'-dimethoxybenzidine, or 3,3'-dichlorobenzi-
dine are human bladder carcinogens (Rye, et al. 1970).
B. Mutagenicity
In the Ames test, benzidine is mu.tagenic to Salmonella
typhimurium strains TA1537, TA1538, and TA98. Benzidine produces
positive results in a DNA synthesis inhibition test using HeLa
cells (Ames, et al. 1973; McCann, et al. 1975; Garner, et al. 1975;
U.S. EPA, 1978; U.S. EPA, 1979).
C. Teratogenicity
No teratogenic effects of benzidine have been reported in
humans. Mammary gland tumors and lung adenomas occurred in progeny
of female mice that received 8 to 10 mg of 3,3'-dimethylbenzidine
in the last week of pregnancy. The tumors may have resulted from
transplacental transmission of the chemical or from its transfer to
neonates in milk from dosed mothers (Golub, et al. 1974).
D. Other Reprodutive Effects
Pertinent data could not be located in the available
literature.
E. Chronic Toxicity
Glomerulonephritis and nephrotic syndrome were produced
in Sprague-Dawley rats fed 0.043 percent N,N'-diacetylaenzidine, a
*
metabolite of benzidine, for at least two months (Harman, et al.
1952; Harman, 1971). Glomerulonephritis also developed in rats fed
-------
benzidine (Christopher and Jairam, 1970), and in rats receiving in-
jections either 100 mg subcutaneously or 100 or 200 mg intraper-
tioneally of N,N' -diacetylbenzidine. The severity of the lesions
in the later study was dose-related (Bremner and Tange, 1966) .
Mice fed 0.01 and 0.08 percent benzidine dihydrochloride
exhibited decreased carcass, liver, and kidney weights, increased
spleen and thymus weights, cloudy swelling of the liver, vacuolar
degeneration of the renal tubules, and hyperplasia of the myeloid
elements in the bone marrow and of the lymphoid cells in the spleen
and thymic cortex. There was a dose dependent weight loss of 20
percent in males and 7 percent in females (Rao, et al. 1971).
F. Other Relevant Information
Dermatitis, involving both benzidine and its dimethyl
derivative, has been reported in workers in the benzidine dyestuff
industry. Individual.sensitivity played a large role in the de-
velopment of this condition (Schwartz, et al. 1947).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available litera-
ture concerning the toxic effects of benzidine to aquatic organisms.
VI. EXISTING.GUIDELINES AND STANDARDS
Both the human health and aquatic criteria derived by U.S.
EPA (1979),.which are summarized below, have not yet gone through
the process of public review; therefore, there is a possibility
that these criteria may be changed.
A. Human
The ambient water concentration standard for benzidine
is zero, due to potential carcinogenic effects of exposure to
-------
benzidine by ingestion of water and contaminated aquatic organisms.
U.S. EPA may set standards at an interim target risk level in
the range of 10 °, 10~°, or 10" with respective corresponding'
criteria of 1.67 x 10~3 ug/1, 1.67 x 10~4, and 1.67 x 10~5 ug/1.
B. Aquatic
Criteria for the protection of freshwater or marine
aquatic organisms were not drafted, due to a lack of toxicological
evidence (U.S. EPA, 1979).
-------
BENZIDINE
- REFERENCES
Ames, B. et al. 1973- Carcinogens are inutagens: A simple test system
combining liver homogenates for activation and bacteria for detection.
Proc. Natl. Acad. Sci. 70: 2281
Baker, R.K., and J.G. Deighton. 1953- The metabolism of benzidine in
the rat. Cancer Res. 13: 529.
Billiard-Duchesne, J.L. 1960. Cas Francais de tumeurs professionelles
de la vessie. Acta (Jnio Int. Contra Cancrum (Belgium) 16: 284.
Bremner, D.A., and J. D. Tange. 1966. Renal and neoplastic lesions
after injection of N,N'-diacetylbenzidine. Arch. Pathol. 81: 146.
Case, R.A.M., et al. 1954. Tumours of the urinary bladder in workmen
engaged in the manufacture and. use of certain dyestuff intermediates in
.the British chemical industry: Part I. The role of aniline, benzidine,
alpha-naphthylamine and beta-naphthylamine. Br. Jour. Ind. Med. 11: 75-
Christopher, K. J. , and B.T. Jairam. 1970. Benzidine (^NCg-HijCsHijN^)
poisoning in white rats. Sci. Cult. (India) 36: 511.
Deichmann, W.B., and H.W.'Gerarde. 1969- Toxicology of drugs and chemicals.
Academic- Press, New.York.
Englebertz, P., and E.. Babel. 1953. Nachweis von benzidin und seinen
uir.wand lungs produkten im harn.und in organteilen. Zentr. Arbeitsmed.
Arbeitsschutz 3: 161. . •
Forni, A.,, et al. 1972. Urinary cytology in workers exposed.to carcinogenic
aromatic amines: A six-year study. Acta Cytol. 16: 142.
Garner, et al. 1975. Testing of some benzidine anologies for microsomal
activation to bacterial mutagens. Cancer Let. 1: 39.
Gehrman, G.H. 1936. Papilloma and,carcinoma of the bladder in dye workers.
Jour. Am. Med. Assoc. 107: 1436.
Goldwater, L.J., et al. 1965. Bladder tumors in a coal tar dye. plant.
Arch. Environ. Health 11: 814.
Golub, N.I., et al. 1974. Oncogenic action of some nitrogen compounds
on the progeny of experimental mice. Bull. Exp. Biol. Med. '(USSR) 78:
1402.
Haley, T.J. 1975. Benzidine revisited: . A review of the literature and
problems associated with the use of benzidine and its congeners. Clin.
Toxicol. 8: 13-
-------
Hamblin, D.O. 1963- Aromatic nitro and amino compounds. Page 2105 in
D.W. Fasset^ and D.D. Irish, eds. Industrial hygiene and toxicology.
Vol. II. Interscience Publishers. Mew York.
Harman, J.W. 1971. Chronic glomerulonephritis and the nephrotic syndrome
induced in rats with N,N!-diacetylbenzidine. Jour. Pathol. (Scotland)
104: 119-
Harman, J.W., et al. 1952. Chronic glomerulonephritis and nephrotic
syndrome induced in rats by N,N'-diacetylbenzidine. Am. Jour. Pathol.
28: 529-
International Agency for Research on Cancer. 1972. IARC monographs on
the evaluation of carcinogenic risk of chemicals to man. Vol. I. Lyon,
France.
Kellner, H .M., et al. 1973- Animal studies on the kinetics of
benzidine and 3,3'-dichlorobenzidine. Arch. Toxicol. (West Germany)
31: 61.
Kuzelova, M., et al. 1969- Sledcvani pracovniku zamestnanych pri
vyrobe benzidinu. Prac. Lek. (Czechoslovika) 21: 310.
Mancuso, T.F., and A.A. El-Attar. 1966. Cohort studies of workers
exposed to betanaphthylamine and benzidine. Ind. Med. Surg. 35: 571.
Mancuso, T.F., and A.A. El-Attar. 1967- Cohort study of workers exposed
to betanaphthylamine and benzidine. Jour. Occup. Med. 9: 2-77-
McCann, J., et al. 1975. Detection of carcinogens as mutagens in the
.Salmonella/microsome test: Assay of 300 chemicals. Prcc. Natl. Acad.
Sci. 72: 5135.
Pliss, G.B., and M.A. Zabezhinsky. 1970. Carcinogenic properties of
orthotolidine (3,3'-dimethylbenzidine). Jour. Natl. Cancer Inst. 45: 283.
Rao, K.V.N., et al. 1971. Subacute toxicity of benzidine in the young
adult mice. Fed. Proc. Am. Soc. Exp. Biol. 30: 344.
Riches, E. 1972. Industrial cancers. Nurs. Mirror (Great 3r.) 134: 21.
Rye, W.A., et al. 1970. Facts and myths concerning aromatic diamine
curing agents. Jour. Occup. Med. 12: 211.
Sax, N.I. 1975. Dangerous properties of industrial materials. 4th ed.
Van.Mostrand Reinhold Co., New York.
Schwartz, L., et al. 1947. Dermatitis in synthetic dye manufacture.
Page 268 _in Occupational diseases of the skin. Lea and Febiger, Philadelphia,
Pa. ' •
-------
Sciarini, L.J., and J.W. Meigs. 1961. The biotransformation of benzidir.e.
II. Studies in mouse and man. Arch. Environ. Health 2: 423.
Scott, T.S. 1952.- The incidence of bladder tumours in a dyestuffs factory.
Br. Jour. Ind. Med. 9: 127.
Soloimskaya, E.A. 1968. The distribution of benzidine in rat organs- and
its effect on the peripheral blood. Vopr. Onkol. (USSR) 14: 51.
Troll, W., et al. 1963- N-hydroxy acetyl amino compounds, urinary metabolites
of aromatic amines in man. Proc. Am. Assoc. Cancer Res. 4: 68.
Tsuchiya, K., et al. 1975- An epidemiological study of occupational
bladder tumours in the dye industry of Japan. Br. Jour. Ind. Med. 32:
203.
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, D.C.
U.S. EPA. 1979. Benzidine: Ambient Water Quality Criteria. (Draft).
Vigliani, E.G., and M. Barsotti. 1962. Environmental tumors 'of the
bladder in some Italian dyestuff factories. Acta Unio Int. Contra Cancrum
(Belgium) 18: 669.
Weast, R.C., ed. 1972. Handbood of chemistry and physics. 53rd ed. CRC
Press, Cleveland, Ohio.
Zavon, M.R., et al. 1973- Benzidine exposure as a cause of bladder
tumors. Arch. Environ. Health 27: 1-
-------
No. 17
Benz(a)anthracene
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 •"! \ available information including all the
adverse health a^..-1 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
benz(a)anthracene and has found sufficient evidence to indi-
cate that this compound is carcinogenic.
- / 9 6'-
-------
BENZ(a)ANTHRACENE
SUMMARY
Benz(a)anthracene is a member of the polycyclic aro-
matic hydrocarbons (PAH) class. Although the PAH class
contains several well-known potent carcinogens, benz(a)an-
thracene displays only weak carcinogenic activity. Benz(a)-
anthracene apparently does not display remarkable acute
or chronic toxicity other than the capability to induce
tumors on the skin of mice. Although exposure to benz(a)-
anthracene in the environment occurs in conjunction with
exposure to other PAH, it is not known how these compounds
may interact in human systems. Furthermore, the specific
effects of benz(a)anthracene in humans are not known.
The only toxicity data for any of the polycyclic aro-
matic hydrocarbons is an 87 percent mortality of freshwater
fish exposed to 1,000 pg/1 benz(a)anthracene for six months.
-------
I. INTRODUCTION
This profile is based primarily on the Ambient Water
Quality Criteria Document for Polynuclear Aromatic Hydrocar-
bons (U.S. EPA, 1979a) and the Multimedia Health Assessment
Document for Polycyclic Organic Matter (U.S. EPA, 1979b).
Benz (a) anthracene (C-jaH]?) ^s one °f fc^e family of
polycyclic aromatic hydrocarbons (PAH) formed as a result
of incomplete combustion of organic material. Benz(a)anthra-
cene has the following physical/chemical properties (U.S.
EPA, 1979b):
Melting point: 159.5-160.5°C
Boiling Point: 4GO°C _?
Vapor Pressue: 1.1C x 10~ torr
PAH, including benz(a)anthracene, are ubiquitous in
the environment, being found in ambient air, food, water,
soils, and sediment (U.S. EPA, 1979b). The PAK class con-
tains a number of potent carcinogens (e.g., benzo (a)pyrenej ,
weak carcinogens (e.g., benz(a)anthracene), and cocarcino-
gens (e.g., fluoranthene), as well as numerous non-carcino-
gens (U.S. EPA, 1979b).
PAH which contain more than three rings (such as benz (a)-
anthracene) are relatively stable in the environment, and
may be transported in air and water by adsorption to particu-
late matter. However, biodegradation and chemical treatment
are effective in eliminating most PAE in the environment.
The reader is referred to the PAH Hazard Profile for
. a more general discussion of PAH (U.S. EPA, 1979c) .
-------
II. EXPOSURE
A. Water
Benz(a)anthracene levels in surface waters or
drinking water have not been reported. However, the concen-
tration of six representative PAH (net including benz(a) -
anthracene) in U.S. drinking water averaged 13.5 ng/1 (Basu
and Saxena, 1977, 1978).
B. Food
Benz(a)anthracene has been detected in a wide
variety of foods including margarine (up to 29.5 ppb), smoked
fish (up to 1.7 ppb), yeast (up to 2C3 ppb), and cooked
or smoked meat (up to 33.0 ppb) (U.S. EPA, 1979a). The
total intake of all types of PAH through the diet has been
estimated at 1.6 to 16 ^ig/day (U.S. EPA, 1979b) . The U.S.
EPA (1979a) has estimated the bioconcer.tration factor for
benz (a)anthracene to be 3,100 for the edible portions of
fish and shellfish consumed by Americans. This estimate
is based on the octanol/water partition coefficient of benz-
(a)anthracene.
C. Inhalation
Benz(a)anthracene has been repeatedly detected
in ambient air at concentrations ranging from 0.18 to 4.6 ..
ng/m3 (U.S. EPA, 1979a). Thus, the hu~an daily intake of
benz (a) anthracene by inhalation of aizbient air may be in
the range of 3.42 to 87.4 ng, assuming that a human breathes
19 m of air per day.
8--
-------
III. PHARMACOKINETICS
There are no data available concerning the pharmaco-
kinetics of benz(a)anthracene, or other PAH, in humans.
Nevertheless, it is possible to make limited assumptions
based on the results of animal.research conducted with sev-
eral PAH, particularly benzo(a)pyrene.
