HEAL'TH AND E N V I R O N 'M- E N T A ,L
E"F PECT PROFILES
APRIL 30, 1980
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF SOLID WASTE
-------
TABLE XII1-2
US METHYL ALCOHOL CONSUMPTION, 1973
Formaldehyde
Dimethyl terephthalate
Solvent usage
Methyl halides
Methylamines
Methyl methacrylate
Inhibitor for formaldehyde
Exports
Glycol methyl ethers
Acetic acid
Miscellaneous
Total
Million Pounds
> .
2,778
435
565
435
232
265
66
824
81
240
1,207
7,128
Million Gallons
420
66
85
66
35
40
10
124
1?
36
181
1,075
From Blackford [5]
-------
TABLE XIII-3
POTENTIAL OCCUPATIONAL EXPOSURES TO METHYL ALCOHOL
Acetic acid makers
Adhesive workers
Alcohol distillery workers
Alcohol lamp users
Aldehyde pumpmen
Antifreeze workers
Art glass workers
Automobile painters
Aviation fuel handlers
Bookbinders
Bronzers
Brushmakers
Denatured alcohol workers
Dimethyl sulfate makers
Drug makers
Drycleaners
Dye makers
Dyers
Ester makers
Explosives workers
Feather workers
Felt-hat makers
Flower makers, artificial
Formaldehyde makers
Foundry workers
Furniture polishers
Gilders
Glassmakers, safety
Hectograph operators
Incandescent lamp makers
Inkmakers .
Japan makers
Japanners
Jet fuel workers
Lacquerers
Lacquer makers
Lasters
Leather workers
Linoleum makers
Lithographers
Metal polishers
Methyl acrylate makers
Methyl alcohol workers
Methyl amine makers
Methylation workers
Methyl bromide makers
Methyl chloride makers
Methyl methacrylate makers
Millinery workers
Motor fuel blenders
Organic chemical synthesizers
Painters
Paintmakers
Paint remover workers
Patent leather makers
Perfume makers
Pho to engravers
Photographic film makers
Polish makers
Printers
Rayon makers
Resin makers
Rocket fuel handlers
Rocket fuel makers
Rubber shoe cementers
Rubber workers
Shellackers
Shellac makers
Shoe factory workers
Shoe finishers
Shoe heel coverers, wood
Shoe stitchers
Soapmakers
Straw-hat makers
Sugar refiners
Textile printers
Type cleaners
Vacuum tube makers
Varnish workers
Vulcanizers
Wood alcohol distillers
Wood stainers
Wood stain makers
From Gafafer [6]
-------
TABLE XIII-4
ANIMAL EXPERIMENTATION RESULTS
OF METHYL ALCOHOL EXPOSURE
Species
Route of
Exposure
Dose
Effect
Ref-
erence
Monkeys
Inhalation
5,000 ppm
duration
unknown
The monkey survived for 47
an unstated period of time.
1,000 ppm
duration
unknown
The monkey died promptly 47
upon exposure at this level.
Dogs
450-500 ppm
8 hr/day
7 days/week
for 379 days
Blood levels of methyl
alcohol were found to range
from 10 to 15 mg/100 ml
of blood and on occassion
went as high as 52 rag/100 ml.
No abnormal eye findings
were reported.
41
Oral
2.5 to 9.0 Of the 9 treated dogs, 2
g/kg died at doses of 4 and
body weight 9 g/kg. C02 combining
capacities dropped below
normal in 2 dogs, and no
ophthalmoscopic changes
were noted.
42
-------
TABLE XIII-4 (CONTINUED)
ANIMAL EXPERIMENTATION RESULTS
OF METHYL ALCOHOL EXPOSURE
Species
Route of
Exposure
Dose
Effect
Ref-
erence
Monkeys
Oral
1.0 to 8.0 Acidosis developed in
g/kg monkeys receiving doses
ranging from 3.0 to 6.0
g/kg. The animal receiving
1.0 g/kg did not develop
acidosis. Definite eye-
ground change occurred to
2 of the acidotic monkeys.
42
Rats
4.75 g/kg 70% mortality 42
4.5 g/kg None of the 9 tested rats 42
developed acidosis.
Rabbits
3.5 g/kg One animal receiving this
dose died in less than 24
hours. No eye fundus
changes were reported.
42
Rabbits
2.1 g/kg Of the 3 animals tested at
this dose, all died between
24 hours and 3 days after
dosing.
42
Intra- 10 mg and At 10 mg, there was no skin 49
cutaneous 35 mg reaction, whereas at 35
mg, a 9-sq" mm skin reaction
occurred.
-------
TABLE XIII-4 (CONTINUED)
ANIMAL EXPERIMENTATION RESULTS
OF METHYL ALCOHOL EXPOSURE
Species
Route of
Exposure
Dose
Effect
Ref-
erence
Monkeys
i.p. inj
0.5 g/kg of
14 C-methyl
alcohol with
an equimolar
amount of
ethyl al-
cohol
The ethyl alcohol reduced
the oxidation of methyl
alcohol 90%.
52
1.0 g/kg The methyl alcohol was
14 C-methyl oxidized at a rate of
alcohol and 37 mg/kg/hour between the
6.0 g/kg first and fourth hour. The
14C-methyl C02 formation was linear at
alcohol the high dose; the oxidation
,. V. rate was 47 mg/kg/hour which
is a significant difference.
52
Rats
1.0/kg 14C- The oxidation rate of the 51
methyl methyl alcohol was 24 mg/kg/hr
alcohol for the first 28 hours. Ac
the end of 36 hours 77% of
the methyl alcohol had been
oxidized to 14C-labled C02
and 24£ was excreted unchanged
in approximately equal amounts
by the pulmonary and combined
urinary and fecal routes.
-------
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-------
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32. Bastrup J: Method for the determination of formic acid in urine.
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33. Von Wartburg JP, Bethune JL, Vallee BL: Human liver alcohol
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38. Greenburg L, Mayers MR, Goldwater LJ, Burke WJ: Health hazards in
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-156
-------
43. Roe 0: The metabolism and coxicity of mechanol. Pharmacol Rev
7:399-412, 1955
i
44. Cooper JA, Kini MM: Editorial—Biochemical aspects of methanol
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36, 1931
48. Cooper JR, Felig P: The biochemistry of methanol poisoning—II.
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49. Renkonen KO, Teir H: Studies on the local reactions of the skin to
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50. Carpenter CP, Smyth HF Jr: Chemical burns of the rabbit cornea. Am
J Ophthalmol 29:1363-72, 1946
51. Tephly TR,. Parks RE Jr, Mannering GJ: Methanol metabolism in the
rat. J Pharmacol Exp Ther 143:292-300, 1964
52. Makar AB, Tephly TR, Mannering GJ: Methanol metabolism in the
monkey. Mol Pharmacol 4:471-83, 1968
53. Clay KL, Murphy RC, Watkins WD: Experimental methanol toxicity in
the primate—Analysis of metabolite acidosis. Toxicol Appl Pharmacol
34:49-61, 1975
54. Saha AK, Khudabaksh AR: Chromosome aberrations induced by methanol
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55. Technology Committee (GA Hedgecock, chtnn), Working Party (SJ Silk,
chmn): Chemical indicator tubes for measurement of the concentration
of toxic substances in air—First report of a working party of the
Technology Committee of the British Occupational Hygiene Society.
Ann Occup Hyg 16:51-62, 1973
»
56. Smith BS, Pierce JO: The use of plastic bags for industrial air
sampling. Am Ind Hyg Assoc J 31:343-48, 1970
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57. Rogers GW: Sampling and determination of methanol in air. J Ind Hyg
Toxicol 27:224-30, 1945
58. Documentation of NIOSH Validation Tests, NIOSH contract No. CDC 99-
74-45. US Dept of Health, Education, and Welfare, Public Health
Service, Center for Disease Control, National Institute for
Occupational Safety and Health, 1975, pp S59-1 to S59-9
59. Feldstein M, Balestrieri S, Levaggi DA: The use of silica gel in
source testing. Am Ind Hyg Assoc J 28:381-85, 1967
60. Methyl alcohol Class B, NIOSH Sampling Data Sheet #36.01. US Dept of
Health, Education, and Welfare, Public Health Service, Center for
Disease Control, National Institute for Occupational Safety and
Health, December 15, 1975, December 16, 1975, January 26, 1976
61. Skoog DA, West DM: Fundamentals of Analytical Chemistry. New York,
Holt, Rinehart and Winston, 1963, pp 667-69
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(Paris) 150:832-34, 1910 (Fr)
63. Ellvove E: A note on the detection and estimation of small amounts
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64. Wright LO: Comparison of sensitivity of various tests for methanol.
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66. Jephcott CM: Determination of methyl alcohol in the air. Analyst
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67. Jansson BO, Larson BT: Analysis of organic compounds in human breath
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1969
68. Matsumura Y: The adsorption properties of active carbon—II.
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71. Occupational Health Hazards in Massachusetts Industries—IV. Wood
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72. Goss AE, Vance GH: Methanol vapors from duplicating machines may be
health hazard. Ind Hyg Newsletter 8:15, 1948
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75. Methyl alcohol (methanol), AIHA Hygienic Guide Series. Southfield,
Michigan, American Industrial Hygiene Association, 1957
76. Methanol, Data Sheet 407, Revision A. Chicago, National Safety
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77. American Conference of Governmental Industrial Hygienists, Committee
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84. Winell MA: An international comparison of hygienic standards for
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-IS!/-
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Massachusetts, National Fire Protection Association, 1975
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Institute Inc, 1968
if/a.-
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No. 127
S,S'-Methylane - 0,0,0',o'-Tetraethyl Phosphorodithioate
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.
-------
PHOSPHORODITHCIC ACID,
S.S'-METHYLENE.O.O.OSO'-TETRAETHYL ESTER (ETHION)
Summary
The S,S'-methylene,0,0,0',0'-tetraethyl ester of phosphorodithoic acid,
ethion, has not shown mutagenic effects in mice or teratogenic effects in
fowl. Subcutaneous injection of the compound into atropinized chickens pro-
duced neurotoxic effects. There is no available information on the possible
carcinogenic effects of ethion.
Ethion has shown acute toxicity in stdnefly naiads at a 96-hour LC5Q
range from 1.8 to 4.2
-------
I. INTRODUCTON
0,0,0',0'-Tetraethyl-S,S'-methylene bisphosphorodithioate (CAS registry
number 563-12-2), also called ethion, is an insecticide and miticide made
from phosphorus pentasulfide (SRI, 1976). Ethion has the following physical
and chemical properties (Windholz, 1976; FAO, 1969):
Formula: C9H22°4P2S4
Molecular Weight: 384.48
Melting Point: -12°C to -13°C
Density: 1.22020
Vapor Pressure: Practically non-volatile at
ordinary temperatures
Solubility: Insoluble in water, soluble in
organic solvents
Consumption: 0.7 million Ibs/year (SRI, 1976)
Ethion is a pre-harvest topical insecticide used primarily on citrus
fruits, deciduous fruits, nuts and cotton (SRI, 1976). It is also used as a
cattle dip for ticks and as a back-line treatment for buffalo flies (FAO,
1969).
II. EXPOSURE
A. Water
Pertinent data could not be located in the available literature.
Water contamination from ethion manufacturing may be minimal due to the com-
mon use of industrial wastewater treatment plants (U.S. EPA, 1977).
B. Food
Residues on a variety of foods have been reported (FAO, 1969). A
sampling shows the residues on fruits and vegetables range from 10.4 ppm for
raisins to less than 0.1 ppm for almonds. The majority are less than 1 ppm.
Treated cotton showed no residue in the seed. Tea at harvest showed "resi-
dues of up to 7 ppm; since tea is blended prior to sale, residues are lower
-------
when consumed. Lactating cows fed up to 20 ppm radioactive ethion showed no
residues in their milk. In meat, the highest radioactivity was in the
liver; however, chemical analysis showed these residues were not ethion but
metabolites. When animals were dipped, residues from skin absorption of
ethion were found in the body fat.
C. Inhalation and Dermal
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
A. Absorption
Results of acute toxicity studies in animals indicate that ethion
is absorbed following oral and dermal exposure (Gaines, 1969).
B. Distribution
Following feeding of dairy cattle with ethion, small amounts of
the unchanged compound were found in milk and fatty tissues (Vettorazzi,
1976).
C. Metabolism
Rao and McKinley (1969) have reported that i.n vitro metabolism of
ethion occurs through oxidative desulfuration of the compound by chicken
liver homogenates.
0. Excretion
Pertinent data could not be located in the available literature.
Based on studies of other organophosphorous insecticides, it may be antici-
pated that ethion metabolites would be eliminated primarily in the urine
(Matsumura, 1975).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature.
-1517-
i
2!
-------
8. Mutagenicity
Vettorazzi (1976) has cited an unpublished study which found no
dominant lethal affects in mice administered ethion.
C. Teratogenicity
Oral administration of ethion (100 ppm) to chickens, chukars, and
quail failed to produce teratogenic or adverse reproductive effects (Abbott
and Walker, 1972).
0. Other Reproductive Effects
Oral feeding of ethion to chickens, chukar, and quail failed to
affect egg hatch (Abbott and Walker, 1972).
E. Chronic Toxicity
Subcutaneous injection of atropinized chickens with 400 mg/kg eth-
ion produced neurotoxic effects (flaccid paralysis) (Gaines, 1969). Ethion
will produce anti-cholinesterase effects in mammals (Vettorazzi, 1976).
V. AQUATIC TOXICITY
A. Acute Toxicity
Sanders and Cope (1968) observed 96-hour LCCO values ranging
from 1.8 to 4.2 ug/1 for stonefly naiads (Pteronarcys californica) exposed
to ethion.
3. Chronic Toxicity, Plant Effects and Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The World Health Organization (FAO, 1969)-has established an ADI
level of.0.005 mg/kg for ethion based on cholinesterase inhibition studies.
*
B. Aquatic
Pertinent data could not be located in'the available literature.
-------
REFERENCES
Abbott, U. and N. Walker. 1972. Effects of pesticides and related com-
pounds on several avian species, chemistry and toxicology of agricultural
chemicals. Summary Report 1971.. Food Protection and Toxicology Center,
University of California at Davis, p. 9.
Food and Agriculture Organization/World Health Organization. 1969. Evalua-
tions of some pesticide residues in food. The monographs FAO/WHO/PL:1968/-
M/9/1.
Gaines, T. 1969. Acute toxicity of pesticides. Toxicol. Appl. Pharmacol.
14: 515.
Matsumura, F. 1975. Toxicology of Insecticides. Plenum Press, New York.
p. 223.
Rao, S. and W. McKinley. 1969. Metabolism of organophosphorus insecticides
by liver homogenates from different species. Can. Jour. Biochem. 47: 1155.
Sanders, H.O. and O.B. Cope. 1968. The relative toxicities of several pes-
ticides to naiads of three species of stoneflies. Limnol. Oceanogr.
13: 112.
Stanford Research Institute. 1976. Chemical Economics Handbook, Insecti-
cides.
U.S. EPA. 1977. Industrial process profile for environmental use: chapter
8, pesticides industry. U.S. Environ. Prot. Agency, U.S. NTIS PB 266 225.
Vettorazzi, G. 1976. State of the art of the toxicological evaluation car-
ried out by the joint FAO/WHO meeting on pesticides residues. II. Carbamate
and organophosphorus pesticides used in agriculture and public health.
Residue Reviews. 63: 1.
Windholz, M. (ed.) 1976. The Merck Index, 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
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No. 128
Methyl Ethyl Ketone
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.
-------
SJ-27-10
Methyl Ethyl Ketone '
I. INTRODUCTION
Methyl ethyl ketone or (MEK) as it is commonly referred
to is a clear, colorless, volatile liquid (VP of 100 mm at 25°C)
with a molecular weight of 72.12. It has a melting point of
-86.35*C.and a boiling point of 76.6°C. It is very soluble
in water (25.5 g/loo at 2 percent) and soluble in all
proportions in alcohol, ether, acetone and benzene.2 it is
also highly fl.ammable (22°F - open cup).3
MEK is produced and used as a solvent in nitrocellulose
coatings and vinyl films; in the synthesis of colorless
resins; in the manufacture of smokeless powder; in paint
removers, cements, adhesives, and cleaning fluids; in printing
industry; as a catalyst carrier; in lube oil dewaxing and in
acrylic coatings.2
II. ROUTES OF EXPOSURE
MEK is rapidly absorbed through the skin by inhalation.
III. PHARMACOKINETICS
MEK occurs in trace amounts in normal human urine and
may have a dietary origin.^- Most probable precursor is
- methylacetoacetic acid.^
Urine of rabbits exposed to MEK reported to contain
glucuronide of 2-butanol.^-
IV. EFFECTS ON MAMMALS
The chief effect of MEK is narcosis.but is also a strong*
irritant of the mucous membranes of the eyes and nose. The
oral LD50 for rats is 3.3 g/kg and the inhalation LC50 is
-------
around 700 ppm.l
Repeated exposure of guinea pigs for 12 weeks to 235 ppm
caused no symptoms.^-
Lethal doses in animals caused marked congestion of
internal organs and slight congestion of brain. Lungs showed
emphysema (see Table 1).
Slight throat irritation in humans occured at 100 ppm
and in eyes at 200 ppm.
Dermatoses among workers having direct contact and
exposed to vapors are not uncommon. Some workers complained
of numbness of fingers and arms-^
-------
Table 1
Effects of Methyl Ethyl Ketone on Animals
Concentration/
Duration
Animal
Methyl
Ethyl
Ke tone
33,000-100,000 ppm/200 min. Guinea Pigs
3,300 ppm/810 min.
1,125 ppm/24 hr/3,55d
1,126 or 2,618 ppm/7 hr/d
on d 6-15 of gestation
Effects
Ga sping , death,
emphysema, slight
congestion of the
brain, marked
congestion of the
sys temic organs
especially the
lungs and corneal
opacities
Guinea Pigs No abnormal signs
Rats No evidence of
peripheral neuro-
pa thy
Pregnant
Rats
Embryo toxici ty,
fetotoxicity and
possible terato-
genici ty
-------
References
1. Toxicity and Metabolism of Industrial Solvents.
2. Ketonic Solvents, Open File Report, Working Draft prepared
by Clement Associates, Inc., September 19, 1978.
3. Sax, N. Irving, Dangerous Properties of Industrial Materials,
Fourth Edition, 1975, Van Nostrand Reinhold, New York,
New York 10001
4. Patty, F. A., Schrenk, H. H. , Yant W. P.: Acute Respone of
guinea Pigs to Vapors of Some New Commercial Organic
Compounds--VIII. Butanone. U.S. Public Health Pep 50:
1217-28, 1935.
5. Spencer, P. S . , Schaumburg, H. H.: Feline Nervous System
Response.to Chronic Intoxication With Commercial Grades
of Methyl n-Butyl Ketone, Methyl Isobutyl Ketone, and
Methyl Ethyl Ketone. Toxicol. Appl. Pharmacol. 37:301-11,
1976.
6. Griggs, J. H., Weller, E. M., Palmisano, P. A., Niedermeier,
W.: The Effect of Noxious Vapors on Embryonic Chick Develop-
ment, Ala. J Mad. Sci. 8:342-45, 1971.
-------
No. 129
Methyl Isobutyl Ketone
Health aiu jvironmental 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.
-------
SJ-27-09
Methyl Isobutyl Ketone
I. INTRODUCTION
Methyl isobutyl ketone (MIK) is a colorless, stable
liquid with a molecular weight of 100.16. It has a melting
point of -84.7°C and a boiling point of 116.85°C. It is
slightly soluble in water, but soluble in chloroform and in
all proportions in alcohol, ether, acetone and benzene.^)
MIK is also flammable (73°F).(2)
MIK is produced and used as a solvent for paints,
varnishes, nitrocellulose and lacquers; in the manufacture of
methyl amyl alcohol and other organic synthesis; in extraction
processes, including extraction of uranium from fission
products; and as a denaturant for alcohol.(^)
II. ROUTES OF EXPOSURE
Exposure occurs through the skin-and by inhalation.^)
III. EFFECTS ON MAMMALS
In a study reported on 19 employees who worked with MID
for 20-30 minutes daily over an 8-hour shift, Linani et. al.
concluded that MIK irritated the conjuctiva and respiratory
tract and produced disturbances of the gastrointstinal tract
and CNS.(^) Other reported effects due to exposure include
weakness, los.' of appetite, headache, eye irritation, stomach
ache, nausea, vomitting and sore throat.(3)
In addition, in various studies conducted on animals an
#
increase in kidney and liver weights were reported after
-------
repeated vapor inhalation (see Table 1).(*»5)
No information was found on the carcinogenicity,
mutagenicity and ter a togenici ty of this compound.
-------
Table 1
Effects of Methyl Isobutyl Ketone on Animals
Concentration Animal Effects
Duration
Methyl 200 ppm/24 hr/d Mice, rats, Heavier liver and
Isobutyl for 2 weeks dogs, and kidneys in rats
Ketone monkeys
100 ppm/24 hr/d Mice, rats, Heavier kidneys
for 2 weeks dogs, and in rats
monkeys
100 ppm at 258 mm Monkeys, Inflammation of
Hg/ 24 hr/d 90d dogs, rats kidneys in 1 mon-
key, hyaline drop-
let degeneration
of proximal tubules
in all rats, normal
clinical and hema-
. tologic measurements
150 mg/kg/twice/ Cats No evidence of peri-
d,5d/week 8.5 mo. pheral neuropathy
-------
References
Keconic Solvents, Open File Report, Working Draft
prepared by Clement Associates, Inc., September 19,
1978.
Sax, N. Irving, Dangerous Properties of Industrial
Materials, Fourth Edition, 1975, Van Nostrand Reinhold,
New York, New York 10001.
Linari, F. Perrelli, G., Varese, D: [Clinical Observations
and Blood Chemistry Tests Among Workers Exposed to the
Effects of a Complex Ketone--Methyl Isobutyl Ketone.]
Arch. Sci. Med. , 1964, pp. 226-237. (Ita).
MacEwen, J. D, Vernot, E. H., Haun C.C: Effect of 90-
Day Continuous Exposure to Methylisobutylketone on Dogs,
Monkeys and Rats, Springfield, Virginia, U.S. Department
of Commerce, National Technical Information Service, 1971,
23 pp. (NTIS AD-730-291).
Spencer, P.S., Schaumburg, H. H.: Feline Nervous System
Response to Chronic Intoxication with Commercial Grades
of Methyl n-3utyl Ketone, Methyl Isobutyl Ketone, and
Methyl Ethyl Ketone. Toxicol. Appl. Pharmacol. 37:301-11,
1976.
-------
No. 130
Methyl Methacrylate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
METHYL METHACRYLATE
Summary •
Oral or skin painting studies in rats have failed to show carcinogenic
effects of administration of methyl metnacrylate. Implantation of the com-
pound in mice also failed to produce tumors.
Exposure of rats to a mixture of chloroprene and methyl methacrylate
produced an increase in lymphocyte chromosome aberrations. Increased chrom-
atid breaks and chromosome breaks have been reported in workers exposed to
this same chemical mixture.
Teratogenic effects (hemangiomas) have been reported following intra-
peritoneal administration of methyl methacrylate to pregnant rats. Inhala-
tion exposure of pregnant rats to an acrylic cement containing methyl metha-
crylate failed to produce significant teratogenic effects.
Ninety-six hour LC5Q values for four species of fish range from 159
to 368 ppm. Inhibition of cell multiplication of an alga begins at 120 ppm.
-------
I. INTRODUCTION
Methyl methacrylate, CAS registry number 80-62-6, is a colorless,
clear, volatile liquid. It is made from acetone cyanohydrin which is hydro-
lyzed in sulfuric acid to yield methacrylamide sulfate, which is then treat-
ed with methanol to yield methyl methacrylate. It has the following physi-
cal and chemical properties (Windholz, 1976; Hawley, 1971; weast, 1972;
Verschueren, 1977):
Formula: C5H802
Molecular Weight: 100.12
Melting Point: -48.2°C
Boiling Point: 101°c
Density: 0.944020
Vapor Pressure: 28 torr d 20°C
Solubilityi Sparingly soluble in water, miscible
in alcohol, benzene, ether, etc.
Production: 706 million Ibs (1973) (Gruber, 1975)
Virtually all the methyl methacrylate produced in this country is used
for polymers, e.g., surface coating resins and plastics (plexiglass, lu-
cite), ion exchange resins, dentures, etc.
II. EXPOSURE
A. Water
According to Gruber (1975), about 1.8 g of methyl methacrylate per
kilogram final product (methyl methacrylate) is present in wastewater. The
amount of methyl methacrylate entering domestic water supplies is probably
small.
3. Food
Polymethyl methacrylate is used for food storage. A very jsmall
amount of residual monomer may migrate into food from the polymer.
-------
C. Inhalation
Fugitive emissions from production, storage, and transportation
probably constitute the only major sources of methyl methacrylate in the
air. The concentration would most likely be highest in production facili-
ties. Production was estimated to be 7.9 million pounds in 1974 (U.S. EPA,
1976). A 550-million pound-per-year production facility with 0.5 percent
loss .emits 39.6 grams of methyl methacrylate per second. If this is consi-
dered to be a virtual point source, the downwind concentration 500 meters
away would be 1.5 ppm one-hour average (U.S. EPA, 1976).
0. Dermal
Pertinent data could not be located in the available literature.
III. PHARMACQKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available literature.
8. Metabolism
Bratt and Hathway (1977) found that up to 88 percent of a single
methyK^Omethacrylate dose of 5.7 mg/kg body weight was expired as C02
within 10 days. Neither the route of- administration nor the specific label-
ling of the propylene residue changed this value. Small amounts of several
metabolites were excreted in the urine, including ^4C-methylmalonate,
l*C-succinate, 2-formylpropionate, and possibly 14C-X-hydroxybutyrate.
Corkill, et al. (1976) found that the disappearance of methyl
methacrylate in human blood _in vitro showed a first order dependence on
methyl methacrylate concentration. The calculated half-life was 20 to 40
minutes, irrespective of the sex or age of the blood donor. More than 40
percent of the initial dose of methyl methacrylate was converted to irfetha-
crylic acid within 90 minutes.
-------
C. Excretion
Pertinent data could not be located in the available literature.
IV. EFFECTS
A. Carcinogenic!ty
The International Agency for Research on Cancer (IARC, 1979) has
evaluated the available data and concluded that there is not enough informa-
tion to determine the potential carcinogenicity of methyl methacrylate to
humans. Borzelleca, et al. (1964) observed no treatment-related tumors in
male and female Wistar rats administered 6, 60, or 2,000 mg/1 methyl metha-
crylate in their drinking water for two years. Oppenheimer, et al. (1955)
found no local tumors in ten Wistar rats painted with methyl methacrylate
three times per week for four months and'observed for their entire life span.
Another study, by Spealman, et al. (1945), in which male and
female mice received implants consisting of 0.075 gm of methyl methacrylate
in a gelatin capsule also yielded negative results.
B. Mutagenicity
The only data available on the mutagenic effects of methyl metha-
crylate are two studies involving exposure to a mixture of chloroprene and
methyl methacrylate (Bagramjan, et al. 1976; Bagramjan and Babajan, 1974).
In both studies, an increased frequency of chromosomal aberrations were
found in rats exposed to the mixture. Bagramjan, et al. (1976) also mea-
sured a significant increase in chromatid breaks and chromosome breaks in
the lymphocytes of workers exposed to a mixture of chloroprene and methyl
methacrylate.
C. Teratogenicity
»
Singh, et al. (1972a,b) and Autian (1975) injected intraperito-
neally three groups of pregnant Sprague-Oawley rats with methyl methacrylate
at doses of 0.1, 0.2, or 0.4 g/kg body weight on days 5, 10, and 15 of ges-
-------
tation. In animals administered the two higher doses, a significantly
greater number of hemangiomas were seen at various sites. All three groups
exhibited reduced fetal weights, but no significant increase in skeletal
defects was observed in any group.
McLaughlin, et al. (1978) exposed pregnant mice to a vapor concen-
tration of 1,330 ppm methyl methacrylate (as acrylic cement, Simplex p) for
two hours two times per day for days 6 through 15 of gestation. No feto-
toxic or teratogenic effects were noted other than a slight decrease in the
average fetal weight.
D. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
Spealman, et al. (1945) conducted a series of subchronic
inhalation ex- periments involving guinea pigs and dogs. Guinea pigs
exposed to 39.0 mg/1 methyl methacrylate for two hours per day for three
days exhibited significant liver' degeneration, while dogs exposed to 46.8
mg/1 methyl methacrylate f.or two hours per day for 8 to 15 days exhibited
liver degeneration and tubular degeneration of the kidneys.
Borzelleca, et al. (1964) administered 6, 60, and 2,000 ppm of
methyl methacrylate in drinking water to male and female rats for a period
of two years. Weight gain was decreased for the first few weeks in animals
given the highest dose.. No changes in hematological values or urine concen-
trations of protein and reducing agents were noted. Females receiving the
highest dose level exhibited an increase in kidney to .body weight ratios.
Blagodatin, et al. (1970) reported symptoms of headache, pain in
the extremities, fatigue, sleep disturbance, loss of memory;, and irritabi-
lity in 152 workers exposed to concentrations of 0.5 to 50 ppm methyl metha-
crylate. Most of the workers had been employed for longer than 10 years.
-------
F. Acute Toxicity
No detectable acute effects were noted in workers employed in
manufacturing polymethyl methacrylate sheets (Cromer and Kronoveter, 1976).
The airborne concentrations of methyl methacrylate varied from 4 to 49 ppm.
V. AQUATIC TOXICITY
A. Acute Toxicity
Pickering and Henderson (1966) observed the following 96-hour
LCjg values for fish exposed to methyl methacrylate: fathead minnow
(Pimephales promelas) - 159 ppm in soft water (20 mg/1); fathead minnow -
311 ppm in hard water (360 mg/1); bluegill (Lepomis macrochirus) - 357 ppm
in soft water (20 mg/1); goldfish (Carassius auratus) - 277 ppm in soft
water (20 mg/1); guppies (Lebistes retieulatus) - 368 ppm in soft water (20
mg/1).
8. Chronic Toxicity
Pertinent data could not be located in the available literature.
C. Plant Effects
Inhibition of cell multiplication of the alga, Microcystis aerugi-
nosa, by methyl methacrylate begins at 120 ppm (Bringmann and Kuhn 1976).
D. Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
Guidelines have been established for exposure to methyl methacry-
late by the American Conference of Governmental Industrial Hygienists and
OSrIA. Both the TLV and the federal standard have been set at 100 ppm (or
410 mg/m3) (ACGIH, 1977; 29 CFR 1910).
-------
8. Aquatic
No guidelines have been established for the protection of aquatic
organisms from acute or chronic methyl methacrylate toxicity because of the
lack of pertinent data.
-------
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Threshold
limit values for chemical substances and physical agents in the workroom
environment. Cincinnati, Ohio.
Autian, J. 1975. Structure-toxicity relationships of acrylic monomers.
Environ. Health Perspect. 11: 141.
3agramjan, S.B. and E.A. Babajan. 1974.. Cytogenetic study of the mutagenic
activity of chemical substances isolated from Nairit latexes MKH and LNT-1.
(Russ.) Biol. Zh. Arm. 17: 102.
Bagramjan, S.B., et'al. 1976. Mutagenic effect of small concentrations of
volatile substances emitted from polychloroprene latexes LNT-1 and MKH, dur-
ing their combined uptake by the animal. (Russ.) Biol. Zh. Arm. 19: 98.
Blagodatin, V.M., et al. 1970. Issues of industrial hygiene and occupa-
tional pathology in the manufacture of organic glass. (Russ.) Gig. Tr.
Prof. Zabol. 14: 11.
Borzelleca, J.F., et al. 1964. Studies on the chronic oral toxicity of
monomeric ethyl acrylate and fr^s/l methacrylate. Toxicol. Appl. Pharmacol.
6: 29. ,}
Bratt, H. and D.E. Hathway. 1977. Fate of methyl methacrylate in rats.
8r. Jour. Cancer. 36: 114.
Bringmann, G. and R. Kuhn. 1976. Vergleichende Befunde der Schadwirkung
wassergefahrdender Stoffe genen Bakterien (Speudomonas putida) und Blaualgen
(Microcystis aeruginosa). Nwf-'^asser/Abwasser, (117) H.9.
j
Corkill, J.A., et al. 1976. Toxicology of methyl methacrylate: The rate of
disappearance of methyl methacrvlate in human blood in vitro. Clinica Chim-
ica Acta. 68: 141. J
Cromer, J. and K. Kronoveter. 1976, A study of methyl methacrylate expo-
sures and employee health. National Institute for Occupational Safety and
Health, Cincinnati, Ohio. DHEW 77-119.
Gruber, G.I. 1975. Assessment of industrial hazardous waste practices,
organic chemicals, pesticides, and explosive industries. TRW Systems Group,
NTIS PB-251 307.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary. 8th ed., Van
Nostrand Reinhold Co., New York.
International Agency for Research on Cancer. 1979. IARC monographs on the
evaluation of the carcinogenic risk of chemicals to humans. Vol. 19, Methyl
methacrylate: 187.
McLaughlin, R.E., et al. 1978. Methyl methacrylate: a study of teratogeni-
city and fetal toxicity of the vapor in the mouse. Jour. Bone Jt. Surgery
Am. Vol. 60A: 355.
-------
Oppenheimer, 3.S., at al. 1955. Further studies of polymers as carcino-
genic agents in animals. Cancer Res. 15: 333.
Pickering, Q.H. and C. Henderson. 1966. Acute toxicity of some important
petrochemicals to fish. Jour. Water Poll. Con. Fed. 38: 1419.
Singh, A.R., et al. 1972a. Embryonic-fetal toxicity and teratogenic ef-
fects of a group of methacrylate esters in rats. Jour. Dent. Res. 51: 1532.
Singh, A.R., et al. 1972b. Embryo-fetal toxicity and teratogenic effects
of a group of methacrylate esters in rats (Abstract NO. 106). Toxicol.
Appl. Pharmacol. 22: 314.
Spealman, C.R., et al. 1945. Monomeric methyl methacrylate: Studies • on
toxicity. Ind. Med. 14: 292.
U.S. EPA. 1976. Assessment of methyl methacrylate as a potential air pol-
lution problem. U.S. Environ. Prot. Agency, NTIS PB-258 361.
Verschueren, K. 1977. Handbook of Environmenal Data on Organic Chemicals.
Van Nostrand Reinhold Co., New York.
Weast, R.C, 1972. Handbook of Chemistry and Physics. 53rd ed., Chemical
Rubber Company, Cleveland, Ohio.
Windholz, M. (ed.) 1976. Merck Index. 9th ed., Merck and Co., Inc., Rah-
way, New Jersey.
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No. 131
Naphthalene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-If 13-
-------
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.
-------
• NAPHTHALENE
Summary
Naphthalene is present in ambient water as well as drinking water.
Naphthalene can be absorbed by any route, although the efficiency of
absorption has not been determined. The toxicological properties are due
to the formation of highly reactive metabolites. Chronic exposure produces
cataracts, hemolytic anemia, and kidney disease. Naphthalene can cross
the placenta and produce these effects on newborns. Naphthalene has been
found to be nonmutagenic in several microsomal/bacterial assay systems.
Chronic toxicity studies of naphthalene have shown it to be noncarcinogenic.
Naphthalene has been shown to be acutely toxic in freshwater fish
with LC5Q values of 150,000 ug/1 being reported in one static bioassay.
Freshwater invertebrates were more sensitive with LC5Q values of 8,570
as were marine fish with LC5Q values ranging from 2,350 to 2,500
-------
INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Naphthalene (U.S. EPA, 1979).
Naphthalene (CiQH3; molecular weight 128.16) is a bicyclic, aromatic
hydrocarbon which in a pure grade, forms a white crystalline solid at
room temperature (Windholz, 1976). Pure naphthalene has a melting point
of 80.2°C, a boiling point of 217.96°C (Manufacturing Chemists Assoc. ,
1956) and a vapor pressure of 0.0492 mm Hg at 19.8°C (Gil'denblat, et
al. 1960). Naphthalene is water soluble, with solubility ranging from
30,000 ug/1 (Mitchell, 1926) to UO.OOO ug/1 (Josephy and Radt, 1948).
Naphthalene vapor and dust can form explosive mixtures with air (Windholz,
1976). Naphthalene is used as an intermediary in the production of dye
compounds, in the formulation of solvents, lubricants and motor fuels,
and as a feedstock in the synthesis of phthalic anhydride. Naphthalene
is also used directly as a moth repellant, insecticide, antihelminthic ,
vermicide, and an intestinal antiseptic (U.S. EPA, 1979). In 197U,
production of naphthalene was approximately 2.9 x 10^ metric tons (U.S.
EPA, 1976).
II. EXPOSURE
A. Water
The two major sources of naphthalene in the aquatic environment
are from .industrial effluents and from oil spills. The final effluents
of sewage treatment plants receiving discharges from these industrial
facilities have been noted to have up to 22 ug/1 naphthalene, while natural
•
waters have up to 2.0 ug/1, and drinking water supplies have up to 1.4
naphthalene (U.S. EPA, Region IV, unpublished data).
y
-------
3. Food
The U.S. ZPH (1979) has estimated the weighted average bio-
concentration factor for naphthalene .to be 60 for the edible portions of
fish and shellfish consumed by Americans. This estimate was based on
octanol/water partition coefficients.