A. Absorption
The absorption of benz(a)anthracene in humans
has not been studied. However, it is known (U.S. EPA, 1979a)
that, as a class, PAH are well-absorbed across the respira-
tory and gastrointestinal epithelia. In particular, benz(a)-
anthracene was reported to be readily transported across
the gastrointestinal mucosa (Rees, et al., 1971). The high
lipid solubility of compounds in the PAH class supports
this observation.
B. Distribution
The distribution of benz(a)anthracene in mammals
has not been studied. However, it is known (U.S. EPA, 1979a)
that other PAH are widely distributed throughout the body
following their absorption in experimental rodents. Rela-
tive to other tissues, PAH tend to localize in body fat
and fatty tissues (e.g., breast).
C. Metabolism
Benz(a)anthracene, like other PAH, is metabolized
by the microsoraal mixed-function oxidase enzyme system in
mammals (U.S. EPA, 1979b). Metabolic attack on one or more
of the aromatic double bonds leads to the formation of phenols
-------
and isomecic dihydrodiols by the intermediate formation
of reactive epoxides. Dihydrodiols are further metabolized
by microsomal mixed-function oxidases to yield diol epoxides,
compounds which are known to be biologically reactive inter-
mediates for certain PAH. Removal of activated intermediates
by conjugation with glutathione or glucuronic acid, or by
further metabolism to tetrahydrotetrols, is a key step in
protecting the organism from toxic interaction with cell
macromolecules.
D. Excretion
The excretion of benz(a)anthracene by" mammals
has not been studied. However, the excretion of closely
related PAH is rapid and occurs mainly via the feces (U.S.
EPA, 1979a). Elimination in the bile may account for a
significant.percentage of administered PAH. However, the
rate of disappearance of various PAH from the body and
the principal routes of excretion are influenced both by
the structure of the parent compound and the route of admini-
stration (U.S. EPA, 1979a). It is unlikely that PAH will
accumulate in the body with chronic low-level exposures.
IV. EFFECTS
A. Carcinogenicity
Benz(a)anthracene is recognized as a weak carcino-
gen in mammals (U.S. EPA, 1979a,b). It is a tumor initiator
on the skin of mice, but failed to yield significant results
in the strain A mouse pulmonary tumor bioassay system.
-200-
-------
B. Mutagenicity
Benz (a)anthracene has shown weak mutagenic activity
in several test system, including Ames Salmonella assay,
somatic cells in culture, and sister chromatic exchange
in Chinese hamster cells (U.S. EPA, 1979b).
.C. Teratogenicity
Pertinent data could not be located in the avail-
able literature concerning the possible teratogenicity of
benz(a)anthracene. Other related PAE are apparently not
significantly teratogenic in mammals (U.S. EPA, 1979a).
D. Other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
E. Chronic Toxicity
The chronic toxicity of benz(a)anthracene has
not been extensively studied. The repeated injection of
benz(a)anthracene in mice for 40 weeks (total dose, 10 mg.)
had little apparent effect on longevity or organ weights
(U.S. EPA, 1979b).
V. AQUATIC TOXICITY
A. Acute
Pertinent data could not be located in the avail-
able information.
B. Chronic
No standard chronic toxicity data have been pre-
sented on freshwater or marine species. The only toxicity •
data available for benz(a)anthracene for fish is an 87 per-
-201-
-------
cent mortality on the freshwater bluegill sunfish, Lepomis
macrochirus, exposed to 1,000 ^jg/1 fcr six months (Brown,
et al., 1975).
C. Plant Effects
Pertinent data could not be located in the avail-
able information.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human nor the aquatic criteria derived
by U.S. EPA (1979a) , which are summarized below, have gone
through the process of review; therefore, there is a pos-
sibility that these criteria will be clianged.
A. Human
There are no established exposure criteria for
benz(a)anthracene. However, PAH as a class are regulated
by several authorities. The World Health Organization (1370)
has recommended that the concentration of PAH in drinking
water (measured as the total of f luorar.thene , benzo(g,h,i)-
perylene, benzo(b)fluoranthene, benzc(/:) fluoranthene, indeno-
(1, 2 , 3-cd) pyrene , and benzo(a)pyrene} r.ot to exceed 0.2
ug/1. Occupational exposure criteria have been established
for coke oven emissions, coal tar products, and coal tar
pitch volatiles, all of which contain large amounts of PAH
including benz(a)anthracene (U.S. EPA, 1979a).
The U.S. EPA (1979a) draft recommended criteria
for PAH in water are based' upon- the extrapolation of animal
carcinogenicity data for benzo (a) pyrer.e and dibenz (a , h) anthra-
cene.
- 202-
-------
B. Aquatic
Data were insufficient to propose criteria for
freshwater or marine environments.
-203-
-------
BENZCa)ANTHRACENE
REFERENCES
Sasu, O.K., and J. Saxena. 1977. Analysis of raw and drinking water sam-
ples for polynuclear aromatic hydrocarbons. EPA PO No. CA-7-2999-A, and
CA-8-2275-8. Expo. Evalu. Branch, HERL, Cincinnati, Ohio.
Basu, O.K., and J.;. Saxena. 1978. Polynuclear aromatic hydrocarbons in
selected U.S. drinking waters and their raw water sources. Environ. Sci.
Technol. 12: 795.
Brown, E.R., et al. 1975. Tumors in fish caught in polluted waters: possi-
ble explanations. Comparative Leukemia Res. 1973. Leu'xerncgenesis. Univ.
Tokyo Press/Karger, Basel, pp. 47-57.
Rees, E.G., et al. 1971. A study of the mechanism of intestinal absorption
of benzo(a)pyrene. Biochem. Biophys. Act. 225: 96.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient Water Quality
Criteria (Draft),
U.S. EPA. 1979b. Multimedia health, assessment document for polycyclic or-
ganic matter. Prepared under contract by J. Santodonato,. et al., Syracuse
Research Corp.
U.S. EPA. 1979c. Environmental"* Criteria and Assessment Office. Polynu-
clear Aromatic Hydrocarbons: Hazard Profile (Draft).
World Health Organization. 1970. European, standards for drinking water.
2nd. ed.; Geneva.
-20H-
-------
No. 18
Benzo(b)fluoranthene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-3.0S-
-------
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. EPA's Carcinogen Assessment Group (GAG) has evaluated
benzo(b)fluoranthene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
BENZO(b)?LUORANTKENE
SUMMARY
Benzo(b)fluoranthene is a member of the polycyclic aro-
matic hydrocarbon (PAH) class. Numerous compounds in the PAH
class are well known for their carcinogenic effects in ani-
mals. Benzo(b)fluoranthene is carcinogenic to the skin of
mice and produces sarcomas when injected in mice. Very
little is known concerning the non-carcinogenic effects pro-
duced by chronic exposure to benzo(b)fluoranthene. Although
exposure to benzo(b)fluoranthene in the environment occurs in
conjunction with exposure to other PAH, it is not known how
these compounds may interact in human systems. Furthermore,
the specific effects of benzo(b)fluoranthene in humans are
not known.
Standard acute or chronic toxicity testing for aquatic
organisms has not been found in the available literature.
/
-------
BEN ZO ( b ) FLUORANTHEN E
I. INTRODUCTION
This profile is based primarily on the Ambient Water
Quality Criteria Document for Polynuclear Aromatic Hydrocar-
bons (U.S. EPA, 1979a) and the Multimedia Health Assessment
Document for Polycyclic Organic Matter (U.S. EPA, 1979b).
Benzo( b) f luoranthene (C2QH12^ ^s one °f ^he family
of polycyclic aromatic hydrocarbons (PAH) formed as a result
of incomplete combustion of organic material. Its physical/
chemical properties have not been well-characterized, other
than a reported melting point of 167°C (U.S. EPA, 1979b).
PAH, including benzo(b)fluoranthene, are ubiquitous in
the environment, being found in ambient air, food, water,
soils, and sediment (U.S. EPA, 1979b). The PAH class con-
tains a number of potent carcinogens (e.g., benzo(a)pyrene),
moderately active carcinogens (e.g., benzo(b)fluoranthene),
weak carcinogens (e.g., benz(a)anthracene), and cocarcinogens
(e.g., fluoranthene), as well as numerous noncarcinogens
(U.S. EPA, 1979b) .
PAH which contain more than three rings (such as benzo-
(b)fluoranthene) are relatively stable in the environment and
may be transported in air and water by adsorption to particu-
lar matter. However, biodegradation and chemical treatment
are effective in eliminating most PAH in the environment.
Refer to the PAH Hazard Profile (U.S. EPA, 1979c) for a more
general treatment of PAH. •
-------
II. EXPOSURE
A. Water
In a monitoring survey of U.S. drinking water, Basu
and Saxena (1977, 1978) were unable to detect benzo(b)fluor-
anthene. However, the concentration of six representative
PAH (fluoranthene, benzo(a)pyrene, benzo(g h i)perylene,
benzo(j)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)
pyrene) averaged 13.5 ng/1.
B. Food
Levels of benzo(b)fluoranthene have not been re-
ported for food. However, the total intake of all types of
PAH through the diet has been estimated at 1.6 to 16 ug/day
(U.S. EPA, 1979b). The U.S. EPA (1979a) has estimated the
weighted average bioconcentration factor of benzo(b)fluor-
anthene to be 6,800 for the edible portion of fish and shell-
fish consumed by Americans. This estimate is based on the
octanol/water partition coefficient of benzo(b)fluoranthene.
C. Inhalation
Benzo(b)fluoranthene has been detected in ambient
air at concentrations ranging from 0.1 to 1.6 ng/ra^ (Gordon
and Bryan, 1973). Thus, the human daily intake of benzo(b)-
fluoranthene by inhalation of ambient air may be in the range
of 1.9 to 30.4 ng, assuming that a human breathes 19 m^ of
air per day.
III.. PHARMACOKIN ETICS
Pertinent data could not be located in the available '
literature concerning the pharrnacckinetics of benzo( b) f luor-
anthene, or other PAH, in hunans. Nevertheless, it is pos-
1
-2/0-
-------
sible to make limited assumptions based on the results of
animal research conducted with several PAH, particularly
benzo(a)pyrene.
A. Absorption
The absorption of benzo(b)fluoranthene in humans or
other animals has not been studied. However, it is known
(U.S. EPA, 1979a) that, as a class, PAH are well-absorbed
across the respiratory and gastrointestinal epithelia. The
high lipid solubility of compounds in the PAH class supports
this observation.
B. Distribution
The distribution of benzo(b)fluoranthene in mammals
has not been studied. However, it is known (U.S. EPA, 1979a)
that other PAH are widely distributed throughout the body
following their absorption in experimental rodents. Relative
to other tissues, PAH tend to localize in body fat and fatty
tissues (e.g., breast).
C. Metabolism
The metabolism of benzo(b)fluoranthene in mammals
has not been studied. Benzo(b)fluoranthene, like other PAH,
is most likely metabolized by the microsomal mixed-function
oxidase enzyme system in mammals (U.S. EPA, 1979b). Meta-
bolic attack on one or more of the aromatic double bonds
leads to the formation of phenols and isomeric dihydrodiols
by the intermediate formation of reactive epoxides. Dihydro-
diols are further metabolized by microsomal mixed-function.
oxidases to yield diol epoxides, compounds which are known to
be biologically reactive intermediates for certain PAH. Re-
moval of activated intermediates by conjugation with gluta-
/
-an-
-------
thione or glucuronic acid, or by further metabolism to tetra-
hydrotetrols, is a key step in protecting the organism from
toxic interaction with cell macromolecules.
D. Excretion
The excretion of benzo(b)fluoranthene by mammals
has not been studied. However, the excretion of closely re-
lated PAH is .rapid and occurs mainly via the feces (U.S. EPA,
1979a). Elimination in the bile may account for a signifi-
cant percentage of administered PAH. It is unlikely that PAH
».
will accumulate in the body with chronic low-level exposures.
IV. EFFECTS
A. Carcinogenicity
Benzo(b)fluoranthene is regarded as a moderately
active carcinogen (U.S. EPA, 1979b). It is carcinogenic by
skin painting on mice, and by subcutaneous injection in mice
(U.S. EPA, 1979b; LaVoie, et al. 1979). The sarcomagenic
potency of benzo(b)fluoranthene is similar to that of benzo-
(a)pyrene (Buu-Hoi, 1964).
B. Mutagenicity
Benzo(b)fluoranthene is mutagenic in the Ames Sal-
monella assay in the presence of a microsomal activating sys-
tem (LaVoie, et al. 1979). It is also positive in the induc-
tion of sister-chromatid exchanges by intraperitoneal injec-
tion in Chinese hamsters (U.S. EPA, 1979b).
C. Teratogenicity
Pertinent data could not be located in the litera-
ture available concerning the possible teratogenicity of
-2.12-
-------
benzo(b)fluoranthene. Other related PAH are apparently not
significantly teratogenic in mammals (U.S. EPA, 1979a).
D. Other Reproductive Effects
Pertinent information could not be located in the
available literature.
E. Chronic Toxicity
Published data are not available regarding the non-
carcinogenic chronic effects of benzo(b)fluoranthene. It is
known, however, that exposure to carcinogenic PAH may produce
widespread tissue damage as well as selective destruction of
proliferating tissues (e.g., hematopoietic and lymphoid sys-
tems) (U.S. EPA, 1979a).
V. AQUATIC TOXICITY
Pertinent information could not be located in the avail-
able literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
There are no established exposure criteria for
benzo(b)fluoranthene. However, PAH as a class are regulated
by several authorities. The World Health Organization has
recommended that the concentration of PAH in drinking water
(measured as the total of fluoranthene, benzo(g,h,i)perylene,
benzo(b)fluoranthene, benzo(k)fluoranthene, indeno{1,2,3-cd)
pyrene, and benzo(a)pyrene} not exceed 0.2 ug/1. Occupa-
tional exposure criteria have been established for coke oven
emissions, coal tar products, and coal tar pitch volatiles,'
all of which contain large amounts of PAH including benzo(b)-
fluoranthene (U.S. EPA, 1979a).
-a/3-
-------
The U.S. EPA (1979a) draft recommended criteria for
PAH in water are based upon 'the extrapolation of animal car-
cinogenicity data for benzo(a)pyrene and dibenzo(a,h)anthra-
cene.
B. Aquatic
The criteria for freshwater and marine life have
not been drafted (U.S. EPA, 1979a).
-------
8ENZO(b)FLUORANTHENE
REFERENCES
Basu, O.K. and J. Saxena. 1977. Analysis of raw and drinking water sam-
ples for polynuclear aromatic hydrocarbons. U.S. Environ. Prot. Agency,
P.O. No. CA-7-2999-A. Exposure Evaluation Branch, HERL, Cincinnati, Ohio.
Basu, O.K. and J. Saxena. 1973. Polynuclear aromatic hydrocarbons in
selected U.S. drinking waters and their raw water sources. Environ. Sci.
Technol. 12: 795.
Buu-Hoi, N.P. 1964. New developments in chemical carcinogenesis by
polycyclic hydrocarbons and related heterocycles: A review. Cancer Res.
24: 1511.
Gordon, R.J. and R.J. Bryan. 1973. Patterns of airborne polynuclear hy-
drocarbon concentrations at four Los Angeles sites. Environ. Sci. Technol.
7: 1050.
La Voie, E., et al. 1979. A comparison of the mutagenicity, tumor-initiat-
ing activity and complete carcinogenicity of polynuclear aromatic hydrocar-
bons. _In: Polynuclear Aromatic Hydrocarbons, P.W. Jones and P. Leber (eds.)
Ann Arbor Science Publishers,. Inc.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient Water Quality
Criteria. (Draft)
U.S. EPA. 1979b. Multimedia health assessment document for polycyclic or-
ganic matter. Prepared under contract by J. Santodonato, et al., Syracuse
Research Corp.
U.S. EPA. 1979c. Environmental Criteria and Assessment Office. Polynucle-
ar Aromatic Hydrocarbons: Hazard Profile. (Draft)
World Health Organization. 1970. European Standards for Drinking Water. 2nd
ed., Geneva.
-------
No. 19
Benzo(a)pyrene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-2/4,-
-------
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 environnental 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
benzo(a)pyrene and has found sufficient evidence to indicate
that this compound is carcinogenic.
-2.!?-
-------
BENZO(a)PYRENE
Summary
The first chemicals shown to be involved in the development of cancer
belong to the polynuclear aromatic hydrocarbons (PAH) class. Benzo(a)pyrene
. is the most widely recognized and extensively studied of all carcinogenic
PAH. It is among the most potent animal carcinogens known and produces
tumors in virtually all species by all routes of administration.
Since humans are never exposed to only benzo(a)pyrene in the environ-
ment, it is not possible to attribute human cancers solely to exposure to
benzo(a)pyrene. However, numerous epidemiologic studies support the belief
that carcinogenic PAH, including benzo(a)pyrene, are also human carcinogens.
Measured steady-state bioconcentration factors are not available for
freshwater or saltwater aquatic species exposed to benzo(a)pyrene. Standard
toxicity data for freshwater and saltwater aquatic life have not been re-
ported.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Polynuclear Aromatic Hydrocarbons (U.S. EPA, 1979a) and the Multimedia
Health Assessment Document for Polycyclic Organic Matter (U.S. EPA, 1979b).
Benzo(a)pyrene (^...H..-) is one of the family of polynuclear aromat-
ic hydrocarbons (PAH) formed as a result of incomplete combustion of organic
material. Its physical and chemical properties have not been well-charac-
terized, other than a reported melting point of 178.8-179.3°C and a vapor
pressure of 5.49 x 10"9 mm Hg (U.S. EPA, 1979b). ''
PAH, including benzo(a)pyrene, are ubiquitous in the environment, being
found in ambient air, food, water, soils and sediment (U.S. EPA, 1979a).
The PAH class contains a number of potent carcinogens (e.g., benzo(a)py-
)
rene), moderately active carcinogens (e.g., benzo(b)fluoranthene), weak car-
cinogens (e.g., benz(a)anthracene), and cocarcincgens (e.g., fluoranthene),
as well as numerous noncarcinogens (U.S. EPA, 1979a).
PAH which contain more than three rings (such as benzo(a)pyrene) are
• r
relatively stable • in the environment and may be transported in air and
water by adsorption- to particulate matter. However, biodegre ">ion and
chemical treatment are effective in eliminating most PAH in the environment.
II. EXPOSURE
A. Water
Basu and Saxena (1977, 1978) have monitored various United States
drinking water .supplies for the presence of PAH, including benzo(a)pyrene.
They reported that the average level of benzo(a)pyrene in drinking water was
0.55 nanograms/liter. This would result in a human daily intake of benzo-
»
(a)pyrene from water of about 0.0011 jjg.
-220-
-------
8. Food
8enzo(a)pyrene has been detected in a wide variety of feeds by
numerous investigators (U.S. EPA, 1979a). 8enzo(a)pyrene levels are espe-
cially high in cooked or smoked meats, where in certain cases (i.e., char-
coal-broiled steak) concentrations as high as 50 ppb have been reported
(Lijinsky and Ross, 1967). It has been estimated (U.S. EPA, 1979b) that the
daily dietary intake of benzo(a)pyrene is about 0.16 to 1.6 ug, and total
PAH intake is about 1.6 to 16 ug. The U.S. EPA (1979a) has estimated the
weighted average bioconcentration factor for benzo(a)pyrene to be 6,800 for
the edible portions of fish and shellfish consumed by Americans. This esti-
mate is based on the octanol/water partition coefficient for benzo(a)pyrene.
C. Inhalation
8enzo(a)pyrene levels have been routinely monitored in the ambient
atmosphere for many years. The average urban-rural ambient benzo(a)pyrene
concentration in the United States has been estimated at 0.5 nancgrams/m
(U.S. EPA, 1979a). Thus., the human daily intake of benzo(a)pyrene by inhala-
tion of ambient air is about 9.5 nanograms, assuming that a human breathes
about 19 m of air per day.
III. PHARMACOKINETICS
Pertinent data could not be found in available literature concerning
the pharmacokinetics of benzo(a)pyrene, or other PAH, in humans. Neverthe-
less, it is possible to make limited assumptions based on the results of
animal research conducted with several PAH, particularly benzo(a)pyrene.
A. Absorption
Toxicity data indicate that, as a class, PAH are capable of passage
»
across epithelial membranes (Smyth, et al. 1962}. In particular, benzo(a)-
pyrene was reported to be readily transported across the intestinal mucosa
-22J-
-------
(Rees, et al. 1971) and the respiratory membranes (Kotin, et al. 1969; Vai-
niok, et al. 1976).
B. Distribution
8enzo(a)pyrene becomes localized in a wide variety of body tissues
following its absorption (Kotin, et al. 1969). Due to its high lipid solu-
bility, benzo(a)pyrene localizes primarily in body fat and fatty tissues
(e.g., breast) (Schlede, et al. 1970a,b).
C. Metabolism
The metabolism of benzo(a)pyrene in mammals has been studied in
great detail (U.S. EPA, 1979a). Benzo(a)pyrene, like other PAH, is metabo-
lized by the microsomal mixed function oxidase enzyme system in mammals
(U.S. EPA, 1979b). Metabolic attack on one or more of the aromatic rings
leads to the formation of phenols and isomeric dihydrodiols by the interme-
diate . formation of reactive epoxides. Dihydrodiols are further metabolized
by microsomal mixed function oxidases to yield diol epoxides, compounds
which are known to be ultimate carcinogens for certain PAH. Removal of
activated intermediates by conjugation with glutathione or glucuronic acid,
or by further metabolism to tetrahydrotetrols, is a key step in protecting
the organism from toxic interaction with cell macromolecules.
D. Excretion
The excretion of benzo(a)pyrene by mammals has been studied by sev-
eral groups of investigators. In general, the excretion of benzo(a)pyrene.
and related PAH is rapid, • and occurs mainly via the feces (U.S. EPA, 1979a;
Schlede, et al. 1970a,b). Elimination in the bile may account for a signi-
ficant percentage- of administered PAH. It is unlikely that PAH will accumu-
»
late in the body as a result of chronic low-level exposures.
-222-
-------
IV. EFFECTS
A. Carcinogenicity
The carcinogenic activity of benzo(a)pyrene was first recognized
decades ago, and since that time it has become a laboratory standard for the
production of experimental tumors which resemble human carcinomas in ani-
mals. The carcinogenic activity of benzo(a)pyrene is distinguished by sev-
eral remarkable features: (1) it is among the most potent animal carcino-
gens known, producing tumors by single exposures to microgram quantities;
(2) it acts both at the site of application and at organs distant to the
site of absorption; and (3) its carcinogenicity has been demonstrated in
nearly every tissue and species tested, regardless of the route of admini-
stration (U.S. EPA, 1979a).
Oral administration of benzo(a)pyrene to rodents can result in
tumors of the forestomach, mammary gland, ovary, lung, liver, and lymphoid
.and hematopoietic tissues .(U.S. EPA, 1979a). Exposure to benzc(a)pyrene by
intratracheal instillation in rodents can also be an effective means of pro-
ducing respiratory tract tumors (Feron, et al. 1973). In addition, benzo-
(a)pyrene has remarkable potency for the induction of skin tumors in mice by
direct dermal application (U.S. EPA, 1979a).
Numerous epidemiologic studies support the belief that carcinogenic
PAH, including benzo(a)pyrene, are responsible for the production of human
cancers both in occupational situations and among tobacco smokers (U.S. EPA,
1979b).
8. Mutagenicity
Benzo(a)pyrene gives positive results in nearly all mutagenicity
test systems including the Ames Salmonella assay, cultured Chinese hamster
cells, the sister-chromatid exchange test, snd the induction of ONA repair
synthesis (U.S. EPA, 1979a).
-223-
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C. Teratogenicity and Other Reproductive Effects
Only limited data are available regarding the teratogenic effects
of benzo(a)pyrene or other PAH in animals. Benzo(a)pyrene had little effect
on fertility or the developing embryo in several mammalian and non-mammalian
species (Rigdon and Rennels, 1964; Rigdon and Meal, 1965).
D. Chronic Toxicity
As long ago as 1937, investigators knew that carcinogenic PAH such
as benzo(a)pyrene produced systemic toxicity as manifested by an inhibition
of body growth in rats and mice (Haddow, et al... 1937). The target organs
affected by chronic administration of carcinogenic PAH are diverse, due
partly to extensive distribution in the body and also to the selective de-
struction of proliferating cells (e.g., hematopoietic and lymphoid system,
intestinal epithelium, testis) (Philips, et al. 1973).
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 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 be
changed.
A. Human
There are no established exposure standards specifically for benzo-
(a)pyrene. However,- PAH as a class are regulated by several authorities.
The World Health Organization (1970) has recommended that the concentration
of PAH in drinking water (measured as the total of fluoranthene, benzo(g,h,-
Dperylene, benzo(b)fluoranthene, benzo(k)fluoranthene, indeno(l,2,3-cd)py-
rene, and benzo(a)pyrene) not .exceed 0.2 ug/1. Occupational exposure cri-
-22M-
-------
teria have been established for coke oven emissions, coal tar products, and
coal tar pitch volatiles, all of which contain large amounts of PAH in water
based upon the extrapolation of animal carcinogenicity data for benzo(a)py-
rene and dibenz(a,h)anthracene. Levels for each compound are derived which
will result in specified risk levels of human cancer as shown in the table
below:
BaP
Exposure Assumptions Risk Levels and Corresponding Draft Criteria
(per day)
0 10-7 ID-6 10-5
2 liters of drinking water 0 0.097 0.97 9.7
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish 0.44 4.45 44.46
and shellfish only.
DBA
Exposure Assumptions Risk Levels and Corresponding Draft Criteria
(per day)
0 10-7 10-6 10-5
2 liters of drinking water 0 0.43 . 4.3 43
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish 1.96 19.6 196
and shellfish only.
B Aquatic
Guidelines are not available for benzo(a)pyrene in aquatic environ-
ments.
-22S-
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BENZO(A)PYRENE
REFERENCES
Basu, O.K., and J. Saxena. 1977. Analysis of raw and drinking
water samples for polynuclear aromatic hydrocarbons. EPA P.O. No.
CA-7-2999-A, and CA-8-2275-B, Expo. Evalu. Branch, HERL., Cincin-
nati .
Basu, D.K., and J. Saxena. 1978. Polynuclear aromatic hydrocarbons
in selected U.S. drinking waters and their raw water sources.
Environ. Sci. Technol. 12: 795.
Feron, V.J., et al. 1973. Dose-response correlation for the induc-
tion of respiratory tract tumors in Syrian golden hamsters by in-
tratracheal instillations of benzo(a)pyrene. Europ. Jour. Cancer.
9: 387.
Haddow, A., et al. 1937. The influence of certain carcinogenic and
other hydrocarbons on body growth in the rat. Proc. Royal Soc. B.
122: 477.
Kotin, P., et al. 1969. Distribution retention and elimination of
C -3, 4-benzopyrene after administration to mice and rats. Jour.
Natl. Cancer Inst. 23: 541.
Lijinsky, W. , and A.E. Ross:. 1967. Production of carcinogenic
polynuclear hydrocarbons in the cooking of food. Food Cosmet.
Toxicol. 5: 343.
Philips, F..S. et al. , 1973. In vivo cytotoxicity of polycyclic hy-
drocarbons. In: Pharmacology and the future of man. Proc. 5th
Intl. Congr. Pharmacology, 1972, San Francisco. 2: 75.
Rees, E.O., et al. 1971. A study of the mechanism of intestinal
absorption of benzo(a)pyrene. Biochem. Biophys. Act. 255: 96.
Rigdon, R.H., and J. Weal. 1965. Effects of feeding benzo(a)py-
rene on fertility, embryos, and young mice. Jour. Natl. Cancer.
Inst. 32: 297.