C. Inhalation
In the ambient air, inhalation of naphthalene is negligible
with vapor concentrations ranging from 0.00005 to 0.0001 ug/m^ and
particulate concentrations ranging from 0.000003 to 0.00025 ug/m3
(Krstulovic, at al. 1977). Industrial exposure can range from 0.72 ug/m3
to 1.1 x 10^ ug/m3 in the vapor phase (Bjrseth, et al., 1978b; Robbins,
195D and from 0.09 ug/m3 to 4.40 ug/m3 in particulates (Bjrseth, 1978a,
1978b). Naphthalene has also been found in cigarette smoke condensate
(Akin, et al. 1976).
III. PHARMACOKINETICS
A. Absorption
Little detailed information is available on the absorption of
naphthalene in man or animals. Adequate amounts of naphthalene can be
absorbed when ingested as a solid, or by inhalation, to cause significant
toxicity (U.S. EPA, 1979). Absorption seems to be facilitated if naphthalene
is dissolved in oil (Solomon, 1957), and hindered if naphthalene is bound
to protein (Sanborn and Malins, 1977).
B. Distribution
Naphthalene distributes widely after absorption. In mallards,
the relative distribution of naphthalene was as follows: greatest? in
skin, followed by liver, brain, blood, muscle, and heart (Lawler, et al.
1978).
"Iff?'
-------
C. Metabolism
Naphthalene is first metabolized by hepatic mixed-function
oxidases to an epoxide, which is an obligatory step in the metabolism of
naphthalene. Further metabolism can occur leading to the formation of a
variety of compounds. Most of these compounds are enzymatically conjugated
with glucuronic acid or sulfate. During metabolism a number of highly
reactive compounds are formed such as 1,2-dihydroxynaphthalene and 1,2-
naphthoquinone (U.S. EPA, 1979).
Naphthalene metabolites undergo further conversions in the eye.
This multi-step pathway can lead to the formation of 1,2-naphthaquinone
which can irreversibly bind to lens protein and amino acids (Van Heyningen
and Pirie, 1966).
D. Excretion
Naphthalene has not been-identified in urine after absorption.
With sufficient absorption of naphthalene to result in toxicity to an 18
month old infant, Mackell, et al. (195D noted metabolites of naphthalene
in the urine that were still identifiable two weeks after exposure but
which had disappeared 18 days after exposure.
1-Napthol is the predominant spontaneous decomposition product of
the epoxide of napbhthalene. 1-Napthol is excreted unchanged as well as
congugated with glucuronic acid or sulfate prior to excretion. The finding
of 1,U-nathoquinone in the urine of a child poisoned with naphthalene
(Mackell, et al. 1951) suggests that 1-napthol can also be further oxidized
in mammals (Cerniglia'and Gibson, 1977).
IV. EFFECTS
A. Carcinogenicity
In attempts to demonstrate its carcinogenicity, naphthalene has
been given orally, subcutaneously, implanted in the bladder, and painted
-------
on the backs of a number of animal species (U.S. EPA, 1979). In these
experiments naphthalene caused no increase in tumor formation. Two
experiments have produced increases in lymphosarcoma and lymphatic
leukemia after treatment with coal tar derived naphthalene. The first of
these studies (Knake, 1956) was complicated by the presence of 10 percent
impurities in the naphthalene and the painting of the injection site with
carbolfuchsin, a known experimental carcinogen, prior to injection. In
the second study (Knake, 1956) where excess leukemia was noted, naphthalene
was dissolved in benzene, a known human leukemogenic agent, and painted on
the backs of mice. Benzene treatment resulted in no leukemia. Skin
papillomas have been produced on mice following painting with 1,U-nathfcha-
quinone, a metabolite of naphthalene (Takizawa, 1940). Also, Pirie (1968)
noted abnormal mitotic figures in tnetaphase and cell overgrowth in the
*
epithelial cells of the lens of. rabbits given-1 g/kg/day of naphthalene
by gavage.
B. Mutagenicity
Naphthalene has been found to be nonmutagenic in several microsomal/
bacterial assay systems (McCann, et al. 1975; Kraemer, et al. 197"O.
C. Teratogenicity
Pertinent data could not be located in the available literature.
D. Other Reproductive Effects
Naphthalene or its metabolites can cross the placenta in sufficient
amounts to cause fetal toxicity (Zinkham and Childs, 1958; Anziulewicz,
et al. 1959)- When a metabolite of naphthalene, 2-naphthol, was admin-
istered to pregnant rabbits, their offspring were born with cataracts and
evidence of retinal damage (Van der Hoeve, 1913)-
-------
E. Toxicity
Oral administration of two percent naphthalene or 2-napthol to
rats for at least 60 days resulted in the development of cataracts
(Fitzhugh adn Busckke, 19^9). Van Heyningen and Pirie (1976) dosed rabbits
daily by gavage with 1000 mg/kg of naphthalene' for a maximum of 28 days.
Lens changes developed after the first dose, and retinal changes developed
after the second dose. Rabbits fed 1000 mg/kg/day developed cataracts
between day 3 and 46. Topical application of a 10 percent solution in oil
to the eyes of rabbits did not produce cataracts after a period of 50 days.
Intraperitoneal injection of 500 mg/kg of naphthalene in an oily solution
produced weight loss over a period of 50 days (Ghetti and Mariani, 1956).
Hernolytic anemia with associated jaundice and occasionally renal disease
from precipitated hemoglobin has been described in newborn infants, ;
children and adults after exposure to naphthalene by ingestion, inhalation,
or possibly by skin contact (U.S. EPA, 1979). The extent or duration of
exposure was not given. Mahvi, et al. (1977) noted a dose related damage
. to bronchiolar epithelial cells in mice given intraperintoneal injections
of naphthalene in corn oil. Bronchiolar epithelial changes were not
noted in two control groups. The authors noted minor bronchiolar epithelial
changes in the treated group receiving 67-4 mg/kg of naphthalene.
Those mice receiving higher doses (128 and 256 mg/kg of naphthalene)
developed reversible necrosis of bronchiolar cells.
F. Other Relevent Information
Alexandrov and Frayssinet (1973) demonstrated that naphthalene
administered intraperitoneally to rats could inhibit the mixed-function
microsomal oxidase enzyme system, and could also inhibit the induction of
these enzymes by 3-methylcholanthrene.
-------
V. AQUATIC TOXICITY
A. Acute
For the freshwater mosquitofish (Gambusia af finis) a 96-hour
static bioassay provided an LC^Q value of 150,000 ug/1 (Wallen, et al.
1957), while the freshwater cladoceran (Daphnia magna) was shown to have
an US-hour LCjo value of 8,570 ug/1 (U.S. EPA, 1978). Marine organisms
tended to be somewhat more sensitive to naphthalene with an 24-hour static
LCqg value of 2,400 ug/1 for the sheepshead minnow (Cyprinodon variegatus ) .
Two 24-hour static LC^g values of 2,500, 2,600 were obtained for two
species of marine shrimp, ( Penaeus aztecus) and (Palaemonetes pugio ) ,
respectively (Anderson, et al. 1974). A 96-hour LC5Q value of 2,350 ug/1
was obtained for grass shrimp (Palaemonetes pugio ) (Tatem, 1976).
3. Chronic Toxicity
A single embryo-larval test on the fathead minnow (Pimephales
promelas.) stated that no effects were observed at concentrations as high
as 440 ug/1 (U.S. EPA, 1978).
Data pertaining to the chronic toxicity of naphthalene for any
marine species could not be located in the available literature.
C. Plant Effects
A 48-hour EC5Q value of 33,000 ug/1 for reduced cell numbers
h»s been reported for the freshwater algae (Chlorella vulgaris) exposed
to naphthalene. Data pertaining to the effects of naphthalene to marine
plants could not be located in the available literature.
D. Residues
Using the octanol/water partition coefficient of 2,300 for
naphthalene, a bioconcentration factor for aquatic organisms with an 3
percent iipid content has been estimated as 210. Bioconcentration
J/
-------
factors determined for marine invertebrates ranged from 50 to 60 in the
marine copepod Calanus helgolandicus after one day (Harris, et al. 1977a,
1977b) to 5,000 in the copepod Surytemcra affinis, after nine days,
(Harris, et al. 1977b) indicating that equilibrium may not occur rapidly.
Bioconcentration factors of 32 to 77 after 1 to 24 hours were reported
for these 3 species of marine fish and one species of mussel (Lee, et al.
1972a; 1972b).
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 possibiliity that these criteria
will be changed.
A. Human
The Occupational Safety and Health Administration standard for
exposure to vapor for a time-weighted industrial exposure is 50 mg/m3.
The American Conference of Governmental Industrial Hygienists (ACGIH,
1971) threshold limit value is 75 mg/m3, while at present the ACGIH also
suggests a maximum 15 minute exposure value of 75 mg/m3 (ACGIH, 1978).
The acceptable daily intake for naphthalene is 448 ^ug/day for a 70 kg
person. -The U.S. EPA (1979) draft ambient water criterion for
naphthalene is 143 ug/1.
B. Aquatic
Criterion can not be derived for naphthalene for either fresh-
water or marine organisms, because of the lack of sufficient toxicological
data. .
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NAPHTHALENE
REFERENCES
Akin, F.J., at ai. 1975. Identification of polynuclear aromatic hydro-
carbons in cigarrette smoke and their importance as tumorigens. Jour. Natl.
Cancer Inst. 57: 191.
Alexandrov, K. and C. Frayssinet. 1973. In vitro effect of some
naphthalene-related compounds on aryl hyrocarbon (benzo(a)pyrene) nydroxy-
lase. Jour. Natl. Cancer Inst. 51: 1067.
American Conference of Governmental Industrial Hygienists. 1971. Docu-
mentation of the threshold limit values for substances in workroom air. 3rd
ad. Cincinnati, Ohio.
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.
Anderson, J.W. at al. 1974. The effects of oil on estuarine animals:
Toxicity uptake and depuration, respiration. In; pollution and physiology
of marine orgasnisms. Academic Press.' New York
Anziulewicz, J.A., et al. 1959. Transplacental naphthalene poisoning. Am.
Jour. Obstet. Gynecol. 78: 519.
Sjorseth, A. et al. 1978a. Polycyclic aromatic hydrocarbons in the work
atmosphere. II. Determination in a coke plant. Scand. Jour. Work. Environ.
Health. 4: 212.
Bjorseth, A. et al. 1978b. Polycyclic aromatic hydrocarbons in the work
atmosphere. I. Determination in an aluminum reduction plant. Scand. Jour.
Work Environ. Health. 4: 212.
Cerniglia, C.E. and D.T. Gibson. 1977. Metabolism of napthalene by
Cunninghamella eleqans. Appl. Environ. Microbiol. 34: 363.
Fitzhugh, O.G. and W.H, Buschke. 1949. Production of cataract in rats by
beta-tetralol and other derivatives of naphthalene. Arch. Ophthal. 41: 572.
Ghetti, G. and L. Mariani. . 1956. Eye changes due to naphthalene. Mad.
Lavoro. 47: 524.
Gil'denblat, I.A., at al. 1960. Vapor pressure over crystalline naphtha-
lene. Jour. Appl. Chem. USSR. 33: 245.
Harris, R.P. at al. 1977a. Factors affecting the retention of a petroleum
hydrocarbon by marine planktonic copepods. In: Fate and Effects of
petroleum hydrocarbons in marine ecosystems and organisms. Proc. Symp. 286.
Harris, R.P. et al. 1977b. Accumulation of carbon-14-l-napthaiene by an
oceanic and an estuarine copepod during long-term exposure to low-level con-
centrations. Mar. 3iol. 42: 137.
•/SSI
-------
Josephy, E. and F. Radt, (eds.) 1948. encyclopedia of organic chemistry:
Series III. .Elsevier Publishing Co., Inc., New York.
Xnake, E. 1956. Uber schwache geschwulsterzengende Wirkung von Naphthalin
und Benzol. Virchows Archiv. Pathol. Anat. Physiol. 329: 141.
Kraemer, M., at al. 1974. S_._ typhimurium and £_.. coli to detect chemical
mutagens. Arch. Pharmacol. 284: 846.
Krstulovic, A.M., et al. 1977. Distribution of some atmospheric poly-
nuclear aromatic hydrocarbons. Am. Lab. 9(7): 11.
Lawier, G.C., et al. 1978. Accumulation of aromatic hydrocarbons in
tissues of petroleum-exposed mallard ducks (Anas platyrhynchos). Environ.
Sci. Technol. 12: 51.
Lee, R.F. et al. 1972a. Uptake, metabolism and discharge of polycyclic aro-
matic hydrocarbons by marine fish. Mar. Biol. 17: 201.
Lee, R.F. et al. 1972b. Petroleum hydrocarbons: uptake and discharge by
the marine mussel Mytilus edulis. Science. 177: 344.
Mackell, J.V., et al. 1951. Acute hemolytic anemia due to ingestion of
napthalene moth balls. Pediatrics. 7: 722.
•^
Mahvi, 0., et al. 1977. Morphology of a naphthalene-induced bronchiolar
lesion. Am. Jour. Pathol. 86: 559.
Manufacturing Chemists Assoc. 1956. Chemical safety data sheets SD-58:
Napthalene. Washington, D.C.
McCann, J., et al. 1975. Detection of carcinogens as mutagen in the
Salmonedla/microsome test. Assay of 300 chemicals. Proc. Natl. Acad. Sci.
72: 5135.
Mitchell, S. 1926. A method for determining the solubility of sparingly
soluble substances. Jour. Chem. Soc. 129: 1333.
Pirie, A. 1968. Pathology in the eye of the naphthalene-fed rabbit. Exp.
Eye Tes. 7: 354.
Robbins, M.C. 1951. Determination of Napthalene in air. Arch. Ind. Hyg.
Occup.Med. 4: 85.
Sanborn, H.R. and D.C. Malins. 1977. .Toxicity and metabolism of naphtha-
lene: a study with marine larval invertebrates. 'Proc. Soc. Exp. Biol. Med.
154: 151.
Solomon, T. 1957. A manual of pharmacology and its applications to thera-
peutics and toxicology. 8th ed. W.3. Saunders Co., Philadelphia.
Takizawa, N. 1940. Carcinogenic action of certain quinones. Proc. Imp.
Acad. (Tokyo) 16: 309.
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Tatem, H.E. 1976. Toxicity and physiological affects of oil and petroleum
hydrocarbons on estuarine grass shrimp, Palaeminetes ougio. Holthuis Ph.D.
dissertation. Texas A and M University. 133 pp.
U.S. EPA. 1971-1977. Unpublished data from Region IV, Atlanta, Ga.
U.S. EPA. 1976. Organic chemical producer's data base program. Chemical
NO. 2701. Radian Corporation.
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.
U.S. EPA. 1979. Naphthalene: Ambient Water Quality Criteria. (Draft)
Van Heyningen, R. and A. Pirie. 1966. Naphthalene cataract. In: M.U.S.
Oardenne, ed. Symposium on the biochemistry of the eye. Karger, Asel,
Switzerland.
Van Heyningen, R. and A. Pirie.. 1976. Naphthalene cataract in pigmented
and albino rabbits. Exp. Eye Res. 22: 393.
Van der Hoeve, J. 1913. wirkung von napbthol auf die augen von menschen,
tieren, und auf fatale augen. Graele Arch. Ophthal. 35: 305.
Wallen, I.E., et al. 1957. Toxicity of Gambusia affinis of certain pure
chemicals in turbid waters. Sewage Ind. Wastes. 29: 695.
Windholz, M., ed. 1976. The Muck Index, 9th ed. Muck and Co. Rahway, N.J.
Zinkham, W.J. and 3. Childs. 1958. A defect of glutathione metabolism in
erythrocytes from patients with a naphthalene-induced hemolytic anemia.
Pediatrics 22: 461.
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No. 132
1,4-Naphthoquinone
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
r '•• )not reflect all available information including all the
aa/erse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-J5T7-
-------
1,4-NAPHTHOQUINONE
SUMMARY
1,4-Naphthoquinone is used as a polymerization regulator and an
intermediate. Some data are available which indicate that 1,4-naphtho-
quinone is biodegradable.
The most consistent findings reported in the literature for health
effects of 1,4-naphthoquinone involve hematological changes, irritant and
allergenic activity, and inhibition of biochemical oxidation processes.
One study found 1,4-naphthoquinone to be oncogenic. Some evidence of
inhibition of in vitro endocrine function and of nerve activity was re-
ported.
I. INTRODUCTION
1,4-Naphthoquinone (1,4-naphthalenedione; C1QH,0 • molecular weight 158.15)
is a solid at room temperature. It occurs as a greenish yellow powder or
as yellow triclinic needles. It has a melting point of 123-126 C and begins
to sublime at 100 C; its density is 1.422. 1,4-Naphthoquinone is only
slightly soluble in water; it is soluble in a variety of organic solvents
(Windholz 1976; Hawley 1971).
Current production (including importation) statistics for 1,4-naphtho-
quinone (CAS No. 130-15-4) listed in the initial TSCA Inventory (U.S. EPA 1979)
show that between 1,000,000 and 9,000,000 pounds of this chemical were
produced/imported in 1977.
1,4-Naphthoquinone is used as a polymerization regulator for rubber
and polyester resins, in the synthesis of dyes and Pharmaceuticals, and as
a fungicide and algicide (Hawley 1971).
II. EXPOSURE
A. Environmental Fate
No specific information on the biological, chemical or photochemical
transformation of 1,4-naphthoquinone under environmental conditions was
identified in the literature. Napthoquinones undergo few substitution
* 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) .
-------
reactions (Thirtle 1965). Like other .quinones, 1,4-naphthoquinone can.
interconvert with its corresponding hydroquinone invan oxidation-reduction
system.
Talakin (1964) reported that 1,4-naphthoquinone in river water apparently
undergoes slow biochemical oxidation, based on an observed increase in
BOD. Verschueren (1977) reports that the BOD5 is 0.81,.using the standard
dilution technique with normal sewage as seed material, and that the theoretical
oxidation demand is 2.1.
B. Bioconcentration
No information was found on the bioconcentration potential of 1,4-naph-
thoquinone. Based on its low water solubility and its solubility in organic
solvents, 1,4-naphthoquinone could be expected to bioconcentrate to some
extent.
C. Environmental Occurrence
No information was found on the presence of 1,4-naphthoquinone in
environmental media.
In addition to its potential entry into the environment from its
manufacture, processing and uses, 1,4-naphthoquinone may also enter the.
environment as a degradation product of certain naphthalene derivatives.
For example, the U.S. EPA (1975) reported studies showing that the pesticide
carbaryl (1-naphthyl-n-methyl-carbamate) undergoes hydrolysis to 1-naphthol,
which is then converted by bacteria to 1,4-naphthoquinone and other products.
III. PHARMACOKINETICS
No information was obtained.
IV. HEALTH EFFECTS
A. Carcinogenicity •
1,4-Naphthoquinone was found to induce neoplasm when applied dermally
to mice for.28 weeks. The total dose applied was 2000 mg/kg. (Proceedings
of the Imperial Academy of Tokyo 16:309, 1940, as cited in NIOSH 1975).
-------
B. Reproductive Effects
1,4-Naphthaquinone completely inhibited the gametokinetic effect
of human chorionic gonadotropin in toads (Pakrashi 1963) .
C. Other Toxicity
The oral LD5Q for rats was reported as 190 mg/kg (NIOSH, 1975). The
LD.QQ of 1,4-naphthoquinone in rats was 0.5 g/kg, 0.25=g/kg, and 0.5 g/kg
for intraventricular, subcutaneous, and intraperitoneal administrations,
respectively. The LC100 in a" was 0.45 mg/L for a one-hour exposure.
Acute (0.5 g/kg) and subchrohic (0.3 g/kg for 4 days) exposure of rats re-
sulted in the formation of 39 and 18% methemoglobin, respectively, followed
by the appearance of Heinz bodies and development of hemolytic anemia.
A decrease in total respiration and hypothermia due to disturbances in
oxidation-reduction processes was also observed. According to the authors,
"threshold concentrations of 1,4-naphthoquinone detected for rats and rabbits
in single-exposure and chronic experiments were 0.0004 and 0.0007 mg/L with
respect to their irritant and toxic effects" (Slyusar et al. 1964). I
D. Other Relevant Information
1,4-Naphthoquinone exerted an allergenic effect in guinea pigs
(Kryzhanovskaya et al. 1966). A possible role for 1,4-naphthoquinone
in drug-induced thrombocytopenia was suggested by Niewig et al. .(1973)
as 1,4-naphthoquinone was found to be involved in the destruction of normal
blood platelets by serum antibodies in vitro. 1,4-Naphthoquinone blocks
the biosynthesis of adrenal steroids by bovine adrenal cortex in vitro
(Kahnt and Neher 1966), and has an inhibitory effect on mixtures of cytochrome
_c and dehydrated succinate oxidase from beef heart (Heymann and Feiser 1966) .
1,4-Naphthoquinone inhibited ATPase and nerve activity in the (American)
cockroach (Baker and Norris 1971, Baker 1972).
V. AQUATIC TOXICITY
Very little information was available. For 1,4-naphthoquinone, a
median threshold limit value (TLM:24-28 hr) of 0.3-0.6 mg/L was listed for
»
an unspecified species of fish (Verschueren 1977) .
VI. GUIDELINES
No guidelines for exposure to 1,4-naphthoquinone were located.
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References
Baker JE. 1972. Effects of feeding-inhibitory quinpnes on the nervous
system of Periplaneta. Experientia. 28(1) :31-32. v
Baker JE, Morris DM. 1971. Neurophysiological and biochemical effects
of naphthoquinones on the central nervous system, of Periplaneta.
J. Insect Physiol. 17:2383-2394.
Hawley GG. 1971. Condensed Chemical Dictionary, 8th edition. Van Nostrand
Reinhold Co.
Heymaan H, Feiser LF. 1948. Naphthoquinone antimalarials. XXI. Anti-
succinate oxidase activity. Jour. Biol. Chem. 176(3):1359-1369.
Kahnt FW, Neher R. 1966. Biosynthesis of adrenal steroids in vitro. II.
Importance of steroids as inhibitors. Helv. Chim. Acta 49(1):123-133. (Ger.)
Kotsifopoulos PN. 1975. In vitro effect of oxidizing and analgesic agents
on the erythrocyte membrane protein electrophoretic pattern. Nouv. Rev.
Fr. Hematol. 15(1):141-146. (Abstract in Chemical Abstracts, 83,72709Z).
Kryzhanovskaya MV, et al. 1966. Allergenic activity of some atmospheric
pollutants of a chemical nature. Gig. Sanit. 31(3):8-11.
National Institute of Occupational Safety and Health. Registry of Toxic
Effects of Chemical Substances. 1975.
Nieweg HO, et al. 1973. Drugs and thrombocytes. Proc. Eur. Soc. Study
Drug Toxic. 14:101-109.
Pakrashi A. 1963. Endocrinological studies of plant products. IV. Effect
of certain coumarins upon the biological potency of human chorionic gonado-
tropin. Ann. Biochem. Exptl. Med. (Calcutta) 23:357-370.
Slyusar MP, et al. 1964. Data on the toxicology of alpha-naphthoquinones'
and its permissible concentration in a working area. Gigiena 95-100.
(Abstract in Zh. Farmakol. Toksikol. 11.54.373, 1965).
Talakin YN. 1965. The experimental determination of the maximum permissible
concentration of alpha-naphthoquinone in water resources. Hyg. and Sanit.
30:184.
Thirtle JR. 1965. Quinones. In: Kirk-Othmer Encyclopedia of Chemical
Technology. 2nd Edition. John Wiley and Sons, Inc., New York.
U.S. EPA 1975. Microbial degradation and accumulation of pesticides in
aquatic systems. EPA 660/3-75-007, PB 241 293.
U.S. EPA 1979. Toxic Substances Control Act Chemical Substance Inventory,
Production. Statistics for Chemicals on the Non-Confidential TSCA Inventory.
-------
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals,
Van Nostrand Reinhold Co.
Windholz, M. ed. 1976. The Merck Index, Merck & Co;-. , Inc., Rahway, New Jersey.
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No. 133
Nickel
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.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
nickel and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
NICKEL
Summary
Nickel is a ubiquitous multi-media environmental contaminant. Al-
though nickel is toxic and appears to be a carcinogen to man, there is an
increasingly strong indication that nickel is an essential element. The
route of exposure to nickel is very important, since oral intake of nickel
metal is comparatively nontoxic. However, exposure to nickel by inhalation
or parenteral administration as well as cutaneous contact can produce toxic
effects. In terms of human health effects, probably the most acutely toxic
nickel compound is nickel carbonyl. Nickel in several chemical forms has
been associated with lung cancer in_ man and experimental animals upon
inhalation; carcinogenic effects, however, are not indicated by the oral
route. The acceptable daily intake (ADI) of nickel is 294 jug per day for a
70 kg man.
The toxicity of nickel to aquatic life is affected by water hardness.
In the aquatic environment nickel is acutely toxic to freshwater fishes at a
concentration of 2,480 jug/1 (26 mg/1 hardness). Chronic toxicity to fishes
has been reported at 527 jjg/1 (210 mg/1 hardness). Nickel toxicity is
affected by water hardness. Algae appears to be more sensitive to nickel
than fish. Based on the limited number of studies performed, the biocon-
centration factor for fish is 61, for algae the factor is 9.8, and the
weighted average bioconcentration factor is 11 for fish and shellfish.
X
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NICKEL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Docu-
ment for Nickel (U.S. EPA, 1979).
Nickel (Ni; atomic weight 58.71), a bright, silver metal of the iron-
cobalt-nickel triad, is a hard and malleable metal with a high tensile
strength used in virtually all areas of metallurgy. Nickel does not readily
form chloro-complexes under environmental conditions and would not be ex-
pected to form significant amounts of sulfate complexes (U.S. EPA, 1979).
In 1972, U.S. consumption of nickel, exclusive of scrap, was estimated
to total about 160,000 tons (Reno, 1974). The estimate consisted mainly of
commercially pure nickel (about 110,000 tons) which is used in stainless
steel, electroplating, and various other alloys.'" 4
II. EXPOSURE
The route by which most people in the general population receive the
largest portion of daily nickel intake is through foods. Total daily di-
etary intake values may range up to 900 ug nickel, depending on the nature
of the diet, with average values of 300 to fon.j jjg daily (NAS, 1975). The
U.S. EPA (1979) has estimated a weighted average bioconcentration factor for
nickel to be 11 for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on measured steady-state bioconcentration
studies in fathead minnow larvae (Pimephales promelas) (Lind, et al. Manu-
script). The values for nickel levels in 969 U.S. public water supplies for
1969-1970 was 4.8 pg/1, with only 11 systems of this-total exceeding 25 pg/1
(NAS, 1975). The levels of nickel in the air are also low, with a 1974
arithmetic mean level for urban air of 9 ng/m3 (U.S. EPA, 1976).
-------
III. PHARMACOKINETICS
A. Absorption
The major routes of nickel absorption are inhalation and ingestion
via the diet. Percutaneous absorption is a less significant factor for
nickel's systemic effects but important in the allergenic responses to nick-
el. Collectively the data of Tedeschi and Sunderman (1957), Perry and Perry
(1959), Nomoto and Sunderman (1970), Nodiya (1972), and Horak and Sunderman
(1973) indicate that 1 to 10 percent of dietary nickel is absorbed. Skin
penetration of nickel has been demonstrated with nickel entering at sweat-
duct and hair-follicle ostia (Wells, 1956). The extent to which nickel en-
ters the bloodstream by way of the skin cannot be stated at the present time
(U.S. EPA, 1979). '•• \
Respiratory absorption of various forms of nickel is probably the
major route of nickel entry into man under conditions of occupational expo-
sure. Pulmonary absorption into the bloodstream is probably greatest for
nickel carbonyl vapor, with animal studies suggesting tha^" .as much as half
of the inhaled amount is absorbed (Sunderman and Selin, 1968). Nickel in
/
particulate matter is absorbed from the pulmonary tract tb .a lesser degree
than nickel carbonyl (Leslie, et al. 1976). Based on animal studies, nickel
appears to have a half-life of several days in the body, yet there is little
evidence for tissue accumulation.
B. Distribution
Blood is the main vehicle for transport of absorbed nickel, with
serum albumin being the main carrier protein, although a specific nickelrich
metalloprotein has been identified in man (NAS, 1975). Tissue distribution
of absorbed nickel appears to.be dependent on the route of intake. Inhaled
nickel carbonyl leads to highest levels in the lung, brain, kidney, liver,
-------
and adrenals (Armit, 1508; Sunderman and Selin, 1968; Mikheyev, 1971). Par-
enteral administration of nickel salts usually results in highest levels in
the kidney, with significant uotake shown by endocrine glands, liver and
lung (Wase, et al. 1954; Smith and Hackley, 1968).
C. Metabolism
A number of disease states and other physiological stresses are
reported to alter the movement and tissue distribution of nickel in man as
well as experimental animals. In man, increased levels of serum nickel are
seen in cases of acute myocardial infarction (D'Alonzo and Pell, 1963; Sun-
derman, et al. 1972), acute stroke and extensive burn injury (McNeely, et
al. 1971). Reduction is seen in hepatic cirrhosis or uremia, possibly sec-
ondary to hypoalbuminemia.
Nickel appears to be an essential element, at least in experimental
animals. Nickel deficient diets have produced decreased growth rates and
impaired reproduction in swine (Anke, et al. 1974) and rats (Schnegg and
Kirchgessner, 1975).
0. Excretion
The routes of elimination for nickel in man and animals depend in
part on the chemical forms of nickel and the mode of nickel intake. Dietary
nickel, due-to the low extent of gastrointestinal absorption, is simply lost
in the feces (U.S. EPA, 1979). Urinary excretion in man and animals is usu-
ally the major clearance route for absorbed nickel. In some instances sweat
can constitute a major route of nickel elimination (Hohnadel, et al. 1973).
Nodiya (1972) reported a fecal excretion average of 258 jjg in Russian stu-
dents. Horak and Sunderman (1973) determined fecal excretion of nickel in
10 healthy subjects and arrived at a value identical to that found in the
Russian study.
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IV. EFFECTS
A. Carcinogenicity
A carcinogenic response to various nickel compounds upon injection
has been observed in a number of animal studies (Lau, et al. 1972; Stoner,
et al. 1976; IARC, 1976). In nickel refinery workers, an excess risk of
nasal and lung cancer has been demonstrated (IARC, 1976). However, there is
no evidence at present to indicate that orally ingested nickel is tumori-
genic.
The qualitative and quantitative character of the carcinogenic effects
of nickel as seen in experimental animal models has been shown to vary with
the chemical form of the nickel, the route of exposure, the animal model em-
ployed, and the amounts of the substance administered (U.S. EPA, 1979).
B. Mutagenicity ;
Pertinent information could-not be located in the available litera-
ture.
C. • Teratogenicity
While Fern (1972) has claimed unspecified malformations in surviv-
ing hamster embryos when mothers were exposed to parenteral nickel (0.7 to
10.0 mg/kg), Sunderman, et al. (1978) found no teratogenic effects from oral
administration of either nickel chloride (16 mg/kg) or nickel subsulfide (80
mg/kg) in rats. Exposure of pregnant rats by inhalation to nickel carbonyl
on days 7 or 8 of gestation frequently caused the progeny to develop ocular
anomalies, including anophthalmia and microphthalmia. The incidence of ex-
traocular anomalies is very low. The specificity of nickel carbonyl for in-
duction of ocular anomalies in rats appears to be unique among known terato-
genic agents (Sunderman, et al. 1979).
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D. Other Reproductive Effects
Schroeder and Mitchner (1971) have demonstrated adverse affects in
a three generation study with rats at a level of 5 mg/1 (5 ppm) nickel in
drinking water. In each of the generations, increased numbers of runts and
enhanced neonatal mortality were seen. A significant reduction in litter
size and a reduced proportion of males in the third generation were also
observed. Nickel sulfate (25 mg/kg) has been demonstrated to be gametotoxic
in rats, with complete obliteration of spermatozoa following exposure for
120 days (Hoey, 1966; Waltschewa, et al. 1972).
E. Chronic Toxicity
Chronic exposure to nickel has resulted in injury to both the upper
and lower respiratory tract in man (Tplot, et al. 1956; McConnell, et al.
1973). Inhalation of nickel particulate matter is likely to play a role in
chronic respiratory infections by effects on alveolar macrophages. Contact
dermatitis in man with nickel sulfate has been observed (Fregert, et al.
1969; Brun, 1975).. Also, dietary nickel can elicit a dermatitic response
(Kaaber, et al. 1978).
. F. Other Relevant Information
There are experimental data that demonstrate that nickel has a syn-
ergistic effect on the carcinogenicities of polycyclic hydrocarbons (Toda,
1962; Maenza, et al. 1971; Kasprzak, et al. 1973). Nickel and other ele-
ments are known to be present in asbestos and may possibly be a factor in
asbestos carcinogenicity (Cralley, 1971). Also, a synergistic action be-
tween nickel and viruses has been suggested (Treagon-and Furst, 1970).
V. AQUATIC TOXICITY
>
A. Acute Toxicity
Water hardness significantly influences the acute toxicity of nick-
el to freshwater fish. For fish, observed LC_Q values range from 2,480
'1571-
-------
for the rock bass (Amblophites ruoestris) (hardness = 26 mg/1) to
110,385 jug/1 for the bluegill (Lepomis macrochirus) (hardness = 42 mg/1).
At a hardness of 20-29 mg/1, six freshwater species have LC _ values of
between 2,916 and 5,360 /jg/1 (Pickering and Henderson, 1966; Lind at al.,
manuscript). At a hardness of 360 jjg/1, values range from 39,600 to 44,500
jug/l. In comparison, acute tests with freshwater invertebrate species have
a greater range of LC5f, values at a fixed hardness. The stonefly (Acro-
neuria lycorias) exhibited the highest LC5Q of 33,500 jug/1 (Warnick and
Bell, 1969) and Oapnnia magna gave the lowest value of 510 jjg/1 (Biesinger
and Christensen, 1972). Lind, et al. (1979)- provide the only data obtained
under relatively high hardness conditions (244 mg/i), an LC5Q value of
2409 jug/1 for Daphnia pulicaria.
Data on the acute toxicity of nickel to saltwater fishes is limit-
ed. The LC^Q values range from 29,000 pg/1 for the Atlantic Silverside
(Menidia menidia) to 350,000 ug/1 for the mummichcg (Fundulus heteroclitus)
(Eisler and Hennekey, 1977). The invertebrate acute toxicity data base con-
sists of 14 results, with a range of LC5Q values from 310 /ug/1 for larvae
of the hard clam (Mercenaria mercenaria) (Calabrese and Nelson, 1974) to
500,000 ug/1 for adults of the cockle Cardium edule (Portmann, 1963).
B. Chronic Toxicity
A life cycle test (Pickering, 1974) and an embryo-larval test
(Lind, et al., manuscript) have, been conducted .with the fathead minnow
(Pimeohales oromelas). The chronic .values.are 527 jug/1 (210 mg/1 hardness)
and 109 ,/jg/l (44 mg/1 hardness) respectively. Biesinger and Christensen
(1972) conducted a life cycle test with Daohnia maona resulting in a chronic
»
value, of 53 /ug/1 at a hardness of 45 mg/1.• There are no chronic saltwater
data available (U.S. EPA, 1979).
-------
C. Plant Effects
Hutchinson (1973) and Hutchinson and Stokes (1975) observed reduced
growth of several algae species at concentrations ranging from 100 to 700
jug/1. A decrease in diatom diversity was observed by Patrick, et al. (1975)
to occur at concentrations as low as 2 ug/1.
0. Residues
Bioconcentration data is limited to the fathead minnow, Pimephales
promelas, (Lind, et al., manuscript) and the alga, Scenedesmes acuminata
(Hutchinson and Stokes, 1975). The bioconcentration factor for the whole
body of the fathead minnow is 61 and for the alga the factor is 9.3.
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 American Conference of Governmental Industrial Hygienists
(ACGIH, 1971) has adopted a threshold limit value (TLV) for a workday expo-
sure of 1 ppb. The acceptable daily intake (ADI) for man has been determin-
ed to be 294 pg/day (U.S. EPA, 1979). The U.S. EPA (1979) draft water qual-
ity criterion for nickel is 133 ug/1.
B. Aquatic
For nickel, the draft criterion (U.S. EPA, 1979) to protect fresh-
water aquatic life is:
(1.01 . In (hardness) - 1.02)
»
as a 24-hour average, and the concentration should not exceed at any time:
e(0.47 . In (hardness) + 4.19)
The draft criterion to protect saltwater aquatic life is 220 ug/1
as a 24-hour average, not to exceed 510 ug/1 at any time (U.S. EPA, 1979).
-------
NICKEL
REFERENCES
American Conference of Governmental Industrial Hygienists.
Threshold limit values for chemical substances and physical
agents in the workroom environment with intended changes for
1978. 94 pp.
Anke, M., et al. 1974. Low nickel rations for growth and
reproduction in pigs. In; Trace Element Metabolism in Ani-
mals-2. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W.
Mertz (eds.). University Park Press, Baltimore, MD., pp.
715.
Armit, H.W. 1908. The toxicology of nickel carbonyl. Part
II. Jour. Hygiene 8: 565.
Biesinger, K.E.-, and G.M. Christensen. 1972. Effects of
various metals on survival, growth, reproduction, and metabo-
lism of Daphnia magna. Jour. Fish. Res. Board Can. 29:
1691.