Rigdon, R.H., and E.G. Rennels. 1964. Effect of feeding benzo-
pyrene on reproduction in the rat. Experientia. 20: 1291.
Schlede, E., et al. 1970a. Stimulatory effect of benzo(a)pyrene
and phenobarbital pretreatment on the biliary excretion of benzo-
(a)pyrene metabolites in the rat. Cancer Res. 30: 2898.
»
Schlede, E. , et al. 1970b. Effect of enzyme induction on the
metabolism and tissue distribution of benzo(a)pyrene. Cancer Res.
30: 2893.
-------
Smyth, H.F., et al. 1962. Range - finding toxicity data: List II.
Am. Ind. Hyg. Jour. 23: 95.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient
water Quality Criteria. (Draft).
U.S. EPA. 1979b. Multimedia Health Assessment Document for Poly-
cyclic Organic Matter. Prepared under contract by J. Santodonato
et al., Syracuse Research Corporation.
Vainioh, et al. 1976. The fate of intracheally installed benzo-
(a)pyrene in the isolated perfused rat lung of both control and 20-
methylcholanthrene pretreated. Res. Commun. Chem. Path. Pharmacol.
13: 259.
World Health Organization. 1970. European standards for drinking
water. 2nd ed. Revised. Geneva.
-22.7-
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No. 20
Benzotrichloride
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-22. S--
-------
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 aec-uracy.
-------
BENZOTRICHLORIDE
Summary
Benzotrichloride has been shown to be mutagenic in a number of micro-
bial tests with and without metabolic activation. One study has described
the carcinogenicity of benzotrichloride in mice. The lowest concentration
producing a lethal effect (LCLQ) has been reported at 125 ppm for rats in-
haling benzotrichloride for four hours. Pertinent data for the toxic
effects to aquatic organisms were not found in the available literature.
-------
I. INTRODUCTION
Benzotrichloride (CAS registry number 98-07-7), is a colorless, oily,
fuming liquid. It is made by the free radical chlorination of boiling
toluene (Sidi, 1964; Windholz, 1976). Benzotrichloride has the following
physical and chemical properties (Windholz, 1976; Sidi, 1964):
Formula: C6H5C13
' Molecular Weight: 195.48
Melting Point: -5°c
Boiling Point: 220.8°C
Density: 1.375620
4
Solubility: alcohol, ether, benzene,
insoluble in water
Benzotrichloride is used extensively in the dye industry for the
production of Malachite green, Rosamine, Quinoline red, and Alizarine yellow
A. It can also be used to produce ethyl orthobenzoate (Sidi, 1964).
II. EXPOSURE
A. Water
Benzotrichloride decompose in the presence of water to benzoic and
hydrochloric acids (Windholz, 1976).
B. Food
Pertinent data were not found in the available literature.
C. Inhalation
Pertinent data were not found in the available literature; -how-
ever, significant exposure could occur in the workplace from accidental
spills. Benzotrichloride decomposes in moist air to benzoic and hydro-
chloric acids (Windholz, 1976).
D. Dermal
Benzotrichloride is irritating to the skin (Windholz, 1976).
-------
III. PHARMACOKINETICS
Pertinent pharmacokinetic data were not found in the available
literature.
IV. EFFECTS
A. Carcinogenicity
In a study by Matsushito and coworkers (1975), benzotrichloride
was found to induce carcinomas, leukemia, and papillomas in mice. The de-
tails of the study were not available for assessment.
8. Mutagenicity
Yasuo, et al. (1978) tested the mutagenicity of several compounds
including benzotrichloride in microbial systems such as the rec-assay using
Bacillus subtilis, reversion assays using £_._ coli, and the Ames assay using
Salmonella typhimurium, with or without metabolic activation. Benzo-
trichloride was positive for mutagenicity in the rec-assay and was highly
positive on certain strains of £_._ coli and S^ typhimurium in the reversion
assay with metabolic activation. Without metabolic activation, however,
benzotrichloride was only weakly positive in the latter assay.,
C. Teratogenicity, Reproductive Effects, and Chronic Toxicity
Pertinent data were not found in the available literature.
0. Acute Toxicity
The lowest lethal concentration (LCLQ) for rats inhaling benzo-
trichloride is 125 ppm for four hours (Smyth, et al. 1951).
Benzotrichloride was severely irritating to the skin of rabbits
that received dermal applications of 10 mg for 24 hours and to the eyes of
rabbits that received instillations of 50 ug to the eye (Smyth, et al. 1951).
2
-232-
-------
V. AQUATIC TOXICITY
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.
-------
REFERENCES
Matsushito, H., et al. 1975. Carcinogenicities of the related compounds in
benzoyl chloride production. 49th Annu. Meeting Japan Ind. Hyg. Soc.,
Sappro, Japan, p. 252.
Sidi, H. 1964. Benzyl chloride, benzal chloride, benzotrichloride. In:
Kirk-Othmer Encyclopedia of Chemical Technology. John Wiley and Sons, New
York, p. 281.
Smyth, H.F., et al. 1951. Range finding toxicity data: List IV. Amer.
Med. Assoc. Arch, of Ind. Health. 4: 119.
Windholz, M. (ed.) 1976. Merck Index, 9th ed. Merck and Co., Inc.,
Rahway, NJ.
Yasuo, K., et al. 1978. Mutagenicity of benzotrichloride and related com-
pounds. Mutat. Res. 58: 143.
-2 VI-
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No. 21
Benzyl Chloride
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.
-------
BENZYL CHLORIDE
Summary
Benzyl chloride has been shown to produce carcinogenic effects in rats
following subcutaneous administration and in mice following intraperitoneal
administration.
Weak mutagenic activity of the compound has been demonstrated in the
Ames Salmonella assay and in £_._ coli.
There is no available information on the possible teratogenic or ad-
verse reproductive effects of benzyl chloride.
Inhibition of cell multiplication in the alga, Microcystis aeruginosa,
started at 30 mg/1. Concentrations of K) mg/1 and 17 mg/1 caused paralysis
in two species of fish.
-------
I. INTRODUCTION
Benzyl chloride (alpha-chlorotoluene), CAS Registry number 100-44-7, is
a colorless-to-light yellow, clear, lachrymatory liquid and is made by free-
radical (photochemical) chlorination of tolene (Hawley, 1971; Austin, 1974).
It has the following physical and chemical properties (Windholz, et al.
1976; Hawley, 1971; Weast, 1972):
Formula:
Molecular Weight: 126.59
Melting Point: -43°C
Boiling Point: 179°C
Density: 1.10020
20
Solubility: Miscible in alcohol, chloroform,
ether;•insoluble in water
Production: approximately 89 million Ibs. 1977
(NIOSH, 1977)
Benzyl chloride is a moderately volatile compound with a vapor pressure
of 1 mm Hg at 22°C (NIOSH, 1978). The compound decomposes relatively
slowly in water with a 15-hour half-life of pH 7 (25°C) (NIOSH, 1978).
Benzyl chloride is used to make benzaldehyde through additional chlori-
nation and hydrolysis, but modest amounts are also used as a benzylating
agent for benzyl benzoate, n-butyl benzyl phthalate, benzyl ethyl aniline,
benzyl cellulose, components of dyes and perfumes, and for production of
phenylacetic acid by benzyl cyanide (Austin, 1974).
II. EXPOSURE
A. Water
Gruber (1975) reports that no benzyl chloride enters the water
from production.
-------
8. Food
Pertinent data could not be located in the available literature.
C. Inhalation
Pertinent data were not found in the available literature; how-
ever, benzyl chloride is used exclusively as a chemical intermediate in
manufacturing and exposure and is most likely limited to the workplace. As
such, the level of exposure is reported to be less than 1 ppm (NIOSH, 1978).
D. Dermal
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available literature.
3. Metabolism and Excretion
The major excretion product following ingestion of benzyl chloride
is a cysteine conjugate, benzylmercapturic acid (Stekol, 1938, 1939; Witter,
1944; Barnes, et al. 1959; Knight and Young, 1958).
Bray, et al. (1958) administered benzyl chloride at 200 mg/kg body
weight orally to rabbits. Urine collected for 24 hours showed 86.4 percent
of the administered dose in the soluble fraction, with 49 percent as benzyl-
mercapturic acid, 20 percent as a glycine conjugate, 0.4 percent as glucosi-
duronic acid, and 17 percent as unconjugated benzoic acid. Maitrya and Vyas
(1970) found 30 percent of the total oral dose of benzyl chloride to be ex-
creted by rats as hippuric acid.
Knight and Young (1958) found that benzyl chloride is converted
directly to benzyl mercapturic acid, unlike related compounds such as chlor-
inated benzenes, which form acid-labile precursors.
-------
Barnes, et al. (1959) found that 27 percent of the total oral dose
of benzyl chloride administered to rats was excreted as benzyl mercapturic
acid. This value compares with 49 percent excreted in rabbits (Bray, et al.
1958) and 4 percent in guinea pigs (Bray, et al. 1959).
Several studies have indicated that glutathione is the source of
the thiol groups for mercapturic acid formation from benzyl chloride
(Barnes, et al. 1959; Simkin and White, 1957; Anderson and Mosher, 1951;
Waelsch and Rittenberg, 1942; Bray, et al. 1969; Beck, et al. 1964). The
turnover rate of glutathione in the liver was found to be 49 .mg/100 g of
liver per hour.(Simkin and White, 1957). An in vitro study by Suga, ,et al.
(1966) revealed that conjugation with glutathione can occur both enzymatic-
ally and non-enzymatically in rat liver-preparations. The enzymic conjuga-
tion has also been observed in human liver preparations (Boyland and Chas-
seaud, 1969).
IV. EFFECTS
A. Carcinogenicity
Benzyl chloride was reviewed by IARC (1976) and found to be car-
cinogenic in rats. Druckrey, et al. (1970) injected 14 rats subcutaneously
with benzyl chloride at 2.1 g/kg body weight (total dose) and 8 rats with
3.9 g/kg body weight (total dose) during 51 weeks. Injection site sarcomas
were noted in three of the rats receiving .the lower dose and six receiving
the higher dose; most of the tumors had metastasized to the lungs. The
vehicle of administration, arachis oil, did not produce local tumors.
Poirier, et al. (1975) administered intraperitoneal injections of
benzyl chloride in tricaprylin to three groups of 20 male and female A/Hes-
ton mice, three times per week for eight weeks, with total doses of 0.6,
1.5, and 2.0 g/kg body weight. After 24 weeks, all survivors were killed;
-------
lung tumors occurred in 4/15, 7/16, and 2/8 surviving mice in the three
groups, respectively. The average number of tumors per mouse was 0.26,
0.50, and 0.25, respectively. The incidence of tumors in mice receiving the
benzyl chloride was not significantly different from the results recorded
for untreated mice on the tricapryiin-vehicle treated mice.
B. Mutagenicity
McCann, et al. (1975a,b) found benzyl chloride to be weakly muta-
genic (less than 0.10 revertants/nanomole) when tested using the Ames assay
(Salmonella/microsomal activation).
Rosenkranz and Poirier (1978), in a National Cancer Institute re-
port, found benzyl chloride to be marginally mutagenic in the Ames assay at
doses of 5 ul and 10 ^I/plate without activation. Microsomal activation had
an inactivating effect on benzyl chloride. The investigators also evaluated
the ONA-modifying activity in bacterial systems using Escherichia coli pol A
mutants. A dose of 10 ul benzyl chloride produced a positive mutagenic ef-
fect.
Benzyl chloride was found to be non-mutagenic in the Ames Salmo-
nella microsomal assay by Simmon (1979). The compound was mutage'nic when
exposure was by vapor phase in a dessicator.
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Pertinent data could not be located in the available literature.
0. Acute Toxicity
A number of studies have been conducted on the acute toxicity of
benzyl chloride vapor to animals and were reviewed in a criteria document
prepared by NIOSH (1978). Respiratory tract inflammation and secondary in-
fections were observed in mice exposed to 390 mg/m3 (LC50) for two fiours
and rats exposed to 740 mg/m? (LC50) for two hours (Mikhailova, 1965).
if
-------
Rabbits exposed to 480 mg/m3 of benzyl chloride for eight hours/day for
six days suffered mild eye and nasal irritation by the sixth day, while cats
exposed to the same- regimen suffered a loss of appetite in addition to eye
and respiratory tract irritation (Wolf, 1912). Death of a dog occurred
within 24 hours of exposure to 1,900 mg/m-5 of benzyl chloride for eight
hours. Corneal turbidity and irritation of the ocular, respiratory, and
oral mucosa were observed before death (Schutte, 1915). Mikhailova (1965)
observed hepatic changes and necrosis of the kidney in rats and mice exposed
to benzyl chloride at 100 mg/m3.
Landsteiner and.Jacobs (1936) investigated the sensitizing proper-
ties of benzyl chloride to guinea pigs. Benzyl chloride, in a saline solu-
tion (0.01 mg/animal) was injected intracutaneously twice per week for 12
weeks. Two weeks later, re-exposure revealed that benzyl chloride had a
sensitizing effect.
Occupational exposures to benzyl chloride have been reported by
several investigators (Wolf, 1912; Schutte, 1915; Mikhailova, 1971; Katz and
'Talbert, 1930; Watrous, 1947). Lacrimination, conjunctivitis, and irrita-
tion of the respiratory tract and eyes have been reported following exposure
to benzyl chloride vapor levels ranging from 6 to 8 mg/m3 for five minutes
to brief exposure at 23,600 mg/m3. Although no cases were reported in the
literature, liquid benzyl chloride has the potential for skin irritation
based on its release of hydrochloric acid upon hydrolysis. The odor thresh-
old and nasal irritation thresholds for benzyl chloride are 0.21 to 0.24
mg/m3 and 180 mg/m3, respectively (Katz and Talbert, 1930; Leonardos, et
al. 1969).
t
-2V2-
-------
V. AQUATIC TOXICITY
A. Acute and Chronic Toxicity
Pertinent data could not be located in the available literature.
3. Plant Effects
Inhibition of cell multiplication in Microcystis aeruginosa start-
ed at 30 mg/1 (Bringmann and Kunn, 1976).
C. Residues
Pertinent data could not be located in the available literature.
D. Other Relevant Information
Hiatt, et al. (1953) found that 1.0 mg/1 of benzyl chloride pro-
duced no irritant response in marine fish, but 10 mg/1 caused a slight irri-
tant activity. This compound caused paralysis in the fish Trutta iridea and
)
Cyprinus carpio at concentrations of 10 mg/1 and 17 mg/1, respectively
(Meinck, et al. 1970),.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
\
The American Conference of Governmental and Industrial Hygienists
(ACGIH, 1977) recommends an "ccupational exposure limit of 1 ppm (5 mg/nv3)
for benzyl chloride. The U.S. federal standard promulgated by OSHA is also
1 ppm (TWA) (29 CFR 1910.1000). NIOSH recommends an environmental exposure
limit of 5 mg/m5 as a ceiling value for a 15-minute exposure (NIOSH, 1978).
8. Aquatic
No guidelines to protect fish and saltwater organisms from benzyl
chloride toxicity have been established because of the lack of available
data.
-273-
-------
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Threshold
Limit Values for Chemical Substances and Physical Agents in the Workroom
Environment. Cincinnati, Ohio.
Anderson, E.I. and W.A. Mosher. 1951. Incorporation of S35 from dl-cys-
tine into glutathione and protein in the rat. Jour. Siol. Chem. 188: 717'.
Austin, G.T. 1974. The industrially significant organic chemicals. Chem.
Eng. 81: 132.
Barnes, M.M., et al. 1959. The formation of mercapturic acids— I. Forma-
tion of mercapturic acid and the levels of glutathione in tissues. Biochem.
Jour. 71: 680.
Beck, L.V., et al. 1964. Effects of bromobenzene on mouse tissue sulfhy-
dryl and insulin -1131 metabolism. Proc. Soc. Exptl. Biol. Med. 116: 283.
Boyland, E. and L. Chasseaud. 1969. Glutathione S-aralkyltransferase.
Biochem. Jour. 115:.985.
Bray, H.G., et al. 1958. Metabolism .of some omega-halogenoalkylbenzenes
and related alcohols in the rabbit. Biochem. Jour. 70: 570.
Bray, H.G., et al. 1959. The formation of mercapturic acids — II. The
possible role of glutathionase. Biochem. Jour. 71: 690.
Bray, H.G., et al. 1969. Some observations on the source of -cysteine for
mercapturic acid formation. Biochem. Pharmacol. 18: 1203.
Bringmann, G. and R. Kuhn. 1976. Vergleichende Befunde der Schadwirkung
wassergefahrdender Stoffe gegen Bakterien (Speudomonas putida) und Blaualgen
(Microcystis aeruqinosa), nwf-wasser/abwasser, (117)H.9.
Druckrey, H., et al. 1970. Carcinogenic alkylating substances — III.
Alkyl-halogenides, -sulfates, -sulfonates and strained heterocyclic com-
pounds. (Trans, of German) Z Krebsforsch 74: 241.
Gruber, G.I. 1975. Assessment of industrial hazardous waste practices, or-
ganic chemicals, pesticides, and explosives industries. TRW. Systems Group,
NTIS-PS-251-307.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary, 8th ed. Van
Nostrand Reinhold Company, New York.
Hiatt, R.W., et al. 1953. Relation of chemical structure to irritant re-
sponses in marine fish. London Nature. 172: 904.
International Agency for Research on Cancer. 1976. Monographs on the eval-
uation of the carcinogenic risk of chemicals to humans. Vol. 11: 217.
-.2V*-/-
-------
Xatz, S.H. and E.J. Talbert. 1930. Intensities of odors and irritating
effects of warning agents for inflammable and poisonous gases, Paper 480.
U.S. Department of Commerce, Bureau of Mines. 37 pp.
Knight, R.H. and L. Young. 1958. Biochemical studies of toxic agents —
II. The occurrence of premercapturic acids. Biochem. Jour. 70: 111.
Landsteiner, K. and J. Jacobs. 1936. Studies on the sensitization of ani-
mals with simple chemical compounds, II. Jour. Exp. Med. 64: 625.
Leonardos, G., et al. 1969. Odor threshold determinations of 53 odorant
chemicals. Jour. Air Pollut. Control Assoc. 29: 91.
Maitrya, 3.9. and C.R. Vyas. 1970. Studies on conjugation of organic com-
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McCann, J., et al. 1975a. . Detection of carcinogens as mutagens — Bacter-
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72: 979.
McCann, J., et al. 1975b. Detection of carcinogens as mutagens in the Sal-
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USA. 72: 5135.
Meinck, F., et al. 1970. Les eaux residuaires industrielles.
Mikhailova, T.V. 1965. Comparative toxicity of chloride derivatives of
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Mikhailova, T.V. 1971. Benzyl chloride In; ILO Encyclopedia of
Occupational Health and Safety, Vol. 1. Geneva, International Labour
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National Institute for Occupational Safety and Health. 1978. Criteria for
a Recommended Standard...Occupational Exposure to Benzyl Chloride. DHEW
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Poirier, L.A., et al. 1975. Bioassay of alkyl halides and nucleotide base
analogs by pulmonary tumor response to strain A mice. Cancer Res. 35: 1411.
Rosenkranz, H.S. and L.A. Poirier. 1978. An evaluation of the mutagenicity
and DNA-modifying activity in microbial systems of carcinogens and noncarci-
nogens. Unpublished report from U.S. Dept. of Health, Education and Wel-
fare, Public Health Service, National Institute of Health, National Cancer
Institute. 56 pp.
»
Schutte, H. 1915. Tests with benzyl and benzal chloride. Dissertation
translated from German. Wurzburg. Royal Bavarian Julius-Maximilians Uni-
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-------
Simkin, J.L. and K. White. 1957. The formation of hippuric acid — The
influence of benzoate administration on tissue glycine levels. 3iochem.
Jour. 65: 574.
Simmon, V.F. 1979. _In vitro mutagenicity assays of chemical carcinogens
and related compounds with Salmonella typhimurium. Jour. Natl. Cancer Inst.
62: 893.
Stskol, J.A. 1938. Studies on the mercapturic acid synthesis in animals —
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Stekol, J.A. 1939. Studies on the mercapturic acid synthesis in animals —
XII. The detoxification of benzyl chloride, benzyl alcohol, benzaldehyde,
and S-benzyl homocysteine in the rabbit and rat. Jour. Biol. Chem.
128: 199.
Suga, T., et al. 1966. Studies on mercapturic acids, effect of some aro-
matic compounds on the level of glutathione and the activity of glutathion-
ase in the rat. Jour. Biochem. 59: 209.
Waelsch, H. and D. Rittenberg. 1942. Glutathione — II. The metabolism of
glutathione studied with isotopic ammonia and glutamic acid. Jour. Biol.
Chem. 144: 53.
Watrous, R.M. 1947. Health hazards of the pharmaceutical industry. Br.
Jour. Ind. Med. 4: 111.
Weast, R.C. 1972. Handbook of Chemistry and Physics, 53rd ed. Chemical
Rubber Company, Cleveland, Ohio.
Windholz, M., et al. 1976. Merck Index, 9th ed. Merck and Co., Inc., Rah-
way, New Jersey.
Witter, R.F. 1944. The metabolism of monobromobenzene, benzene, benzyl
chloride and related compounds in the rabbit. Ann Arbor, University of
Michigan, University Microfilms, Dissertation. 1-7, 32-35, 37-66, 93, 197,
113-118, 126-138.
Wolf, W. 1912. Concerning the Effect of Benzyl Chloride and Benzal Chlor-
ide on the Animal Organisms. Translation of dissertation from German, Wurz-
burg, Royal Bavarian Julius-Maximilians University. Franz Staudenraus Book
Printing, 25 pp.
-------
No. 22
Beryllium
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.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
beryllium and has found sufficient evidence to indicate
that this compound is carcinogenic.
-249-
-------
BERYLLIUM
SUMMARY
Beryllium was shown to be carcinogenic in three animal
species, producing cancers of the lung and bone when admin-
istered by injection, inhalation, or intratracheal instilla-
tion. Ingestion of beryllium has failed to produce cancers
in animals, possibly due to its poor gastr'ointestinal absorp
tion. Several epidemiology studies support the hypothesis
that beryllium is a human carcinogen.
Beryllium is toxic to freshwater organisms at concentra
tions as low as 5.3 pg/1. Pertintent data for marine or- •<
ganisms were not found in the available literature (U.S.
EPA, 1979).
-2SO-
-------
BERYLLIUM
. I. INTRODUCTION
This profile is primarily based upon the Ambient Water
Quality Criteria Document for Beryllium (U.S. EPA, 1979).
Recent comprehensive reviews on the hazards of beryllium
have also been prepared by the National Institute for Occupa-
tional Safety and Health (NIOSH, 1972) and the International
Agency for Research on Cancer (IARC, 1972).
Beryllium (Be; atomic weight 9.01) is-.a dark gray metal
of the alkaline earth family. Beryllium has the following
physical-chemical properties (IARC, 1972):
Boiling point: 2970°C
Melting point: 1284 - 1300°C
Hardness: 60 - 125
Density: 1.84 - 1.85
Solubility: Soluble in acids and alkalis
World production of beryllium was reported as approximately
250 tons annually, but much more reaches the environment
as emissions from coal burning operations (Tepper, 1972} .
Most common beryllium compounds are readily soluble in water.
The hydroxide is soluble only to the extent of 2 mg/1 (Lange,
1956). Beryllium forms chemical compounds in which its
valence is +2. At acid pH, it behaves as a cation but forms
anionic complexes at pH greater than 8 (Krejci and Scheel,
1966). The major source of beryllium in the environment
is the combustion of fossil fuels (Tepper, 1972). Beryl-
lium enters the waterways through weathering of rocks and
soils, through atmospheric fallout and through discharges
from industrial and municipal operations.
-is >-
-------
II. EXPOSURE
A. Water
Kopp and Kroner (1967) reported the results of
trace metal analyses of 1,577 drinking water samples obtained
throughout the United States. Beryllium was detected in
5.4 percent of the samples. Concentrations ranged from
0.01 to 1.22 jag/1, with a mean value of 0.19 ug/1.
B. Food
Beryllium has been detected in a- variety of vege-
tables, and in eggs, milk, nuts, bread, and baker's yeast
(Meehan and Smythe, 1967; Petzow and Zorn, 1974). Measured
levels of beryllium were generally in the range of 0.01
to.0.5 ppm. Using the data for consumption and bioconcen-
tration for freshwater and saltwater fishes, mollusks, and
decapods, and the measured steady-state bioconcentration
factor (BCF) for beryllium in bluegills, the U.S. EPA (1979)
has estimated .a weighted average BCF for beryllium to be
19 for the edible portions of fish and shellfish consumed
by Americans.
C. Inhalation
The detection of beryllium in air is infrequent
and usually in trace amounts. In urban areas beryllium
levels may reach 0.008 jag/m , while in rural areas beryllium
concentrations have been measured at 0.00013 ^g/m (Tabor
and Warren, 1958; National Air Sampling Network, 1968).
»
At a beryllium extraction plant in Ohio, beryllium concen-
trations were generally around 2 pg/rn over a seven year
period (Breslin and Harris, 1959).
/
-2S2-
-------
III. PHARMACOKINETICS
Ingested - beryllium is poorly absorbed within the gastro-
intestinal tract, presumably due to solubility problems
in the alimentary canal (Hyslop, et al. 1943; Reeves, 1965).
When inhaled, soluble beryllium compounds are rapidly re-
moved from the lung, whereas insoluble beryllium compounds
can remain in the lung indefinitely (Van Cleave and Kaylor ,
1955; Wagner, et al. 1969; Sprince, et al . 1976). When
parenterally administered, beryllium is distributed to all
tissues, although it shows preferential accumulation in
bone, followed by spleen, liver, kidney and muscle (Van
Cleave and Kaylor, 1955; Crowley, et al. 1S49; Klemperer,
et al. 1952; Kaylor and Van Cleave, 1953; Spencer, et al.
1972) . Absorbed beryllium tends to be either excreted in
the urine or deposited in kidneys and bone (Scott, et al.
1950) . Once deposited in the skeleton, beryllium is removed
very slowly, with half-lives of elimination reported to
be 1,210, 390, 1,770 and 1,270 days in mice, rats, monkeys,
and dogs, respectively (Furchner, et al. 1973).
IV. EFFECTS
A. Carcinogenicity
Beryllium was shown to be carcinogenic in three
animal species. Intravenous injection of beryllium, zinc
.beryllium silicate, and beryllium phosphate produced osteo-
sarcomas in the rabbit (Gardner and Heslington, 1946; Dutra
and Largent, 1950; Komitowski, 1969; Fodor, 1971; IARC,
1972) . Inhalation and intratracheal instillation of beryl-
-2S-*,-
-------
lium compounds have .produced lung cancers in the rat and
monkey (Vorwald and Reeves, 1959; Vorwald, et al. 1966;
Reeves, et al. 1967). Ingestion of beryllium by rats and
mice has failed to induce tumors, possibly due to the poor
absorption of beryllium from the gastrointestinal tract.
Several epidemiological studies have failed to
establish a clear association between beryllium exposure
and cancer development (Stoeckle, et al. 1969; Mancuso,
1970; Niemoller, 1963). However, other re-cent studies sup-
port the hypothesis that beryllium is a human carcinogen
(Berg and Burbank, 1972; Wagoner, et al. 1978; Discher,
1978).
B. Mutagenicity
Pertinent data were not found in the available
literature.
C. Teratogenicity
Beryllium has been implicated as a teratogen in
snails (Raven and Sprok, 1953) and has inhibited limb re-
generation in the salamander, Amblystoma punctatum (Thorton^
1950).
D. Other Reproductive Effects
Pertinent data were not found in the available
literature.