Brun, R. 1975. Epidemiology of contact dermatitis in Geneva--
(1,000 cases). Dermatol. 150: 193. (French) ^
Calabrese, A., and D.A. Nelson. 1974. Inhibition of embry-
onic development of the hard shell clam, Mercenaria mercen-
aria, by heavy metals. Bull. Environ. Contain. Toxicol. 2:
92. . .
Cralley, L.J. 1971. Electromotive phenomenon in metal and
mineral particulate exposures. Relevance to exposure to as-
bestos and occurrence of cancer. Am. Ind. Hyg. Assoc. Jour.
32: 653.
D'Alonzo, C.A., and S. Pell. 1963. A study of trace metals
.in myocardial infarction. Arch. Environ. Health 6: 38.1.
Eisler, R., and R.J. Hennekey. 1977. Acute toxicities of
Cd^+, Cr^ + , Ni^"1". amd Zn^+ to estaurine macro fauna.
Arch. Environ. Contam. Toxicol. 6: 315.
Ferm, V.H. 1972. The teratogenic effects-of metals on mam-
malian embryos. In: Advances in Teratology, Vol. 5. D.H.M.
Wollam (ed.) Academic Press, New York. pp. 51-75.
Fregert, S., et al. 1969. Epidemiology of contact dermati-
tis. Trans. St. Johns Hosp. Derm. Soc. 55: 71.
Hoey, M.J. 1966. The effects of metallic salts on the his-
tology and functioning of the rat testes. Jour. Reprod.
Fertil. 12: 461.
-------
Hohnadel, D.C., et al. 1973. Atomic absorption spectrometry
of nickel, copper, zinc, and lead in sweat collected from
health subjects during sauna bathing. Clin. Chem. 19:
1288.
Horak, E., and P.W. Sunderman. 1973. Fecal nickel excretion
by healthy adults. Clin. Chem. 29: 429.
Hutchinson, T.C. 1973. Comparative studies of the toxicity
of heavy metals to phytoplankton and their synergistic inter-
actions. Water Pollut. Res. (Canada) 8: 68.
Hutchinson, T.C., and P.M. Stokes. 1975. Heavy metal toxi-
city and algal bioassays. ASTM STP 573, Am. Soc. Test.
Mater. pp. 320-343.
International Agency for Research on Cancer. 1976. Nickel
and nickel compounds. In; Evaluation of Carcinogenic Risk of
Chemicals to Man (International Agency for Research on Cancer
Monographs., 11) I ARC, Lyon, p. 111.
Kaaber, K., et al. 1978. Low nickel diet in the treatment
of patients with chronic nickel .dermatitis. Brit. Jour.
Derm. 98: 197.
Kasprzak, K.S., et al. 1973. Pathological reactions in rat
lungs following intratracheal injection of nickel subsulfide
and 3,4-benzpyrene. Res. Comm. Chem. Pathol. Pharmacol. 6:
237.
Lau, T.J., et al. 1972. The carcinogenicity of intravenous
nickel carbonyl in rats. Cancer Res. 32: 2253.
Leslie, A.C.D., et al. 1976. Prediction of health effect of
pollution aerosols. In; Trace Substances in Environmental
Health - X. D.D. Hemphill (ed.), University of Missouri,
Columbia, Mo. pp. 497-504.
Lind, D., et al. Regional copper-nickel study, Aquatic Tox-
icology Study, Minnesota Environmental Quality Board, State
of Minnesota (Manuscript).
Maenza, R.M. et al. 1971. Rapid induction of sarcomas in
rats by combination of nickel sulfide and 3,4-benzypyrene.
Cancer Res. 31: 2067.
McConnell, L.H., et al. 1973. Asthma caused by nickel sen-
sitivity. Ann. Ind. Med. 73: 888.
McNeely, M.D., et al. 1971. Abnormal concentrations of ,
nickel in serum in cases of myocardial infarction, stroke,
burns, hepatic cirrhosis, and uremia. Clin. Chem. 17:
1123.
-//rr-
-------
Mikheyev, M.I. 1971. Distribution and excretion of nickel
carbonyl. Gig. Tr. Prof. Zabol. 15: 35.
National Academy of Sciences. 1975. Nickel. National Acad-
emy of Sciences Committee of Medical and Biological Effects
of Environmental Pollutants. Washington, DC.
Nodiya, P.I. 1972. Cobalt and nickel balance in students of
an occupational technical school. Gig. Sanit. 37: 108.
Nomoto, S., and F.W. Sunderman, Jr. 1970. Atomic absorption
spectrometry of nickel in serum, urine, and other biological
materials. Clim. Chem. 16: 477.
Patrick, R., et al. 1975. The role of trace elements in
management of nuisance growths. U.S. Environ. Prot. Agency,
EPA 660/2-75-008, 250 p.
Perry, H.M., Jr., and E.F. Perry. 1959. Normal concentra-
tions of some trace metals in human urine: Changes produced
by ethylenediametetracetate. Jour.-Clin. Invest. 38: 1452.
Pickering, Q.H. 1974. Chronic toxicity of nickel to the
fathead minnow. Jour. Water Pollut. Control Fed. 46: 760.
Pickering, Q.H., and C. Henderson. 1966. The acute toxicity
of some heavy metals to different species of warmwater
fishes. Air Water Pollut. Int. Jour. 10: 453.
Portmann, J.E. 1968. Progress report on a program of
insecticide analysis and toxicity testing in relation to the
marine environment. Helgolander wiss. Meeresunters 17:
247.
Reno, H.T. 1974. Nickel. In; Minerals Yearbook 1972, Vol.
I. Metals, Minerals and Fuels. Washington, DC, U.S. Gov-
ernment Printing Office, pp. 871.
Schnegg, A., and M. Kirchgessner. 1975. The essentiality of
nickel for the growth of animals. Z. Tierphysiol., Tierer
naehr. Futtermittelkd. 36: 63.
Schroeder, H.A., and M. Mitchner. 1971. Toxic effects of
trace elements on the reproduction of mice and rats. Arch.
Environ. Health 23: 102.
Smith, J.C., and B. Hackley. 1968. Distribution and excre-
tion of nickel-63 administered intravenously to rats. Jour.
Nutr. 95: 541.
Stoner, G.D., et al. 1976. Test for carcinogenicity of me-
tallic compounds by the pulmonary tumor response in strain A
mice. Cancer Res. 36: 1744.
-------
Sunderman, F.W. , et al. 1978. Erabryotoxicity and fetal
toxic ity of nickel in rats. Toxicol. Appl. Pharmacol. 43:
381.
Sunderman, F.W., Jr. 1978. Carcinogenic effects of metals.
Fed. Proc. 37: 40.
Sunderman, F.W., Jr., and C.E. Selin. 1968. The metabolism
of nickel-63 carbonyl Toxicol. Appl. Pharmacol. 12: 207.
Sunderman, F.W., Jr., et al. 1972. Nickel metabolism in
health and disease. Ann. N.Y. Acad. Sci. 199: 300.
Sunderman, F.W., Jr., et al. 1979. Eye malformation in
rats: Induction by prenatal exposure to nickel carbonyl.
Science 203: 550.
Tedeschi, R.E., and F.W. Sunderman. 1957. Nickel poisoning.
V. The metabolism of nickel under normal conditions and
after exposure to nickel carbonyl. Arch. Ind. Health 16:
486.
Toda, M. 1962. Experimental studies of occupational lung
cancer. Bull. Tokoya Med. Dent." Univ. 9: 441.
Tolot, F., et al. 1956. Asthmatic forms of lung disease in
workers exposed to chromium, nickel and aniline inhalation.
Arch. Mol. Prof. Med. Tran. Secur. Soc. 18: 288.
Treagon, L., and A. Furst. 1970. Inhibition of interferon
synthesis in mammalian cell cultures after nickel treatment.
Res. Comm. Chem. Pathol. Pharmacol. 1: 395.
U.S. EPA. 1976 (August). Air quality data for metals 1970
through 1974 from the national air surveillance network.
SPA-600/4-76-041, U.S. Environ. Prot. Agency, Research
Triangle Park, NC.
U.S. EPA. 1979. Nickel: Ambient Water Quality Criteria.
Waltschewa, V.W. et al. 1972. Hodenveranderungen bei
weissen Ratten durch chronische Verabreichung von Nickel sul-
fate. (Testicular changes due to long-term administration of
nickel sulphate, in rats.) Exp. Pathol. 6: 116. In German
with Engl. abstr.
Warnick, S.L., and H.L. Bell. 1969. The acute toxicity of
some heavy metals to different species of aquatic insects.
Jour. Water Pollut. Control Fed. 40: 280.
Wase, A.W., et al. 1954. The metabolism of nickel. I.
Spatial and temporal distribution of Ni°^ in the mouse.
Arch. Biochem. Biophys. 51: 1.
-I f77-
-------
Wells, G.C. 1956. Effects of nickel on the skin. Brit.
Jour. Dermatol. 68: 237.
-------
No. 134
Nitrobenzene
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.
-------
NITROBENZENE
Summary
Nitrobenzene is a pale yellow oily liquid with an almond-like odor.
There is little or no information available on its teratogenic, mutagenic or
carcinogenic effects. Nitrobenzene yielded negative results in the Ames
assay for mutagenicity. Gross abnormalities were observed in 4 fetuses of
30 rats administered nitrobenzene.
Chronic exposure to nitrobenzene produces cyanosis, methemoglobinemia,
jaundice, anemia, and sulfhemoglobinemia in man.
Static tests with the bluegill, sunfish, Daohnia maqna, and an alga,
Selenestrum capricornutum, indicates little difference in sensitivity with
no 50 percent effective concentration lower than 27,000 ug/1. An embryo-
larval test with the fathead minnow demonstrated no adverse chronic effects
at the highest concentration tested (32,000 ug/1). Static tests with salt-
water fish, shrimp, and alga gave repeated 96-hour LC5Q or EC-- values
of 58,538 jjg/1, 6,676 ug/1 and 9,600 ug/1, respectively.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Nitrobenzene (U.S. EPA, 1979). The principal uses of nitrobenzene are
for reduction to aniline (97 percent), solvent for Friedel-Crafts reaction,
metal polishes, shoe black, perfume, dye intermediates, crystallizing sol-
vent for some substances, and as a combustible propellant (Dorigan and
Hushon, 1976).
Nitrobenzene ^^^ is a pa^8 ve-'-^ow °^ liquid with an
almond-like odor. Its physical properties include: melting point, 6°C;
vapor pressure, 0.340 mm Hg at 25°C; and solubility in water of 1000 mg/1
at 20°C (U.S. EPA, 1979). Nitrobenzene is miscible with most organic sol-
vents, a fairly strong oxidizing agent, and undergoes photoreduction when
. irradiated with ultraviolet light in organic solvents that contain abstrac-
table hydrogen atoms.
II. EXPOSURE
A. Water
Levels of nitrobenzene in wastewater are monitored by plants pro-
ducing and using the chemical, but nitrobenzene levels in city water systems
are usually too low to measure (Pierce, 1979).
9. Food
Nitrobenzene is not an approved food additive (Dorigan and Hushon,
1976). There have been reports of nitrobenzene poisoning resulting from its
contamination of alcoholic drinks and food (Nabarro, 1948).
The U.S. EPA (1979) has estimated the weighted average bioconcentration
factor for nitrobenzene to be 4.3 for the edible portions of fish and^shell-
fish consumed by Americans. This estimate was based on octanol/water par-
tition coefficients.
-------
C. Inhalation
Atmospheric nitrobenzene levels outside a plant are not monitored
by industry. Since inner plant levels are below the Threshold Limit Value
(TLV) of 5 mg/m and nitrobenzene vapors accumulate at the floor level due
to their high density, the external concentrations are expected to be very
low (Dorigan and Hushon, 1976).
III. PHARMACOKINETICS
A. Absorption
Nitrobenzene absorption can jDccur by all possible routes, but it
takes place mainly through the respiratory tract and skin. On the average,
80 percent of" the nitrobenzene vapors are retained in the human respiratory
tract (Piotrowski, 1977).
Nitrobenzene, as liquid and vapor, will pass directly through the
skin. The rate of vapor absorption depends on the air concentration, rang-
ing from 1 mg/hr at 5 mg/m concentration to 9 mg/hr at 20 mg/m . Maxi-
2
mal cutaneous absorption of liquid nitrobenzene is 0.2 to 3 mg/cm /hr de-
pending on skin temperature.
8. Distribution
Upon entry into the body, nitrobenzene enters the bloodstream.
Nitrobenzene is a very lipid soluble with an oil to water coefficient of
800. In a rat study, the ratio of concentration of nitrobenzene in adipose
tissue versus blood in internal organs and muscle was approximately 10:1 one
hour after an intravenous injection (Piotrowski, 1977). Oorigan and Hushon.
(1976) .found that 50 percent of the nitrobenzene administered to rabbits
accumulated unchanged in tissues within two days after intubation.
-------
C. Metabolism
There are two main pathways for the metabolism of nitrobenzene: 1)
reduction to aniline followed by hydroxylation to aminophenols, and 2)
direct hydroxylation of nitrobenzene to form nitrophenols. Further reduc-
tion of nitrophenols to aminophenols may also occur (Piotrowski, 1977). The
first pathway proceeds via the unstable intermediates, nitrosobenzene and
phenylhydroxylamine, both of which are toxic and have pronounced methemo-
globinemic capacity. These reactions occur in the cytoplasmic and micro-
somal fractions of liver cells by the nitro-reductase enzyme system (Fouts
and Srodie, 1957). The aniline is then excreted as an acetyl derivative, or
hydroxylated and excreted as an aminophenol. The second pathway does not
occur in the microsomal fraction. This .reaction proceeds via peroxidase in
the presence of oxygen (Piotrowski, 1977).
Robinson, at al. (1951) found p-aminophenol to be the main metabol-
ic product of nitrobenzene metabolism in rabbits. Little unchanged nitro-
benzene was excreted in the urine and only 1 percent was expired as carbon
dioxide. Together with nitrophenols and nitrocatechol, p-aminophenol con-
stituted 55: percent of the urinary metabolites. Metabolites were detected
in the urine up to.one week after dosing.
D. Excretion
In man, the primary known excretion products of nitrobenzene are
p-aminophenol and p-nitrophenol which appear in the urine after, chronic or
acute- exposure. In experimental . inhalation exposure to nitrobenzene,
p-nitrophenoi was formed with the efficiency of 6 to 21 percent. The
efficiency of p-aminophenol formation is estimated from. acute poisoning
-------
cases where the molar ratio of excreted p-nitrophenol to p-aminophenol is
two to one, since p-aminophenol is not formed at a detectable level in short
subacute exposure (Piotrowski, 1977).
. Ikeda and Kita (1964) found the rate of excretion of these two
metabolites to parallel the level of methemoglobin in the blood.
Nitrobenzene remains in the human body for a prolonged period of
time. The excretion coefficient of urinary p-nitrophenol (followed for
three weeks) in man is about 0.008 per hour. The extended systemic reten-
tion and slow excretion of metabolites in man is determined by the low rates
of metabolic transformation (reduction and hydroxylation) of the nitroben-
zene itself. . The conjugation and excretion of the metabolites, p-nitrophe-
nol and p-aminophenol, is rapid (Piotrowski, 1977). The urinary metabolites
in man account for only 20 to 30 percent of the nitrobenzene dose; the fate
-.•»
of the rest of the metabolites is not known (Piotrowski, 1977).
IV. EFFECTS
A. Carcinogenicity
The available literature does not demonstrate the carcinogenicity
of nitrobenzene, although it is suspect (Dorigan and Hushon, 1976).
Some nitrobenzene derivatives have demonstrated carcinogenic capa-
cities. Pentachloronitrobenzene (PCNB) induced hepatomas and papillomas in
mice (Courtney, et al. 1976).
l-Fluoro-2,4-dinitrobenzene (ONFB) was found to be a promoter of
skin tumors in mice, although it does hot induce them when administered
alone (Bock, et al 1969).
B. Teratogenicity
There is a paucity of information on the teratogenic effects of
nitrobenzene. In one study, 125 mg/kg was administered to pregnant rats
J<
-------
during prsimplantation and placentation periods (Kazanina, 1963). Delay of
embryogensis, alteration of normal placentation, and abnormalities in the
fetuses were observed. Gross morphogenic defects were seen in 4 of 30
fetuses examined.
C. Mutagenicity
Nitrobenzene was not found to be mutagenic in the Ames Salmonella
assay (Chiu, et al., 1978). Trinitrobenzene and other nitrobenzene deriva-
tives have demonstrated mutagenicity in the Ames Salmonella microsome assay
and the mitotic recombination assay in yeast (Simmon, et al. 1977), thus
raising questions concerning the mutagenicity of nitrobenzene.
0. Other Reproductive Effects
Changes in the tissues of the chorion and placenta of pregnant
women who worked in the production of a rubber catalyst that used nitro-
benzene were observed. NO mention was made of the effects on fetal develop-
ment .or viability (Dbrigan and Hushon, 1976). Menstrual disturbances after
chronic nitrobenzene exposure have been reported.
Garg, et. al. (1976) tested substituted nitrobenzene derivatives for
their ability to inhibit pregnancy in albino rats. Two of the compounds
tested (p-methoxy and p-ethoxy derivatives) inhibited implantation and preg-
nancy 100 percent when administered on days 1 through 7 after, impregnation.
£. Chronic Toxicity
Symptoms of chronic occupational nitrobenzene absorption are cyan-
osis, methemoglobinemia, jaundice, anemia, sulfhemoglobinemia, presence of
Heinz bodies in the erythrocytes, dark colored 'urine, and the presence of
nitrobenzene metabolites (e.g., nitrophenol) inp the urine (Pacseri and
Magos, 1958; Hamilton, 1919: Wuertz, et al. 1964; Browning, 1950; Maiden,
1907; Piotrowski, 1967).
-------
Chronic exposure of laboratory animals to nitrobenzene (via inhala-
tion, ingestion or subcutaneous injection) produced symptoms similar to
those mentioned above for humans as well as tissue degeneration of the
heart, liver, and kidney, and reductions in erythrocytes and hemoglobin
levels in the .blood (U.S. EPA, 1979).
F. Other Relevant Information
Alcohol ingestion has been found to act synergistically with nitro-
benzene in man and animals (Dorigan and Hushon, 1976; Smyth, et al., 1969).
Kaplan, et al. (1974) showed that caffeine, an inducer of microsom-
al enzymes, increases the rate of metabolism and excretion of nitrobenzene
. thus causing a rapid decline in nitrobenzene induced methemoglobin levels.
Metabolism and excretion of nitrobenzene in humans is slower by an
order of magnitude than in rats or rabbits (Piotrowski, 1977). ^
V. AQUATIC TOXICITY
A. Acute Toxicity
The 96-hour LC~ reported value for the bluegill (Leoomis macro-
chirus) is 42,600 ug/1 and the observed 48-hour LC5Q for Daphnia manna is
• 27,000 ug/1. Saltwater species tested are the sheepshead minnow, Cyprinodon
variegatus, which has a reported 96-hour LC.g of 58,539 jug/1 and the mysid
shrimp, Mysidopsis bahia, with a reported 96-hour LC5Q of 6,676 ug/1 (U.S.
EPA, 1979).
B. Chronic Toxicity
In the only chronic data available, no adverse effects were
observed during an embryo-larval test with the fathead minnow (Pimephales
oromelas) at nitrobenzene test concentrations as high as 32,000 pg/1 (U.S.
EPA, 1978).
-------
C. Plant Effect
Based on cell numbers and chlorophyll a concentration, reported
£C5Q values for the freshwater alga, Selenastrum caoricornutum, are 42,000
and 4A,100 ug/1; and for the marine alga, Skeletonema costatum, there are
reported EC5Q values of 9,600 and 10,300 jug/1 (U.S. EPA, 1979).
0. Residues
A bioconcentration factor of 15 was estimated for aquatic organisms
that contain 8 percent lipids.
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 TLV for nitrobenzene is 5 mg/m . This 'is the OSHA Federal
standard, the value set by the ILO/WHO committee on Occupational Health, and
the TLV suggested by the American Conference of Governmental and Industrial
Hygienists (Goldstein, 1975, ACGIH, 1977).
The draft water quality criteria for nitrobenzene is 30 ug/1 (U.S.
EPA, 1979). This value is based on the TLV and organoleptic level (minimum
detectable odor limit in water) of nitrobenzene.
8. Aquatic
For nitrobenzene the drafted criterion to protect freshwater aquat-
ic life is 480 ug/1 as a 24-hour average concentration not to exceed 1,100
ug/1 at any time. To protect saltwater aquatic life, the 24-hour average is
*
53 ug/1 and this concentration should not exceed 120 ug/1 at any time (U.S.
EPA, 1979).
-------
NITROBENZENE
REFERENCES
American Conference of Governmental Industrial Hygiensts. 1977. Docu-
mentation of the threshold limit value for substances in workroom air.
Cincinnati, Ohio.
Bock, A.G., et al. 1969- Tumor promotion by 1-fluoro-2, 4-dinitrobenzene,
a potent skin sensitizer. Cancer Res. 29: 179.
Browning, E. 1950. Occupational jaundice and anemia. Practitioner
164: 397.
Chiu, C.W., et al. 1978. Mutagenicity of some commercially available nitro
compounds for Salmonella typhinurium. Mut. Res. 58: 11.
Courtney, K.D., et al. 1976. The effects of pentachloronitrobenzene, hexa-
chlorobenzene, and related compounds on fetal development. Toxicol. Appl.
Pharmacol. 35: 239-
Dorigan, J.f and J. Hushon. 1976. A_ir pollution assessment of nitro-
benzene. U.S. Environ. Prot. Agency.
Fouts, J.R., and B.B. Brodie, 1957. The enzymatic reduction of cloram-
.phenicol, p-nitrobenzoic acid and other aromatic nitro compounds in
mammals. Jour. Pharaiacol. Exp. Ther. 119: 197.
Garg, S.X., et al. 1976. Potent female antifertility agents. Indian Jour.
Med. Res. 64: 244.
Goldstein, I. 1975. Studies on MAC values of nitro and amino-derivatives
of aromatic hydrocarbons. Adverse Effects Environ. Chem. Psychotropic
Drugs 1: 153-
Hamilton, A. 1919- Industrial poisoning by compounds of the aromatic
series. Jour. Industr. Hyg. 1: 200.
Ikeda, M., and A. Kita. 1964. Excretion of p-nitrophenol and p-aminophenol
in the urine of a patient exposed to nitrobenzene. 8r. Jour. Ind. Med.
21: 210.
Kaplan, A.M., et al. 1974. Methemoglobinemia and metabolism of nitro com-
pounds. Toxicol. Appl. Pharmacol. 29: 113.
Kazanina, S.S. 1968. Morphology and histochemistry "of hemochorial placen-
tas of white rats during poisoning of the maternal organisms by nitro-
benzene. Bull. Exp. Biol. Med. (U.S.S.R.) 65: 93-
»
Maiden, W. 1907. Some observations on the condition of the blood in men
engaged in aniline dyeing and the manufacture of nitrobenzene and its com-
pounds. Jour. Hyg. 7: 672.
-------
Nabarro, J.D.N. 1948. A case of acute mononitrobenzene poisoning. Br.
Med. Jour. 1: 929.
Pacseri, I., and L. Magos. 1958. Determination of the measure of exposure
to aromatic nitro and amino compounds. Jour. Hyg. Spidemiol. Microbiol.
Immunol. 2: 92.
Pierce, M. 1979. Personal communication. Quality Control Dep.,
Philadelphia Water Treatment Div., Philadelphia, Pa.
Piotrowski, J. 1967. Further investigations on the evaluation of exposure
to nitrobenzene. Br. Jour. Ind. Med. 24: 60.
Piotrowksi, J. 1977. Exposure tests for organic compounds in industrial
toxicology. NIOSH 77-144. U.S. Dep. Health, Edu. Welfare.
Robinson, D., et al. 1951. Studies in detoxication. 40. The metabolism
of nitrobenzene in the rabbit. o-, m-, and p-nitrophenols, o-, m-, and
p-aminophenols and 4-nitrocatechol as metabolites of nitrobenzene.
Biochem. Jour. 50: 228.
Simmon, V.F., et al. 1977. Munitions wastewater treatments: Does chlori-
nation or ozonation of individual components produce microbial mutagens?
Toxicol. Appl. Pharmacol. 41: 197.
Smyth, H.F., Jr., et al. 1969. An exploration of joint toxic action:
Twenty-seven industrial chemicals intubated in rats in all possible pairs.
Toxicol. Appl. Pharmacol. 14: 340.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants." Contract No. 68-01-4646.
U.S. EPA.. 1979. Nitrobenzenes. Ambient Water Quality Criteria (Draft).
Wuertz, R.L., et al. 1964. Chemical cyanosis - anemia syndrome. Diag-
nosis, treatment, and recovery. Arch. Environ. Health 9: 478.
-------
No. 135
4-Nitrophenol
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.
-------
4-NITROPHENOL
SUMMARY
There is no evidence to indicate that 4-nitrophenol is carcin-
ogenic.
Weak mutagenic effects in Saccharomyces and in Proteus have
been observed. Results from the Ames assay, the E. coli, and
the dominant lethal assay failed to show mutagenic effects from
4-nitrophenol.
No information on the teratogenic or adverse reproductive
effects of 4-nitrophenol is available.
A single animal study indicates cumulative chronic toxicity;
" " )
the methodology of this study was not available for review.
For freshwater organisms, acute values for the toxic effects
of 4-nitrophenol ranged from 8,280 to 60,500 pg/1, and 7,170
to ^27,100 ug/1 for marine organisms. Effective concentrations
1 -
for "aquatic plants fall within these ranges of concentrations.
-/57J-
-------
4-NITROPHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Nitrophenols (U.S. EPA, 1979).
The mononitrophenols are a family of compounds composed
of the isomers resulting from nitro group substitution at the
2,3, and 4 position of phenol (the ortho, meta, and para isomers,
respectively). The para isomer, 4-nitrophenol, has a molecular
weight of 139.11, a boiling point of 279°C, a melting point of
113-114°C, a ^density of 1.479 g/ml; it is soluble in water (U.S.
EPA, 1979).
Uses of the mononitrophenols include the following: produc-
tion of dyes, pigments, Pharmaceuticals, rubber chemicals, lumber
preservatives, photographic chemicals, and pesticidal and fungici-
dal agents (U.S. EPA, 1979). Production was 17.5 x 103 tons
per year in 1976 (Chem. Market. Reporter, 1976).
The nitrophenols may be formed via microbial degradation
or photodegradation of pesticides (e.g., parathion) containing
the nitrophenol moiety. 4-Nitrophenol may be produced in the
atmosphere through the photochemical reaction between benzene
and nitrogen monoxide (U.S. EPA, 1979). Partial microbial.degrada-
tion of certain nitrophenols has been shown,, particularly by
acclimated microorganisms. Mononitrophenols appear to be effi-
ciently degraded by unacclimated microorganisms' (Haller, 1978) .
II. EXPOSURE
The lack of monitoring data . on the mononitrophenols makes
it difficult to assess exposure from water, inhalation, and foods.
-------
Mononitrophenols in water have been detected in the effluents
of chemical plants (U.S. EPA, 1975, 1979). 4-Nitrophenol has
been shown to penetrate the skin and to produce damage at thres-
hold concentrations of 0.8 and 0.9 percent (w/v), respectively
(U.S. EPA, 1979).
Exposure to nitrophenols appears to be primarily through
occupational contact (chemical plants, pesticide applications).
Contaminated water may result in isolated poisoning incidents.
The U.S. EPA (1979) has estimated the weighted average bio-
concentration factor for 4-nitrophenol to be 4.9 for the edible
portions of fish and shellfish consumed by Americans. This esti-
mate is based on the octanol/water partition coefficient.
III. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available
literature regarding absorption or distribution.
B. Metabolism
Metabolism of the mononitrophenols occurs primarily
by conjugation. Other possible routes are reduction of the nitro
group to an araino group or oxidation to dihydric-nitrophenols
(U.S. EPA, 1979). These reactions are mediated primarily by
liver enzyme systems, although other tissues show lower metaboliz-
ing activity (U.S. EPA, 1979).
B. Excretion
An animal study has indicated that oral or intraperi-
•
toneal administration of 4-nitrophenol leads to rapid elimination
in all species tested, and that the total elimination period
is not likely to exceed one week (Lawford, et al. 1954).
-------
IV. EFFECTS
A. Carcinogenicity
There is no evidence available regarding the carcinogeni-
city of mononitrophenols.
B. Mutagenicity
A weak mutagenic effect was detected in Saccharomyces
cerevisiae by 4-nitrophenol (Fahrig, 1974); this was also indi-
cated by testing 4-nitrophenol for growth inhibition in a DNA
repair deficient strain of Proteus mirabilis (Adler, et al. ,
1976). This compound has also induced chromosome breaks in plants
(U.S. EPA, 1979). 4-Nitrophenol has failed to show mutagenic
effects in the Ames assay, in E. coli, or in the dominant lethal
assay (U.S. EPA, 1979).
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
A single Russian study (Makhinya, 1969) reported that
chronic administration of mononitrophenol to mammals .produced
hepatitis, splenic hyperplasia, and neurological symptoms. Method-
ology of this study was not available for review.
V. AQUATIC TOXICITY
A. Acute Toxicity
LC50 va^ues have been obtained for two species of fresh-
water fish: 8,280 ug/1 for bluegills, Lepomis macrochirus, in
»
a 96-hour static assay (U.S. EPA, 1978), and 60,510 ug/1 for
the fathead minnow, Pimephales promelas, in a 96-hour flow-through
assay (Phipps, et al. unpublished manuscript). For the fresh-
-------
water invertebrate, Daphnia magna, determined LC.-Q values range
from 8,396 to 21,900 jig/1 (U.S. EPA, 1979). The marine fish,
sheepshead minnow, Cyprinodon variegatus, has produced deter-
mined LCcg value of 27,100 816 ug/1 in a 96-hour static assay,
while the marine mysid shrimp, Mysidopis bahia, was more sensi-
tive, with a reported 3LC50 value of 7,170 }ig/l.
B. Chronic Toxicity
No chronic studies on freshwater organisms are available.
In an embryo-larval test of the marine fish, sheepshead minnow,
a chronic value of 6,325 pg/1 was obtained. No chronic testing
for marine invertebrates was available.
C. Plant Effects
Four species of freshwater plants have been tested
with 4-nitrophenol. . The algae, Selenastrum capricornutum and
Chlorella vulgar is, and the duckweed, Lemna minor, were most
sensitive with effective concentrations of 4,190, 6,950, and
9,452 ug/1, respectively; while the alga, Chlorella pyrenoidosa,
was much more resistant, with an effective concentration of 25,000
jag/1. The marine alga, Skeletonema costatum, provided effective
concentrations of 7,370 to 7,570 pg/1 (U.S. EPA, 1979).
D. Residues
No bioconcentration factors for either freshwater or
marine species were available.
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 review; therefore, there is a possibility that
these criteria will be changed.
-------
A. Human
Available data pertaining to 4-nitrophenol is insuffi-
cient for deriving a criterion to protect human health.
B. Aquatic
A criterion for protecting freshwater organisms has
been drafted as 240 ug/1, for a 24-hour average concentration,
not to exceed 550 ug/1. For marine life/ a criterion has been
drafted as 53 ^g/1 for a 24-hour average, not to exceed 120 ;jg/l
(U.S. EPA, 1979) .
-------
4-NITROPHENOL
REFERENCES
Adler, B., et al. 1976, Repair-defective mutants of Pro-
teus mirabilis as a prescreening system for the detection
of potential carcinogens. Siol. Zbl. 95: 463.
Chemical Marketing Reporter. 1976. Chemical profile:
p-nitrophenol. Chem. Market. Reporter p. 9.
Fahrig, R. 1974. Comparative mutagenicity studies with
Pesticides. Pages 161-181 Jn: R. Montesano and L. Tomatis
eds. Chemical carcinogenesTs essays. Proc. workshop on
approaches to assess the significance of experimental chemi-
cal carcinogenesis data for man organized by IARC and the
Catholic University of Louvain, Brussels, Belgium. IARC
Sci. Publ. No. 10, Int. Agency Res. Cancer, World Health
Organization.
Haller, H.D. 1978. Degradation of mono-substituted ben-
zoates and phenols by wastewater. Jour. Water Pollut. Con-
trol Fed. 50: 2771.
Lawford, D.J., et al. 1954. On the metabolism of some
aromatic nitro-compounds by different species of animals.
Jour. Pharm. Pharmacol. 6: 619.
Makhinya, A.P. 1969. Comparative hygienic and sanitary-
toxicological studies of nitrophenol isomers in relation
to their normalization in reservoir waters. Prom Zagryazneniya
Vodoemov. 9: 84.
Phipps, G.L., et al. The acute toxicity of phenol and sub-
stituted phenols to the fathead minnow. (Manuscript).
U.S. EPA. 1976. Frequency of organic compounds identified
in water. U.S. Environ. Prot. Agency. Contract No. EPA
600/4-76-062.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. Contract No.
68-01-4646.
U.S. EPA. 1979. Nitrophenols: Ambient Water Quality Cri-
teria (Draft) .
-------
No. 136
Nitrophenols
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
1600-
-------
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.
-------
NITROPHENOLS
SUMMARY
None of. the nitrophenols have shown carcinogenic activity.
Mutagenicity testing has indicated positive effects
of: 2,4-dinitrophenol in mouse bone marrow cells and E.
coli; 2,4,6-trinitrophenol in E. coli and Salmonella; and
4,6-dinitro-ortho-cresol in Proteus. Weak mutagenic effects
of 4-nitrophenol have been reported in Saccharomyces and
in Proteus. Other mutagenic test assays have shown negative
results for these compounds.
Teratogenic effects have been reported in the develop-
ing chick embryo following administration of 2,4-dinitro-
phenol. This compound did not produce teratogenic effects
*
in mammalian studies. Adverse reproductive effects (embryo
toxicity) were seen in rats exposed to 2,4-dinitrophenol..
The chronic effects of 2,4-dinitrophenol ingestion
have included cases of agranulocytosis, neuritis, functional
heart damage, and cataract formation. Ingestion of 4,6-
dinitro-ortho-cresol has also produced cataracts in humans.
One Russian study has reported cumulative toxic effects
in animals produced by the mononitrophenols; methodology
of this study was not available for review.
Freshwater fish appeared to be the most sensitive or-
ganism to the action of nitrophenols, with acute values
ranging from 230 to 167,000 pg/1. The reactivities of vari-
ous nitrophenols in order of decreasing toxicity are, in .
general: 2,4-dinitro-6-methylphenol, 2,4-dinitrophenol,
2-nitrophenol, 4-nitrophenol, and 2,4,6-trinitrophenol.
-------
NITROPHENOLS
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Nitrophenols (U.S. EPA, 1979).
The nitrophenols are a family of compounds which, de-
pending on the extent and position of nitro group substituents,
include the mononitrophenols, dinitrophenols, and trinitro-
phenols. Dinitrocresols are related compounds bearing an
additional 2-position methyl group. The mononitrophenols
(molecular weight 139.11) show boiling points from 194-279°C
(depending on the isomeric form) and melting points of 44-
114°C. They have a density of 1.485 and are soluble in
'"' )
water. The dinitrophenols (molecular weight 184.11) have
i
melting points from 63.5-144°C and show a density of 1.67
to 1.70. Water solubility is from 0.42 to 2.3 g/1. Tri-
nitrophenols (molecular weight 229.11) have melting points
'X
from 96-123°C; they are slightly soluo'le in water. 2,4,6-
Trinitrophenol, the most widely used. '-i6mer, has a density
of 1.763 g/ml and a solubility of 1.28 g/1. Of the six
isomers of dinitrocresol, 4,6-dinitro-o-cresol is the only
one of any commercial importance. The physical properties
of 4,6-dinitro-o-cresol, hereafter referred to as dinitro-
ortho-cresol, include a molecular weight of 198.13, a melt-
ing point of 85.8°C and a solubility of 100-mg/1 in water
(U.S. EPA, 1979).
»
Uses of the mononitrophenols include the following:
production of dyes, pigments, Pharmaceuticals, rubber chemi-
-1603-
-------
cals, lumber preservatives, photographic chemicals, and
pesticidal and fungicidal agents. The dinitrophenols are
used as chemical intermediates for sulfur dyes, azo dyes,
photochemicals, pest control agents, wood preservatives,
and explosives. 2,4,6-Trinitrophenol (picric acid) is used
for dye intermediates, germicides, tanning agents, fungi-
cides, tissue fixative, photochemicals, Pharmaceuticals,
and for the etching of metal surfaces. Dinitro-ortho-cresol
is used primarily as a blossom-thinning agent on fruit trees
and as a fungicide, insecticide, and miticide on fruit trees
during the dormant season (U.S. EPA, 1979).
Current Production: 2-nitrophehol 5- 7.5x1 ^tons/year .(1976)
4-nitrophenol 17.5x10 tons/year ?1976)
2,4-dinitrophenol 4.3xl02 tons/year (1968)
The nitrophenols may be formed via microbial Degrada-
tion or photodegradation of pesticides (e.g., parathion)
' /
containing the nitrophenol moiety (U.S. EPA, 1979).-1 Partial
microbial degradation of certain nitrophenols has been shown,
particularly by acclimated microorganisms. Mononitrophenols
appear to be efficiently degraded by unacclimated microorgan-
isms (Haller, 1978).