E. Chronic Toxicity
Chronic beryllium inhalation in humans produces
a progressive,, systemic disease which may follow the ces-
sation of exposure by as long as five years (Tapper, et
-------
al. 1361; Hardy and Stoeckle, 1959). -Symptoms include pneu-
monitis with cough, chest pain, and general weakness. Sy-
stemic effects include right heart enlargement with cardiac
failure, enlargement of liver and spleen, cyanosis, digital
clubbing, and kidney stones (Hall, et al. 1959). Chronic
beryllium disease can be produced in rats and monkeys by
inhalation of beryllium sulfate at 35 ug/m (Schepers, et
al. 1957; Vorwald, et al. 1966).
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute toxicity data for beryllium for freshwater
fishes are taken from 22 static and 5 flow-through bioassays,
all 96 hours in duration. U.S. EPA (1979) presents the
most sensitive species, the guppy Poecilia reticulata, with
LCcQ values ranging from 71 to 17,500 pg/1. The data re-
flect that the toxicity of beryllium to freshwater fish
is decreased in hard water. This has also been confirmed
by U.S. EPA (1979) in the fathead minnow, Pimephales prome-
las, with LCeQ values ranging from 82 to 11,000 ug/1. Acute
toxicity for aquatic invertebrates provides two 48-hour
LCCQ values of 7,900 and 2,500 ug/1, with water hardness
values of 180 and 200 pq/1 as CaCo-j. The source of these
invertebrate studies is the same for chronic freshwater
studies. No data for acute toxicity to marine species was
found in the available literature.
-------
B. Chronic Toxicity
No chronic tests for freshwater fish were found
in the available literature. The cladoceran, Daphnia magna,
was the only freshwater species tested for chronic effects;
chronic values of less than 36 ug/1 and 5.3 ug/1 were ob-
tained by the U.S. EPA (1979). No chronic data for marine
species of fish or invertebrates was found in the available
literature.
C. Plant Effects
The only plant study available reveals that the
green algae, Chlorella vannieli, displayed growth inhibition
at a concentration of 100,000 ug/1 (U.S. EPA, 197y).
D. Residues
Exposure of the bluegill for 28 days producea
a bioconcentration factor of 19 (U.S. .EPA, 1978). No other
data was found in the available literature.
E. Other Relevant Information
The only marine data presented showed reduced
alkaline phosphatase activity in the mummichog, Fundulus
heteroclitus, at concentrations as low as 9 ,ug/l. A tera-
togenic response was observed by Evola-Maltese (1957) in
sea urchin emoryos at concentrations of 9.010 ug/1.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The present standard for occupational exposure
to beryllium prescribes an 8-hour time-weignted average
-------
of 2.0 ug/m with a ceiling concentration of 5.0 pg/m .
This is the same value recommended by the American Confer-
ence of Governmental Industrial Hygienists (1977). The
National Institute 'for Occupational Safety and Health (NIOSH,
1972) recommends that occupational exposure to beryllium
and its compounds not exceed 1 jag/m (8-hour time-weighted
average) with a ceiling limit of 5 pg/m (measured over
a 15 minute sampling period).
National Emission Standards for Hazardous Air
Pollutants set their criterion as not more than 10 g in
24 hours or emissions which result in maximum outplant con-
centrations of 0.01 pg/m , 30-day average (U.S. EPA, 1977).
Based on animal bioassay data for beryllium to
which the linear model was applied, the U.S. EPA (1979)
has estimated levels of beryllium in ambient water which
will result in carcinogenic risk for humans. As a result
of the public comments received, additional review and re-
evaluation of the data base is required before a final cri-
terion level can be recommended.
B. Aquatic
The U.S. EPA proposed a water quality standard
of 11 pg/1 for the protection of aquatic life in soft fresh-
water; 1,100 pg/1 for the protection of aquatic life in.
hard freshwater; and 100 jjg/1 for continuous irrigation
on all soils, except 500 mg/1 for irrigation on neutral
to alkaline lime-textured soils (U.S. EPA, 1977).
-------
The National Academy of Science/National Academy
of Engineering (1973) Water Quality Criteria recommendation
for marine aquatic life is: hazard level - 1.5 ug/1; minimal
risk of deleterious effects'- 0.1 mg/1; and application
factor - 0.01 (applied to 96-hour LC5Q). Their recommenda-
tion for irrigation water is: 0.10 mg/1 for continuous use
on all soils.
The U.S. EPA (1979) has derived a draft criterion
for beryllium to protect freshwater aquatic organisms.
The 24-hour average concentration in ug/1 is dependent on
water hardness and is derived by the following equation:
,-D - a(1.24 In (hardness) - 6.65)
^t\ — e
The concentration not to be exceeded at any time is:
„-. . ^ (1.24 In (hardness) - 1.46)
\-t\ — e
No draft criterion was derived for marine organisms (U.S.
EPA, 1979).
-------
BERYLLIUM
REFERENCES
American Conference of Governmental Industrial Hygienists
1977. Threshold limit values for chemical substances in
workroom air adopted by ACGIH for 1977. ACGIH, P.O. Box
1937, Cincinnati, Ohio 45201.
Berg, J.W., and F. Burbank. 1972. Correlations between
carcinogenic trace metals in water supply and cancer mor-
tality. Ann. N.Y. Acad. Sci. 199: 249.
Breslin, A.J., and W.B. Harris. 1959. Health protection
in beryllium facilities. Summary of ten years of experience.
AMA Arch Ind. Health 19: 596.
Crowley, J.F., et al. 1949. Metabolism of carrier-free
radioberyllium in the rat. Jour. Biol. Chem. 177: 975.
Discher, D.P. 1978. Letter to W.H. Foege, Director, Center
for Disease Control HEW (published in 3NA Occupational Safety
and Health Reporter) 8: 853.
Dutra, F.R., and F.J. Largent. 1950. Osteosarcoma induced
by beryllium oxide. Am. Jour. Pathol. 26: 197.
Evola-Maltese, C. 1957. Effects of beryllium on the develop-
ment and alkaline phosphatase activity of Paracentrotus
embryos. Acta Embryol. Morphol. Exp. 1: llTT
Fodor, J. 1971. Histogenesis of bone tumors induced by
beryllium. Magyar Onkol. 15: 180.
Furchner, J.E., et al. 1973. Comparative metabolism of
radionucleotides in mammals. VIII: Retention of beryllium
in the mouse, rat, monkey, and dog. Health Physics 24:
293.
Gardner, L. U., and H.F. Heslington. 1946. Osteo-sarcoma
from intravenous beryllium compounds in rabbits. Fed. Proc.
5: 221.
Hall, T.C., et al. 1959. Case data from the beryllium
registry. AMA Arch. Ind. Health 19:100.
Hardy, H.L., and J.D. Stoeckle. 1959. Beryllium disease.
Jour. Chron. Dis. 9: 152.
Hysloo, F., et al. 1943. The toxicology of beryllium.
U.S. Pub. Health Serv. Natl. Inst. Health Bull. 181.
IARC. 1972. Monographs on the evaluation of carcinogenic
risk of chemicals to man. Beryllium: 1: 17.
-------
Kaylor, C.T., and C.D. Van Cleave. 1953. Radiographic
visualization of the deposition of radioberyllium in the
rat. Anat. Record 117: 467.
Klemperer, F.W., et al. 1952. The fate of beryllium com-
pounds in the rat. Arch. Biochem. Biophys. 41: 148.
Komitowski, D. 1969. Morphogenesis of beryllium-induced
bone tumors. Patol. Pol (supol.) 1: 479.
Kopp, J.F., and R.C. Kroner. 1967. A five year study of
trace metals in waters of the United States. Fed. Water
Pollut. Control Admin., U.S. Dep. Inter., Cincinnati, Ohio.
Krejci, L.E., and L.D. Scheel. 1966. Ir\ H.E. Stokinger,
ed. Beryllium: Its industrial hygiene aspects. Academic
Press, Inc., New York.
Lange, N.A. ed. 1956. Lange's handbook of chemistry.
9th ed. Handbook Publishers, Inc., Sandusky, Ohio.
Mancuso, T.F. 1970. Relation of duration of employment
and prior illness to respiratory cancer among beryllium
workers. Environ. Res. 3: 251.
Meehan, W.R., and L.E. Smythe. 1967. Occurrence of beryl-
lium as a trace element in environmental materials. Environ.
Sci. Technol. 1: 839.
National Academy of Sciences, National Academy of Engineer-
ing. 1973. Water quality criteria 1972. A .report. Natl.
Acad. of Sci., Washington, D.C.
National Air Sampling Network, Air Quality Data. 1968.
National Air Sampling Network, Durham, N.C., U.S. Dep. Health
Education and Welfare, Pub. Health Serv.
National Institute of Occupational Safety and Health. 1972.
Criteria for a recommended standard...Occupational exposure
to beryllium. DHEW (NIOSH) ?ubl. No. 72-10806.
Niemoller, H.K. 1963. Delayed carcinoma induced by beryl-
lium aerosol in man. Int. Arch. Gewerbepthol. Gewerbehyg.
20: 18.
Petzow, G., and H. Zorn. 1974. Toxicology of beryllium-
containing materials. Chemlxer Vig. 98: 236.
Raven, C.P., and N.S. Spron.s. 1953. Action of beryllium
on the development of Limnaea stagnalis. .Chem. Abstr.
47: 6561.
-------
Reeves, A.L. 1965. Absorption of beryllium from the gastro-
intestinal tract. AMA Arch. Environ. Health 11: 209.
Reeves, A.L., et al. 1967. Beryllium carcinogenesis. I.
Inhalation exposure of rats to beryllium sulfate aerosol.
Cancer Res. 27: 439.
Schepers, G.W.H., et al. 1957. The biological action of
inhaled beryllium sulfate. A preliminary chronic toxicity
study in rats. AMA Arch. Ind. Health 15: 32.
Scott, J.K., et al. 1950. . The effect of add^d carrier
on the distribution and excretion of soluble Be. Jour.
Biol. Chem. 172: 291.
Spencer, H.C., et al. 1972. Toxicological evaluation of
beryllium motor exhaust products. AMRL-TR-72-118. Aero-
medical Res. Lao. Wright-Patterson AFB, Ohio.
Sprince, N.L., et al. 1975. Current (1975) problems of
differentiating between beryllium disease and. sarcoidosis.
Stoeckle, J.D., et al. 1969. Chronic beryllium disease:
Long-term follow-up of 60 cases and selective review of
the literature. Am. Jour. Med. 46: 545.
Tabor, E.G., and W.V. Warren. 1958. Distribution of cer-
tain metals in the atmosphere of some American cities.
Arch. Ind. Health. 17: 145.
Tepper, L.B. 1972. Beryllium. CRC critical reviews in
toxicology. 1: 235.
Tepper, L.B., et al. 1961. Toxicity of beryllium compounds.
Elsevier Publishing Co., New York.
Thornton, C.S. 1950. Beryllium inhibition of regenerations.
Jour. Exp. Zool. 114: 305.
U.S. EPA. 1977. Multimedia environmental goals for environ-
mental assessment. Vol. II. MEG charts and background•inform-
ation. EPA-b0017-77-136b. U.S. Environ. Prot.Agency.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. U.S. Environ. Prot.
Agency, Washington, D.C.
U.S. EPA. 1979. Beryllium: Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.
Van Cleave, C.D., and C.T. Kaulor. 1955. Distribution,
retention and elimination of Be in the rat after intratra-
cheal injection. AMA Arch. Ind. Health 11: 375.
-2C.I-
-------
Vorwald, A.J., and A.L. Reeves. 1959. . Pathologic changes
induced by beryllium compounds. AMA. Arch. Ind. Health
19: 190.
Vorwald, A.J., et al. 1966. Experimental beryllium toxi-
cology. Ln H.E. Stokinger, ed. Beryllium, its industrial
hygiene aspects. Academic Press, New York.
Wagner, W.D., et al. 1969. Comparative inhalation toxicity
of beryllium ores bertranaite and beryl with production
of pulmonary tumors by beryl. Toxicol. Appl. Pharmacol.
15: 10.
Wagoner, J.K., et al. 1978. Beryllium: carcinogenicity
studies. Science 201: 298.
-------
No. 23
Bis(2-chloroethoxy)methane
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.
-------
3IS(2-CHLORDETHOXY)METHANE
Summary
Pertinent data could not be located in the available literature search-
es on the mutagenic, carcinogenic, teratogenic, or adverse reproductive ef-
fects of bis(2-chloroethoxy)methane (3CEXM) in mammals. A closely related
compound, bis(2-chloroethoxy)ethane (8CEXE) has been shown to produce skin
tumors and injection site sarcomas in animal studies.
Pertinent information could not be located in the available literature
on bis(2-chloroethoxy)methane toxicity to aquatic organisms.
-------
BIS(2-CHLOROETHOXY)METHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
The chloroalkyi ethers are compounds in which a hydrogen atom in one or
both of the aliphatic, ether chains are substituted with chlorine. Bis(2-
chloroethoxy)methane (8CEXM, dichloroethyl formal, . C1CH2CH2-0-CH2-
OCH2-CH2C1) is a colorless liquid at room temperature with a boiling
point of 218.1°C and a specific gravity of 1.2339. The compound is
slightly soluble in water but miscible with most organic solvents.
The chloroalkyi ethers have a wide variety of industrial uses in organ-
ic synthesis, treatment of textiles, the manufacture of polymers and insec-
ticides, as degreasing agents and solvents, and in the preparation of ion
exchange resins (U.S. EPA, 1979a).
The chloroalkyi ethers, like 8CEXM, have a higher stability in water
than the alpha chloroalkyi ethers, which decompose. 8CEXM is decomposed by
y
mineral acids.
II. EXPOSURE ') '
No specific information on exposure to BCEXM is available. The reader
is referred to a more general treatment of chloroalkyi ethers (U.S. EPA,
1979b). BCEXM has been monitored in rubber plant effluents at a maximum
level of 140 mg/1 (Webb, et al. 1973). Bis-l,2-(2-chloroethoxy)ethane
(BCEXE), a closely related compound, has been reported in drinking water at
a maximum level of 0.03 pg/1 (U.S. EPA, 1975). Data on levels of BCEXM in
foods was not found in the available literature.
NO bioaccumulation factor for BCEXM has been derived.
-------
III. PHARMACOKINETICS
Pertinent information could not be located in the available literature
on 3CEXM. The reader is referred to a more general treatment of chloroalkyl
ethers (U.S. EPA, 1979b).
IV. EFFECTS
A. Carcinogenicity
Pertinent information could not be located in the available litera-
ture on carcinogenic effects of 8CEXM. The reader is referred to a more
general treatment of chloroalkyl ethers (U.S. EPA, 1979b). A closely re-
lated compound, 8CEXE, has been shown to produce skin tumors in mice and in-
jection site sarcomas (Van Ouuren, et al. 1972).
8. Mutagenicity, Teratogenicity, Other Reproductive Effects and Chron-
ic Toxicity
Pertinent data could not be located in the available literature for
BCEXM.
V. AQUATIC TOXICITY
Pertinent information could not be located in the available literature
on the aquatic toxicity of BCEXM.
•
VI. EXISTING GUIDELINES AND STANDARDS
No standards or recommended criteria exist for the protection of human
health or aquatic organisms to bis(2-chloroethoxy)methane.
-J2&7-
-------
SIS(2-CHLOROETHOXY)METHANE
REFERENCES
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drink-
ing water: Interim report to Congress, Washington, D.C.
U.S. EPA. 1979a. Chloroalkyl Ethers: Ambient Water Quality Criteria.
(Draft)
U.S. EPA. 19795. Environmental Criteria and Assessment Office. Chloro-
alkyl Ethers: Hazard Profile. (Draft)
Van Duuren, et al. 1972. Carcinogenicity of haloethers. II. Structure-
activity relationships of analogs of bis(chloromethyl)ether. Jcur. Natl.
Cancer Inst. 48: 1431.
Webb, R.G., et al. 1973. Current practice in GC-MS analysis of organics in
water. Publ. EPA-R2-73-277. U.S. Environ. Prot. Agency, Corvallis, Oregon.
-------
No. 24
Bis(2-chloroethyl)ether
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.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.
-3.70-
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
bis(2-chloroethyl)ether and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
BIS(2-CHLOROETHYL)ETHER
Summary
Oral administration of bis(2-chloroethyl)ether (8CEE) did not produce
an increase of tumors in rats. Male mice showed a significant increase in
hepatomas after ingestion of 8CEE. 3CEE has also shown activity as a tumor
initiator for mouse skin.
Testing of SCEE in the Ames1 Salmonella .assay, in §_._ coli, and in
Saccharomyces cerevisiae has shown that this compound induces mutagenic
effects.
There is no. available evidence to indicate that BCEE produces adverse
reproductive effects or teratqgenic effects.
The data base for bis(2-chloroethyl-)ether is limited to three studies.
The 96-hr LC5Q value for the bluegill is reported to be over 600,000 ^ig/1.
Adverse chronic effects were not observed with the fathead minnow at test
concentrations as high as 19,000 jug/1. A bioconcentration factor of 11 was
observed during a 14-day exposure of bluegills. The half-life was 4-7 days.
-------
BIS(2-CHLOROETHYL)ETHER
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for 'Chloraikyl Ethers (U.S. EPA, 1979a).
The chloroaikyl ethers are compounds in which a hydrogen atom in one or
both of the aliphatic ether chains are substituted with chlorine. Bis(2-
chloroethyDether (8CEE, molecular weight 143.01) is a colorless liquid at
room temperature with a boiling point of 176-178°C at 760 mm Hg, and a'
density of 1.213. The compound is practically insoluble in water, but is
miscible with most organic solvents (U.S. EPA, 1979a).
The chloroalkyl ethers have a wide variety of industrial and laboratory
uses in organic synthesis, in textile treatment, the manufacture of polymers
and insecticides, as degreasing agents, and in the preparation of ion ex-:
change resins (U.S. EPA, 1979a).
The B-substituted chloroalkyl ethers, such as BCEE, are generally more
stable and hence less reactive in aqueous systems than the a-substituted
compounds (U.S. EPA, 1979a).
For additional information regarding chloroalkyl ethers in general, the
reader is referred to the EPA/ECAO Hazard Profile on Chloroalkyl Ethers
(U.S. EPA 1979b).
II. EXPOSURE
The B-chloroalkyl ethers have been monitored in water. Industrial dis-
charges from chemical plants involved in the manufacture of glycol products,
rubber, and insecticides may contain high levels of BCEE (U.S. EPA, 1979a).
•
The highest concentration of BCEE in drinking water reported by the U.S. EPA
-------
(1975) is 0.5 ug/1. There is no evidence of the occurrence of the chloro-
alkyl ethers in the atmosphere; human exposure appears to be confined to
occupational settings.
Human exposure to chloroalkyl ethers via ingestion of food is unknown
(U.S. EPA, 1979a). The 8-chloroalkyl ethers, due to their stability and low
water solubility, may have a high tendency to be bioaccumulated. The U.S.
EPA (1979a) has estimated the weighted average bioconcentration factor for
BCEE to be 25 for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on a measured steady-state biocon-
centration factor using bluegills.
III. PHARMACOKINETICS
A. Absorption
Experiments with radiolabelled' BCEE have indicated that the com-
pound is readily absorbed following oral administration (Lingg, et al.
1978). .Information on inhalation or dermal absorption of chloroalkyl ethers
is not available (U.S. EPA, 1979a).
B. Distribution
Pertinent information on the distribution of BCEE could not be
located in the literature.
C. Metabolism
The biotransformation of BCEE in rats following oral administration
appears to involve cleavage of the ether linkage and subsequent conjugation
with non-protein-free sulfhydryl groups, the major route, or with glucuronic
acid (Lingg, et al. 1978). Thiodiglycolic . acid and 2-chloro-
ethanol-B-0-glucuronide were identified as urinary metabolites of BCEE in
»
rats.
--271-/-
-------
0. Excretion
BCEE administered to rats by intubation was eliminated rapidly in
the urine, with more than 60 percent of the compound excreted within 24
hours (Lingg, et al. 1978).
IV. EFFECTS
A. Carcinogenicity
BCEE has shown activity as a tumor initiator in mouse skin (U.S.
EPA, 1979a). Preliminary results of an NCI study indicate that oral admin-
istration of BCEE does not produce an increase in tumor incidence in rats
(U.S. EPA, 1979a); however, mice administered BCEE by ingestion showed a
significant increase in hepatomas (Innes, et al. 1969).
B x. Mutagenicity
Testing of the chloroalkyl ethers in the Ames1 Salmonella assay and.
in §_._ cgli have indicated that BCEE induces mutagenic effects (U.S. EPA,
1979a). BCEE has also shown mutagenic effects in Saccharomvces cerevisiae
(Simmon .t et al. 1977), but none were found in the heritable translocation
test for mice (Jorgenson, et al. 1977).
C. .".reratogenicity, Chronic Toxicity and other Reproductive Effects
Pertinent, information could not be located in the available liter-
ature .
D. Other Relevant Information
Acute physiological responses of the guinea pig to inhalation of
high concentrations of BCEE were congestion, emphysema, edema and hemorrhage
of the lungs (Shrenk, et al. 1933). Brief exposure of man to BCEE vapor, at
levels 260 ppm, irritated the nasal passages and eyes with profuse lacri-
mation. Deep inhalation produced nausea. The highest concentration with no
noticeable effect was 35 ppm (Shrenk, et al. 1933).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
96-hr LC5_ value for the bluegill, Lepomis macrochirus, cculd not
be determined for bis(2-chloroethyl)ether with exposure concentrations as
high as 600,000 ug/1 (U.S. EPA, 1978).
8. Chronic Toxicity
An embryo-larval test has been reported with bis(2-chloroethyl)
ether and the fathead minnow, Pimeohales promelas. Adverse effects were not
observed at test concentrations as high as 19,000 ^ig/1 (U.S. EPA, 1978).
C. Plant Effects
Pertinent data could not be located in the available literature.
D. Residues
A bioconcentration factor of 11 w&^ .determined during a 14-day ex- .
posure of bluegills to bis(2-chloroethyl)ether. The half-life was 4-7 days.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979a) which are summarized below, have goi.J through the process of public
review; therefore, there is a possibilitv .that these criteria will be
changed.
A. Human
Based on the results of an animal carcinogenesis bioassay, and
using a linear, non-threshold model, the U.S. EPA (1979a) has estimated that
an ambient water level of 0.42 ug/1 will present an increased risk of 10"5
or less for BCEE, assuming water and the injection of contaminated aquatic
organisms to be the only sources of exposure.
-------
The 3-hour, time-weighted average threshold limit value (TLV-TWA)
for 3CEE determined by the American Conference of Governmental Industrial
Hygienists (ACGIH, 1978) is 5 ppm for 8CEE.
3. Aquatic
Freshwater or saltwater criteria cannot be derived for bis(2-chlo-
roethyDether because of insufficient data (U.S. EPA, 1979a).
If
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8IS(2-CHLOROETHYl) ETHER
REFERENCES
American Conference of Governmental Industrial Hygienists. 1978. Threshold
limit values for chemical substances and physical agents in the workroom
environment with intended changes for 1978. Cincinnati, Ohio.
Fishbein, L. 1977. Potential industrial carcinogens and mutagens. Publ.
EPA-560/5-77-005, Off. Toxic Subst. Environ. Prot. Agency, Washington, D.C.
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.
Jorgenson, T.A., et al. 1977. Study of the mutagenic potential of
bis(2-chloroethyl) and bis(2-chloroisopropyl) ethers in mice by the heri-
table translocation test. Toxicol. Appl. Pharmacol. 41: 196.
Lingg, R.D., et al. 1978. Fate of bis (2-chloroethyl)ether in rats after
acute oral administration. Toxicol. Appl. Pharmacol. 45: 248.
Schrenk, H.H., et al. 1933. Acute response of guinea pigs to vapors of
some new commercial organic compounds. VII. Oichloroethyl ether. Pub.
Health Rep. 48: 1389.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals identified in
drinking water. In: 0. Scott, et' al. (ed.) Progress in genetic toxicology.
Elsevier/North Holland Biomedical Press, New York.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drink-
ing water. Rep. Cong. U.S. Environ. Prot. Agency, Washington, O.C.
U.S. EPA. 1977a. National organic monitoring survey. General review of
results and methodology: Phases I-III. U.S. Environ. Prot. Agency, Off.
Water Supply, Tech. Support Div. Presented before Water Supply Res. Oiv.
Phys. Chem. Removal Branch, Oct. 21.
U.S. EPA. 1977b. Potential industrial carcinogens and mutagens. Office of
Toxic Substances. EPA-560/5-77-005. Washington, O.C.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. -Environ. Prot. Agency, Contract No.
68-1-4646.
U.S. EPA. 1979a. Chloroalkyl Ethers: Ambient Water Quality Criteria.
(Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Hazard
Profile: Chloroalkyl Ethers. (Draft).
Van Ouuren, 3.L. 1969. Carcinogenic epoxides, iactones, and halcethers and
their mode of action. Ann. N.Y. Acad. Sci. 163: 633.
-------
Van Ouuren, 8.L. et al. 1969, Carcinogenicity of haloethers. Jour. Natl.
Cancer Inst. 43: 481.
Van' Duuren, B.L., et al. 1972. Carcinogenicity of haloethers. II. Struc-
ture-activity relationships of analogs of bis(chloromethyl)ether. Jour.
Natl. Cancer Inst. 48: 1431.
-------
No. 25
3is(2-Chloroisopropyl)ether
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.
-------
SIS(2-CHLDROISOPROPYL)ETHER
Summary
Preliminary results from an NCI carcinogenesis bioassay do not show an
increase in tumors following oral administration of bis(2-chloroisopropyl)-
ether (BCIE).
BCIE has produced mutagenic effects in two bacterial test systems (Sal-
monella and §_._ coli) but has failed to show mutagenicity in one mammalian
study.
No information is available on the teratogenic or adverse reproductive
effects of BCIE.
Chronic exposure to BCIE has produced liver damage in animals.
Data on the toxicity of bis(2-chloroisopropyl)ether to aquatic organ-
isms are not available.
-•38.1-
-------
8IS(2-CHLOROISOPROPYL)ETHER
I. INTRODUCTION
This profile is bassd on the Ambient Water Quality Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
The Chloroalkyl ethers are compounds in which a hydrogen atom in one or
both of the aliphatic ether chains are substituted with chlorine. Bis(2-
chloroisopropyDether (8CIE, molecular weight 171.07) is a colorless liquid
at room temperature with a boiling point of 187-188°C at 760 mm Hg. The
compound is practically insoluble in water but is miscible with organic sol-
vents .
The Chloroalkyl ethers have a wide variety of industrial and laboratory
uses in organic synthesis, treatment of textiles, the manufacture of poly-
mers and insecticides, as degreasing agents, and in the preparation of ion
exchange resins (U.S. EPA, 1979a).
The beta-chloroalkyl ethers, like BCIE, are more stable in aqueous sys-
tem than the alpha-chloroalkyl ethers, which decompose rapidly. For addi-
tional information regarding the Chloroalkyl ethers as a class, the reader
is referred to the Hazard Profile on Chloroalkyl Ethers (U.S. EPA, 1979b).
II. EXPOSURE
The beta-chloroalkyl ethers have been monitored in water. Industrial
discharges from chemical plants involved in the manufacture of glycol pro-
ducts, rubber, and insecticides may present high effluent levels (U.S. EPA,
1979a). The highest concentration of BCIE monitored in drinking water by
the U.S. EPA (1975) was reported as 1.58jug/l.