II. EXPOSURE
The lack of monitoring data on the nitrophenols makes
it difficult to assess exposure from water, inhalation,
#
and foods. Nitrophenols in water have been detected in
-------
effluents from chemical plants (U.S. SPA, 1976; 1979) or
following dumping of explosives (Harris, et al. 1946).
Dermal absorption of mononitrophenols, dinitrophenols, tri-
nitrophenols (picric acid), and dinitro-ortho-cresol (DNOC)
has been detected (U.S. EPA, 1979).
Exposure to nitrophenols appears to be primarily through
occupational contact (chemical plants, pesticide applica-
tion) . Contaminated water may result in isolated poisoning
incidents.
The U.S. EPA (1979) has estimated weighted average
bioconcentration factors for the following nitrophenols:
2-nitrophenoi, 4.0; 4-nitrophenoJ., 4.9; 2,4-dinitrophenol,
2.4; 2,4,6-trinitrophenol, 6.0; and 4,6-dinitrocresol, 7.5
for fish and shellfish consumed by Americans. This estimate
is based on octanol/water partition coefficients.
III. PHARMACOKINETICS
A. Absorption
Specific data on the absorption of the mononitro-
phenols is not available. The dinitrophenols are readily
absorbed following oral, inhalation, or dermal administra-
tion. Data on the absorption of trinitrophenols is not
available. Animal studies with oral:administration of 2,4,6-
trinitrophenol indicate that it is readily absorbed from
.the gastrointestinal tract. Dinitro-ortho-cresol is readily
absorbed through the skin, the respiratory tract, and the
»
gastrointestinal tract in humans (NIOSH, 1978).
-------
B. Distribution
No information on the distribution of the mono-
nitrophenols is available. Dinitrophenol blood levels rise
rapidly after absorption, with little subsequent distribu-
tion or storage at tissue sites (U.S. EPA, 1979). 2,4,6-
Trinitrophenol and dinitro-ortho-cresol have been found
to stain several body tissues; however, the compounds may
be bound to serum proteins, thus producing non-specific
organ distribution (U.S. EPA, 1979).
C. Metabolism
Metabolism of the nitrophenols occurs through
.conjugation, reduction of nitro groups to amino groups,
or oxidation to dihydric-nitrophenols (U.S. EPA, 1979).
These reactions are mediated primarily by liver enzyme, systems,
although other tissues show lower metabolizing activity
(U.S. EPA, 1979). The metabolism of dinitro-ortho-cresol
is very slow in man as compared to that observed in animal
studies (King and Harvey, 1953) .
D. Excretion
Evidence from human poisoning with parathion indi-
cates that excretion of 4-nitrophenol in the urine is quite
rapid (Arteberry, et al. 1961). Experiments with urinary
clearance of dinitrophenolS:in several animal species indi-
cate rapid .elimination of these compounds (Harvey, 1959).
2,4,6-Trinitrophenol has been detected in the urine of ex-
posed human subjects indicating at least partial urinary
elimination (Harris, et al. 1946). The experiments of Parker
-------
and coworkers (1951) in several animal species indicate
that dinitro-ortho-cresol is rapidly excreted following
injection; however, Harvey, et al. (1951) have shown slow
excretion of dinitro-ortho-cresol in human volunteers given
the compound orally.
IV. EFFECTS
A. Carcinogenicity
There are no available data to indicate that the
mononitrophenols are carcinogenic. Both 2- and 4-nitrophenol
failed to show promoting activity for mouse skin tumors
(Boutwell and Bosch, 1959); this same study failed to show
promoting activity for 2,4-dinitrophenol. No evidence is
available to indicate that dinitrophenols, trinitrophenols,
or dinitro-ortho-cresol produce any carcinogenic effects
(U.S. EPA, 1979) .
B. Mutagenicity
A weak mutagenic effect was detected in Saccharo-
myces cerevisiae for 4-nitrophenol (Fahrig, 1974); this
was also indicated by testing 4-nitrophenol for growth in-
hibition in a DNA repair deficient strain of Proteus mirabilis
(Adler, et al. 1976). This compound has also induced chromo-
some breaks in plants (U.S. EPA, 1979). 4-Nitrophenol has
failed to show mutagenic effects in the Ames assay, in E.
coli, or in the dominant lethal assay (U.S.,EPA, 1979).
Testing of 2,4-dinitrophenol has indicated muta-
genic effects in E. coli (Demerec, et al. 1951) and damage*
in murine bone marrow cells (chromatid breaks) (Mitra and
Manna, 1971). Ir\ vitro assays of unscheduled DNA synthesis
-------
(Friedman and Staub, 1976) and DNA damage induced during
cell culture (Swenberg, et al. 1976) failed to show positive
results with this compound.
2,4,6-Trinitrophenol has produced mutations in
E. coli and Salmonella assays (Demerec, et al. 1951; Yoshikawa,
et al. 1976). Testing in Drosophila has failed to indicate
mutagenic activity.
Adler , et al. (1976) have reported that dinitro-
ortho-cresol shows some evidence of producing DNA damage
in Proteus mirabilis . Testing of this compound in the Ames
Salmonella system (Anderson, et al. 1972) or in E. coli
(Nagy, et al. 1975) failed to show any mutagenic effects.
C. Teratogenicity
No information is available to indicate that mono-
nitrophenols , 2,4, 6-tr initrophenol, or dinitro-ortho-cresol
produce teratogenic effects.
2 ,4-Dinitrophenol has produced developmental abnor-
malities in the chick embryo (Bowman, 1967; Miyamoto, et
al. 1975) . No teratogenic effects were observed following
intragastric administration to rats -(Wulff, et al. 1935)
or intraper itoneal administration to mice (Gibson, 1973).
D. Other Reproductive Effects
Feeding of 2 , 4-dini.trophenol to pregnant rats
produced an increased mortality in offspring (Wulff, et
al. 1935) ; similarly, intraper itoneal administration of
the compound to mice induced embryotoxicity (Gibson, 1973) .'
it
-------
Influence of the compound on maternal health may have contri-
buted to these effects (U.S. EPA, 1979).
E. Chronic Toxicity
Chronic administration of mononitrophenols to
mammals has been reported to produce hepatitis, splenic
hyperplasia, and neurological symptoms in a single Russian
study (Makhinya, 1969) . Methodology of this study was not
available for review.
Use of 2, 4-dinitrophenol as a human dieting aid
has produced some cases of agranulocytosis , neuritis, func-
tional heart damage, and a large number of cases of cataracts
(Homer, 1942). Cataracts have also been reported in patients
poisoned with dinitro-ortho-cresol (NIOSH, 1978) .
Human effects resulting from 2 ,4 , 6-trinitrophenol
exposure have been reported as temporary impairment of speech,
memory, walking, and reflexes (Dennie, et al. 1929).
F. Other Relevant Information
A synergistic action in producing, teratogenic
effects in the developing chick embryo has been reported
with a combination of 2, 4-dinitrophenol and insulin (Landauer
and Clark, 1964) .
The combination of 2 , 4 , 6-trinitrophenol and opioids
or minor analgesics produced an increase in analgesia (Huidobro,
1971) .
2,4-Dinitrophenol is a classical uncoupler of
oxidative phosphorylation, which accounts for its marked
acute toxicity. Dinitro-ortho-cresol is also well known
for its activity as an uncoupler.
-fto?-
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Freshwater fish LC5Q values reported for the blue-
gill (Lepomis macrochinus) ranged from 230 to 167,000 ug/1
and for the juvenile fathead minnow (Pimephales promelas) ,
from 2,040 to 60,510 ug/1. The order of decreasing toxicity
for five nitrophenols examined was: 2,4-dinitro-6-methyl
phenol, 2,4-dinitrophenol, 2-nitrophenol, 4-nitrophenol,
2,4,6-trinitrophenol (U.S. EPA, 1979). For three of the
phenols tested with both the bluegill and fathead minnow,
the bluegill appeared more sensitive. In static bioassays
with the freshwater invertebrate, Daphnia magna, 48-hour
LC50 values of 4,090 to 4,710; 8,396 to 21,900; and 84,700
pg/1 were reported for 2,4-dinitrophenol, 4-nitrophenol
and 2,4,6-trinitrophenol, respectively (U.S. EPA, 1979).
The marine fish, sheepshead minnow (Cyprinodon variegatus) ,
was the only fish species acutely tested for three nitro-
phenols, with reported LC5Q values of 29,400; 27,100 and
134,000 ug/1 being obtained for 2,4-dinitrophenol, 4-nitro-
phenol, and 2,4,6-trinitrophenol. Observed LCqQ values
of 4,350; 7,170 and 19 >700 ^ig/1 were reported for the mysid
shrimp (Mysidopsis bahia) for the same three formulations,
respectively.
B. Chronic Toxicity
Pertinent information on the chronic effects on
freshwater species could not be located in the available
literature searches. The only chronic test on a marine
-------
species was an embryo-larval assay of the sheepshead minnow
that produced a chronic value of 6,325 ug/1 (U.S. EPA, 1978).
Pertinent information relative to chronic effects on marine
invertebrates could not be located in the available literature.
C. Plant Effects
The effects of various nitrophenols vary widely
among species of freshwater plants and according to the
formulation of nitrophenol tested. The duckweed, Lemna
minor, was the most sensitive plant tested with 2,4-dinitro-
phenol and was the most resistant with 2-nitrophenol, hav-
ing effective concentrations (50 percent growth reduction,
time unspecified)ranging from 1,472 to 62,550 ug/1 for the
two respective formulations. The marine alga, Skeletonema
costaturn, appeared to be slightly more resistant than fresh-
water species tested, with effective concentrations ranging
from 7,370 to 'l41,000 jjg/1 for 4-nitrophenol and 2,4,6-tri-
nitrophenol, respectively.
D. Residues
Bioconcentration factors were not determined for
any freshwater or marine species. However, based on octanol/
water partition coefficients, bioconcentration factors were
estimated as 8.1, 21, and 26 for 2,4-dinitrophenol, 2,4,6-
trinitrophenol, and 2,4-dinitro-6-dimethylphenol, respectively.
VI. EXISTING GUIDELINES AND STANDARDS
The human health and aquatic criteria derived by U.S.
SPA (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
Eight-hour TWA exposures for 2,4,6-trinitrophenol
(0.1 mg/m ) and 4,6-dinitro-ortho-cresol (0.2 mg/m ) have
been established by the ACGIH (1971).
Draft water quality criteria for the following
nitrophenols have been estimated by U.S. EPA (1979) based
on adverse effects data: dinitrophenols - 68.6 jjg/1; tri-
nitrophenols - 10 pg/l; and dinitrocresols - 12.3 /ag/1.
B. Aquatic
Criteria drafted to protect freshwater life from
nitrophenols follow: 57 pg/1 as a 24-hour average concen-
tration, not to exceed 130 ug/1, for 2,4-dinitro-6-methyl-
phenol; 79 jug/1, not to exceed 180 pg/1, for 2,4-dinitro-
phenol; 240 pg/1, not to exceed 550 pg/1, for 4-nitrophenol;
2,700 ug/1, not to exceed 6,200 jag/1, for 2-nitrophenol;
and 1,500 ug/1, not to exceed 3,400 yg/1, for 2,4,6-trinitro-
phenol. For marine life the following criteria have been
drafted as 24-hour average concentrations: 37 /jg/1, not
to exceed 84 pg/1, for 2,4-dinitrophenol; 53 ;jg/l, not to
exceed 120 jjg/1, for 4-nitrophenol; and 150 pg/1, not to
exceed 340 pg/1, for 2,4,6-trinitrophenol.
-------
NITROPHENOLS
REFERENCES
Adler, 3., et al. 1976. Repair-defective mutants of Proteus
mirabilis as a prescreening system for the detection of po-
tential carcinogens. Biol. Zbl. 95: 463.
American Conference of Governmental Industrial Hygienists.
1971. Documentation of the threshold limit values for sub-
stances in workroom air. Vol. 1. 3rd ed. Cincinnati, Ohio.
Anderson, K.J., et al. 1972. Evaluation of herbicides for
possible mutagenic properties. Jour. Agric. Food Chem. 20:
649.
Arterberry, J.D., et al. 1961. Exposure to parathion: Mea-
surement by blood cholinesterase level and urinary p-nitro-
phenol excretion. Arch. Environ. Health 3: 476.
Boutwell, R.K., and D.K. Bosch. 1959. The tumor-promoting
action of phenol and related compounds for mouse skin.
Cancer Res. 19: 413.
Bowman, P. 1967. The effect of 2,4-dinitrophenol on the
development of early chick embryos. Jour. Smbryol. Exp.
Morphol. 17: 425.
Demerec, M., et al. 1951. A survey of chemicals for muta-
genic action on _E. coli. Am. Natur. 35: 119.
Dennie, C.C., et al. 1929. Toxic reactions produced by the
application of trinitrophenol (picric acid). Arch. Dermatol.
Sypnilol. 20: 698.
Fahrig, R. 1974. Comparative mutagenicity studies with Pes-
ticides. Pages 161-181 In; R. Montesano and L. Tomatis.
(eds.) Chemical carcinogenesis essays. Proc. workshop on
approaches to assess the significance of experimental chemi-
cal carcinogenesis data for man. Organized by IARC and the
Catholic University of Louvain, Brussels, Belgium. IARC Sci.
Publ. No. 10. Int. Agency Res. Cancer, World Health Organi-
zation.
Friedman, M.A., and J. Staub. 1976. Inhibition of mouse
testicular DMA synthesis by mutagens and carcinogens as a po-
tential simole mammalian assay for mutagenesis. Mutat. Res.
37: 67.
Gibson, J.E. 1973. Teratology studies in mice with 2-saq-
butyl-4, 6-dinitrophenol (dinoseb). .Food Cosmet. Toxicol.
11: 31.
-1613
-------
Haller, H.D. 1978. Degradation of mono-substituted benzo-
ates and phenols by wastewater. Jour. Water Pollut. Control
Fed. 50: 2771.
Harris, A.H., et al. 1946. Hematuria due to picric acid
poisoning at a naval anchorage in Japan. Am. Jour. Pub.
Health 36: 727.
Harvey, D.G. 1959. On the metabolism of some aromatic nitro
compounds by different species of animal. Part III. The
toxicity of the dinitrophenols, with a note on the effects of
high environmental temperatures. Jour. Pharm. Pharmacol.
11: 462. - " A .
Harvey, D.G., et al. 1951. Poisoning by dinitro-ortho-cre-
sol. Some observations on the effects of dinitro-ortho-cre-
sol administration by mouth to human volunteers. Br. Med.
Jour. 2: 13.
Horner, W.D. 1942. Dinitrophenol and its relation to forma-
tion to cataracts. Arch. Ophthal. 27: 1097.
.Huidobro, F. 1971. Action of picric acid on the effects of
some drugs" "jting on the central nervous system, with special
reference u^-'opiods. Arch. Int. Pharmacodyn Ther. ; 192:
362.
King, E., and D.G. Harvey. 1953. Some observations on the
absorption and excretion of 4,6-dinitro-o-creosol (DNOC). I.
Blood dinitro-o-cresol levels in the rat and rabbit following
different methods of absorption. Biochem. Jour. 53: 185.
Landauer, w.1, and E. Clark. 1964. Uncouplers of oxidative
phosphorylation and teratogenic activity of insulin. Nature
204: 285.. ~ '
Makhinya, A.P. 1969. Comparative hygienic and sanitary
toxicological studies of nitrophenol isomers in relation to
their normalization in reservoir waters. Prom. Zagryazneniya
Vodoemov. 9: 84. (Translation).
Mitra, A.B., and G.K. Manna. 1971. Effect of some phenolic
compounds on chromosomes of bone marrow cells of mice. In-
dian Jour. Med. Res. 59: 1442.
Miyamoto, K., et al. 1975. Deficient-myelination by 2,4-
dinitrophenol administration in early stage of development.
Teratology 12: 204.
Nagy, A., et al. 1975. The correct mutagenic effect of pes-
ticides on Escherichia coli WP2 strain. Acta. Microbiol.'
Acad. Sci. Hung. 22: 309.
16IV-
-------
National Institute for Occupational Safety and Health. 1978.
Criteria for a recommended standard: Occupational exposure to
dinitro-ortho-creosol. Dep.. Health Edu. Welfare, Washing-
ton, D.C.
Parker, V.H., et al. 1951. Some observations on the toxic
properties of 3,5-dinitro-ortho-cresol. 3r. Jour. Ind. Med.
9: 226.
Swenberg, J.A., et al. 1976. In vitro DNA damage/akaline
elution assay for predicting carcinogenic potential.
Biochem. Biophys. Res. Commun. 72: 732.
U.S. EPA. 1976. Frequency of organic compounds identified
in water. U.S. Environ. Prot. Agency. Contract No. EPA
600/4-76-062.
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No.
6801-4646.
U.S. EPA. 1979. Nitrophenols: Ambient Water Quality Cri-
teria. (Draft).
Wulff, L.M.B., et al. 1935. Some effects of alpha-dinitro-
phenol on pregnancy in the white rat. Proc. Soc. Exp. Biol.
Med. 32: 678.
Yoshikawa, K., et al. 1976. Studies on the mutagenicity of
hair-dye. Kokuritsu Eisei Shikenjo 94: 28.
161?
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No. 137
Nltrosamines
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 acc-uracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
nitrosamines and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
NITROSAMINE5
Summary
Nitrosamines and nitrosamides are widespread in the environment and can
also be produced endogenously by nitrosation of constituents of food. Ni-
trosamines and nitrosamides are considered to be among the most potent of
all carcinogenic, mutagenic, and teratogenic agents known. The livers of
rats chronically exposed to nitrosamines exhibit pathological changes.
Toxicity data examining the effects of nitrosamines on aquatic organ-
isms is scant. For freshwater life forms, acute toxicity levels of 5,850 to
7,760 ug/1 were reported, while for marine fish an acute value of nearly
3,300,000 ug/1 was reported (both values for N-nitrosodiphenylamine). N-ni-
trosodimethylamine has been shown to induce hepatocellular carcinoma ."in
rainbow trout.
-IU1-
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. NITROSAMINES
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Nitrosamines (U.S. EPA, 1979).
The nitrosamines (and nitrosamides) belong to a large group of chemi-
cals generally called N-nitroso compounds. Because they frequently coexist
with N-nitrosamines in the environment and are structurally related to ni-
trosamines, nitrosamides are also included in the U.S. EPA (1979) document
and in this profile.
The nitrosamines vary widely in their physical properties and may exist
as solids, liquids or gases. Nitrosamines of low molecular weight are vola-
tile at room temperature, while those of high molecular weight are steam
% ' •
volatile. Nitrosamines are soluble in water and organic solvents (U.S. EPA,
1976).
Synthetic production of nitrosamines is limited to small quantities.
The only nitrosamine produced in quantities greater than 450 kg per year is
N-nitrosodiphenylamine, which is used in rubber processing and in the manu-
facture of pesticides. Other N-nitroso compounds are produced primarily as
research chemicals (U.S. EPA, 1976).
Nitrosamines are rapidly decomposed by sunlight and thus do not persist
in ambient air or water illuminated by sunlight (U.S. EPA, 1979; Fine, et
al. 1977a). Some nitrosamines have been found to persist for extended peri-
ods of time in the aquatic environment (Fine, et al. 1977a; Tate and Alex-
ander, 1975).
II. EXPOSURE
»
Nitrosamines are widespread in the environment. The most probable
source of environmental nitrosamines is nitrosation of amine and amide pre-
cursors which are ubiquitous in the environment (Bogovski, et al. 1972).
-------
It has been estimated that air, diet, and smoking all play a roughly
equivalent role in human exposure to preformed nitrosamines, contributing a
few micrograms per day; intake from drinking water is probably much less
than 1 ug per day (U.S. EPA, 1976).
A. Water
Significant concentrations of nitrosamines have been reported for a
limited number of samples of ocean water, river water, and waste treatment
plant effluent (3 to 4 jjg dimethylnitrosamine/1) adjacent to or receiving
wastewater from industries using nitrosamines or secondary amines in produc-
tion operations (Fine, et al. 1977b). Well water with high nitrate levels
and coliform counts had nitrosamine concentrations of less than 0.015 pg/1
(U.S. EPA, 1977). Non-volatile nitrosamines have been tentatively identi-
fied in New Orleans drinking water at levels of 0.1 to 0.5 ug/1 (Fine, fit
al. 1976).
Contamination of water can occur both from industrial wastewater
and from agricultural runoff.
3. Food
Nitrosamines have been found in foods, particularly in meats such
as sausages, ham, and bacon which have been cured with nitrite. N-nitroso-
dimethylamine was present in a variety of foods in the 1 to 10 ug/kg range
and occasionally at levels up to 100 ug/kg (Montesano and Sartsch, 1976).
N-nitrosopyrrolidine has been consistently found in cooked bacon in the
range of 10-50 ug/kg (Fine, et al. 1977a).
Many food constituents can either be converted directly to N-nitro-
50 compounds or give rise to nitrosatable products after a metabolic inter-
mediate step which can be involved directly or indirectly in such reactions.
-------
Constituents include nitrate, nitrite, some amino acids, choline, phospholi-
pids, purines, pyrimidines, some vitamins, caffeine, and some pesticides
(Walters, 1977; Elsperu and Lijinsky, 1973).
Nitrate and nitrite are well supplied in the diet. Eighty-six per-
cent of the nitrate ingested comes from vegetables; 9 percent comes from
cured meats. Only 2 percent of the nitrite ingested comes from vegetables,
while 21 percent comes from cured meat (White, 1975).
The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor to be 500 for N-nitrosodiphenylamine in the edible portions
of fish and shellfish consumed by Americans. This estimate is based on mea-
sured steady-state bioconcentration studies with bluegills. Based on the
octanol/water partition coefficient for. each compound, the U.S. EPA (1979)
has estimated weighted average bioconcentration factors for the following;
compounds in the edible portions of fish and shellfish consumed by Ameri-
cans: N-nitrosodimethylamine, 0.06; N-nitrosodiethylamine, 0.39; N-nitroso-
di-n-butylamine, 4.9; and N-nitrosopyrrolidine, 0.12.
C. Inhalation
Due to the photolabile nature of nitrosamines, concentrations in
ambient air are very low, except near sources of direct emissions of nitros-
amines (i.e. chemical plants) (Fine, et al. 1977a). Nitrosamines were de-
tected only twice at 40 collection points in New Jersey and New York City,
and then -only below the 0.01 jug/m level.
Tobacco and tobacco smoke contain both secondary amines and nitros-
amines (Hoffman, et al..1974). The intake of nitrosamines from smoking 20
cigarettes per day has been estimated at approximately 6 ug/day (U.S.. EPA,
1979).
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III. PHARMACOKINETICS
A. Absorption
Pertinent data could not be located in the available literature.
8. Distribution
Following intravenous injection into rats, nitrosamides and nitros-
amines are rapidly and fairly, uniformly distributed throughout the body
(Magee, 1972; Stewart, et al. 1974). Both nitrosamides and nitrosamines ap-
pear to cross the placenta since they induce neoplasms in offspring if ad-
ministered maternally to rats in late pregnancy (Magee, et al. 1976).
C. Metabolism and Excretion
Nitrosamides- are rapidly metabolized in animals and excreted in the
urine within 24 hours (Magee, et al. 1976)..
Nitrosamines are metabolized less rapidly and persist in the body
unchanged for a longer period. The rate of metabolism depends upon the
chemical structure (U.S. EPA, 1979).
After administration of C-labeled dimethylnitrosamine, diethyl-
nitrosamine, or nitrosomorpholine, the amount of isotope appearing as
14
CO- within 12 hours is 60, 45, and 3 percent, respectively, while the
corresponding urinary excretions are 4, 14, and 80 percent. Urinary metabo-
lites include other nitroso compounds formed by oxidation of the alkyi
groups to the alcohols and carboxylic acids (Magee, et al. 1976). Dimethyl-
nitrosamine is excreted in the milk of female rats (Schoental, et al. 1974).
The liver appears to be the major site for metabolism of nitrosa-
mines: kidney and lung also metabolize nitrosamines (Magee, et al. 1976).
The metabolites of nitrosamines are thought to be the active teratogenic,
mutagenic and carcinogenic forms (U.S. EPA, 1979).
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IV. EFFECTS
A. Carcinogenicity
The epidemiological studies conducted to date have been inadequate
to establish any correlation between exposure to N-nitroso compounds or
their precursors and human cancer (U.S. EPA, 1979).
In animals, nitrosamines and nitrosamides are potent carcinogens,
inducing tumors in essentially all vital organs via all routes of admini-
stration (Montesano and Bartsch, 1976; Druckrey, et al. 1967).
Many of the N-nitroso compounds which have been tested are carcino-
genic. There is a strong relationship between chemical structure and type
of tumors produced. Symmetrically substituted dialkylnitrosamines and some
cyclic nitrosamines produced carcinomas_of the liver. Asymmetrical dialkyl-
nitrosamines produced carcinomas of the esophagus (Druckrey, et al. 1967)..
Apparently all N,N-dialkylnitrosamines containing a tert-butyl group are
noncarcinogenic (Heath and Magee, 1962).
There are large differences in species response to carcinogenic
nitrosamines and nitrosamides, both in type of tumor produced and in suscep-
tibility, . but all animal species tested are vulnerable. The late fetus and
neonate appear to be . highly susceptible (U.S. EPA, 1979). Exposure to
nitrosamides during pregnancy may result in a risk not only to the immediate
offspring, but also for at least two more generations of animals (Montesano
and Bartsch, 1976). There is no evidence to indicate that nitrosamines pose
a similar threat (U.S. EPA, 1979).
Daily oral doses of N-nitroso compounds 'of 2.5 percent of the
LD5g values were sufficient to induce cancer in rats (Druckrey, et al.
1967).
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8. Mutagenicity
The N-nitroso compounds include some of the most powerful mutagens
known. Nitrosamides are mutagenic in almost all test systems, due to non-
V
enzymic formation of active degradation products. Nitrosamines must be
metabolically activated to be mutagenic in microbial assays (U.S. EPA, 1979).
Oimethylnitrosamine and diethylnitrosamine have been reported to
induce forward and reverse mutations in S_._ typhimurium, §_._ coli, Neurospora
crassa and other organisms; gene recombination and conversion in Saccharo-
mvces cerevisiae; "recessive lethal mutations" in Drosophila; and chromosome
aberrations in mammalian cells (Montesano and Bartsch, 1976). Negative re-
sults were obtained in the mouse dominant lethal test.
C. Teratogenicity
N-nitroso compounds can be potent teratogens (U.S. EPA, 1979.).
Nitrosamides are teratogenic over an extended period of gestation, whereas
nitrosamines are active only when administered late in pregnancy (Druckrey,
1973) probably because of the inability of the embryonic tissue to metabo-
lize nitrosamines during early pregnancy (Magee, 1973).
0. Other Reproductive Effects :
Nitrosamines and nitrosamides are embryotoxic (Druckrey, 1973).
E. Chronic Toxicity
The livers of rats and other species chronically exposed to nitros-
amihes exhibit pathological changes including biliary hyperpiasia, fibrosis,
nodular parenchymal hyperpiasia, and the formation of enlarged hepatic par-
enchymal cells with large nuclei (Magee, et al. 1976).
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F. Other Relevant Information
Unlike nitrosamines, nitrosamides cause tissue injury at the site
of contact (Magee, et ai. 1976). This is thought to be due to the nonenzy-
matic decomposition of nitrosamides into active products upon contact with
tissues.
Aminoacetonitrile, which inhibits the metabolism of dimethylnitros-
amine, prevented the toxic and carcinogenic effects of dimethylnitrosamine
in rat liver (Magee, et al. 1976).
Ferric oxide, cigarette smoke, volatile acids, aldehydes, methyl
nitrite, and benzo(a)pyrene have been suggested to act in a cocarcinogenic
manner with dimethylnitrosamine (Stenback, et al. 1973; Magee, et al. 1976).
V. AQUATIC TOXICITY
A. Acute Toxicity . -
The LC5_ value of 5,850 ug/1 for bluegill sunfish (Leoomis macro-
chirus) exposed to N-nitrosodiphenylamine represents the sole acute toxicity
data for freshwater fish, while an LC5Q value of 7,760 /ug/1 was obtained
for the freshwater invertebrate, Oaphnia magna (U.S. EDA, 1978). .The marine
mummichog (Fundulus heteroclitus) was relatively resistant to N-nitrosodi-
methylamine in a 96-hour static test, where an adjusted LC,-n value of
3,300,000 ug/1 was reported (Ferraro, et al. 1977). No additional data con-
cerning marine organisms was presented in the Ambient Water Quality Criteria
Document (U.S. EPA, 1979).
8. Chronic Toxicity
The chronic effects of N-nitrosodiphenyl amine have been examined
in Daohnia maqna., with no adverse effects being reported at a concentration
"^^^"^ : »
of 48 ug/1. NO•chronic data concerning marine organisms were found in the
.available literature.
-------
C. Plant Effects
Pertinent data could not be located in the available literature.
D. Residues
A bioconcentration factor of 217 was reported, as was a biological
half-life of less than one day in the freshwater bluegill sunfish (U.S. SPA,
1978). NO data on residues in marine life were found in the available lit-
erature.
€.. Miscellaneous
Shasta strain .rainbow trout (Salmo gairdneri) fed N-nitrosodi-
methylamine in their diet for 52 weeks developed a dose-response occurrence
of hepatocellular carcinoma at doses of 200, 400, and 800 mg N-nitrosodi-
methylamine per kg body weight (Grieco, et al. 1978).
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
Using the. "one-hit" model, the U.S. EPA (1979) has estimated the
following levels of nitrosamines in ambient water which will result in spe-
cified risk levels of human cancer.
The water concentration of dimethylnitrosamine corresponding to a
lifetime cancer risk for humans of 10" is 0.026 ug/1, based on the induc-
tion of liver tumors in rats (Druckrey, 1967).
The water concentration of dibutylnitrosamine corresponding to a
lifetime cancer risk for humans of 10" is 0.013 jug/1, based on induction
of tumors of the bladder and esophagus in mice (Bertram and Craig, 1970).
-------
The water concentration of N-nitroso-pyrrolidine corresponding to a
lifetime cancer risk for humans of 10 is 0.11 /ug/1, based on the induc-
tion of hepatocellular carcinomas in rats (Preussman, et al. 1977).
No other guidelines or standards are available.
8. Aquatic
No criteria for freshwater or marine life have been drafted (U.S.
EPA, 1979).
sf
-------
NITROSAMINES
REFERENCES
Bertram, J.S., and A.W. Craig. 1970. Induction of bladder
tumours in mice with dibutvlnitrosamine. Br. Jour. Cancer
24: 352.
Bogovski, P., et al. 1972. N-nitroso compounds, analysis
and formation. IARC Sci. Pub. No. 3. Int. Agency Res.
Cancer, Lyon, France.
Druckrey, H., et al. 1967. Organotropic carcinogenic action
of 65 different N-nitroso compounds in BD rats. Z. Krebs-
forsch. 69: 103.
Druckrey, H. 1973.. , Specific carcinogenic and teratogenic
effects of "indirect" alkylating methyl and ethyl compounds,
and their dependency on stages of oncogenic development.
Xenobiotica 3: 271.
--"Slsperu, R., and W. Lijinsky. 1973. The formation of N-
nitroso compounds from nitrite and some agricultural chemi-
cals. Food Cosmet. Toxicol. 11: 807.
Ferraro, A.F., et al. 1977. Acute toxicity of water-borne
dimethylnitrosaraine (DMN) to Fundulus heteroclitus (L).
Jour. Fish. Biol. 10: 203.
Fine, D.H., et al. 1976. N-Nitroso compounds in air and
water. IARC Sci. Publ. No. 14. Int. Agency Res. Cancer,
,Lyon, France.
. *
Fine, D.H., et al. 1977a. Human exposure to N-nitroso
compounds in the environment. In: H.H. Hiatt, et al.,
eds. Origins of human cancer. Told Spring Harbor Lab.,
Cold Spring Harbor, New York.
Fine, D.H., et al. 1977b. Determination of diraethylnitro-
samine in air, water and soil by thermal energy analysis:
measurements in Baltimore, Md. Environ. Sci. Technol. 11:
581.
Grieco, M.P., et al. 1978. Carcinogenicity and acute toxi-
city of dimethylnitrosamine in rainbow trout (Salmo gaird-
neri). Jour. Natl. Cancer Inst. 60: 1127.
Heath, D.F., and P.N. Magee. 1962. Toxic properties of .
dialkylnitrosamines and some related compounds. 3r. Jour.
Ind. Med. 19: 276.
-------
NITROSAMINES
REFERENCES
Bertram, J.S., and A.W. Craig. 1970. Induction of bladder
tumours in mice with dibutylnitrosamine. Br. Jour. Cancer
24: 352.
Bogovski, P., et al. 1972. N-nitroso compounds, analysis
and formation. IARC Sci. Pub. No. 3. Int. Agency Res.
Cancer, Lyon, France.
Druckrey, H., et al. 1967. Organotropic carcinogenic action.
of 65 different N-nitroso compounds in BD rats. Z. Krebs-
forsch. 69: 103.
Druckrey, H. 1973.. Specific carcinogenic and teratogenic
effects of ."indirect" alkylating methyl and ethyl compounds,
and their dependency on stages of oncogenic development.
Xenobiotica 3: 271.
Elsperu, R., and W. Lijinsky. 1373. The formation of N-
nitroso compounds from nitrite and some agricultural chemi-
cals. Food Cosmet. Toxicol. 11: 807.
Ferraro, A.F., et al. 1977. Acute toxicity of water-borne
dimethylnitrosamine - (DMN) to Fundulus heteroclitus (L).
Jour. Fish. Biol. 10: 203.
Fine, D.H., et al. 1976. N-Nitroso compounds in air and
water. IARC Sci. Publ. No. 14. Int. Agency Res. Cancer,
Lyon, France.
• <*
Fine, D.H., et al. 1977a. Human exposure to N-nitroso
compounds in the environment. In: H.H. Hiatt, et al.,
eds. Origins of human cancer. Cold Spring Harbor Lab.,
Cold Spring Harbor, New York.
Fine, D.H., et al. 1977b. Determination of dimethylnitro-
samine in air, water and-soil by thermal energy analysis:
measurements in Baltimore, Md. Environ. Sci. Technol. 11:
581.
Griecp, M.P.., et al. 1978. Carcinogenicity and acute toxi-
city of dimethylnitrosamine in rainbow trotit (Salmo gaird-
nerl). Jour. Natl. Cancer Inst. 60: 1127.
Heath, D.F., and P.M. Magee. 1962. Toxic properties of •
dialkylnitrosamines and some related compounds. Br. Jour.
Ind. Med. 19: 276.
-/63t> -
-------
Hoffman, D., et al. 1974. Chemical studies on tobacco
smoke. XXVI. On the isolation and identification of vola-
tile and non-volatile N-nitrosamines and hydrazines in ciga-
rette smoke. In: N-Nitroso compounds in the environment.
IAHC Sci. Pub. No. 9. Int. Agency Res. Cancer, Lyon, France.
Magee, P.N. 1972. Possible mechanisms of carcinogenesis
and mutagenesis by nitrosamines. In: W. Nakahara, et al. ,
eds. .Topics in chemical carcinogenesis. University of
Tokyo Press, Tokyo.
Magee, P.N. 1973. Mechanisms of transplacental carcino-
genesis by nitroso compounds. In; L. Toraatis and U. Mohr,
eds. Transplacental carcinogenesis. IARC Sci. Pub. No. .
4. Int. Agency Res. Cancer, Lyon, France.
Magee, P.N., et al. 1976. N-Nitroso compounds and related
carcinogens. In: C.S. Searle, ed. Chemical Carcinogens.
ACS Monograph No. 173. Am. Chem. Soc., Washington, D.C.
Montesano, R., and H. Bartsch. 1976. Mutagenic and carcino-
genic N-nitroso compounds: Possible environmental hazards.
Mutat. Res. 32: 179.
Preussmann, R., et al. 1977. Carcinogenicity of N-nitroso-
pyrrolidine: Dose-response study in rats. Z. Krebsforsch.
90: 161.
Schoental, R., et al.- 1974. Carcinogens in milk: Transfer
of ingested diethylnitrosamine into milk by lactating rats.
Br. Jour. Cancer 30: 238.
Stenback, F., et al. 1973. Synergistic effect of ferric
oxide on dimethylnitrosamine carcinogenesis in the Syrian
golden hamster. 2. Krebsforsch. 79: 31.
Stewart, B.W., et al. 1974. Cellular injury and carcino-
genesis. Evidence for the alkylation of rat liver nucleic
acids in vivo by N-nitrosomorpholine. Z. Krebsforsch. 82:
1.
Tate, R.L., and M. Alexander. 1975. Stability of nitro-
samines' in samples of lake water, soil and sewage. Jour.
Natl. Cancer Inst. 54: 327.
U.S. EPA. 1976. Assessment of scientific information on
nitrosamines. A report of an ad hoc study group of the
U.S. Environ. Prot. Agency Sci. Advis. Board Executive Comm.
Washington, D.C.
U.S. EPA. 1977. Scientific and assessment report on nitro-
saraines. EPA 600/6-77-001. Off. Res. Dev. U.S. Environ.
Prot. Agency, Washington, D.C.