The concentrations of Chloroalkyl ethers in foods have not been moni-
»
tdred. The beta-chloroalkyl ethers, however, due to their relative stabili-
ty and low water solubility, may have a high tendency to be bioaccumulated.
y
--23S-
-------
The U.S. EPA (1979a) has estimated the weighted average bioconcentration
factor for bis(2-chloroisopropyl)ether to be 106 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
Experiments with radio-labeled BCIE have indicated that the com-
pound is readily absorbed following oral administration (Smith, et al.
1977). No information on inhalation or dermal absorption of the chloroalkyl
ethers is available (U.S. EPA, 1979a).
B. Distribution
Species differences in the distribution of radio-labeled BCIE have
been reported by Smith, et al. (1977). Monkeys retained higher amounts of
radioactivity in the liver,-muscle, and brain than did rats. Urine and ex-
pired air from monkeys also contained higher levels of radioactivity than
those determined in the rat. Blood levels of BCIE in monkeys reached a peak
within 2 hours following oral administration and then declined in a biphasic
manner (t 1/2 = 5 hours and 2 days, respectively).
C. Metabolism
Urinary metabolites of labeled BCIE identified in studies with rats
included l-chloro-2-propanol, propylene oxide, 2-(l-methyl-2-chloro-ethoxy)
propionic acid, and carbon dioxide (Smith., et al. 1977).
0. Excretion
Smith, et al. (1977) found that in the rat, 63.36 percent, 5,87
percent, and 15.96 percent of a 30 mg orally-administered dose of BCIE were
recovered after 7 days in the urine, feces, and expired air, respectively.
In the monkey, the corresponding figures were 28.61 percent, 1.19 percent,
and 0 percent, respectively.
-------
IV. EFFECTS
A. Carcinogenicity
Preliminary results of an NCI Carcinogenicity bioassay indicate
that oral administration of BCIE does not produce an increase in tumor inci-
dence (U.S. EPA, 1979a).
B. Mutagenicity
Testing of BCIE in the Ames Salmonella assay and in £_._ coli have
indicated that the compound shows mutagenic activity (U.S. EPA, 1979a).
BCIE did not show mutagenic effects in the murine heritable translocation
test (Jorgenson, et al. 1977).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the -vulable literature.
. x
0. Chronic Toxicity
Chronic oral exposures of mice to BCIE produced centrilobular liver
necrosis' in mice. The major effects in rats were pulmonary congestion and
pneumonia (U.S. EPA, 1979a).
y
E. Other Relevant Information
Several chloroalkyl ethers show initiatin._, ^activity and therefore
may interact with other agents to produce skin papillomas (Van Duuren, et
al. 1969, 1972); however, data specific to BCIE is not available.
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 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 be
changed.
-------
A. Human
BCIE is an isomer of a group of chloroalkyl ethers which have been
shown to have carcinogenic potential. BCIE has been shown to be mutagenic;
however, definitive proof of carcinogenicity has not been demonstrated. The
available data is presently under review and a definitive determination as
to the carcinogenicity of this isomer cannot be made at this time.
B. Aquatic
No draft criteria to protect fish and saltwater aquatic organisms
from bis(2-chloroisopropyl)ether toxicity have been derived (U.S. EPA, 1979).
-------
BIS(2-CHLOROISOPROPYL)ETHER (BCIE)
REFERENCES
Jorgenson, T., et al. 1977. Study of the mutagenic potential of bis(2-
chloroethyl) and bis(2-chloroisopropyl) ethers in mice by the heritable
translocation test. Toxicol. Appl. Pharmacol. 41: 196.
Smith, C., et al. 1977. Comparative metabolism of haloethers. Ann. N.Y.
Acad. Sci. 298: 111.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drink-
ing water: Interim report to Congress, Washington, O.C.
U.S. EPA. 1979a. Chloroalkyl Ethers: Ambient Water Quality Criteria.
(Draft)
U.S. EPA. i979b. Environmental Criteria and Assessment Office. Chloro-
alkyl Ethers: Hazard Profile. (Draft)
Van Duuren, B., et al. 1969. Carcinogenicity of haloethers. Jour. Natl.
Cancer Inst. 43: 481.
Van Duuren, B., et al. 1972. Carcinogenicity of haloethers. II. Struc-
ture-activity relationships of analogs of bis(chloroethyl)ether. Jour.
Natl. Cancer Inst. 48: 1431.
-------
No. 26
Bis(Chlororaethyl)ether
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. EPA's Carcinogen Assessment Group (GAG) has evaluated
bis(chloromethyl)ether .and has found sufficient evidence to
indicate that this compound is carcinogenic.
-290-
-------
315(CHLOROMETHYL)ETHER
Summary
Bis(chloromethyl)ether (8CME) has been shown to produce tumors in ani-
mals following administration by subcutaneous injection, inhalation, or der-
mal application. Epidemiological studies of workers in the United States,
Germany, and Japan who were exposed to 8CME and chloromethyl methyl ether
(CMME) indicate that these compounds are human respiratory carcinogens.
BCME has produced mutagenic effects in the Ames' Salmonella assay and
in §._ cpli. Increased cytogenetic abnormalities have been observed in the
lymphocytes of workers exposed to BGME and CMME; this effect appeared to be
reversible.
There is no available evidence to indicate that the chloroalkyl ethers
produce' adverse reproductive effects or teratogenic effects.
Information has not been found on the toxicity of bis(chloromethyl)
ether to aquatic organisms. The hazard profiles on the haloethers and the
chloroalkyl ethers should be consulted for the toxicity of related compounds.
-------
BIS(CHLOROMETHYL.)ETHER
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
The Chloroalkyl ethers are compounds in which hydrogen atoms in one or
both of the aliphatic ether chains are substituted with chlorine. Bis-
(chloromethyl)ether, (BCME; molecular weight 115.0), is a colorless liquid
at room temperature with a boiling point of 104°C at 760 mm Hg, and a den-
sity of 1.328. The compound immediately hydroly±es in water, but is misci-
ble with ethanol, ether, and many organic solvents (U.S. EPA, 1979a).
The Chloroalkyl ethers have a wide variety of industrial and laboratory
uses in organic synthesis, textile treatment, the manufacture of polymers
and insecticides, the preparation of ion exchange resins, and as degreasing
agents (U.S. EPA, 1979a).
While BCME is very unstable in water, it appears to be relatively sta-
ble in the atmosphere (Tou and Kallos, 1974). Spontaneous formation of BCME
occurs in the presence of both hydrogen chloride and formaldehyde (Frankel,
et al. 1974). For additional information regarding the Chloroalkyl ethers
in general, the reader is referred to the EPA/ECAO Hazard Profile .on Chloro-
alkyl Ethers (U.S. EPA, 1979b).
II. EXPOSURE
As might be expected from the reactivity of BCME in water, .monitoring
studies have not detected its presence in water. Human exposure by inhala-
tion appears to be confined to occupational settings (U.S. EPA, 1979a).
Data for human exposure to Chloroalkyl ethers by ingestion of food is
*
not available, nor is data relevant to human dermal exposure to chloralkyl
ethers (U.S. EPA, 1979a).
-------
The U.S. EPA (1979a) has estimated the- weighted average bioccncentra-
tion factor for BCME to be 31 for the edible portions of fish and shellfish
consumed by Americans. This estimate is based on the octanol/water parti-
tion coefficient.
III. PHARMACOKINETICS
There is no specific information relating to the absorption, distribu-
tion, metabolism, or excretion of BCME (U.S. EPA, 1979a). Because of the
high reactivity and instability of BCME in aqueous systems, it is difficult
to generate pharmacokinetic parameters.
IV. EFFECTS
A., Carcinogenicity
BCME has been shown to produce tumors in several animal systems.
Inhalation exposure of male rats to BCME produced malignant respiratory
tract tumors-(Kuschner, et al. 1975), while dermal application to mouse skin
led to the appearance of skin tumors (Van Duuren, et al. 1968). Administra-
tion of BCME to newborn mice by ingestion has been shown to increase the
incidence of hepatocellular carcinomas in males (Innes, et al. 1969).
Epidemiological studies of workers in the United States, Germany,
and Japan who were occupationally exposed to BCME and CMME have indicated
that these compounds are human respiratory carcinogens (U.S. EPA, 1979a).
BCME has been shown to accelerate the rate of lung tumor formation
in strain A mice following inhalation exposure (Leong, et al. 1971). BCME
has also shown activity as a tumor initiating agent for mouse skin (Slaga,
et al. 1973).
B. Mutagenicity
*
Testing of the chloroalkyl ethers in the Ames Salmonella assay and
in §_._ coli have indicated that BCME produced direct mutagenic effects (U.S.
EPA, 1979a).
t
-293-
-------
The results of a study on the incidence of cytogenetic aberrations
in the lymphocytes of workers exposed to BCME and CCME indicate higher fre-
quencies in this cohort. Follow-up indicates that removal of workers from
exposure led to a decrease in the frequency of aberrations (Zudova and
Landa, 1977).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in • the available literature
regarding teratogenicity and other reproductive effects.
D. Chronic Toxicity
Chronic occupational exposure to CMME contaminated with 8CME has
produced bronchitis in workers (U.S. EPA, 1979a). Cigarette smoking has
been found to act synergistically with this type of exposure to produce
bronchitis (Weiss, 1976, 1977).
E. Other Relevant .Information
The initiating activity of several chloroalkyl ethers indicates
that these compounds will interact with other agents to produce skin papil-
lomas (Van Duuren, et al. 1969, 1972).
V. AQUATIC TOXICITY
Pertinent information could not be found in the. available literature
regarding aquatic toxicity for freshwater or marine, species.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the 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 will be
changed.
. A. Human
Based on animal carcinogenesis data, and .using a linear, non-
threshold model, the U.S. EPA Oi979a) has recommended a maximum permissible
-.294-
-------
concentration of BCME for ingested water at .02 ng/1. Assuming water is the
only source of exposure, compliance to this level should limit the risk car-
cinogenesis to not more than 10" .
Based on animal studies, the 8-hour, time-weighted threshold limit
value (TLV-TWA) has been recommended for BCME as one ppb by the American
Conference of Governmental and Industrial Hygienists (1978).
B. Aquatic
Criterion for the protection of freshwater or marine aquatic organ-
isms were not drafted due to lack of toxicological'-evidence.
/
-------
BIS (CHLOROMETHYL)ETHER
REFERENCES
American Conference of Governmental Industrial Hygienists.
1978i Threshold limit values for chemical substances and
physical agents in the workroom environment with intended
changes for 1978. Cincinnati, Ohio.
Frankel, L.S., et al. 1974. Formation of bis(chloromethyl)
ether from formaldehyde and hydrogen chloride. Environ.
Sci. Technol. 8: 356.
Innes, J.R.M.., et al. 1969. Bioassay of pesticides and
industrial chemicals for tumorigenicity in'-mice: A prelimi-
nary note. Jour. Natl. Cancer Inst. 42: 1101.
Kuschner, M.-, et al. 1975. Inhalation carcinogenicity
of alpha halo ethers. III. Lifetime and limited period
inhalation studies with bis(chloromethyl)ether at 0.1 ppm.
Arch. Environ. Health 30: 73.
Leong, B.K.J., et al. 1971. Induction of lung adenomas
by chronic inhalation of bis(chloromethyl}ether. Arch.
Environ. Health 22: 663.
Slaga, T.J., et al. 1973. Macromolecular synthesis fol-
lowing a single application of alkylating agents used as
initiators of mouse skin tumorigenesis. Cancer Res. 33:
769.
Tou, J.C., and G.J. Kallos. 1974. Kinetic study of the
stabilities of chloromethyl methyl ether and bis(chloromethyl)
ether in humid air. Anal. Chem. 46: 1866.
U.S. EPA. 1979a. Chloroalkyl Ethers: Ambient Water Quality
Criteria (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment
Office. Hazard Profile: Chloroalkyl Ethers (Draft).
Van Duuren, B.L., et al. 1968. Alpha-haloethers: A new
type of alkylating carcinogen. Arch. Environ. Health 16:
472.
Van Duuren, B.L., et al. 1969. Carcinogenicity of halo-
ethers. Jour. Natl. Cancer Inst. 43: 481.
Van Duuren, B.L., et al. 1972. Carcinogenicity of halo-
ethers. II. Structure-activity relationships of analogs
of bis(chloromethvl)ether. Jour. Natl. Cancer Inst. 48:
1431.
-------
Weiss, W. 1976. Chloromethyl ethers, cigarettes, cough
and cancer. Jour. Occup. Med. 18: 194.
Weiss, W. 1977. The forced end-expiratory flow rate in
chloromethyl ether workers. Jour. Occup. Med. 19: 611.
Zudova, Z., and K. Landa. 1977. Genetic risk of occupa-
tional exposures to haloethers. Mutat. Res. 46: 242.
-2e)7-
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No. 27
Bis ( 2-ethylexyl)phthalate
Health a " jnvironmental 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.
-------
BIS-(2-ETHYLHEXYL)PHTHALATE
SUMMARY
Bis-(2-ethylhexyl)phthalate has been shown to produce
mutagenic effects in the Ames Salmonella assay and in the
dominant lethal assay.
Teratogenic effects in rats were reported following
interperitoneal (i.p.) administration and oral administra-
tion of bis-(2-ethylhexyl)phthalate. Additional reproductive
*'
effects produced by bis-(2-ethylhexyl)phthalate include
impaired implantation and parturition, and decreased fertility
in rats. Testicular damage and decreased spermatogenesis
have been reported in rats, following i.p. or oral adminis-"
tration, and in mice, given bis-(2-ethylhexyl)phthalate
by oral intubation.
Evidence has not been found indicating that bis-(2-
ethylhexyl)phthalate has carcinogenic effects. Chronic
animal feeding studies of bis-(2-ethylhexyl)phthalate have
shown effects on the liver and kidneys.
Bis-(2-ethylhexyl)phthalate is acutely toxic to fresh-
water invertebrates at a concentration of 11,000 ug/1.
The same species has been shown to display severe reproduc-
tive impairment when exposed to concentrations.less than
3 ug/1.
-Sao-
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