1631-
-------
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. Contract No.
68-01-4646. U.S. Environ. Prot. Agency.
U.S. SPA. 1979. Nitrosamines: Ambient Water Quality Cri-
teria (Draft).
Walters, C.L. 1977. Nitrosamines - environmental carcinogens?
Chem. Br. 13: 140.
White, J.W., Jr. 1975. Relative significance of dietary
sources of nitrate and nitrite. Jour. Agric. Food Chem.
23: 886.
-------
No. 138
N-Nitrosodiphenylamine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
•1.623-
-------
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.
-------
N-NITROSODIPHENYLAMINE
SUMMARY
Formation of N-nitrosodiphenylamine (NDPhA) has been shown
experimentally in the stomachs of individuals receiving nitrite
and diphenylamine. N-nitrosodiphenylamine undergoes photochemi-
cal decomposition in solution or in the atmosphere in the
presence of sunlight. Bacterial degradation of NDPhA has been
demonstrated in soil.
Prior to the release of recent findings from the NCI bio-
assay program, NDPhA was considered a non-carcinogenic nitros-
amine. In the NCI lifetime rat feeding study, however, NDPhA was
found to induce a significant incidence of urinary bladder tumors
in both males and females. Few urinary bladder tumors were
observed in mice in a similar experiment, although there was a
high incidence of non-neoplastic bladder lesions.
N-nitrosodiphenylamine has consistently been found negative
in a variety of mutagenicity assays.
I. INTRODUCTION
This document is based on the Ambient Water Quality Criteria
Document on Nitrosamines (U.S. EPA, 1979b), the Scientific and
Technical Assessment Report on Nitrosamines (U.S. EPA, 1977), and
other selected references. The term "N-nitrosodiphenylamine"
(NDPhA) in this report refers specifically to that compound; the
term "nitrosamine" when used in this report refers to nitrosa-
mines in general.
-------
N-nitrosodiphenylamine (NDPhA; molecular weight 198.23;
molecular formula CJ-HIQM O) ^s a yeiiow to brown or orange
powder or flakes. It has the following physical/chemical
properties (Hawley, 1977):
Melting Point: 64-669C
Solubility: insoluble in water;
soluble in organic
solvents.
NDPhA is used as a vulcanization retarder in the rubber '
industry (Hawley, 1977).
A review of the production range (includes importation)
statistics for N-nitrosodiphenylamine (CAS No. 86-30-6) which is
listed in the initial TSCA Inventory (1979a.) has shown that
between 400,000 and 900,000 pounds of this chemical were pro-
duced/imported in 1977.—/
II. EXPOSURE
A. Formation
The chemistry of formation of nitrosamines is quite complex,
however, they are in general formed by the combination of amines
(R^R2N~) with some nitrosating agent. Formation has been shown
to occur with primary, secondary, and tertiary amines, as well as
_V This production range information does not include any produc-
tion/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).
-------
other amino compounds. The nitrosating agent can be derived from
nitric oxides (NO, NC^, ^O^, or N2°4^ or inor?anic nitrite (U.S.
EPA, 1977).
The in vivo formation of nitrosamines following ingestion of
precursors has been demonstrated in human and animal studies
(U.S. EPA, 1977) Sander and Seif (1969) showed the formation of
NDPhA in the stomachs of humans given nitrite and diphenylamine.
B. Environmental Fate
In the absence of light, nitrosamines are quite stable and
will decompose hydrolytically only following prolonged contact
with strong acid. There is no evidence of thermal instability of
nitrosamines in the gas phase; however, they do undergo photo-
chemical decomposition in solution or in the atmosphere in the
presence of sunlight or ultra-violet light (U.S; EPA, 1977).
Transnitrosation reactions involving direct transfer of the
nitroso group from NDPhA to other amines have been demonstrated
(Challis and Osborn, 1972). Such a reaction yields a new
N-nitroso compound and diphenylamine.
In unamended soil, 70% of added NDPhA was lost within 30
days. In soil amended with bacteria, added NDPhA had disappeared
completely at the end of day 10 (Mallik, 1979).
C. . Bioconcentration
See Section V.C.
~/637-
-------
III. PHARMACOKINETICS
Intestinal bacteria common in the gastrointestinal tract of
many animals and humans have been shown capable of degrading
NDPhA (Rowland and Grasso, 1975).
IV. HEALTH EFFECTS IN MAMMALS
A. Carcinogenicity
In a one-year study, Argus and Hoch-Ligeti (1961) adminis-
tered NDPhA by gavage to 25 male rats for 45 weeks (total dose
244 mg/rat). No tumors were observed. In other studies (Boyland
_et_ _al_. , 1968) no tumors were seen when 20 rats were given the
test compound in the diet for 100 weeks .at daily doses of 120
mg/kg, or when 24 male rats were administered DNPhA by intra-
peritoneal injection once per week for 6 months at a dose of 2.5
mg/week. Both tests were terminated after 2 years. When two
groups of mice (18 male and 18 female per group) were admin-
istered NDPhA by gavage daily for 3 weeks at 1,000 mg/kg, then in
diet at 3,769 ppm for 18 months, no significant incidences of
tumors were observed. However, in another assay reticulum cell
sarcomas were observed in the mice when the chemical was injected
subcutaneously (NCI, 1968; Innes et._ _al_., 1969). Druckrey et al.
(1967) reported a lack of tumorigenicity in rats administered 120
mg/kg/day of NDPhA for 700 days, for a total dose of 65 g/kg.
Taken together, these studies were viewed as a demonstration of
the non-carcinogenicity of NDPhA.
»
Recent results from the NCI bioassay program, however, have
demonstrated that NDPhA is a carcinogen in rats (NCI, 1979; Cardy
-------
et_ ^1_. , 1979). In these studies NDPhA was administered in the
diet to rats and mice at two doses, the "maximum tolerated dose"
for each species and one-half that amount. Groups of 50 animals
of each sex were tested at each dose for approximately 100
weeks. The study found that dietary exposure to MDPhA gave rise
to a significant incidence of urinary bladder tumors in both male
(40%) and female (90%) rats. Few urinary bladder tumors were
observed in the mice, although there was a high incidence of non-
neoplastic bladder lesions. The authors (Cardy _et_ _al_. , 1979)
ascribed the strong carcinogenic effect seen in rats in this
study to the higher doses used; they estimated that the maximum
)
daily intake of NDPhA was 320 mg/kg in females and 240 mg/kg in
males. These levels are somewhat higher than those used by
Druckrey _et_ _a_l_. (1967) in the only other known chronic feeding
study done in rats.
B. Mutagenicity
NDPhA has consistently been repo-""yd negative in a variety
of mutagenicity assays: S. typhimurium (Ames test), with and
without activation (Yahagi _et_ _al_. , 1977; Bartsch _et_ _al_. , 1976;
Simmon, 1979a; Rosenkranz and Poirier, 1979); E. coli, with
activation (Nakajima £t_ _al_. , 1974); (Pol A~) E. coli (Rosenkranz
and Poirier, 1979); 1ST, crassa (Marquardt _et: _al_. , 1963); Chinese
hamster V79 (lung) cell line, with and without activation (Kuroki
et al., 1977); Saccharomyces cerevisiae D3, with activation
(Simmon, 1979b); host mediated assay (tester strains: S.
typhimurium and S. cerevisiae D3) (Simmon jst_ _al_., 1979); in vivo
mouse testicular DNA synthesis assay (Friedman and Staub, 1976).
•163?-
-------
G. Other Toxicity
The oral LD^Q in rats is 1650 mg/kg; in mice the oral LD^Q
is 3,850 mg/kg (NIOSH, 1978).
V. AQUATIC EFFECTS
A. Acute
The 96-hour LCg0 for NDPhA in bluegill sunfish under static
test conditions is 5.9 mg/1 (nominal concentration). The 43-hour
ECcg (static conditions) in Daphnia magna is 7.7 mg/1 (nominal
concentration). The adjusted 96-hour LC5Q for the mummichog (a
marine fish) under static conditions is 3,300 mg/1 (nominal con-
centration) (U.S. EPA, 1979b).
B. Chronic
No adverse effects were reported at any test concentration
in a chronic toxicity study in Daphnia magna at concentrations
' N
below 0.048 mg/1 (U.S. EPA, 1979b) . ' ''
C. Other , ~j '
Bioconcentration of NDPhA by bluegill sunfish reached equi-
librium within 14 days; the bioconcentration factor was 217. The
half-life of the compound in bluegill sunfish was less than one
day (U.S. EPA, 1979b).
VI. EXISTING GUIDELINES
Criteria for the protection of aquatic species from excess
NDPhA exposure have not been established (U.S. EPA, 1979b). '
-------
REFERENCES
Argus, M.F., and Hoch-Ligeti, C. 1961. Comparative study of the
carcinogenic activity of nitrosamines. J. Natl. Cancer Inst. 27,
695.
Bartsch, H., C. Malaveille, and R. Montesano. 1976. The predic-
tive value of tissue-mediated mutagenicity assays to assess the
carcinogenic risk of chemicals. IARC Scientific Publications
(Lyon), No. 12, 467.
Boyland, E., R.L. Carter, J.W. Gorrod, and F.J.C. Roe. 1968.
Carcinogenic properties of certain rubber additives. Europ. J.
Cancer 4_, 233. (as cited in NCI, 1979).
Cardy, R.H., W. Lijinsky, P.K. Hilderbrandt. 1979. Neoplastic
and non-plastic urinary bladder lesions induced in Fischer 344
rats and B6C3F, hybrid mice by N-nitrosodiphenylamine. Ectotox-
icol. Env. Safety, 3_(1), 29.
Challis, B.C. and M.R. Osborn. 1972. Chemistry of nitroso
compounds. The reaction of N-nitrosodiphenylamine with N-methyl-
aniline—a direct transnitrosation. Chem. Comm. 518
Druckrey, H., R. Preussmann, S. Ivankovic, and D. Schmahl. 1967.
Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-
Verbindungen an BD-Ratten. Z. Krebsforsch. 69, 103. (as cited
in NCI, 1979 and Cardy _e_t _al_. , 1979).
Friedman, M.A., J. Staub. 1976. Inhibition of mouse testicular
DNA synthesis by mutagens and carcinogens as a potential simple
mammalian assay for mutagenesis. Mutat. Res., .3_7_(1), 67-76.
Hawley, G.G. 1977. The Condensed Chemical Dictionary, 9th ed.,
Van Nostrand Reinhold Co.
Innes, J.R.M., B.M. Ulland, M.G. Valerio, L. Petrucelli,
L. Fishbein, E.R. Hart, A.J. Pallotta. R.R. Bates, H.L. Falk,
J.J. Gart, M. Klein, I. Mitchell, and J. Peters. 1969. Bioassay
of pesticides and industrial chemicals for tumorigenicity in
mice: a preliminary note. J. Natl. Cancer Inst. ^_2_(6), 1101-
1106. (as cited in NCI, 1979).
Kuroki, T., C. Drevon, and R. Montesano. 1977. Microsome-
mediated mutagenesis in V79 Chinese hamster cells by various
nitrosamines. Cancer Res. 37, 1044-1050.
Mallik, M.A. 1979. Microbial contribution to nitrosamine
formation in soil. Smithsonian Scientific Information Exchange
No. GY 70884 2.
Marquardt, H., R. Schwaier, and F. Zimmerman. 1963. Nicht-
Mutagenitat von Nitrosamininen bei Neurospora Crassa. Natur-
wissenschaften 5Q_, 135. (as cited in Cardy _et_ _al_. , 1979).
-------
Nakajima, T. , A. Tanaka, and K.I. Tojyo. 1974. The effect of
metabolic activation with rat liver preparations on the mutagen-
icity of several N-nitrosamines on a streptomycin-dependent
strain of Escherichia coli. Mutat. Res. 26, 361-366.
National Cancer Institute. 1968. Evaluation of Carcinogenic,
Teratogenic, and Mutagenic Activities of Selected Pesticides and
Industrial Chemicals. Vol. I. Carcinogenic Study. (as cited in
NCI, 1979).
National Cancer Institute. 1979. Bioassay of N-Nitrosodiphenyl-
amine for Possible Carcinogenicity. NIH Publication No. 79-1720.
National Institute for Occupational Safety and Health. 1978.
Registry of Toxic Effects of Chemical Substances.
Rosenkranz, H.S. and L.A. Poirier. 1979. Evaluation of the
mutagenicity and DNA-modifying activity of carcinogens and non-
carcinogens in microbial systems. J. Natl. Cancer Inst. 62, 873-
892.
Rowland, I.R. and P. Grasso. 1975. Degradation of N-nitros-
amines by intestinal bacteria. Appl. Microbiol. _2_9_(1), 7-12.
(Abstract only).
Sander, J. and F. Seif. 1969. Bakterielle reduction von nitrat
in Magen des Menschen als Ursoche einer nitrosaminbildung.
Arnz.-Forsch 19, 1091. (as cited in U.S. EPA, 1977).
Simmon, V.F. 1979a. In vitro mutagenicity assays of chemical
carcinogens and related compounds with Salmonella typhimurium.
J. Natl. Cancer Inst. 62, 893-899.
Simmon, V.F. 1979b. In vitro assays for recombinogenic activity
of chemical carcinogens and related compounds with Saccharomyces
cerevisiae D3. J. Natl. Cancer Inst. 62, 901-909.
Simmon, V.F., H.S. Rosenkranz, E. Zeiger et al. 1979. Mutagenic
activity of chemical carcinogens and related compounds in the
intraperitoneal host-mediated assay. J. Natl. Cancer Inst. 62,
911-918.
U.S. EPA. 1977. Scientific and Technical Assessment Report on
Nitrosamines, EPA-600/6-77-001.
U.S. EPA. 1979a. Toxic Substances Control Act Chemical Sub-
stances Inventory, Production Statistics for Chemicals on the
Non-Confidential Initial TSCA Inventory.
»
U.S. EPA. 1979b. Ambient Water Quality Criteria: Nitrosamines.
PB 292 438.
Yahagi, T., M. Nagao, Y. Seino, T. Matsushima, T. Sugimura, and
M. Okada. 1977. Mutagenicities of N-nitrosamines on Salmonella.
Mutat. Res. 48, 121.
-------
No. 139
N-Nitrosodi-n-propylamlne
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
-J6V3 -
-------
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 (CAG) has evaluated
n-nitrosodi-n-p^Iopj((ylamine and has found sufficient evidence
to indicate that this compound is carcinogenic.
-------
N-NITROSODI-n-PROPYLAMINE
SUMMARY
The International Agency for Research on Cancer has con-
cluded that "N-nitrosodi^-n-propylamine should be regarded for
practical purposes as if it were carcinogenic in humans." The
conclusion is based on positive findings in several long-term
animal studies with the compound. It has also been found muta-
genic in several test systems with activation.
The chemistry of formation of nitrosamines is quite complex,
however, they are formed in general by the combination of amines
with some nitrosating agent. Nitrates, nitrites, and amines
(primary, secondary, and tertiary), the precursors in the
formation of nitrosamines, are ubiquitous in the environment.
Significant quantities of the precursors are also produced
through human activities.
The in vivo formation of nitrosamines following ingestion of
precursors has been demonstrated in humans and animals.
Nitrosamines degrade in the presence of sunlight; however,
in the dark they are quite stable. Microorganisms can function
both in the formation and degradation of nitrosamines. The half-
life of aliphatic, nitrosamines in the environment ranges from one
hour in the atmosphere in sunlight to more than 40 days in soils
and water (in the absence of light).
»
I. INTRODUCTION
This document is.based on the Ambient Water Quality Criteria
Document for Nitrosamines (U.S. EPA, 1979a), Volume 17 of the
-------
IARC Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Humans (IARC, 1978), the Scientific and Technical
Assessment Report on Nitrosamines (U.S. EPA, 1977), and other
selected references. The term "N-nitrosodi-n-propylamine" (NDPA)
in this report refers specifically to that compound; the term
"nitrosamine" when used in this report refers in general to
simple aliphatic nitrosamines.
N-nitrosodi-n-propylamine (NDPA; CgH14N20; molecular weight
130.2) is a yellow liquid having the following physical chemical
properties (IARC, 1978).
Boiling Point: 81'C
Density: d^° 0.9160
Solubility: soluble in water, organic
solvents, and lipids.
Volatility: can be steam distilled
quantitatively.
A review of the production range (includes importation)
statistics for NDPA (CAS No. 621-64-7) which is listed in the
initial TSCA Inventory (1979b) has shown that between zero and
900 pounds of this chemical were intentionally produced/imported
in 19.7 7.-I/
—' This production range information does not include any pro-
duction/importation data claimed as confidential by the per-
son(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).
-------
No information on the .commercial uses of NDPA.was located,
however, it appears likely that most, if not all, of that pro-
duced is used solely in the laboratory.
II. EXPOSURE
Nitrates, nitrites, and amines (in this case the propyl-
amines), which are precursors in the formation of nitrosamines,
are ubiquitous in the environment and occur in food, water, soil,
and air. The natural occurrence of nitrates, nitrites, and
secondary and tertiary amines results from their formation during
the nitrogen cycle. In addition to the naturally formed precur-
sors, significant quantities are produced through human activi-
ties (U.S. EPA, 1977). Some of the major man-made sources of the
precursors are listed in Table 1.
A. Formation
The chemistry of formation of nitrosamines is quite complex,
however, they are formed in general by the combination of amines
(R^R2N-) with some nitrosating agent. Formation has been shown
to occur with primary, secondary, and tertiary amines, as well as
other amino compounds. The nitrosating agent can be derived from
nitric oxides (NO, NOj, N2°3' or N2°4^ or i-nor9anic nitrite.
Certain factors (catalysts) can affect the rate of nitrosation.
Depending on the reactants and catalysts that are present, nitro-
sation can occur under acidic, neutral, or alkaline conditions.
Nitrosation of amines can also occur by transnitrosation involv-
t
ing other, more labile N-nitroso compounds (U.S. EPA, 1977;
Mirvish, 1977).
-------
Table 1. Man-Made Sources of Nitrosamine Precursors (U.S. EPA, 1977)
Nitric Oxides Amines
Transportation
Motor vehicles
Aircraft
Railroads
Fuel combustion in stationary sources
Coal
Fuel Oil
Natural gas
Wood
Industrial processes
Solid waste disposal
Miscellaneous
Forest fires
Structural fires
Coal refuse
Agricultural
Feedlots
Rendering plants
Antioxidants
Vulcanization
accelerators
Pharmaceuticals
Self-polishing waxes
Synthetic detergents
Pesticides
Solvents
Corrosion inhibitors
Animal glues
Photographic products
Leather tanning
Primary amine
production
The in vivo formation of nitrosamines following the inges-
tion of precursors has been demonstrated in human and animal
studies (U.S. EPA, 1976,).
. - Nitrosamines can be formed in soil, water, and sewage under
appropriate conditions (Ayanaba _et_ _al_. , 1973a, b; Ayanaba and
Alexander, 1974; Kohl et al., 1971). Microorganisms in soil and
water can participate in the formation of nitrosamines (Ayanaba
£t_ _al_. , 1973b; Mills and Alexander, 1976), although microbial
involvement in such formation reactions is not essential (Mills,
1976; Mills and Alexander, 1976).
B. Environmental Fate
In the absence of light, nitrosamines are quite stable and
will decompose hydrolytically only following prolonged contact
»
with strong acid. There is no evidence of thermal instability of
nitrosamines in the gas phase; however, they do undergo photo-
-------
chemical decomposition in solution or in the atmosphere in the
presence of sunlight or ultra-violet light. There are very few
quantitative studies on the rate of photochemical degradation of
nitrosamines or on the rate effects of other factors (U.S. EPA,
1977; IARC, 1978). Nonetheless, it has been shown that N-nitro-
sodimethylamine has an atmospheric half-life (during ambient
atmospheric conditions) of between 30 minutes and one hour in
sunlight (Hanst et al., 1977). The atmospheric half-life of NDPA
should be similar (U.S. EPA, 1979a).
N-nitrosodi-n-propylamine appears to be fairly resistant to
microbial atta-'1- -under environmental conditions. The soil half-
•••• r~
life of NDPA under varying conditions has been reported as rang-
ing between 10 and 40 days^ (Tate and Alexander, 1975; Saunders et
al., 1979; Oliver e_t_ _al_., 1978). In lake water under laboratory
conditions, NDFVpersisted for more than 4 months (Tate and
Alexander, 1975).
A laboratory soil leaching study (Saunders _et_ _al_. , 1979) has
indicated .that NDPA (which is about 1% soluble in water) will
leach under heavy simulated rainfall conditions. In a field
study, however, NDPA did not leach below a depth of 20 cm. The
authors suggest that under field conditions, NDPA is dissipated
due to volatilization and degradation.
C. Bioconcentration
No information on the bioaccumulation potential of NDPA was
»
located, although it should be fairly low.
D. Environmental Occurrence
NDPA has been detected in food, alcoholic beverages,and
several pesticides (IARC, 1978). It has also been detected in
-------
the waste-water from several chemical plants (Cohen and Bachman,
1978) .
III. PHARMACOKINETICS
A. Absorption
In goats, one hour after oral administration, NDPA was found
in milk and blood, indicating fairly rapid uptake. Only traces
were found in the milk after 24 hours (Juszkiewicz and Kowalski,
1974).
B. Distribution
No information was located on the distribution of NDPA;
however, simple aliphatic nitrosamines tend to distribute rapidly
and fairly uniformly in the body (U.S. EPA, 1979a).
C. Metabolism
Available evidence suggests that NDPA must be metabolically
activated to exert its toxic and carcinogenic effects. Urine
collected during the 43 hours after oral administration of an
LDcQ dose of NDPA to rats contained the following compounds:
N-nitroso-3-hydroxy-n-propyl-n-propylamine, N-nitroso-2-carboxy-
ethyl-n-propylamine, and to a lesser extent, N-nitrosocarboxy-
methyl-n-propylamine, and N-nitroso-2-hydroxy-n-propyl-n-
propylamine (Blattman and Preussmann, 1973). The last named
metabolite, N-nitroso-2-hydroxy-n-propyl-n-propylamine, has been
found carcinogenic in rats (Reznik et al., 1975) and hamsters
(Pour £t_ _al_. , 1974a,b), thus it may be the active carcinogenic
metabolite (proximate and/or ultimate carcinogen) of NDPA.
-------
IV. HUMAN HEALTH EFFECTS
A. Carcinogenicity
Groups of rats were given NDPA in the drinking water at
doses of 4, .8, 15, or 30 mg/kg day. Of the 48 animals on test,
45 developed liver carcinomas, 8 developed papillomas or car-
cinomas of the esophagus, and 6 showed carcinomas of the tongue
(Druckrey et al., 1967).
Groups of rats were injected subcutaneously with 1/5, 1/10,
or 1/20 the LD5Q of NDPA (LD50: 487 mg/kg) once weekly for
life. The average total dose of NDPA ranged between 0.93 and 2.7
g/kg. A high incidence of neoplasms was observed in the nasal
cavities. In addition, tumors of the liver, lung, kidney, and
esophagus were observed (Althoff et al., 1973a; Reznik et al. ,
1975).
Groups of Syrian golden hamsters were injected
subcutaneously with 1.2% NDPA 'in olive oil once weekly for life
at 5 dose levels (highest dose was 60 mg/kg). Tumors were
observed in the nasal cavities, laryngobronchial tract, lungs,
and a variety of other organs (Althoff et al., 1973b; Pour et
al., 1973).
The International Agency for Research on Cancer (1978) has
concluded:
There is sufficient evidence of a carcinogenic effect of
N-nitrosodi-n-propylamine in two experimental animal
species. Although no epidemiological data were avail-
able. . .N-nitrosodi-n-propylamine should be regarded for
practical purposes as if it were carcinogenic to humans.
B. Mutagenicity
NDPA was positive in the Ames test (S. typhimurium strains
TA 1530, TA 1535, and TA 100) with activation (Barstch et al. ,
-------
1976; Camus _et_ ^1_. , 1976; Olajos and Cornish, 1976; Sugimura et
al., 1976)-. NDPA was also mutagenic in E. coli (Nakajima et al. ,
1974) and in Chinese hamster V79 cells (Kuroki _et_ _al_. , 1977), in
both cases with activation.
C. Other Toxic Effects
The acute oral LDg0 of NDPA was 480 mg/kg in rats (Druckrey
et al. , 1967); the subcutaneous LD^g was 487 mg/kg in rats and
600 mg/kg in hamsters (Pour _et_ _al_. , 1973; Reznik .et_ _al_- , 1975).
V. AQUATIC EFFECTS
No data on the aquatic effects of NDPA were located.
VI. EXISTING GUIDELINES
The class of compounds "nitrosamines" was included in the
American Conference of Governmental Industrial Hygienists (1977)
list of "Industrial Substances Suspected of Carcinogenic Poten-
tial for Man." No threshold limit value (TLV) was given.
As noted in Section IV.A, the International Agency for
Research on Cancer (1978) has concluded that "N-nitrosodi-n-
propylamine should be regarded for practical purposes as if it
were carcinoaenic to humans."
-------
REFERENCES
Althoff, J., F.W. Kruger, J. Hilfrich, D. Schmahl, and U. Mohr.
1973a. Carcinogenicity of B-hydroxylated dipropylnitrosamine.
Naturwissenschaften, 60, 55 (as cited in IARC, 1978).
Althoff, J., F.W. Kruger, and U. Mohr. 1973b. Carcinogenic
effect of dipropylnitrosamine and compounds related by 3-oxida-
tion. J. Nat. Cancer Inst., 51, 287-288 (as cited in IARC,
1978) .
American Conference of Governmental Industrial Hygienists,
Threshold Limit Values for Chemical Substances and Physical
Agents in the Workroom Environment, 1977.
Ayanaba, A., W. Verstraete, and M. Alexander. 1973a. Formation
of dimethylnitrosamine, a carcinogen and mutagen in soils treated
with nitrogen compounds. Soil Sci. Soc. Amer. Proc. 37, 565-568.
(as cited in U.S. EPA, 1977).
Ayanaba, A., W. Verstraete, and M. Alexander. 1973b. Possible
microbial contribution to nitrosamine formation in sewage and
soils. J. Nat. Cancer Inst. 50, 811-813. (as cited in U.S. EPA,
1977) .
Ayanaba, A. and M. Alexander. Transformation of methylamines and
formation of a hazardous product, dimethylnitrosamine, in samples
of treated sewage and lake water. J. Environ. Qual. _3_, 83-89.
(as cited in U.S. EPA, 1979).
Bartsch, H., C. Malaveille, and R. Montesano. 1976. The predic-
tive value of tissue-mediated mutagenicity assays to assess the
carcinogenic risk of chemicals. In: Montesano, R. , Bartsch, H.
and Tomatis, L., eds. Screening Tests in Chemical Carcinogen-
esis, Lyon (IARC Scientific Publications No. 12), pp. 467-491.
(as cited in IARC,1978).
Blattman, L. and R. Preussmann. 1973. Struktur von metaboliten
carcinogener dialkylnitrosamine im rattenurin. Z. Krebsforsch.,
79, 3-5. (as cited in IARC, 1978).
Camus, A., B. Bertram, Kruger, F.W., C. Malaveille, and
H. Bartsch. 1976. Mutagenicity of B-oxidized N,N-di-n-propyl-
nitrosamine.derivatives in S. typhimurium mediated by rat and
hamster tissues. .Z. Krebsforsch., 86, 293-302 (as cited in IARC,
1978) .
Cohen, J.B. and J.D. Bachman. 1978. Measurement of environ-
mental nitrosamines. In: Walker, E.A., Castegnaro, M.,
Gricuite, L. and Lyle, R.E., eds., Environmental Aspects of
N-Nitroso Compounds, Lyon (IARC Scientific Publications No. 19) .
(as cited in IARC, 1978).
Druckrey, H., R. Preussmann, S. Ivankovic, D. Schmahl. 1967.
Organotrope carcinogene Wirkungen bei 65 verschiedenen N-nitroso-
verbindungen an BD-ratten. Z. Krebsforsch., 69, 103-201. (as
cited in IARC, 1978). //Cz/-*
J*
-------
Hanst, P.L., J.W. Spence, and M. Miller. 1977. Atmospheric
chemistry of N-nitroso dimethylamine. Env. Sci. Tech., 11(4) ,
403.
Juskiewicz, T. and B. Kowalski, 1974. Passage of nitrosamines
from rumen into milk in goats. In: Bogavski, P. and E.A. Walker,
eds., N-Nitroso Compounds in the Environment, Lyon (as cited in
IARC, 1978).
International Agency for Research on Cancer. 1978. IARC Mono-
graphs on the Evaluation of the Carcinogenic Risk of Chemicals to
Humans, Vol. 17.
Juskiewicz, T. and B. Kowalski, 1974. Passage of nitrosomines
from rumen into milk in goats. In: bogaski, P. and E. A. Walker,
eds., n-Nitroso Compounds in the Environment, Lyon (as cited in
IARC, 1978).
Kuroki, T., C. Drevon, and R. Montesano. 1977. Microsome-
mediated mutagenesis in V79 Chinese hamster cells by various
nitrosamines. Cancer Res., 37, 1044-1050. (as cited in IARC,
1978).
Mills, A.L. 1976. Nitrosation of secondary amines by axenic
cultures of microorganisms and in samples of natural ecosystems.
Ph.D. Thesis. Cornell University, Ithaca, New York. 95 pp. (as
cited in U.S. EPA, 1977).
Mills, A.L. and M. Alexander. 1976. Factors affecting dimethyl-
nitrosamine formation in samples of soil and water. J. Environ.
Qual. , _5_(4), 437.
Mirvish, S.S. 1977. N-Nitroso compounds: Their chemical and in
vivo formation and possible importance as environmental carcino-
gens. J. Toxicol. Env. Hlth., _2_, 1267.
Nakajima, T., A. Tanaka, and K.I. Tojyo. 1974. The effect of
metabolic activation with rat liver preparations on the mutagen-
icity of several N-nitrosamines on a streptomycin-dependent
strain of Escherichia coli. Mutat. Res., 26, 361-366. (as cited
in IARC, 1978).
Olajos, E.J. and H.H. Cornish. 1976. Mutagenicity of
dialkylnitrosamines: metabolites and derivatives (Abstract No.
43). Toxicol. Appl. Pharmacol., 37, 109-110. (as cited in IARC,
1978).
Oliver, J.E., P.C. Kearney, and A. Kontson. 1978. Abstract
presented at the 175th National Meeting of the American Chemi-cal
Society, Paper Mo. 80, Pesticide Division. (as cited by Saunders
et_al_- , 1979).
Pour, P., F.W. Kruger, A. Cardesa, J. Althoff, and U. Mohr.
1973. Carcinogenic effect of di-n-propylnitrosamine in Syrian
golden hamsters. J. Nat. Cancer Inst., 51, 1019-1027. (as cited
in IARC, 1978).
XT
-------
Pour, P., F.W. Kruger, A. Cardesa, J. Althoff, and U. Mohr.
1974a. Effect of beta-oxidized nitrosamines on Syrian golden
hamsters. I. 2-Hydroxypropyl-n-propylnitrosamine. J. Nat.
Cancer Inst., 52, 1245-1249. (as cited in IARC, 1978).
Pour, P., J. Althoff, A. Cardesa, F.W. Kruger, and U. Mohr.
1974b. Effect of beta-oxidized nitrosamines on Syrian golden
hamsters. II. 2-Oxopropyl-n-propylnitrosamine. .J. Nat. Cancer
Inst., 52, 1869-1874. (as cited in IARC, 1978).
Reznik, G., U. Mohr, F.W. Kruger. 1975. Carcinogenic effect of
di-n-propylnitrosamine, B-hydroxypropyl-n-proylnitrosamine, and
methyl-n-propylnitrosamine on Sprague-Dawley rats. J. Nat.
Cancer Inst., 54, 937-943. (as cited in IARC, 1978).
Saunders, D.G., J.W. Mosier, J.E. Gray, and A. Loh. 1979. Dis-
tribution and movement of N-nitrosodipropylamine in soil. J.
Agric. Fd. Chem., _2_7_(3), 584.
Sugimura, T., T. Yahagi, M. Nagao, .M. Takeuchi, T,. Kawachi,
K. Kara, E. Yamakaki, T. Matsushiii. ^.)Y. Hashimoto, and M. Okada.
1976. Validity of mutagenicity tests using microbes as a rapid
screening method for environmental carcinogens. In: Montesano,
R., Bartsch, H. and Tomatis, L., eds., Screening Tests in Chemi-
cal Carcinogenesis, Lyon (IARC Scientific Publication No. 12),
pp. 81-101. (as cited in IARC, 1978).
Tate, R.L. and M. Alexander. 1975., Stability of N-nitrosamines
in samples of lake water, soil, an \sewage. J. Nat. Cancer Inst.
54, 327-330. (as cited in U.S. EPA; 1977).
U.S. 'EPA. 1977. Scientific and T. "nnical Assessment Report on
Nitrosamines. EPA-600/6-77-001.
U.S. EPA. 1979a. Ambient Water Quality Criteria: Nitrosamines,
PB 292 438.
U.S. EPA. 1979b. Toxic Substances Control Act Chemical Sub-
stances Inventory, Production Statistics for Chemicals on the
Non-Confidential Initial TSCA Inventory.
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No. 140
Paraldehyde
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.
-------
PARALDEHYDE
Summary
There is no evidence in the available literature to indicate that
paraldehyde, a central nervous system depressant, is carcinogenic, muta-
genic, or teratogenic.
In low doses (4-8 ml) paraldehyde has a hypnotic effect on the central
nervous system. Following chronic and acute exposures at higher concen-
trations, paraldehyde affects the respiratory and circulatory systems.
Data concerning the effects of paraldehyde on aquatic organisms were
not found in the available literature.
Guidelines or standards concerning air or water exposures were not
found in the available literature.
X
•it ft-
-------
PARALDEHYDE
I. INTRODUCTION
Paraldehyde, 2,4,6-trimethyl-l,3,5-trioxane, also known as para-
acetaldehyde, is a colorless liquid with a molecular weight of 132.2. This
compound melts at 13°C and boils at 125°C. It has a specific gravity of
0.994 at 20°C, and its solubility in water Is 120,000 mg/1 at 13°C and
58,000 mg/1 at 100°C (Verschueren, 1977). The odor of paraldehyde is not
pungent or unpleasant, but it is characterized by a disagreeable taste
(Wilson, et al. 1977).
Paraldehyde was introduced into medicine by Ceruello in 1882 as
the second synthetic organic compound to be used as a sedative hypnotic
(Wilson, et al. 1977). It is used frequently in delirium tremens and in
treatment of psychiatric states characterized by excitement when drugs must
be given over a long period of time (Wilson, et al. 1977).. It also is ad-
ministered for intractable pain which does not respond to opiates and for
basal and obstetrical anaesthesia (Goodman and Oilman, 1970). It is
effective against experimentally induced convulsions and has been used in
emergency therapy of tetanus, eclampsia, status epilepticus, and poisoning
*
by convulsant drugs (Goodman and GiJjnan, 1970).
It is used primarily in medicine, and therefore, the chance of
accidental human .exposure or environmental contamination is low. However,
paraldehyde: decomposes to acetaldehyde and acetic acid (Gosselin, et al.
1976); these compounds have been found to be toxic. In this sense, occupa-
tional exposure or environmental contamination is possible. Since paral-
dehyde is prepared from acetaldehyde by polymerization in the presence of an
acid catalyst, there exists a potential for adverse effects, although none
have been reported in the available literature.
-------
II. EXPOSURE
No monitoring data are available to indicate ambient air or water
levels of the compound. Human exposure to par aldehyde from ingestion cannot
be assessed, due to a lack of monitoring data. No data on dermal exposure
of humans were found in the available literature.
III. PHARMACOKINETICS
Paraldehyde is rapidly absorbed from the gastrointestinal tract
and parenteral sites. Following oral administration to rats, the maximum
concentration in the brain is reached within 30 -minutes (Figot, et al.
1953). A significant percentage is excreted unchanged through the lungs.
Lang, et al. (1969) reported that human - subjects given unspecified oral
doses exhaled 7 percent of the administered dose within 4 hours. Only
traces are observed in the urine; the rest is metabolized by the liver.
There is indirect evidence that paraldehyde is depolymerized to acetaldehyde
in the liver, then oxidized by aldehyde dehydrogenase to acetic acid which,
in" turn, is ultimately metabolized to carbon dioxide and water in mice
(Hitchcock and Nelson, 1943).
No data on bio accumulation of paraldehyde were found in the
available literature. Based on the evidence of metabolism above, however,
significant bio accumulation would appear unlikely.
IV. EFFECTS
A. Carcinogenicity
Paraldehyde has been designated a "suspect carcinogen" (NIOSH,
1978), although no increase in neoplasms was observed in the mouse-skin
painting study (Row and Salaman, 1955), which was cited by NIOSH.
8. Mutagenicity, Teratogenicity and Other Reproductive Effects.
Pertinent data could not be located in the available literature.
-------
C. Chronic Toxicity
In low doses (4-8 ml), paraldehyde has found use as a therapeutic
agent. However, if used for a prolonged period of time, intoxication
results in tolerance and dependence. Paraldehyde addiction resembles alco-
holism; withdrawal may result in delirium tremens and vivid hallucinations
(Goodman and Gil/nan, 1570).
Acidosis, bleeding gastritis, muscular irritability, azotemia,
oliguria, albuminuria, leukocytosis, fatty changes in the liver and kidney
with toxic hepatitis and nephrosis, pulmonary hemorrhages, edema, and dila-
tion of the right heart have all been observed in cases of chronic paral-
dehyde poisoning. Metabolic acidosis is a manifestation of paraldehyde in-
toxication in the paraldehyde addict. The etiology of the acidosis is un-
certain (Beier, et al. 1963).
0. Acute Toxicity
Figot, et al. (1953) reported an oral LD5Q Of 1.55 g/kg for
paraldehyde in rats. These investigators reported that the level of paral-
dehyde in the brain was predictive of the degree of toxicity. The median
brain concentration lethal to rats was 47 mg percent.
In humans, therapeutic oral doses of 4-8 ml induce sleep. At this
dose, little effect on respiration or blood pressure is seen. There appears
to be little margin of safety, and slight increases in dosage, may result in
poisoning. The poisoned patient commonly exhibits very rapid, labored
respiratory movements (Goodman and Gilman, 1970). Accompanying the rapid
respiration . is a marked depression of blood pressure which persists for
several hours. Degenerative changes in the kidney and liver have also been
»
observed (Kirk and Othmer, 1979). Unfortunately, it is not absolutely cer-
tain whether these effects are due to paraldehyde or to its decomposition
products, acetaldehyde and acetic acid.
-------
Toxic doses of unspecified amounts, given intravenously, cause
diffuse, massive pulmonary hemorrhages and edema, as well as dilation of the
right heart. Adverse effects, as seen in cases of severe acute paraldehyde
intoxication, resemble those seen in chronically exposed individuals, e.g.,
addicts.
Metabolic acidosis is also- found in the severe acute cases. Hay-
ward and Boshell (1557) produced metabolic acidosis and other toxic effects,
including pulmonary edema in dogs, by administering unspecified amounts of
deteriorated par aldehyde through gastric tubes over a period of 18 hours.
In this case it is uncertain whether the paraldehyde or the deteriorated
*
product was' the cause of the observed .effects. The same is true in another
study where a deteriorated product (40 percent acetic acid) produced sudden
death with intense corrosion of buccal mucosa and upper air passages.
Rectal administration (a common route in therapeutic settings) in another
poisoning victim caused great pain and sloughing of rectal mucosa (Gosselin,
et al. 1576).
High concentrations (unspecified) depressed cholinergic junctions
in frogs, apparently by reducing the amount of acetylcholine liberated from
nerve endings (Nicholls and Quillam, 1556; Quillam, 1959).
The lethal dose in humans is disputable. Less than one ounce by
mouth has been shown to be lethal in some cases, while others have tolerated
four ounces. Death results from respiratory failure preceded by prolonged
and profound coma (Goodman and Gilman, 1970).
Paraldehyde has been used in obstetrics; however, it readily
crosses the placental barrier and appears in the fetal circulation. Unde-
sirable effects, including delay in respiratory movements, have been
-------
observed in neonates following administration to the mother during labor
(Goodman and Oilman, 1970). Consequently, paraldehyde finds little or no
use in obstetrics today.
The lowest dose of paraldehyde reported to produce any toxic
effect (unspecified) in humans is 121 mg/kg. Oral LD5Q values have been
reported for the following species: rats, 1530 mg/kg; rabbits, 3304 mg/kg;
and dogs, 3500 mg/kg. NIOSH (1978) has reported the lowest lethal inhala-
tion concentration to be 2000 ppm.
V. AQUATIC TOXICITY
Data concerning the effects of paraldehyde on aquatic organisms
were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
No exposure limits or standards were found in the available liter-
ature to exist for air or water.
-------
References
Beier, L.", et al. 1963. Metabolic acidosis occurring during paraldehyde
intoxication. Chem. Abst. 59: 1022.
Figot, P., et al. 1953. Estimation and significance of paraldehyde levels
in blood and brain. Chem. Abst. 47: 660.
Goodman, L. and A. Gilnan. 1970. The Pharmacological Basis of Thera-
peutics. 4th ed. MacMillan Co., New York.
Gosselin, R.E., et al. 1976. Clinical Toxicology of Commercial Products.
Williams and Wilkins Co., Baltimore, Maryland.
Hayward, J. and 8. Boshell. 1957. Paraldehyde intoxication with metabolic
acidosis. Am. Jour. Med. 23: 965.
Hitchcock, P. and E. Nelson. 1943. The metabolism of paraldehyde: II.
Jour. Pharmac. Exp. Ther. 79: 286.
""ark, R.E. and D.F. Othmer. 1979. Encyclopedia of Chemical Technology.
,-uhn Wiley and Sons, New York.
Lang, 0., et al. 1969. Data of puJjnonary excretion of paraldehyde in man.
Chem. Abst. 71: 202.
Nicholls, J. and J. Quillam. 1956. Mechanism of action of paraldehyde and
methyIpentyno1 on neuromuscular transmission in the frog. Chem. Abst.
-50: D295.
)'
National Institute for Occupational Safety and Health. 1978. Suspected
Carcinogens. A Subfile on the Registry of Toxic Effects of Chemical Sub-
oCance. U.S. Department of Health, Education and Welfare, Cincinnati, Ohio.
Quillam, J. 1959. Paraldehyde and methyIpentyno 1 and ganglionic trans-
mission. Chem. Abst. 53: 20562.
Row, .F.J.C. and M.H. Salaman. 1955. Further studies on incomplete carcin-
ogenesis: Triethylene melsmine (TEM), 1,2-benzanthracene, and g-propiolac-
tone as initiators of skin tumor formation in the mouse. Brit. Jour. Cancer
(London). 9: 177.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Company, New York.
Wilson, C., et al. (ed.) 1977. Textbook of Organic Medicinal and Pharma-
ceutical Chemistry. J.B. Lippincott Co., Philadelphia, Pa.
-------
No. 141
Pentachlorobenzene
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 acc-uracy.
-------
PENTACHLOROBENZENE
Summary
Oral feeding of pentachlorobenzene to pregnant rats has produced devel-
opmental effects and decreased body weights in fetuses. No adverse repro-
ductive or developmental effects were seen in mice following maternal admin-
istration of the compound orally.
There is no information available on the mutagenic effects of penta-
chlorobenzene.
A single study has alluded to carcinogenic effects of pentachloroben-
zene in mice and lack of carcinogenic effects in dogs and rats. The details
of this study were not available for evaluation.
Reported 96-hour LC5Q values for the bluegill, mysid shrimp, and
sheepshead minnow range from 250 to 830 ;ug/l. Daphnia is considerably less
sensitive-. Studies with algae, with 96-hour EG5Q values based on chloro-
phyll a_ concentration, have reported values ranging from 2,000 to 7,000
,ug/l. The steady-state bioconcentration factor for the bluegill is 1,800.
-------
I. INTRODUCTION
Pentachlorcbenzene, CAS registry number 608-93-5, is a colorless crys-
talline solid with a pleasant aroma. It is produced mainly as a byproduct
of other chlorobenzenes and has the following physical and chemical proper-
ties (Windholz, 1976; Weast, 1972; Hawley, 1971):
Formula: C6HC15
Molecular. Weight: 250.34
Melting Point: 86°c
Boiling Point: 277°c
Density: 1.334216-5
Solubility: Soluble in carbon disulfide,
chloroform, and hot alcohol,
insoluble in water
Pentachlorobenzene is used primarily as a precursor in the synthesis of
the fungicide pentachloronitrobenzene, and as a flame retardant.
II. EXPOSURE
A. Water
Burlingame (1977) has identified pentachlorobenzene in the efflu-
ent from a wastewater treatment plant in southern California. Access to
water can occur by industrial discharge or from the degradation of other
organochlorine compounds.
B. Food
Pentachlorobenzene has been detected in plants (Balba and Saha,
1974; Kohli, et al. 1976a) and in animal fat (Stijve, 1971; Saha and Bur-
rage, 1976; Greve, 1973), and was shown to arise from the metabolic break-
down of lindane or other organochlorine compounds. The U.S. EPA (1979) has
estimated the weighted average bioconcentration factor for pentachloroben-
zene to be 7,800 for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on steady-state bioconcentration studies
in bluegills.
-------
C. Inhalation
The primary site for inhalation exposure pould be the workplace in
industries utilizing or producing pentachlorobenzene.
0. Dermal
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
A. Absorption
From studies with rabbits it would appear that pentachlorobenzene
is very poorly absorbed from the gastrointestinal tract (Parke and Williams,
1960) .
8 . Distribution
The distribution of pentachlorobenzene favors retention in the fat
(Parke and Williams, 1960). Khera and Villeneuve (1975) have found wide-
spread tissue distribution of the compound following oral administration to
pregnant rats and accumulation in fetal tissues.
C. Metabolism
There appear to be some qualitative and quantitative differences
between species in the metabolism of pentachlorobenzene. In the rat and
rabbit, pentachlorobenzene was shown to be metabolized to a variety of iso-
mers of tetrachlorophenol , with the amount of unchanged pentachlorobenzene
excreted in the urine of the rabbit being one percent (Kohli, et al. 1976b),
and in the rat being nine percent (Koss and Koransky, 1977). Kohli and co-
workers (1976b) suggest that the dechlorination hydroxylation step to the
tetrachlorophenol derivative proceeds through an arene oxide intermediate.
0. Excretion
»
In rats and rabbits urinary excretion of metabolites or unchanged
pentachlorobenzene predominated. Rozman, et al. (1978) found the biological
half-life of pentachlorobenzene to be two to three months in rhesus monkeys.
It 70 -
-------
After 40 days, ten percent of the total dose was secreted in the urine; of
this, 53 percent was pentachlorophenol. After the same period, about 40
percent of the dose was excreted in the feces, 99 percent as pentachloroben-
zene. The authors suggest that biliary excretion was occurring.
IV. EFFECTS
A. Carcinogenicity
There is one report, which could not be critically evaluated,
which alludes to pentachlorobenzene being carcinogenic in mice but not in
rats or dogs (Preussman, 1975).
3. Mutagenicity
Pertinent data could not be located in the available literature.
C. Teratogenicity
Rats receiving 50, 100, and 200 mg/kg pentachlorobenzene on days 6
to 15 of gestation had pups with increased suprauni ribs at all doses (Khera
and Villeneuve, 1975). The high dose also produced sternal defects consist-
ing of unossified or nonaligned sternabrae with cartilagenous precursors
present. The authors did not consider these, defects to be teratogenic.
0. Other Reproductive Effects
Oral administration of pentachlorobenzene (50 or 100 mg/kg) to
pregnant mice on days 6 to 15 of gestation produced no teratogenic or ad-
verse reproductive effects (Courtney, et al. 1977).
E. Chronic Toxicity
Pertinent data could not be located in the available literature.
V. AQUATIC TOXICITY
A. Acute
The U.S. EPA (1978) reported 96-hour LC.Q values for the blue-
gill (Leoomis macrochirus) exposed to pentachlorobenzene to be 250 ug/1.
-------
The 48-hour EC— value reported for Daohnia maqna is 5,280 ug/1 (U.S. EPA,
,-U , f
1978). For the saltwater species, sheepshead minnow (Cyprinodon variegatus)
and mysid shrimp (Mysidopsis bshia), the determined 96-hour LCgg values
are 830 and 160/jg/l, respectively.
8. Chronic
Pertinent data could not be located in the available literature.
C. Plant Effects
The reported 96-hour EC5Q vaiue for Selenastrum capricornatum
based on chlorophyll a concentration is 6,780 jug/1 (U.S. EPA, 1978). For
the marine alga Skeletonema costatum, a 96-hour EC__ value on the same
basis is 1,980 ug/1 (U.S. EPA, 1978).
0. Residue
After a 28-day exposure, the steady-state bioconcentration factor
for the bluegill for pentachlcrocenzene is 1,800. The half-life is greater
than seven days (U.S. EPA, 1973).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The U.S. EPA (1979) has drafted a criterion of 0.5>jg/l for the
protection of human health.
8. Aquatic
No criteria have been developed or proposed to protect aquatic
organisms from pentachlorobenzene toxicity due to the lack of pertinent data.
-/{,7 is
-------
REFERENCES
3alba, M.H. and J.G. Saha. 1974. Metabolism of LLndane—l*c by wheat
plants grown from treated seed. Environ. Let. 7: 181.
Burlingame, A.L. 1977. Assessment of the trace organic molecular composi-
tion of industrial and municipal wastewater effluents by capillary gas
chromatography/real time high resolution mass spectrometry: a preliminary
report. Ecotoxicol. Environ. Saf. 1: 111.
Courtney, K.D., et al. 1977. Teratology study of pentachlorobenzene in
mice: no teratogenic effect at 50 or 100 mg/kg/day from day 6 to day 15 of
gestation. IRCS Med. Sci. 5: 587.
Greve, P.A. 1973. Pentachlorobenzene as a contaminant of animal feed.
Meded. Fac. Lanbouwwet Rijksuniv Gent. 38: 775.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary. 8th ed., Van
Nostrand Reinhold Co., New York.
Khera, X.S. and D.C. Villeneuve. 1975. Teratogenicity studies on haloge-
nated benzenes (pentachloro-, pentachloronitro-, and hexabromo-) in rats.
Toxicology. 5: 117.
Kohli, 3., et al. 1976a. Balance of conversion of carbon-14 labeled lin-
danes in lettuce in hydroponic culture. Pestic. Biochem. Physiol. 6: 91.
Kohli, J., et al. 1976b. The metabolism of higher chlorinated benzene iso-
mers. Can Jour. Biochem. 54: 203.
Koss, G. and W..Koransky. 1977. Pentachlorophenol in different species of
vertebrates after administration of hexachlorobenzene and pentachloroben-
zene. Pentachlorophenol, K.R. Rao, (ed.), Plenum Press, New York. p. 131.
Parke, D.V. and R.T. Williams. 1960. Studies in detoxification LXXXI.
Metabolism of halobenzenes: (a) Penta- and hexachlorobenzene: (b) Further
observations of 1,3,5-trichlorobenzene. Biochem. Jour. 74: 1.
Preussman, R. 1975. Chemical carcinogens in the human environment. Hand.
Allg. Pathol. 6: 421.
Rozman, K., et al. '1978. Metabolism and body distribution of pentachloro-
benzene after single oral dose in rhesus monkeys. Toxicol. Appl. Pharmacol.
45: 283.
Saha, J.G. and R.H. Burrage. 1976. Residues of lindane and its metabolites
in eggs, chicks and body tissues of hen pheasants after ingesticn of Lindane
carbon-14 via treated wheat seed or gelatin capsules. Jour. Environ. Sci.
Health Bull. 67.
Stijve, T. 1971. Determination and occurrence of hexachlorobenzene resi-
dues. Mitt. Geb. Lebenmittelunters. Hyg. 62: 406.
'1673
-------
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.
U.S. EPA. 1979. Chlorinated Benzenes: Ambient Water Quality Criteria.
(Draft)
Weast, R.C. 1971. Handbook of Chemistry and Physics. 53rd ed., Chemical
Rubber Company, Cleveland, Ohio. .
Windholz, M. (ed.) 1976. The Merck Index. 9th ed., Merck and Co., Inc.,
Rahway,.New Jersey.
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No. 142
Pentachloronitrobenzene
' ' )
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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SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
pentachloronitrobenzene and has found sufficient evidence
to indicate that this compound is:carcinogenic.
~6 77-
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DISCLAIMER
The mention of company trade names or products does not constitute
endorsement by the U.S. EPA or the Federal government.
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PENTACHLQRCNITROBENZENE
Summary
Increased incidence of hepatoma formation was reported in hybrid mice
treated with pentachlorobenzene (PCNB). PCNB was found to be mutagenic in
the hcr-strain of Escherichia coli ochre, but not in another §_._ coli strain.
PCNB containing a number of contaminants produced renal agenesis and
cleft palate in C57B1/6 mice, cleft palate in CD-I mice, but was not terato-
genic in CO rats. Purified PCNB (less than 20 ppm. hexachlorobenzene) re-
sulted in fewer cleft palates in the fetuses. No significant teratogenic
effects in rats were detected at dosages as high.as 1,563 ppm. In a three
generation study using doses as high as 500 ppm, PCNB had no significant ef-
fects on the reproduction of rats.
Acute toxicity data for fish were: a 96-hour LC5n j_n bluegill from
0.29 to 0.38 ppm and a 96-hour LC5Q Of Q.31 ppm in rainbow trout.
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I. INTRODUCTION
This profile is based on the Initial Scientific Review of Pentachloro-
nitrobenzene, PCNB, plus relevant scientific research articles published
subsequent to that document (U.S. EPA, 1976).
Pentachloronitrobenzene (molecular weight, 295.34) is a pale yellow-to-
white solid, depending on purity, that melts between 142° and 146°C, has
a boiling point of 328°C at 760 mm Hg, and a density of 1.718 g/cnv5 at
25°C. Reported vapor pressure values for PCNB are: 1.16 x 10~5 mm Hg
at 1QOC, 5.0 x 10~5 mm Hg at 20°C, and 11.3 x 10~5 mm Hg at 25°C
(U.S. EPA, 1976). PCNB has a relative vapor density (air = 1) of 10.2
(Verschueren, 1977). Water solubility of PCNB is 0.44 mg/1 at 20°C and 2
mg PCNB will dissolve in one liter ethanol at 25°C. PCNB is freely sol-
uble in carbon . disulfide, benzene, chloroform, ketones, and aromatic and
chlorinated hydrocarbons, and slightly soluble in alkanols (U.S. EPA, 1976).
PNCB is primarily registered as a soil fungicide for a wide variety of
crops and is also used as a seed-treatment fungicide. It is effective
against bunt of wheat, Botrytis, Rhizoctonia, and Sclerotinia spp. There
are no current nonagricultural uses of PCNB (U.S. EPA, 1976). PCNB is manu-
factured domestically under the trade name Terracloi£5/ with an estimated
annual production in 1971 of 3 million pounds (U.S. EPA, 1972). According
to the Olin Corporation (1974), 60 to 70 percent of the PCNB produced will
be used in the United States. The United States has imported from 20,000 to
132,000 Ibs. between 1966 and 1969 (U.S. EPA, 1976). PCNB manufactured in
Europe is marketed under the common name Quintozene (Dejonckheere, et al.
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1976). It may be worth noting that commercial PCNB fungicides contain im-
purities such as hexachlorobenzene, pentachlorobenzene and tetrachloronitro-
benzene, which may be more hazardous than PCNB itself (Dunn, et al. 1978;
Simon, et al. 1979).
No data are available for the disassociation of PCNB in aqueous sys-
tems. Crosby and Hamadmad (1971) studied the photoreduction of PCNB. The
compound remained unchanged in sunlight, probably excluding photolysis as a
major route of environmental degradation. At temperatures above 328°C,
some decomposition of PCNB-has been noted (U.S. EPA, -1976).
PCNB can be biodegraded by pure cultures of actinomycetes and filamen-
tous fungi during their active growth phase (Chacko, et al. 1966).
II. EXPOSURE
PCNB is prepared by either chlorination or nitration reactions. The
reaction temperature for the chlorination process is 60 to 70°C. Although
this reaction is well below the boiling point of PCNB, atmospheric emissions
are possible because of PCNB's relatively high vapor pressure. Furthermore,
there exists a potential for environmental release via wastewater effluents
at the manufacturing sites. No monitoring data are available for ambient
air or water levels of the compound. The major source of environmental con-
tamination is through its application as a fungicide. In the United States,
PCNB is used primarily on cotton:and peanut crops. . Geographic use distribu-
tion is mainly concentrated west of the Mississippi River (U.S. EPA, 1976).
Carey, et al. (1979) in their study of pesticide residues in the soil detec-
ted PCNB in only three of the 1,483 sample sites. The-detected residue con-
centration was from 0.22 to 2.61 ppm. It should be noted, however, that
»
their study was primarily confined to the eastern United States.
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Routes of human exposure to PCN8 include water, air, contaminated
foods, and fish. Casanova and Oubroca (1973) studied the residues of PCNB
found in lettuce grown in soil treated with the fungicide. Residue values
were 0.73 ppm (15 kg PCNB/ha) and 1.56 ppm (45 kg PCNB/ha). Goursaud, et
al. (1972) detected PCNB contamination in endive roots. Since the main ob-
jective of their study was the uptake of hexachlorobenzene, actual PCNB
concentrations were not noted. However, in a subsequent experiment
Goursaud, et al. (1972) fed cows endive roots containing 2.16 ppm PCNB.
PCNB residues found in the cows' milk were negligible. Bioaccumulation of
PCNB in White Leghorn cockerels (Dunn, et al. 1978) was also found to be
negligible . (accumulation ratio 0.001 = tissue concentration/dietary
concentration). Broiler chickens (Reed, et al. 1977) did not -accumulate
PCNB or its metabolites to any appreciable extent (0.002 ppm). No
additional information on the levels of PCNB in foods is available.
Bioaccumulation data on PCNB were not found in the literature for aqua-
tic organisms. Ko and Lockwood (1968) reported that the mycelium of fungi
had accumulated a concentration of PCNB seven times that of the surrounding
soil.
III. PHARMACOKINETICS
A. Absorption
Absorption data on PCNB were restricted to oral administration in-
volving three test species. Betts, et al. (1955) reported that 60 percent
of the oral dosage was not absorbed from the gastrointestinal tract in rab-
bits. Two subsequent studies, however, report that PCNB is readily absorbed
from the gastrointestinal tract and/or metabolized by gut flora to another
compound and then almost fully absorbed. Kogel, et al. (1979) found that
PCNB was readily and almost completely absorbed from- the gastrointestinal
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tract of Rhesus monkeys. After a single dose of 2 mg/kg given in methyl
cellulose suspension, only 7.4 percent of the administered amount was ex-
creted as unmetabolized PCNB in the feces. When 91 mg/kg PCNB was given in
sesame oil, only 4.3 percent of the dose was excreted unmetabolized. Uptake
occurs mainly by the portal venous route, with little involvement of the
lymphatic system, bringing the absorbed PCNB directly to the liver where
biotransformation can begin. Studies of Comet Red and White Leghorn chick-
ens yielded similar results. Chickens fed 300 ppm PCNB in laying mash for
sixteen weeks excreted only 1.1 ppm PCNB (Simon, et ai. 1979).
B. Distribution
Several studies have been conducted on the distribution and stor-
age of ingested PCNB. Due to rapid metabolism and elimination, this com-
pound shows very little accumulation in body tissues. Setts, et al. (1955)
used rabbits and Borzelleca, et al. (1971) employed beagles and rats. In
neither experiment was PCNB detected in liver, kidney, muscle, or adipose
tissue. Other studies have indicated very low concentrations of PCNB in
various tissues. Simon, et al. (1979) found PCNB at concentrations of 0.85
ppm in fat and 0.005 ppm in egg whites of chickens fed 300 ppm PCNB for six-
teen weeks. Other tissues examined contained no detectable levels of PCNB.
Dunn, et al. (1978) found the highest tissue residues of PCNB in adipose
tissue (1.14 and 1.87 ppm) and the gizzard (1.60 and 0.84 ppm) in chickens
given 100 ppm and.1,000 ppm PCNB in feed, respectively. Leg and breast mus-
cles and heart, kidney, and liver contained very low (0.16 to 0.07 ppm) or
trace amounts of PCNB.
Concentrations of PCNB in various organs of Rhesus monkeys after
•
chronic feeding of 2 ppm PCNB in the daily diet were (in ppm): blood, 0.07;
muscle, 0.01; brain, 0.03; liver, 0.19; kidney, 0.14; adrenal cortex, 0.08;
Jf
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thymus, 0.20; lymph nodes (large intestine), 0.12; bone marrow, 0.13; and
omental fat, 0.21 (Mueller, et al. 1978). Kb'gel, et al. (1979) found the
highest concentration of PCNB and/or its metabolites occurring in bile (7.73
+_ 0.2 ppm in males and 3.72 _+ 0.05 in females) after feeding of 2 ppm PCNB
for 70 days.
C. Metabolism
PCNB metabolism has been studied in rats, dogs, cows, and rabbits.
Pentachloroaniline and methyl pentachlorophenyl sulfide are the major metab-
olites. Tissue retention of these compounds is found primarily in body fat
with minimal concentrations found in muscle (U.S. EPA, 1976). Two major
pathways for the biotransformation of PCNB in Rhesus monkeys are: 1) the
reduction of the nitro-moeity to the corresponding aniline, and 2) the clea-
vage of the C-N bond, presumably via conjugation with sulfur-containing
amino acids (Ko'gel, et al. 1979).
D. Excretion
PCNB and its metabolites are excreted mainly in the urine and
feces. Mueller, et al. (1978) reported that Rhesus monkeys excreted almost
80 percent of the ingested PCNB within 5 days; of the excreted radio-
activity, 91.2 percent was in the form of metabolites.
IV. EFFECTS.
A. Carcinogenicity
Very little information on possible carcinogenic effects of PCNB
was found in the available literature. Courtney, et al. (1976) cite one
study which found PCNB to be carcinogenic in a hybrid mouse with an in-
creased incidence of hepatoma formation. Levels of exposure were not given.
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8. Mutagenicity
PCNB was found to be mutagenic in the hcr-strain of Escherichia
coll 3/r ochre, but not in another £._ coli strain. In the host-mediated as-
say in mice, no significant increase in mutation rates in Salmonella
typhimurium and Serratia morcescens was observed after subcutaneous injec-
tion of PCNB. The compound also gave negative results in spot tests (U.S.
EPA, 1976).
C. Teratogenicity and Other Reproductive Effects
PCNB was administered to pregnant rats by intubation on days 6 and
15 of gestation at dosages from 100 to 1,563 ppm. Fetuses were examined for
gross malformations. No significant effects on the number of corpora lutae,
the position and numbers of dead or resorbed fetuses, or the fetal weights
and sex ratios were observed at any dose level. No significant skeletal or
soft tissue anomalies were reported in the fetuses (U.S. EPA, 1976).
A three-generation study with groups of rats fed diets containing
0, 5, 50 or 500 ppm (Olin technical PCNB) showed no significant effects on
fertility, gestation, viability, lactation, rats born per litter, or rats
weaned per litter or their average weaning weights (U.S. EPA, 1976).
PCNB containing a number of contaminants, however, produced renal
agenesis and cleft palate in C56B1/6 mice and cleft palate in CD-I mice, but
was not teratogenic in CD rats. Purified PCNB (less than 20 ppm hexachloro-
benzene) resulted in few cleft palates in fetuses (Courtney, et al. 1976).
D. Chronic Toxicity
PCNB does not appear to be chronically toxic'when administered in
feeding'studies. Rhesus monkeys given 2 ppm or 91 ppm PCNB in their diet
for 70 days were monitored for clinical chemistry and hematology parameters
throughout the study. These parameters remained unchanged, indicating that
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organ function and hematopoiesis was not affected by PCNB or its metabolites
(KSgel, et al. 1979).
White Leghorn chickens fed PCNB at concentrations up to 1,000 ppm
for the first 8 weeks of life did not develop tissue lesions and hens fed up
to 1,000 ppm for 35 weeks failed to develop histopathological changes (Dunn,
et al. 1978).
Kb'gel, et al. (1979) cite studies which report that the toxic ef-
fect of TerraclorR in rats and dogs is limited to liver enlargement due to
hepatocellular hypertrophy. Also, cats had increased methemoglobin levels
after moderate and high doses of Terraclor1^ and dogs fed a very high dose
(5,000 ppm) of PCNB of undetermined purity for two years were found to have
reduced hematopoiesis. These effects, however, may be due to the presence
of hexachlorobenzene as a contaminant (Kb'gel, et al. 1979).
E. Acute Toxicity
Cholakis, under contract with the U.S. EPA, administered single
doses of pentachloronitrobenzene by gavage to several species of microtine
rodents (voles) (U.S. EPA, 1978). The acute oral LD.- values in male and
female M_._ montanus were 4,194 mg/kg and 3,717 mg/kg, respectively. In M._
ochrogaster, M_._ canicaudus, and NT._ pennsylvanicus, values were greater than
5,000 mg/kg for both sexes. Toxicologic signs observed were some piloerec-
tion, loss of righting reflex and lachrymation. Most signs disappeared
after 24 hours. Most deaths occurred within two to six days of dosing.
V. AQUATIC TOXICITY
A. Acute Toxicity
In static, acute toxicity bioassays using various PCNB formula-
tions, bluegill (Lepomis macrochirus) had 96-hour median lethal concentra-
tion (LC5Q) values ranging from 0.29 to 0.38 ppm. Rainbow trout (Salmo
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qairdneri) had a 96-hour LC5Q value of 0.31 ppm (U.S. EPA, 1976).
8. Chronic Toxicity, Plant Effects and Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
No guidelines or standards were located in the available literature for
humans or aquatic life.
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REFERENCES
Setts, J.J., et al. 1955. The metabolism of PCNB and 2,3,4,6-tetrachloro-
nitrobenzene and the formulation of meriapturic acids in rabbit. Biochem.
Jour. 61: 611.
Borzelleca, J.F., et al. 1971. Toxicologic and metabolic studies on PCNB.
Toxicol. Appl. Pharmacol. 18: 522.
Carey, A.E., et al. 1979. Pesticide residue levels in soils and crops from
37 states, 1972. Pest. Monit. Jour. 12: 209.
Casanova, M. and J. Dubroca. 1973. Etude des residues de divers fongicides
utilises dans le traitement des cultures de laitures en serre. Ann. Phyto-
pathol. 5: 65.
».
Chacko, C.I., et al. 1966. Chlorinated hydrocarbon pesticides: degradation
by mirobes. Science 154: 893.
Courtney, K.D., et al. 1976. The effects of pentachloronitrobenzene, hexa-
chlorobenzene, and related compounds on fetal development. Toxicol. Appl.
Pharmacol. 35: 239..
Crosby, O.G. and N. Hamadmad. 1971. The photoreduction of pentachloroben-
zenes. Jour. Agr. Food Chem. 19: 1171.
Dejonckheere, w., et al. 1976. Residues of Quinotozene. Pest. Monit.
Jour. 10: 68.
Dunn, J.S., et al. 1978. The accumulation and elimination of tissue resi-
dues after feeding PCNB to White Leghorn cockerels. Poultry Sci. 57: 1533.
Goursaud, J., et al. 1972. Sur la pollution du lait par les residues HC8.
Industries Alimientoires et Agr. 89: 31.
Ko, W.H. and J.L. Lockwood. 1968. Accumulation and concentration of chlor-
inated hydrocarbon pesticides by microorganisms in soil. Can. Jour. Micro-
biol. 14: 1075.
Kogel, W., et al. 1979. Biotransformation of PCNB - 14c in Rhesus mon-
keys after single and chronic oral administration. Chemosphere 8: 97. .
Mueller, W.F., et al. 1978. Comparative metabolism of HCB and PCNB in
plants, rats, and Rhesus monkeys. Ecotoxicol. Environ. Safety. 2: 437.
Olin Corporation. 1974. Agricultural Products Division, Little Rock, Ark.
Personal communication to Econ. Branch, Criteria and Evaluation Division,
Office of Pesticide Programs, U.S. EPA.
Reed, E.L., et al. 1977. Tissue residues from feeding PCNB to broiler
chickens. Toxicol. Appl. Pharmacol. 42: 433.
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Simon, G.S., et al. 1979. Distribution and clearance of pentachlorcnitro-
benzene in chickens. Toxicol. Appl. Pharmacol. 50:. 401.
U.S. EPA. 1972. The pollution potential in pesticide manufacturing. Mid-
west Research Institute. EPA Rep. No. OWP-TS-00-72-04. NTIS PB-213 782.
U.S. EPA. 1976. Initial Scientific Review of PCN8. Office of Pesticide
Programs, Washington, D.C. EPA-540/1-75-016.
U.S. EPA. 1978. Study of the chemical and behavioral toxicology of
substitute chemicals in microtine rodents. EPA-600/3-78-082. Midwest
Research Institute, Kansas City, MO.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals.
Van Ncstrand Reinhold Co., New York.
•J6X1-
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No. 143
Pentachlorophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
1690
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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 acc-uracy.
-lit'-
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PENTACHLOROPHENOL
SUMMARY
Pentachlorophenol has shown no evidence of carcinogenicity.
Evidence for mutagenicity is equivocal. Pentachlorophenol is
teratogenic in experimental animals at levels which produce mater-
nal or fetal toxicity. Adverse health effects have been minimal
in workers chronically exposed to pentachlorophenol. Relatively
high levels of continous exposure produce muscle weakness, head-
ache, anorexia, abdominal pain, weight loss, and irritation of
skin, eyes, and respiratory tract. Pentachlorophenol is a strong
uncoupler of oxidative phosphorylation.
Pentachlorophenol has been demonstrated to, be acutely toxic
to freshwater salmonids at levels as low as 37 jjg/1. Comparable
levels of toxicity were observed for marine fish. Freshwater
plants were also highly susceptible to the action of this chemi-
cal with effective concentrations_as low as 7.5 ug/1.
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PENTACHLOROPHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Pentachlorophenol (U.S. SPA, 1979).
Pentachlorophenol (PCP; CgCl5OH; molecular weight 266.35)
has the following physical and chemical properties (Stecher,
1966; Natl. Fire Prot. Assoc., 1973; Sax, 1975; Spector, 1956;
Weast, 1975-76):
Melting Point Range 190 - .191° C
Boiling Point Range 309 - 310 (decomposes)
Vapor Pressure 0.12 mm Hg at 100° C
Solubility Water: 14 mg/1 at 20° C
Commercial preparations of pentachlorophenol contain
"caustic insolubles" or "nonphenolic. neutral impurities" such
as octachlorodibenzofurans and tetra-, penta-, hexa-, hepta-,
and octachlorodibenzo-p-dioxins (Johnson, et al. 1973; Schwetz,
et al. 1974). In addition, commercia'l pentachlorophenol contains
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three to ten percent tetrachlorophenol (Goldstein, et al. 1977;
Schwetz, et al. 1978).
Pentachlorophenol is a commercially produced bactericide,
fungicide, and slimicide used primarily for the preservation
of wood, wood products, and other materials. As a chlorinated
hydrocarbon, PCP is also used as a herbicide, insecticide, and
molluscicide (U.S. EPA, 1979).
Pentachlorophenol and its sodium salt are widely dissemi-
nated in the environment (U.S. EPA, 1979). Pentachlorophenol
undergoes photochemical degradation in solution in the presence
of sunlight (Mitchell, 1961; Hanadmad, 1967; Wong and Crosby,
1977) and is reported to persist in warm moist soils for a period
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of 12 months (Harvey and Crafts, 1952). in laboratory experiments,
some microorganisms have been reported to metabolize pentachloro-
phenol and its sodium salt (Watanabe, 1973; Suzuki and Nose,
1971; Cserjesi, 1967; Reiner, et al. 1977).
II. EXPOSURE
Residues of pentachlorophenol have been found in food,
water and human tissues. Pentachlorophenol levels of 0.06 ug/1
in finished, drinking water prepared from untreated water contain-
ing 0.17 ug/1 have been reported (Buhler, et al. 1973). Penta-
chlorophenol has been detected in 13 of 240 food composites at
levels of 0,01 to 0.04 mg/kg (Johnson and Manske, 1977) . The
calculated . daily dietary exposure is one to six ;ag/person/day
(Duggan and Corneliusen, 1972).
The U.S. EPA (1979)- has estimated the weighted average
bioconcentration factor of pentachlorophenol at 53 for the edible
portion of fish and shellfish consumed by Americans. This esti-
mate is based on measured steady-state bioconcentration studies
in goldfish (Carassius auratus), bluegill (Lepomis macrochirus),
eastern oyster (Crassostrea . virginica) , and sheepshead minnow
(Cyprinodon variegatus).
Inhalation and dermal exposure data for the general popula-
tion are not available (U.S. EPA, 1979). These routes of expo-
sure are more likely to occur occupationally.
Total body exposures, based on reported' urine levels of
pentachlorophenol, appear to be in the range of 10-17 jug/person/
day for the general population and 1500-4400 .pg/person/day for
occupational exposures (U.S. EPA, 1979). These values may be
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due not only to direct exposure to pentachlorophenol, but also
to exposure to hexachlorobenzene (pesticide, fungicide) and lin-
dane (pesticide), which are degraded in part to pentachlorophenol
{Yang, et al. 1975; Lui and Sweeney, 1975; Mehendale, et al.
1975; Koss and Koransky, 1978; Karapally, et al. 1973; Engst,
et al. 1976) .
III. PHARMACOKINETICS
A. Absorption
The half-life for absorption in humans after oral
ingestion of pentachlorophenol is 1.3 + 0.4 hr. In humans, a
peak plasma concentration of 0.248 mg/1 was observed four hours
after ingestion of a 0.1 mg/kg dose {Braun, et al. 1978). Absorp-
tion in rats is similar to that found in humans (Braun, et al. '
1977) .
Pentachlorophenol is readily, absorbed through the skin
as indicated by its lethality after dermal exposure (Deichmann,
et al. 1942; Armstrong, et al. 1969).
B. Distribution
In humans (fatal pentachlorophenol intoxication) and
in rats (non-lethal exposure) , the highest levels of pentachloro-
phenol are found in liver, kidney, and blood, with the lowest
levels in brain, spleen, and fat (Cretney, 1976; Armstrong, et
al. 1969; Braun, et al. 1977; Larsen, et al. 1975).
C. Metabolism
In four male volunteers ingesting 0.1 mg pentachloro-
phenol/kg, approximately 74 percent of the dose was elimina'ted
in the urine as pentachlorophenol (PGP) and 12 percent as PGP
glucuronide; four percent was eliminated in feces as pentachloro-
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phenol and PGP glucuronide (Braun, et al. 1978). Rats excrete
75 percent of administered pentachlorophenol as the unchanged
PCP, 16 percent as tetrachlorohydroquinone, and nine percent
as PCP glucuronide (Braun, et al. 1977). In another study (Ahlborg,
1978) , trichloro-g-hydroquinone was found as an additional metabo-
lite of pentachlorophenol in rats. Mice also metabolize penta-
chlorophenol to tetrachlorohydroquinone (Jakobson and Yllner,
1971) .
D. Excretion
In humans and in experimental animals, the primary
mode of excretion for pentachlorophenol is in the urine (Diechmann,
et al. 1942; Braun, et al. 1977, 1978; Larsen, et al. 1975; Jakobson
and Yllner, 1971).
In humans, the plasma pentachlorophenol half-life
is 30.2 + 4.0 hours. The half-lives for elimination of penta-
chlorophenol and PCP glucuronide from urine are 33.1 + 4.5 and
12J7 + 5.4 hours, respectively (Braun, et al. 1978). Elimination
of pentachlorophenol by the rat is similar to elimination by
humans (Braun, et al. 1977).
The available literature indicates that pentachloro-
phenol does not accumulate in body tissues to any significant
extent (U.S. EPA, 1979). Long term, low level tissue binding
has not been adequately studied.
IV. EFFECTS
A. Carcinogenicity
Pentachlorophenol has not shown evidence of carci'no-
genicity. Pentachlorophenol did not promote papillomas or car-
cinomas when applied repeatedly to the skin at high concentra-
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tions after initiation with dimethylbenzanthracene (Boutwell
and Bosch, 1959). Mice receiving commercial pentachlorophenol
in the diet throughout their lifespans (about 18 months) did
not have a significant incidence of tumors (Innes, et al. 1969).
Pentachlorophenol, with low levels of nonphenolic contaminants,
was non-carcinogenic when fed to rats for 22 to 24 months (Schwetz,
et al. 1978).
B. - Mutagenicity
Pentachlorophenol has .been shown to be mutagenic in
a few test systems. Recrystallized pentachlorophenol increased
the frequency of mutations and mitotic gene conversion in Sac-
charomyces cerevisiae when used at a level (400 mg/1) which re-
sulted in a 59 percent survival rate of test organisms (Fahrig,
et al. 1978). Four of the 473 offspring of female mice injected
with a single high dose of pure pentachlorophenol during gesta-
tion were reported to have changes in hair coat color (spots)
of genetic significance (Fahrig, et al. 1978).
No mutagenic activity was detected in male germ cells
of Drosophila (Vogel and Chandler, 1974), in the mouse host-mediated
assay, in _iri vitro spot tests (Buselmaier, et al. 1973), or in
histidine-required mutants of Salmonella typhimurium (Anderson,
et al. 1972) .
C. Teratogenicity
Information suggesting pentachlorophenol is a human
teratogen was not encountered. .Pentachlorophenol of both com-
mercial and purified grades produced fetal anomalies in rats
at levels considered to be toxic either to the maternal rat or
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to the fetus (Larsen, et al. 1975; Schwetz, et al. 1974; 1978).
Abnormalities included, subcutaneous edema, dilated ureters, de-
layed ossification of the skull, skeletal anomalies, dwarfism,
exencephaly, macropthalmia, and taillessness.
D. Other Reproductive Effects
In a study in which male and female rats were fed
3 or 30 mg/kg pentachlorophenol continuously starting 62 days
before mating, no adverse effects were observed at the 3 mg/kg
level. At 30 mg/kg, the following indices were decreased: maternal
body weight; percent liveborn pups; 7, 14, 21 day survival; 1,
7, 14, 21 day body weight-pups; 7, 14, 21 day litter size. Selected
abnormalities were also seen at this dose.(Schwetz, et al. 1978).
E. Chronic Toxicity
Adverse health effects have been minimal in workers
chronically exposed to pentachlorophenol (Klemmer, 1972; Takahashi,
et all 1976). Increased levels of serum enzymes SCOT, SGPT,
and- LDH, and elevated levels of total bilirubin and creatine
phosphokinase were noted, but all levels were still within normal
limits. A significantly higher prevalence of gamma mobility
C-reactive protein (CRP) was detected in the sera of chronically
exposed workers. CRP levels are often elevated in acute states
of various inflammatory disorders or tissue damage (Takahashi,
•et al. 1976). A chronic health effect which has been associated
with human exposure to certain types of commercial PCP is chlor-
acne (Baader and Bauer, 1951; Nomura, 1953). Chloracne could
have resulted from impurities in the pentachlorophenol; commercial
PCP containing high levels of chlorodioxins produced chloracne
in the rabbit ear test, while pure pentachlorophenol or penta-
-------
chlorophenol with reduced dioxin content did not (Johnson, at
al. 1973).
Chronic intoxication in humans results from relatively
high levels of continuous exposure. Symptoms include muscle
weakness, headache, anorexia, abdominal pain, and weight loss
in addition to skin, eye, and respiratory tract irritation (U.S.
EPA, 1979).
Rats fed pentachlorophenol containing low levels of
nonphenolic contaminants at daily levels of 1 to 30 mg/kg for
eight months (Goldstein, et al. 1977) and 22 to 24 months (Schwetz,
et al. 1978) had decreased body weight gains at dosage levels
of 30 and 10 mg/kg, respectively. In the 22 to 24 month study,
the 30 mg/kg dose resulted in increased serum enzyme SGPT levels
and increased specific gravity of .the urine.
F. Other Relevant Information
Pentachlorophenol is a strong uncoupler of oxidative
phosphorylation (Weinbach and Garbus, 1965; Mitsuda, et al. 1963).
V. AQUATIC TOXICITY
A. Acute Toxicity
The results of 33 freshwater flow-through bioassays
reveal a range of 96-hour LC-Q values of from 63 ug/1 for the
sockeye salmon (Oncorhynchus nerka) (Webb and Brett, 1973) to
340 pg/1 for the fathead minnow (Pimephales promelas) (Ruesink
and Smith, 1975). In 19 static assays, ^CCQ values ranged from
37 ug/1 for the coho salmon (0. kisutch) to 600 pq/1 for the
fathead minnow. Five species of salmonids were more sensitive
than 4 other species of minnows or centrachids. Freshwater in-
vertebrates displayed LC5Q values ranging from 310 ug/1 to 1,400
-------
for the tubificid worm (Tub if ex tubifex) and were affected
by increasing the PH from 7.5 to 9.5. The acute toxicity of
pentachlorophenol to saltwater fish ranged from 38 ug/1 in a
96-hour static pinfish (prolarvae) (Lagodon rhomboides) assay
(Borthwick and Schimmel, 1978) to 442 ug/1 for juvenile sheeps-
head minnows (Cyprinodon variegatus) (Parrish, et al. 1978).
For three marine invertebrate species tested, LC5Q values ranged
from 40 to 5,600 ug/1, with the eastern oyster (Crassostrea vir-
ginica) being the most sensitive marine invertebrate.
B. "Chronic Toxicity
Freshwater chronic studies for fish or invertebrates
were not available. A life-cycle chronic test of 151 days in
the marine sheepshead minnow produced a chronic value of 64 ug/1
(Parrish, et al. 1978). Data for marine invertebrates was not
available (U.S. EPA, 1979).
C. Plant Effects
For freshwater plants,_ the lowest effective concentra-
tion was 7.5 jjg/1, which resulted in the total destruction of
chlorophyll in the alga Chlorella pyrenoidosa after 72 hours.
A drastic decrease in cell numbers of the marine alga Monochrysis
lutheri was observed after 12 days of exposure to 293 pg/1 (Woelke,
1965), and 50 percent inactivation of photosynthesis was seen
in kelp (Macrocystis pyr if era) exposed for 4 days to 300 jug/I
(Clendenning and North, 1960).
D. Residues
»
Equilibrium levels of PCP in water and tissues of
aquatic organisms are attainable within four days; and when pre-
viously exposed marine eastern oysters (Crassostrea virginica)
X
7 760 -
-------
or freshwater bluegills (Lepomis macrochirus) were held in PCP-
free water, a rapid loss of PCP from the organism occurred (Schim-
mel, et al. 1978; Pruitt, et al. 1977). Bioconcentration factors
in marine organisms ranged from 0.26 for the juvenile brown shrimp
(P'enaeus aztecus) to 78 for the eastern oyster. In freshwater
fish, bioconcentration factors of 1,000 for the whole body of
the goldfish (Carassius auratus) and of 13 for the muscle tissue
of the bluegill have been reported (Kobayashi and Akitake, 1975;
Pruitt, et al. 1977).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The U.S. EPA (1979) draft criterion for pentachioro-
*- - \
,) • .
prienol in ambient water is 680 ug/1.
The maximum air concentration established by the Ameri-
can Industrial Hygiene Association (1970) is 0.5 mg pentachloro-
phenol or 0.5 mg sodium pentachlorophenate/m"3 for an 8-hour expo-
sure (TLV) . The code of Federal Regulations 21, part 121, para-
/ ~;aph 121:2556 allows up to 50 ppm pentachlorophenol in treated
wood which will come in contact with food.
A NOEL in drinking water of 0.021 mg pentachlorophenol/1
is suggested by the National Research Council (1977), based on
a NOEL of 3 mg/kg in 90 day and 8 month rat studies and an uncer-
tainty factor of 1,000.
B. Aquatic
The draft criterion to protect marine life is 6.2
ug/1 as a 24-hour average, not to exceed 14 ug/1 at any time.
The draft criterion to protect marine life is 3.7 ug/1 for a
24-hour average, not to exceed 8.5 pg/1 at any time (U.S. EPA,
1979).
-------
PgNTACHLOROPHENOL
REFERENCES
Ahlborg, U.D. 1978. Oechlorination of pentachiorophenol in vivo and .in
vitro, pp. 115-130. In: K.R. Rao (ed.), Pentachiorophenol: Chemistry,
pharmacology and environmental toxicology. Plenum Press, New York.
American Industrial Hygiene Association. 1970. Hygienic Guide Series:
Pentachlorophenol and sodium pentachlorophenate. Am. Ind. Assoc. Jcur.
31: 521.
Anderson, K.J., et al. 1972. Evaluation of herbicides for possible muta-
genic properties. Jour. Agri. Food Chem. 20: 649.
Armstrong, R.W., et al. 1969. Pentachlorophenol poisoning in a nursery for
newborn infants. II. Epidemiologic and toxicoiogic studies. Jour.
Pediatr. 75: 317.
Baader, E.W. and H.J. Bauer. 1951. .Industrial intoxication due to penta-
chiorophenol. Industr. Med. 4 Surg. .20: 286.
Borthwick, P.W., and S.C. Schimmmel. 1978. Toxicity of pentachiorophenol
jand related compounds to early life stages of selected estuarine animals.
Pages 141-146 _In: K.R. Rao (ed.), Pentachlorophenol: Chemistry, pharma-
cology and environmental toxicology. Plenum Press, N.Y.
Boutwell, R.K. and K.K. Bosch. 1959. The tumor-promoting action of phenol
and related compounds for mouse skin. Cancer Res. 19: 413.
Braun, W.H., et al. 1977. The pharmacokinetics and metabolism of penta-
chiorophenol in rats. Toxicql. Appl. Pharmacol. 41: 395.
.Braun, W.H., et al. 1978. The. metabolism/pharmacokinetics of pentachloro-
)phenol in man, and a comparison with the rat and monkey model. Toxicol.
Appl. Pharmacol. 45: 135.
Buhler, O.R., et'al. 1973. Occurrence of hexachlorophene and pentachioro-
phenol in sewage and water. Environ. Sci. Technol. 7: 929.
Buselmaier, et al. 1973. Comparative investigations of the mutagenicity of
pesticides in mammalian test systems. Mutat. Res. 21: 25.
Clendenning, K.A. and W.J. North. 1960. Effects of wastes on the giant
kelp'i. Macrocystis. pyrifera. Pages 82-91 In: - Proc. 1st Conf. on waste dis-
posal in the marine environment. Pergamon Press, New York
Cretney, M.J. 1976. Pentachlorophenol death. Bull. T.I.A.F.T. 12 10.
In: T.J. Haley, 1977. Human poisoning with pentachiorophenol and its
treatment. Ecotoxicol. Environ. Safety (In press).
Cserjesi, A.J. 1967. The adaptation of fungi to pentachiorophenol and its
biodegradation. Can. Jour. Microbiol. 13: 1234.
-J703L-
-------
Deicnmann, W., et al. 1942. Acute and chronic effects of pentachiorophenol
and sodium pentachlorophenate upon experimental animals. Jour. Pharm. Exp.
Therap. 76: 104.
Ouagan, R.E., and ?.£. Corneliussen. 1972. Dietary intake of pesticide
chemicals in the United States (III), June 1968-April 1970. Pestic.
Monitor. Jour. 5: 331.
Engst, R., et al. 1976. The metabolism of lindane and its metabolites
gamma-2,3,4,5,6-pentachlorocyclohexene, pentachlorobenzene and pentachloro-
phenol in rats and the pathways of lindane metabolism. Jour. Environ. Sci.
Health 2: 95.
Fahrig, R., et al. 1978. Genetic activity of chlorophenols and chlcro-
phenol impurities. Pages 325-338 In: K.R. Rao (ed.), Pentachlorophenol:
Chemistry, pharmacology and environmental toxicology. Plenum Press, New
York.
Goldstein, J.A., et al. 1977. Effects of pentachiorophenol on hepatic
drug-metabolizing enzymes and porphyria related to contamination with chlor-
inated dibenxo-p-dioxins and dibenzofurans. Biochem. Pharmacol. 26: 1549.
Hanadmad, N. 1967. Photolysis of pentachloronitrobenzene, 2,3,5,6-tetra-
chloronitrobenzene and pentachiorophenol. Ph.D. dissertation. University
of California, Davis.
Harvey, W.A. and A.S. Crafts. 1952. Toxicity of pentachiorophenol and its
sodium salt in three yolo soils. Hilgardia 21: 487.
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.
Jakobson, I. and S. Yllner. 1971. Metabolism of l^C-pentachlorophenol in
the mouse. Acta. Pharmacol. Toxicol. 29: 513.
Johnson, R.D. and D.D. Manske. 1977. Pesticides in food and- feed: Pes-
ticide and other chemical residues in total diet samples (XI). Pestic.
Monitor. Jour. 11: 116.
Johnson, R.L., et al. 1973. Chlorinated dibenzodioxins and pentachioro-
phenol. Environ. Health Perspec. Exp. Issue 5: 171.
Karapally, J.C., et al. 1973. Metabolism of lindane-l^C in the rabbit:
ether-soluble urinary metabolites. Jour. Agric. Food Chem. 21: 311
Klemmer, H.W. 1972. Human Health and Pesticides - community pesticide
studies. Residue Rev. 41: 55.
Kobayashi, K. and H. Akitake. 1975. Studies on the metabolism of chloro-
phenols in fish. I. Absorption and excretion of PCP by goldfish. Bull.
Jap. Soc. Sci. Fish. 41: 87.
~/7o3
-------
Koss, G. and W. Koransky. 1978. Pentachlorophenol in different species of
vertebrates after administration of hexachlorobenzene and pentachloro-
benzene. Pages 131-137 In; K.R. Rao (ed.), Pentachlorophenol: Chemistry,
pharmacology and environmental toxicology. Plenum Press, New York.
Larsen, R.V., et al. 1975. Placental transfer and teratology of penta-
chlorophenol in rats. Environ. Lett. 10: 121.
Lui, H., and C.D. Sweeney. 1975. Hepatic metabolism of hexachlorobenzene
in rats. FEBS Lett.' 51:'225.
Mehendale, H.M., et al. 1975. Metabolism and effects of hexachlorobenzene
on hepatic microsomal enzymes in the rat. Agric. Food Chem. 23: 261.
Mitchell, L.C. 1961. Effect of ultraviolet light (2537A) on 141 pesticide
chemicals by paper chromatography. Jour. Off. Anal. Chem. 44: 643.
Mitsuda, W., ,et al. 1963. Effect of chlorophenol analogues on the oxida-
tive phosphorylation in rat liver mitochondria. Agric. Biol. Chem. 27: 366.
National Fire Protection Assoc. 1973. Fire protection guide;on hazardous
materials. 5th ed. Natl. Fire Prot. Assoc. Int., Boston.
National Research Council. 1977. Drinking water and health. Natl. Acad.
of Sci. Washington, D.C.
Nomura, S. 1953. Studies on chlorophenol poisoning. Podo Kaguku Jour.
Sci. Labor 29: 474.
Parrish,. P.R., et al. 1978. Chronic toxicity of chlordane, trifluralin,-
.and pentachlorophenol to sheepshead minnows, Cyprinoden variegatus. Report
No. EPA 60013-78-010:1. '
Pruitt, G.W., et al. 1977. Accumulation and eliminatrion of pentachloro-
phenol by the bluegill, Lepomis macrochirus. Trans. Am. Fish. Soc.
106: 462.
Reiner, E.A., et al. 1977. Microbial metabolism of pentachlorophenol.
Proc. Symp. on Pentachlorophenol, June 27-29. U.S. Environ. Prot. Agency
and Univ. West Florida.
Ruesink, R.G. and L.L. Smith, Jr. 1975. The relationship of the 96-hour
LCso to the lethal threshold concentration of.hexavalent chromium, phenol,
and sodium pentachlorophenate for fathead minnows,• Pimeohales oromelas
rafinesoue. Trans. Am. Fish. Soc. 104: 567.
Sax, N.I. 1975. Dangerous properties of industrial materials. 4th ed.
Van Nostrand Reinhold Co., New York.
Schimmel, S.C., .et al. .1978. Effects of sodium pentachlorophenol' on
several estuarine animals: toxicity, uptake, and depuration. Pages 147-155
_In: K.R. Rao .(ed.), Pentachlorophenol: Chemistry, pharmacology and
environmental toxicology. Plenum Press, N.Y.
-------
Schwetz, B.A., et al. 1974. The affact of purified and commercial grade
pentachiorophenol on rat embryonal and fatal development. Toxicol. Appl.
Pharmacol. 28: 151.
Schwetz, B.A., et al. 1973. Results of two-year toxicity and reproduction
studies on pentachlorophenol in rats. In: K.R. Rao (ed.), Pentachloro-
phenol: Chemistry, pharmacology and environmental toxicology. Plenum
Press, New York.
Spector, U.S. 1956. Handbook of toxicology. W.B. Saunders Co.,
Philadelphia.
Stecher, P.G. (ed.). 1968. The Merck Index. 8th ed. Merck and Co., Inc.,
Rahway, N.J.
Suzuki, T. and K. Nose. 1971. Decomposition of PCP in farm soil. Part
II. PCP metabolism by a microorganism isolated from soil. Moyaku Seisan
Gijutsi (Japan) 26: 21.
Takahashi, W., et al. 1976. Acute phase proteins and pesticide exposure.
Life Sci. 19: 1645.
U.S. EPA. 1979. Pentachlorophenol: Ambient Water Quality Criteria (Draft).
Vogel, E. and J.L.R. Chandler. 1974. Mutagenicity testing of cyclamate and-.
some pesticides in Drosophila aielanogaster.. Experientia 30: 621.
Watanabe, I. 1973. Decomposition of pesticides by soil microorganisms.
Jap. Agric. Res. Q. 7: 15.
Weast, R.C. (ed.). 1975-1976. Handbook of chemistry and physics. 5th ed.
CRC Press, Cleveland, Ohio.
Webb, P.W. and J.R. Brett. 1973. -Effects of sublethal concentrations of
sodium pentachlorophenate on growth rate, food conversion efficiency, and
swimming performance in underyearling sockeye salmon (Oncorhynchus nerka).
Jour. Fish. Res. Board Can. 30: 499.
Weinbach, E.C. and J. Garbus. 1965. The interaction of uncoupling phenols
with Mitochondria and with Mitochondrial protein. Jour. Biol. Chem.
240: 1811.
Woelke, C.E. 1965. Development of a bioassay method using the marine
algae, Monochrysis lutheri. Wash. Dep. Fish. Shellfish Progress Rep. 9p.
- Wong, A.S. and D.G. Crosby. 1977. Photodecomposition of pentachlorophenol
(PCP). Proc. Symp. on Pentachlorophenol, June 27-29., U.S. Environ. Prot.
Agency and Univ. West Florida.
Yang, R.S.H., et al. 1975. Chromatographic methods for the analysis, of
hexachlorobenzene and possible metabolites in monkey fecal samples. Jour.
Assoc. of Anal. Chem. 58: 1197.
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No. 144
Phenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
'1706-
-------
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.
-V 70 7-
-------
PHENOL
SUMMARY
Insufficient data exist to indicate that phenol is a
carcinogenic agent. In skin painting studies, phenol appears
to function primarily as a nonspecific irritant. Information
on the mutagenicity of phenol is equivocal. Phenol does not
appear to be teratogenic. Chronic exposure to phenol at rel-
atively high levels causes liver damage in humans and ani-
mals, and kidney damage in animals. Exposure to acutely tox-
ic levels of phenol causes CNS depression.
The toxic effects of phenol have been extensively exam-
ined in freshwater organisms by acute studies in 13 fish and -
13 invertebrate species. Considerable interspecies and intra
species variation were described, with acute values ranging
from 5,020 to 780,000 ug/1. Only three marine species were
examined in acute tests, and LC5Q values ranged from
5,200 to 58,250 ug/1.
y
-I "7 0
-------
PHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Phenol (U.S. EPA, 1979).
Phenol (CgH^OH; molecular weight 94.11) is a clear,
colorless (light pink when impurities are present) hygro-
scopic, crystalline solid at 25° C with the following physi-
cal and chemical properties (Manufacturing Chemist Assoc.,
1974; Kirk and Othmer, 1963; Weast, 1974).
Melting Point 43° C
Boiling Point 182° C at 760 mm Hg
Flash Point open cup 85° C
closed cup 79° C
Vapor Pressure 0.35 mm Hg at 25° C
Solubility Waters- 6.7 g/100 ml at 16° C and
is soluble at all proportions at
66° C. Also soluble in ether, al-
cohol, acetic acid, glycerol, liq-
uid sulfur dioxide, benzene, and
oils.
Industrial capacity for production is 1.44 to 10^ tons
per year (Chem. Eng. News, 1975). About 90 percent of the
phenol produced is used in the production of phenolic resins,
caprolactam, bisphenol-A, alkylphenols, and adipic acid
(Chemical Profiles, 1972).
Phenol may be biochemically hydroxylated to ortho- and
para-dihydroxybenzenes and readily oxidized to the corres-
ponding benzoquinones. These may in turn react with numer-
ous components of industrial waters or sewage such as mercap-
tans, amines, or the -SH or -NH groups of proteins (Stom,
1975). When ambient water containing phenols is chlorinated,
various chlorinated ohenols may be produced in sufficient
-------
quantities to produce an objectionable taste and odor (Aly,
1968; Barnhart and Campbell, 1972; Jolley, 1973; Jolley, et
al. 1975).
II. EXPOSURE
A. Water
There have been no market basket surveys of free
and conjugated phenols with which to estimate the average
daily dietary intake of phenols. The National Organic Moni-
toring Survey (U.S. EPA, 1977} reported finding unspecified
concentrations of phenol in 2 out of 110 raw water supplies.
The Survey found no phenol in any finished water supplies.
The National Commission on Water Quality (1975) reported an
annual mean concentration of 1.5 ug phenol/1 in raw water
from the lower Mississippi River.
B. Food
Phenol is produced endogenously in the mammalian
intestinal tract through microbial metabolism (Harborne,
1964) and free and conjugated phenol is a normal constituent
of animal.matter (U.S. EPA, 1979). Phenol concentrations of
7 mg/kg in smoked summer sausage and 28.6 mg/kg in smoked
pork belly have been reported (Lustre and Issenberg, 1970).
Several mouthwashes and lozenges contain phenol in amounts of
up to 32.5 mg total phenol/lozenge.
The U.S. EPA (1979) has estimated the.weighted average
bioconcentration factor for phenol to be 2.3 in the edible
portions of fish and shellfish consumed by Americans. This
estimate is based on the octanol/water partition coefficient
of phenol.
-------
C. Inhalation
The inhalation of phenol vapor appears to be large-
ly restricted to the occupational environment (U.S. EPA,
1979). Dermal exposures, can be from a number of medicinal
preparations for skin application (lotions, powders, oint-
ments) containing up to 4.75 percent phenol, or from certain
feminine hygiene products, and hemorrhoidal products (U.S.
EPA, 1979).
III. PHARMACOKINETICS
A. Absorption
Phenol is readily absorbed by all routes. This is
illustrated by the fact that acr^ply toxic doses of phenol
can .produce symptoms within minutes of administration regard---
less of the route of entry (U.S. EPA, 1979). Sixty to 80
percent of inhaled phenol is retained in the lungs. Piotrow-
ski (1971) found that phenol vap^r could be readily absorbed
by intact human skin. The rate of dermal absorption for
phenol vapor can be represented •-._/ the formula A=(0.35)C,
when A is the amount of phenol absorbed in mg/hour and C is
the phenol concentration in mg/m^ (piotrowski, 1971; recal-
culation of data of Ohtsuji and Ikeda, 1972 by U.S. EPA,
1979).
3. Distribution
Free and conjugated phenol appear to be normal
trace constituents in humans and other mammals (Harborne,
1964). Values reported for free and conjugated phenol in'
normal human blood vary greatly due in part to the specifi-
city of the analytical methods used in and in part to the
-------
amount of the dietary protein which increases urinary phenol
excretion. Recent values in normal human blood are between
0.04 to 0.56 mg/1 for the free phenol and 1.06 to 5.18 mg/1
for conjugated phenols (Dirmikis and Darbre, 1974). For the
total phenol (free and conjugated) a range between 2 and 18
mg/1 has been reported (Van Haaften and Sie, 1965).
Upon absorption, phenol is rapidly distributed to
all organ systems, followed by relatively rapid metabolism
and excretion. Within 15 minutes of an oral dose, the high-
est concentrations are found in the liver, followed by heart,
kidneys, lungs, brain and blood (Deichmann, 1944).
C. Metabolism
The major metabolites "of phenol are sulfate and
glucuronic acid conjugates of phenol and 1,4-dihydroxyben-
zene. There are, however, species differences in the excre-
tion pattern of these metabolites (Capel, et al. 1972). The
cat, which is sensitive to phenol, in addition to sulfate
conjugated phenols, excretes also, as a major metabolite,
1,4-dihydroxybenzene (Miller, et al. 1976). The metabolic
pattern is also dose dependent.. Other agents, which are nor-
mally metabolized.to phenol, such as benzene or phenylsalicy-
late, produce increased urinary excretion of phenol metabo-
lites (Koclba, et al. 1976).
D. Excretion
In humans and in all mammals that have been tested,
nearly all of the phenol and its metabolites are excreted .in
the urine within 24 hours (U.S. EPA, 1979; Piotrbwski, 1971;
Deichmann and Keplinger, 1963). Reported normal background
•nti-
-------
values for human urinary phenol range from 1.5 to 5 mg/1
(Fishbeck, et al. 1975; U.S. EPA, 1979). Urinary excretion
levels of phenol metabolites in workers exposed to phenylsal-
icylate ranged from 150 to 1,371 mg/1. Upon ingestion of
eight chloraseptic lozenges at the recommended dosing sched-
ule, the total phenol and the free phenol concentrations in
the urine peaked at 270 and 10 mg/1, respectively. When dogs
were fed 125 rag phenylsalieylate/kg/day for 41 days, the peak
urinary phenol concentration was 6,144 mg/1 and the treatment
was not associated with ill effects (Kociba, et al. 1976).
The half-life of phenol in man is approximately 3.5 hours
(U.S. EPA, 1979).
IV. EFFECTS
A. Carcinogenicity
There is no convincing evidence that phenol acts as
a carcinogen, particularly at concentrations within normal
physiologic limits. Phenol appears to function primarily as
a nonspecific irritant (NIOSH, 1976). Only one case of human
cancer associated with exposure to phenol was found in the
literature. A 72-year old man who had applied a salve of
phenol and ergot to his back daily for 20 years developed an
invasive squammous cell epithelioma (Stevens and Gallaway,
1940) .
Phenol produced papillomas but not carcinomas when ap-
plied to the skin of some strains of mice. Phenol has car-
cinogenic activity when applied repeatedly to the skin of a
»
specially bred strain of Sutter mice at concentrations which
produce repeated skin damage (Boutwell and Bosch, 1959; Sala-
713
-------
man and Glendenning, 1956). Phenol promotes skin cancer in
mice when repeatedly applied after initiation with known car-
cinogens (Boutwell and Bosch, 1959; Salaman and Glendenning,
1956; Van Duuren, et al. 1971). Tumorigenesis is highest at
dose levels of phenol which have some sclerosing activity.
Phenol has no cocarcinogenic activity when applied simultane-
ously and repeatedly with benzo(a)pyrene to mouse skin (Van
Duuren, et al. 1973).
B. Mutagenicity
Phenol was found to be mutagenic in Drosphila (Ha-
dorn and Niggli, 1946) and also, reported to be nonmutagenic
for Neurospora (Dickey, et al. 1_949). Phenol produced back
mutations in E. coli from streptomycin dependence to non-de-
pendence at phenol concentrations high enough that the
survival of bacteria was only 0.5 to 1.7 percent (Demerec, et
al. 1951).
C. Teratogenicity
Studies dealing directly with teratogenicity were
not reported in the U.S. EPA (1979) or NIOSH (1976) docu-
ments. In a study, not designed specifically as a teratogen-
icity study, rats were given phenol at concentrations of 100
- to 12,000 mg/1 in their drinking water over three to five
generations. Specific teratogenic effects were not noted
(Heller and Pursell, 1938).
D. Other Reproductive Effects
In the study mentioned under teratogenicity, higher
concentrations of phenol in the drinking water (7,000 mg/1)
produced stunted growth in the young, death of the offspring
-------
at birth (10,000 mg/1), and failure to reproduce (12,000
mg/1) (Heller and Pursell, 1938).
E. Chronic Toxicity
Repeated exposures to phenol at high concentrations
have resulted in chronic liver damage in humans (Merliss,
1972). In unpublished studies by Dow Chemical Company
(1976), rats received 135 doses of 100 mg phenol/kg or 50 mg
phenol/kg by gavage over a six month period. The growth of
the rats was comparable to that of controls. Very slight
liver changes and slight to moderate kidney damage were seen
at the higher dose of phenol. The lower dose of phenol pro-
duced only slight kidney damage;
Rats given phenol in their drinking water at 300,
1,200, 1,600, 2,000, and 2,400 mg/1 had corresponding average
intakes of 21, 30, 49, 56, and 55 mg phenol per rat per day
based on actual water consumption data. The rats at the
three lower dosage levels showed no overt symptoms of toxic-
ity. The weight gain of the rats at the two highest dose
levels was depressed (Deichmann and Oesper, 1940).
F. Other Relevant Information
The primary effect of exposure to acutely toxic
levels of phenol is CNS depression. Significant evidence
could not be found to support the occurrence of synergistic
or antagonistic actions of phenol with other compounds in
mammals (U.S. EPA, 1979).
-/r/r-
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute toxicity data for phenol display a wide range
of interspecific variability and intraspecific sensitivity.
The range of LC5Q values for 13 species of freshwater
fish is 5,020 ug/1 for the rainbow trout (Salmo gairdneri) to
200,000 ug/1 for the goldfish (Carassius auratus) (Cairns, et
al. 1978). Several studies have indicated an inverse rela-
tionship between survival time and temperature for rainbow
trout, golden shiner (Notemigonius crysoleueus) (U.S. EPA,
1979). Similar intraspecific sensitivity and interspecific
variability was demonstrated by bioassays with freshwater in-
vertebrates as test organisms. The cladocerans, Daphnia
magna and D. longispina, displayed the greatest sensitivity
to phenol with LC$Q values as low as 7,000 ug/1 reported.
The freshwater clam, Sphaerium corneum, was the most resis-
tant species with an LC50 value of 780,000 ug/1 (U.S.
EPA, 1979).
Data for the acute toxicity of phenol to marine or-
ganisms is not nearly as extensive as that for freshwater
species. For marine fish, LC5Q values of 5,200 and 6,014
ug/1 were obtained for rainbow trout in saline waters and
mountain bass (Kuhlia sandvicensis), respectively (U.S. EPA,
1979). Eastern oyster embryos (Crassostrea virginica) and
hardclam embryos (Mercenaria mercenaria) were much more re-
sistant with LC5Q values of 58,250 and 52,630 v.q/1,
respectively (Davis and Hidu, 1969).
-17/6-
nr
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3. Chronic
Data for the chronic effects of phenol on fresh-
water fish are not available. In a life cycle chronic test,
a chronic value of 3,074 ug/1 was obtained for the freshwater
cladoceran, Daphnia magna (U.S. EPA, 1978). Chronic data
for marine organisms were not available.
C. Plant Effects
Plants are relatively insensitive to phenol expo-
sure with effective concentrations ranging from 20,000 to
1,504,000 ug/1 for three species of algae, one species of
diatom, and duckweed. Marine plants species have not been
examined for toxic effects of phenol.
D. Residues
Measured bioconcentration factors of 1.2 to 2.3
have been determined for goldfish (Kobayashi, et al. 1976;
Kobayashi and Akitake, 1975). Bioconcentration factors have
• not been determined for freshwater invertebrates or plants,
or for any marine species.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health, nor the aquatic criteria de-
rived 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
On the basis of chronic toxicity data for rats and
an uncertainity factor of 500, the U.S. EPA (1979) has de-
rived a draft criterion of 3.4 mg/1 for phenol in ambient
water corresponding to the calculated acceptable daily intake
-------
of 0.7 mg. The draft criterion for phenol is 1.0 ug/1 in
those instances where chlorination of phenol may take place
during water purification processes.
The 1974 Federal standard and the ACGIH (1977)
recommendation for phenol in air in the workplace is 19
mg/m^ (5 ppm) as a time-weighted average.
The NIOSH (1976) criterion for a recommended stand-
ard for occupational exposure to phenol is 20 mg/m^ in air
as a time weighted average for up to a 10-hour work day and a
40-hour work week, with a ceiling concentration of 60 mg/m^
for any 15-minute sampling period.
The U.S. EPA interim drinking water limit for
phenol . is 1 ug/1/ which is largely an organoleptic standard
based on the objectionable taste and odor produced by chlori-
nated phenols. In response to a phenol spill in southern
Wisconsin, the U.S.. EPA proposed on November 26, 1974 an
emergency standard of 0,1 mg phenol/1 as being temporarily
acceptable for human consumption.
B. Aquatic
The draft criterion for protecting freshwater or-
ganisms is 600 ug/1, not to exceed 3,400 ug/1. No criterion
for marine organisms was derived (U.S. EPA, 1979).
-17 n
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PHENOL
REFERENCES
Aly, O.M. 1963. Separation of phenols in watars by thin-layer chromato-
graphy. Water Res. 2: 287.
American Council for Governmental Industrial Hygienists. 1977. Threshold
limit values for chemical substances and physical agents in workroom envi-
ronment with intended changes for 1977.
Barnhart, E.L. and G.R. Campbell. 1972. The effect of chlorination on
selected organic chemicals. U.S. Environ. Prot. Agency.
Boutweil, R.K. and O.K. Bosch. 1959. The tumor-promoting action of phenol
and related compounds. Cancer Res. 19: 413.
Cairns, J., Jr., et al. 1978. Effects of temperature on aquatic organisms
sensitivity to selected chemicals.. Project 8-084-VA. Bull. 106. Virginia
Polytechnic Inst. State University.
Capel, I.O., et al. 1972. Species variations in the metabolism of phenol.
Siochem. Jour. 127: 25.
Chemical and Engineering News. July 28, 1975.
Chemical Profiles. 1972. Phenol. Schnell Publishing Co., New York.
Davis, H.C. and H. Hidu. 1969. Effects of pesticides on embryonic devel-
opment of clams and oysters and on survival and growth of the larvae. Fish
Wildl. Fish. Bull. 67: 393. U.S. Oep. Inter.
Deichmann, W.8. 1944. Phenol studies. V. The distribution, detoxifica-
tion, and excretion of phenol in the .mammalian body. Arch. Biochem. 3: 345.
Deichmann, W.B. and M.L. Keplinger. 1963. Phenols and phenolic compounds.
Page 1363 In: F.A. Patty (Ed.), Industrial hygiene and toxicology. Inter-
science Publishers, New York.
Oeichmann, W.B. and P. Oesper. 1940. Ingestion of phenol — Effects on the
albino rat. Ind. Med. 9: 296.
Demerec, M., et al. 1951. A survey of chemicals for mutagenic action on E.
coli. Am. Natur. 35: 119.
Oickey, F.H., et al. 1949. The role of organic peroxides in the induction
of mutations. Proc. Natl. Acad. Sci. 35: 581.
Oirmikis, S.M. and A. Oarbre. 1974. Gas-liquid chromatography of'simple
phenols for urinalysis. Jour. Chromatogr. 94: 169.
-------
Dow Chemical Co. 1976. References and literature review pertaining to
toxicological properties of phenol. Toxicol. Res. Lab. Unpubl. Manuscript.
Fishbeck, W.A., et- al. 1975. Elevated urinary phenol levels not related to
benzene exposure. Am. Ind. Hyg. Jour. 36: 820.
Hadorn, E. and H. Niggli. 1946. Mutations in Drosophila after chemical
treatment of gonads in vitro. Nature 157: 162.
Harborne, J.3. 1964. Biochemistry of phenolic compounds. Academic Press,
New York.
Heller, V.G. and L. Pursell. 1938. Phenol-contaminated waters and their
physiological action. Jour. Pharmacol.. Exp. Ther. 63: 99.
Jolley, R.L. 1973. Chlorination effects on organic constituents in efflu-
ents from domestic .sanitary sewage treatment plants. Ph.D. dissertation,
University of Tennessee, Knoxville.
Jolley, R.L.-, et al. 1975. Chlorination of cooling water: a source of
envi- rorimentally significant chlorine-containing organic compounds. Proc.
4th Natl. Symp. Radioecolcgy. Corvallis, Ore.
Kirk, R.-E. and D.F. Othmer. 1963. Kirk-Othmer encyclopedia of chemical
technology. 2nd ed. John Wiley and Sons, Inc., New York. ;
Kobayashi, K. and H. Akitake. 1975. Metabolism of chlorophenols in fish.
IV. Absorption and excretion of phenol by goldfish. Nippon Suisan
Gakkaishi. 41: 1271.
Kobayashi, K., et al. 1976. Studies on the metabolism of chlorophenols in
fish. VI. Turnover of absorbed phenol in goldfish. Bull. Jap. Soc. Sci.
Fish. 42: 45.
Kociba, R.J., et al. 1976. Elevated urinary phenol levels in beagle dogs
treated with salol. Am. Ind. Hyg. Jour. 37: 183.
Lustre, A.O. and P. Issenberg. 1970. Phenolic components of smoked meat
products. Jour. Agric. Food Chem. 18: 1056.
Manufacturing Chemists Assoc. 1974. Chemical safety data sheet SD-4;
Phenol. Washington, D.C.
Merliss, R.R. 1972. Phenol moras. Mus. Jour. Occup. Med. 14: 55.
Miller, J.J., et al. 1976. The toxicity of dimethylphenol and related com-
pounds on the cat. Toxicol. Appl. Pharmacol. 38: 47.
National Commission on Water Quality. 1975. Water quality and environ-
. mental assessment and predictions to 1985 for the lower Mississippi River
and Barataria Bay. Vol. 1. Contract WQ5AC062.
National Institute for Occupational Safety and Health. 1976. Criteria for
a recommended standard...Occupational exposure to phenol. NIOSH 76-196.
-------
Ontsuji, J. and M. Ikeda. '1972. Quantitative relationship between atmos-
pheric phenol vapor and phenol in the' urine of workers in bakelite fac-
tories. 8r. Jour. Ind. Med. 29: 70.
Piotrowski, J.K. 1971. Evaluation of exposure to phenol: absorption of
phenol vapour in the lungs and through the skin and excretion of phenol in
urine. Br. Jour. Ind. Med. 28: 172.
Salaman, M.H. and O.M. Glendenning. 1956. Tumor promotion in mouse skin by
sclerosing agents. Sr. Jour. Cancer 11: 434.
Stevens, J.B. and J.L. Callaway. 1940. Mixed epithelioma of the back
arising from daily applicaton of a phenl and ergot ointment. Am. Jour.
Cancer. 38: 364.
Stom, D.J. 1975. Use of thin-layer and paper chromatography for detection
of ortho- and. para- quinones formed in the course of phenol oxidation.
Acata Hydrochim. Hydrobiol. 3: 39.
U.S. EPA. 1977. National Organic Monitoring Survey. General review of
results and methodology: phases I-III. Water Supply Res. Oiv.
U.S. EPA. 1973. In-depth studies on" health and environmental impacts of
selected water pollutants. Contract No. 63-01-4646. 4
U.S. EPA. 1979. Phenol: Ambient Water Quality Criteria. (Draft)
Van Ouuren, 3.L., et al. 1971. Cocarcinogenesis studies on mouse skin and
inhibition of tumor production. Jour. Natl. Cancer Inst. 46: 1039.
Van Duuren, B.L., et al. 1973. Cocarcinogenic agents in tobacco carcino-
genesis. Jour. Natl. Cancer Inst. 51: 703.
Van Haaften, A.8. and S.T. Sie. 1965. The measurement of phenol in urine
by gas chromatography as a check on benzene exposure. Am. Ind. Hyg. Assoc.
Jour. 26: 52.
Weast, R.C. (Ed.) 1974. Handbook of chemistry and physics. 55th ed. CRC
Press, Cleveland, Ohio.
-} 73L/-
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No. 145
Phorate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
•I 7 SSL-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
-y/w-
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PHORATE
Summary
Phorate is an organophosphorous insecticide used on a variety of crops,
mainly in south-central states. Phorate is readily absorbed through inhala-
tion and skin contact and is highly toxic to humans and other animals. Pri-
marily, it affects the central and peripheral nervous systems by inhibiting
cholinesterase activity. Information concerning carcinogenic and mutagenic
effects was not located in the available literature. The threshold limit
value for phorate is 50 ug/m3, based on dermal contact. Additionally,
phorate has been classified for restrictive use by the U.S. EPA.
Although phorate is highly toxic to certain aquatic organisms, no ap-
parent adverse effects have been observed in the aquatic environment.
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I. INTRODUCTION
Phorate is a highly toxic organophosphorous insecticide used on a vari-
ety of agricultural crops. It was introduced in 1954 by the American Cyana-
mid Co. under the trade name Thin zt® (Martin and Worthing, 1974). Phorate
is prepared by the reaction of phosphorous pentasulfide with ethanol, for-
maldehyde, and ethyl mercapton. Production in the U.S. totaled 3400 tonnes
in 1977 (NAS, 1977). Virtually all of the phorate is used on root and field
cropsoils to control sucking insects and nematodes (NAS, 1975). Phorate is
slightly soluble in water and hydrolyzes in moisture. It has an overall
degradation rate constant of 0.02/day and .a bioconcentration factor of 5.2.
Other properties are listed in Table 1.
II. EXPOSURE
A. water
Phorate is produced in the United States by the American Cyanamid
Co. at Hannibal, Mo. (SRI, 1977). Available information on an annual U.S.
production shows that 1900 tonnes were produced in 1971, 3600 tonnes in
1974, and 3400 tonnes in 1977 (NAS, 1975, 1977). Berg, et al. (1972) noted
an application rate of 1 pound of actual material per acre (1.1 kg/ha; in
this case, to control corn borers). Application rates vary according'to use.
Phorate has found increasing use on croplands in the south-central
states to protect cotton, hops, alfalfa, barley, sorghum, peanuts, sugar
beets, sugar cane, potatoes, rice, and tomatoes. Only small amounts are
used in the southeastern and northeastern U.S. American Cyanamid Co. re-
ported that phorate may fill the void left by the removal from the market of
chlorinated hydrocarbons and projected a strong demand for phorate in the
corn rootworm market (Berg, et al. 1977).
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TABLE 1. PHYSICAL AND CHEMICAL PROPERTIES OF PHORATE
Synonyms : 0 , 0-diethy 1-S- ( ethy 1 thiomethy 1 ) phosphorodithioate ;
0 , 0-diethyl -S-ethy Imercaptomethy i dithiophosphate ;
THIMET American Cyanamid (3911): timet (USSR);
CAS Registry No. (298-02-2); Dranutox; Rampart; Vergfru
Structural Formula: (C2H50)2(P=S)SCH2SC2H5
Molecular Weight: 260.4
Description: Clear liquid
Miscible with: CC14, dioxan, vegetable oils, xylene, alco-
hols, ethers, esters
Soil Attenuation: Kd approx. 5 x 1Q2; Koc = 3199
Specific Gravity and/or Density: d25 - 1.157
Melting and/or Boiling Points: bp 118 to 12QQC at 0.8 mm
mp less than -150C
Stability: Stable at room temperature
Hydrolyzed in the presence of moisture
Overall degradation rate constant (0.02/day)
. Soil half-life: 1-4 weeks
Bacterial/Hydrolysis: constant = 8 x 10-4hr-l
Solubility (water): 50 ppm at room temp.
sediment . 4.5
~~ ' T" •
Vapor Pressure: 8.4 x 10-4 mm Hg at 20OC
Bioconcentration Factor (BCF) and/or
Octanol/water partition coefficient (Kgy,): «ow = 18
BCF =5.2
Source: Martin and Worthing, 1974; Fairchild, 1977; Windholz, 1976-
U.S. EPA, 1980
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Little information was found on phorate production processes.
Lawless, et al. (1977) noted that in the production, crude phorate was wash-
ed and filtered. No information was given on the treatment of the waste
water or filter cake associated with this process. No information on waste
sludge or landfill disposal was found in the available literature.
Phorate can enter water by runoff or by ground water drainage
after application. Phorate is relatively stable in ground water. Only 10
percent decomposition was estimated in a river environment in 5 days (50 to
250 mile transport; 80-400 km). Also, estimates show that less than 90 per-
cent decomposition per year occurs in a lake environment (U.S. EPA, 1980).
There are no estimates on the amount of phorate entering the environment or
on the levels of phorate in ambient water. Menzie (1974) noted that phorate
decomposes to phorate sulfoxide and phorate —.ifone and the sulfoxide and
sulfone of the oxygen analog.
Walter-Echols and Lichtenstein (1977) showed that some oxidation
products of phorate (phorate sulfoxide) reduce to phorate in lake mud under
certain conditions. Using a flooded phorate-!sulfoxide-treated loam soil,
they noticed the production of only small anoints of phorate. After lake
mud was added, the reduction of phorate sulfoxide to phorate increased dra-
matically andj after two weeks' incubation, accounted for 44 .percent of the
recovered residues. They related the reduction process to the activity of
microorganisms in an environment of organic nutrients.
B. Food
Information available in the open literature does not quantify the
amount of phorate detected on foods. In a study reported by Menzie (1974),
phorate was applied to bermuda grass and corn at the rate of 2 pounds .per
y
-------
acre (2.2 kg/ha). Fourteen days after treatment, less than 1 ppm phorate
residue was noted on the corn; after 21 days less than 1 ppm was found on
bermuda grass.
C. Inhalation and Dermal
Data are not available indicating the number of people subject to
inhalation or dermal exposure to phorate. The primary human exposure would
appear to occur during production and application. The U.S. EPA (1976) list-
ed by occupational group the frequency of illness caused by exposure to or-
ganophosphorous pesticides. Of 1157 reported cases, most illnesses occurred
among ground applicators (229) and mixer/loaders (142); the lack of, or re-
fusal to use, safety equipment was a major factor of this contamination.
Other groups affected were gardeners (101), field workers exposed to pesti-
cide residues (117), nursery and greenhouse workers (75), soil fumigators in
agriculture (29), equipment cleaners and mechanics (28), tractor drivers and
irrigators (23), workers exposed to pesticide drift (22), pilots (crop dust-
ers) (17), and flaggers for aerial application (6). Most illnesses were a
result of carelessness, lack of knowledge of the hazards, and/or lack of
safety equipment. Under dry, hot conditions, workers tended not to wear
protective clothing. Such conditions also tended to increase pesticide
levels and dust on the workers.
III. PHARMACOKINETICS
A. Absorption
Newell and Dilley (1978) exposed four different groups of rats to
phorate via four routes of administration. They compared LD5Q ancj LQ,.-)
values and found that inhalation was the most toxic route, followed, in de-
creasing order, by intravenous, oral, and dermal routes. The phorate ae.ro-
-------
sol generated in the laboratory had a particle size range of 0.3-3.0 )jm dia-
meter, a size small enough to enter the gas exchange regions of the lung.
Young, et al. (1979) reported on two occupational exposure inci-
dents that suggested absorption in the lungs was the most effective route of
entry. In both cases, the individuals wore protective clothing, goggles,
and respirators while working in the dust house where technical grade phor-
ate was produced. Gas chromatographic analyses of air samples from the dust
house showed phorate levels ranging from 0.7 to 14.6 mg/m^. NQ estimate
of particle size was reported by the authors.
8. Distribution
. Phorate would be expected to distribute in the body like organo-
phosphorous pesticides of similar solubility . A report by Pugh and Forest
(1975) described the distribution in calves exposed to phorate in a manger
containing 1200 ppm. Phorate concentrations in the liver ranged from 0.004-
0.26 ppm; in the kidney, 0.002-0.021 ppm; and in the brain, 0.025-0.19 ppm.
C. Metabolism
The major phorate metabolites found in blood after oral admini-
stration to rats are phorate sulf oxide, phorate sulfone, and phoratoxon sul-
fone (MAS, 1977). Bowman and Casida (1958) showed that phorate hydrolyzes
in rats to produce urinary diethylphosphorodithioic acid, diethylphosphoro-
thioic acid, and diethylphosphoric acid. Oxidative metabolites are not
found as components of excretory products of animals treated with phorate
(MAS,- 1977). However, OuBois, et al. (1950) showed that in rat liver
slices, phorate was converted to its oxidative products.
0. Excretion
The previous section notes that phorate is eliminated primarily
through the urinary system.
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IV. EFFECTS
A. Carcinogenicity and Mutagenicity
Pertinent data could not be located in the available literature on
the carcinogenicity or mutagenicity of phorate. Formaldehyde, a suspected
carcinogen, and other contaminants may be present in technical grade phorate.
B. Teratogenicity
In a study described in the absorption section of this report,
Newell and Dilley (1978) did not find dose-related teratogenesis in rats ex-
posed to phorate via inhalation, intravenous, dermal, or oral routes. In
the chick embryo test, Richert and Prahlad (1972) injected 1.5 or 2.0 ppm in
a peanut oil medium into eggs on the tenth day of incubation. Controls re-
ceived only peanut oil. Hatchability of the eggs decreased in a dose-depen-
dent manner. Malformations were produced, but these did not seem to be
dose-related. The relevance of these studies to mammalian teratology is
unclear (MAS, 1977).
C. Other Reproductive Effects
In a study in which CFI mice were fed diets containing 98.7 per-
cent phorate at 0.6, 1..5, and 3.0 ppm, the no-adverse-effect level for re-
productive performance was 1.5 ppm (MAS, 1977).
D. Chronic Toxicity and Other Relevant Information
Pertinent data on chronic toxicity could not be located in the
available literature. Several subchronic studies have been reported. In
subchronic feeding studies of 1, 5, and 25 ppm phorate for 28 days, choli-
nesterase in the 1 ppm group was not decreased (Tusing, 1955). In a second
rat study, Tusing (1956) fed groups of 50 males and females 92 percent phor-
ate for 13 weeks at 0.22, 0.66, 2.0, 6.0, 12.0, and 18.0 ppm. He noted a
no-adverse-effect dosage at 0.66 ppm.
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Tusing (1956) fed three dogs 92 percent phorate at 0.01, 0.05,
0.25 and 1.24 mg/kg 6 days per week for 13-15 weeks. The no-adverse-effect
dosage was judged to be 0.01 mg/kg; even at this level, a very slight de-
crease in plasma cholinesterase resulted. Higher dosages, caused significant
depression of cholinesterase, culminating in death at the two highest
dosages.
Rat feeding studies showed higher subchronic toxicities on phorate
oxidative metabolites than on phorate, according to Rombunski, et al.
(1958). Others have also noted that phorate metabolites are more potent
cholinesterase inhibitors than phorate (Curry, et al. 1961).
Young, et al. (1979) reported on acute exposures to high levels of
phorate (up to 14.6 mg/m3) in a production facility (see absorption sec-
tion). The symptoms accompanying the exposures were confusion, dizziness,
nausea, vomiting, pupil constriction, respiratory distress, cardiac arrhyth-
mia, and unconsciousness. Treatment involved a regime of PAM and atropine.
According to Gleason (1969), the symptoms produced by a sublethal dose are
typical of central and peripheral nervous system toxicity. EPA's accident
files contain reports of 21 episodes of poisoning involving phorate for
1971-1973. Eleven were agriculturally related. There are no controlled
studies in humans from which no-adverse-effect dosages could be derived.
For humans, the lowest published lethal d-D,-) value is estimat-
ed to be 5 mg/kg. The following studies list acute phorate toxicity levels
for human and nonhuman species, reported by Fairchild (1977):
-------
Species Exposure LDsn (mq/kq)
Rat Oral 1.1
Rat Skin 2.5
Rat Intravenous 1.2
Mouse . Oral 11
Guinea pig Oral 20
Guinea pig Skin 20
Duck Oral 2.55
Duck Skin 203
Wild Bird Oral 1
V. AQUATIC TOXICITY
A. Acute and Chronic Toxicity
Phorate is highly toxic to certain species of fish, crustaceans,
and terrestrial wildlife (NAS, 1977). MAS noted that there were no reported
killings of these species in the environment.
B. Plant Effects and Residues
Pertinent data could not be located in the available literature.
VI.- EXISTING GUIDELINES
A. Human
The threshold limit value for phorate is 50 jug/m3, based on skin
contact (Fairchild, 1977). An 8-hour time-weighted average of 50 mg/nv5
was adapted for phorate by the Tennessee Department of Health (Young, et al.
1979). In addition, phorate is classified for restrictive use by the U.S.
EPA for liquid formulations containing 65 percent and greater active ingre-
dients. The restriction was influenced by the acute dermal toxicity of
phorate and by residue effects on avian species (applicable to foliar appJLi-
cations only).
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B. Aquatic
Pertinent data could not be located in the available literature.
-------
REFERENCES
Berg, G.L., et al. (ed.) 1977. Farm Chemicals Handbook. Meister Publish-
ing Company, Willoughby, Ohio.
Bowman, J.S. and J.E. Casida. 1958. Further studies on the metabolism of
Thimet by plants, insects and mammals. Jour. Econ. Entomol. 51: 838.
Curry, A.M., et al. 1961. Determination of residue of phorate and its in-
secticidally active metabolites by cholinesterase inhibition. Jour. Agric.
Food Chem. 9: 469.
CuBois, K.P., et al. 1950. Studies on toxicity and pharmacological action
of octamethyl pyrophosphoramide. Jour. Pharmacol. Exp. Ther. 99: 376.
Fairchild,'E.J. (ed.) 1977. Agricultural Chemicals and Pesticides. A Sub-
file of the NIOSH Registry of Toxic Effects of Chemical Substances. U.S.
DHEW.
Gleason, M.N., et al. 1969. Clinical Toxicology of Commercial Products.
Acute Poisoning. 3rd ed.
Lawless, E.W., et al. 1972. The Pollution Potential in Pesticide Manufac-
turing. U.S. EPA, Office of Water Programs, Technical Studies Report TS-00-
72-04.
Martin, H. and C.R. Worthing (eds.) 1974. Pesticide Manual. 4th ed.
Menzie, C.M. 1974. Metabolism of Pesticides: An Update. U.S. Dept. of the
Interior Special Scientific Report - Wildlife No. 184, Washington, D.C.
National Academy of Sciences. 1975. Pest Control: An Assessment of Pre-
sent and Alternative Technologies, Vol. I.
National Academy of Sciences. 1977. Drinking Water and Health. Natl.
Acad. Sci., Washington, D.C.
Newell, G.W. and J.V. Dilley. 1978. Teratology and Acute Toxicology of
Selected Chemical Pesticides Administered by Inhalation. U.S. NTIS, PB Rep.
PB-277077, 66 pp.
Pugh, W.S. and O.N.T. Forest. 1975. Outbreak of organophosphate poisoning
(Thimet) in cattle. Can. Vet. Jour. 16: 56.
Richert, E.P. and K.V. Prahlad. 1972. The effect of the organophosphate
0,0 diethyl S-C(ethylthio)methyl]phosphorodithioate on the chick. Poultry
Sci. 51: 613..
Rombunski, et al. 1958. Cited in National Academy of Sciences, 1977.
Stanford Research Institute. 1977. Directory of Chemical Producers. Stan-
ford Research Institute, Menlo Park, California.
-------
Tusing, T.W. 1955. Unpublished report of American Cyanamid. Cited in U.S.
EPA Initial Scientific and Minieconomic Review of Phorate, 1974.
Tusing, T.W. 1956. Unpublished report of American Cyanamid. Cited in U.S.
EPA Initial Scientific and Minieconomic Review of Phorate, 1974.
U.S. Environmental Protection Agency. 1976. Organophosphate Exposure from
Agricultural Usage, EPA 600/1-76-025.
U.S. Environmental Protection Agency. 1980. Aquatic Fate and Transport Esti-
mates for Hazardous Chemical Exposure Assessments. Environmental Research
Laboratory, Athens, Georgia.
Walter-Echols, G. and E.P. Lichtenstein. 1977. Microbial reduction of phor-
ate sulfoxide to phorate in a soil-lake mud-water microcosm. Jour. Econ.
Entomol. 70: 505.
Windholz, M. (ed.) 1976. The Merck Index, 9th ed. Merck Co., Inc., Rahway,
New Jersey.
Young, R.J., et al. 1979. Phorate intoxication at an insecticide formulating
plant. Am. Ind. Hyg. Assoc. Jour. 40: 1013.
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No. 146
Phthalate Esters
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-/ 737-
-------
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.
jecause of the limitations of such sources, this short profile
may not reflect all available infon-ation including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
PHTHALATE ESTERS
Summary
Certain phthaiatas (dimethyl phthalate, diethyl phthalate, mono-2-
ethyl-hexyl phthalate and dimethoxyethyl phthaiate), have shown mutagenic
effects in both bacterial systems and the dominant lethal assay.
All eight phthalates tested by injection in pregnant rats produced
teratogenic effects. These effects were not noted when DEHP or dibutyl
phthalate were administered orally to pregnant rats. Additional reproduc-
tive effects produced include impaired implantation, parturition and de-
creased fertility in rats. Testicular damage has been reported following
intraperitoneal (i.p.) or oral administration of DEHP, or oral administra-
tion of dibutyl phthalate. No evidence of carcinogenic effects produced by"
phthalates is available.
Chronic toxicity includes toxic polyneuritis in workers exposed primar-
ily to dibutyl phthalate. OEHP animal studies show induced liver and kidney
changes while dimethyl phthalate induced only kidney effects. Following in-
jection dibutoxyethyl phthalate, di-(2-methoxyethyl) phthalate, and octyli-
sodecyl phthalate have caused damage to the developing chick embryo nervous
system.
Toxicity of the phthalate esters to aquatic organisms varies within
this group of chemicals. Freshwater organisms have appeared somewhat more
sensitive than marine species. The data is insufficient to allow for the
drafting of.criteria to protect aquatic life for any of the phthalates.
-------
PHTHALATE ESTERS
I. INTRODUCTION
This profile is based primarily on the draft Ambient Water Quality Cri-
teria Document for Phthalate Esters (U.S. EPA, 1979).
The phthalate esters are esters of the benzenedicarboxylic acid ortho
form. Esters of the parent compound meta and para forms will not be review-
ed in this' profile. The phthalate esters are colorless liquids of low vola-
tility, poorly soluble in water and soluble in organic solvents and oils.
Some physical and chemical properties of the phthalate esters are indicated
in Table 1 on the following page (U.S. EPA, 1979).
The phthalate esters are widely used as placticizers, and through this
application are incorporated into wire and cable covering, floor tiles,
swimming pool liners, upholstery and seat covers, footwear, and in food and.
medical packaging materials. Non-plasticizer uses include incorporation
into pesticide carriers, cosmetics, fragrances, munitions, industrial oils,
and insect repellants (U.S. Int. Trade Commission, 1978). The most current
production figure is 6 xlO tons/year in 1977 (U.S. EPA, 1979).
Phthalate esters are ubiquitous. Monitoring surveys have detected
phthalates in soil, air, water, animal and human tissues, and certain vege-
tation. Some plants and animal tissues may synthesize phthalic acid esters
(Peakall, 1975). From in vitro studies indications, certain bacterial flora
may be capable of metabolizing phthalates to the monoester form (Englehardt,
et al. 1975).
II. EXPOSURE
Phthalate esters appear in all areas of the environment. Environmental
release of the phthalates may occur .through leaching of plasticizers 'from
polyvinyl chloride (PVC) materials, volatilization of phthalates from PVC
-------
materials, and the incineration of PVC items. Human exposure to phthalates
includes contaminated foods and fish, dermal application of phthalates in
cosmetics and insect repellants, and parenteral administration by use of PVC
blood bags, tubings, and infusion devices (U.S. E?A, 1979).
TABLE 1
PHYSICAL AND CHEMICAL PROPERTIES OF PHTHALATE ESTERS
Phthalate
Compounds
Dimethyl
Oiethyl
Oiallyi ' ' ,)
Oiisobutyl
Oibutyl
Dimethoxy ethyl
.Oicyclohex:, \-
Butyl octyl
Oihexyl
Butylphthayl
butyl glycolate
Dibutoxyethyl
athyl
Oi-2-ethyihexyl
Oiisooctyl
Di-n-octyl
Oinonyl
Molecular
Weight
194.18
222.23
246.27
278.30
278.34
282.00
330.00
334.00
334.00
336.37
366.00
391.00
391.00
391.00
419.00
Specific
Gravity
1.189 (25/25)
1.123 (25/4)
1.120 (20720)
1.040
1.047 (21)
1.171 (20)
1.200 (25/25)
—
0.990
1.097 (25/25)
1.063
0.985 (20/20)
0.981
. 0.978
0.965
3p , Percent
°C Solubility in
H20, g/100 ml
282
296.1
290
327
340
190-210
220-228
340
—
219/5 mm
210
386.9/5 mm
239/5 mm
220/5 mm
413
0.5
Insoluble
0.01
Insoluble
0.45 (25°C)
0.85
Insoluble
—
Insoluble
0.012
0.03
Insoluble
Insoluble
Insoluble
Insoluble1
Source: U.S. EPA, 1979
-------
Monitoring studies have indicated that most water phthalate concentra-
tions are in the ppm range, approximately 1-2 ug/1 (U.S. EPA, 1979). Air
levels of phthalates in closed PVC tiled rooms have been reported to be from
0.15 to 0.26 mg/m (Peakall, 1975), while industrial monitoring has mea-
sured air levels of phthalates from 1.7 to 66 mg/m (Milkov, et al. 1973).
Phthalate levels in various foods have ranged from non-detectable to 82 ppm
(Tomita, et al. 1977). Cheeses, milk, fish and shellfish present potential
sources of high -phthalate intake (U.S. EPA, 1979). Estimates of patient
parenteral exposure to di-2-ethylhexyl phthalate (DEHP) during use of PVC
medical appliances have indicated approximately 150 mg OEHP exposure from a
single hemodialysis course. Through application of certain cosmetics and
insect repellants dermal exposure to phthalates is possible (U.S. EPA, 1979).
Using average human fish and shellfish consumption data, the U.S. ERA
(1979) has derived the following bioconcentration factors for the edible
portions of fish and shellfish consumed by Americans - diethyl phthalate,
270; dibutylphthalate, 1500; DEHP, 95; dimethyl phthalate, 130. OMP, OEP
and 8BP are based on the steady-state bioconcentrations in bluegills and in
fathead minnows for OEHP. A weighted average bioconcentration factor of 26
was calculated for dibutyl phthalate utilizing the octanol water partition
coefficient (U.S. EPA, 1979).
III. PHARMACOKINETICS
A. Absorption
The phthalic acid esters and/or their metabolites are readily ab-
sorbed from the intestinal tract, the peritoneal cavity, and the lungs (U.S.
EPA, 1979). Daniel and Sratt (1974) found that seven -days following admin-
»
istration of radiolabelled-OEHP, 42 percent of the dose is recovered in the
urine and 57 percent recovered in the feces of rats. Biliary excretion of
-------
orally administered DEHP has been noted by Wallin, et al. (1974). Limited
human studies indicate that 2 to 4.5 percent of orally administered OEHP is
recovered in the urine within 24 hours (Shaffer, et al. 1945). Lake, et ai.
(1975) suggest orally administered phthalates are absorbed after metabolic
conversion to the monoester form in the gut.
Dermal absorption of DEHP in rabbits has been reported at 16 to 20
percent of the initial dose within three days following administration
(Autian, 1973).
3. Distribution
Studies in rats injected with radiolabelled-OEHP have shown that
from 60 to 70 percent of the administered dose was detected in the liver and
lungs within 2 hours after injection (Daniel and Bratt, 1974). Wadell, et
al. (1977) have reported rapid accumulation of radiolabelled-OEHP in the'
kidney and liver of rats after intravenous (i.v.) injection, followed by
rapid excretion into the urine, bile, and intestine. Seven days after i.v.
administration of radiolabelled-OEHP to mice, levels of the compound were
found preferentially in the lungs and to a lesser extent in the brain, fat,
heart, and blood (Autian, 1973).
An examination of tissue samples from two deceased patients, recip-
ients of large volumes of transfused blood, detected DEHP in the spleen,
liver, lungs, and abdominal fat (Jaeger and Rubin, 1970). Daniel and Bratt
(1974) have suggested phthalates achieve a steady-state concentration, after
which the compounds or metabolites are rapidly eliminated by various routes.
Injection of radiolabelled-OEHP and diethyl phthalate in pregnant
rats has shown the phthalates may cross the placental barrier (Singh, et ai.
1975).
-------
C. Metabolism
Various metabolites of DEHP have been identified following oral
feeding of rats (Albro, et al. 1973). These results indicate that OEHP is
initially converted from the diester to the mdnoester, followed by the oxi-
dation of the monoester side chain forming two different alcohols. The al-
cohols are then oxidized to the corresponding carboxylic acid or ketone.
Enzymatic clearance of phthalates to the monoester form may take place in
the liver or in the gut (Lake, et al. 1977). This enzymatic conversion has
been observed in stored whole blood indicating widespread distribution of
this metabolic activity (Rock, et al. 1978).
0. Excretion
Elimination of orally administratered OEHP is virtually completed
within: four days in the rat (Lake, et al. 1975). Major excretion is through.
the urine and feces, with biliary excretion increasing the content of DEHP
(or metabolites) in the intestine (U.S. EPA, 1979). Schulz and Rubin (1973)
have noted a progressive increase in total water soluble metabolites in the
first 24 hours following injection of radioiabelled OEHP to rats. Within
one hour, eight percent of the OEHP was found in the liver, intestine and
urine. After 24 hours, 54.6 percent DEHP was recovered in the intestinal
tract, excreted feces.and urine, and only 20.5 percent OEHP was recovered in
organic extractable form.
The half-life of phthalate elimination from the tissues and total
body is short (U.S. EPA, 1979). Siphasic elimination of DEHP from the blood
of rats showed half-life values of 9 minutes and 22-minutes, respectively
(Schulz and Rubin, 1973).
-------
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be found in the available literature.
8. Mutagenicity
Testing of several phthalates in the Ames Salmonella assay has
shown that diethyl phthalate has some mutagenic activity (Rubin, et al.
1979). Oibutyl, mono-2-ethylhexyl, di-(2-ethylhexyl) and butylbenzyl phtha-
late all produced negative effects in this test system. Yagi, et al.
(1978) have reported mutagenic effects of mono-2-ethylhexyl phthalate in a
Bacillus subtillus recombinant assay system.
Results of a dominant lethal assay in mice have indicated DEHP and
dimethoxyethyl phthalate showed some mutagenic activity (Singh, et al. 1974).
C. Teratogenicity ;
The teratogenic affects of a number of phthalate esters (DEHP, di-
methyl, dimethoxyethyl, diethyl, diisobutyl, butylcarbobutoxymethyl, and di-
octyl phthalates) have been reported in rats (Singh, et al. 1972). Terato-
genic effects were not seen following oral administration of OEHP and dibu-
tyl phthalate to rats (Nikonorow, et al. 1973). Damage to the nervous sys-
tem or developing chick embryos has been produced by injection of dibutoxy-
ethyl phthalate, di-(2-methoxy-ethyl) phthalate, and octyl-isodecyl phtha-
late (Bower, et al. 1970).
0. Other Reproductive Effects
Effects on implantation and parturition have been observed in preg-
nant rats injected intraparenteneally with OEHP, dibutyl phthalate, and di-
methyl phthalate.(Peters and Cook, 1973). A three generation rat reproduc-
»
tion study has indicated decreased fertility following maternal OEHP treat-
ment (Industrial Bio-Test, 1978).
-------
Testicular damage has been reported in rats administered OEHP in-
traparenteneally or orally. Seth, et al. (1976) found degeneration of the
seminiferous tubules and changes in spemnatagonia; testicular atrophy and
morphological damage was noted in rats fed OEHP or dibutyl phthalate (Car-
ter, et al. 1977).
E. Chronic Toxicity
An increase in toxic polyneuritis has been reported by Milkov, et
al. (1973) in workers exposed primarily to dibutyl phthalate. Lesser levels
of exposure to dioctyl, diisooctyl, benzylbutyl phthalates, and tricresyl
phosphate were also noted. Neurological symptoms have been observed in sev-
eral phthalate plasticizer workers (Gilioli, 1978). Animal studies have
shown central nervous system degeneration and encephalopathy in rats admin-
istered large oral or intraperitoneal doses of butylbenzyl phthalate (Mai-
lette and Von Hamm, 1952).
Oral DEHP feeding has produced.liver and kidney weight increases in
several animal studies (U.S. EPA, 1979). Chronic exposure to transfused
blood containing OEHP has produced liver damage in monkeys (Kevy, et al.
1978). Lake, et al. (1975) have produced liver damage in rats by adminis-
tration of mono-2-ethylhexyl phthalate.
Two-year feeding studies with female rats have shown some kidney
effects produced by dimethyl phthalate (Draize, et al. 1948).
F. Other Relevant Information
Several animal studies have demonstrated that DEHP pretreatment of
rats resulted in increased hexobarbital sleeping times (Daniel and Sratt,
1974; Rubin and Jaeger, 1973; Swinyard, et al. 1976).
-17 H-
sf
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute values for freshwater fish were derived from eight 96-hour
bioassays for four phthalate esters. LC5Q values ranged from 730 ug/1 for
di-n-butyl phthalate in the bluegill sunfish (Lepomis macrochirus) (Mayer
and Sanders, 1973) to 98,200 ug/1 in diethyl phthalate for the bluegill,
Leoomis macrochirus. Butylbenzyl and dimethyl phthalates were intermediate
in their toxicity in bluegill assays with LC^Q values of 43,300 to 49,500
ug/1 respectively (U.S. EPA, 1978). The scud, Gammarus pseudolimnaeus, was
the most sensitive of freshwater species tested, producing a static 48-hour
adjusted LCqQ value of 765 ug/1 (Mayer and Sanders, 1973). In 48-hour
/static Daphnia magna assays, the adjusted LC5Q values for butylbenzyl, di-
ethyl dimethyl, and di-n-ethylhexyl phthalates were 92,300, 52,100, 33,000n
and 11,100 ug/1, respectively. Among marine fish, juvenile sheepshead min-
nows, Cyprinodon varieaatus, were most susceptible to diethyl phthalate,
.producing a static 96-hour LC _ value of 29,600 ug/1. In similar assays,
the LC5Q values for butylbenzyl and dimethyl phthalate were 445,000 ug/1
and 58,000 ug/1 respectively. The marine mysid shrimp, Mysidopsis bahia,
was tested with diethyl phthalate, and produced a 96-hour LC,-Q value of
7,590 ug/1. LC5Q values of 9,630 and 73,700 ug/1 were reported for butyl-
benzyl and dimethyl phthalates, respectively, in mysid shrimp assays.
8. Chronic Toxicity
The only chronic studies available are for one species of fresh-
water fish and one species of freshwater invertebrate (Mehrle and Mayer,
1976; Mayer and Sanders, 1973). A chronic value of 4.2 ug/1 was obtained in
»
a rainbow trout, Salmo gairdneri. embryo-larval study of di-(2-ethylhexyl)
-1717-
a
-------
phthaiate. In Daohnia maona significant reproductive impairment was observ-
ed for di-2(-ethylhexyl) phthaiate at 3.0 pg/1, the lowest concentration
tested. Chronic marine data was not available.
C. Plant Effects
In the freshwater algae, Selenastrum capricomutum, effective con-
centration ranges of 110 to 130 )jg/l; 85,600 to 90,300 ug/1 and 39,800 to
42,700 pg/1 were obtained for butylbenzyl, diethyl and dimethyl phthalates
respectively. Effective concentrations were based on chlorophyll a content
and cell number.
D. Residues
Bioconcentration factors have been obtained for five of the phtha-
lates. In the scud, bioconcentration factors' of 1400 were reported for di-
n-butyl phthaiate, and 54,2680 for di-(2-ethylhexyl) phthaiate. In the.'
bluegill, bioconcentration factors of 57, 117, and 663 were obtained for di-,
methyl, diethyl, and butylbenzyl phthalates, respectively. For-di-(2-ethyl-
hexyi) phthaiate bioconcentration factors were reported from 24 to 150 for
the sowbug, Ascellus brevicaudus, 42 to 113 for the rainbow trout, and 155
to 386 for the fathead minnow.
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
Based on "no effect" levels observed in chronic feeding studies of
rats or dogs, the U.S. EPA calculated acceptable daily intake (ADI) levels
for several phthalates, and established recommended water quality criteria
-------
levels to protect human health for dimethyl phthalate, diethyl phthalate,
dibutyl phthalate, and DEHP. These levels are listed in Table 2 (U.S. EPA,
1979)
8. Aquatic
Data are insufficient to derive draft criteria for any of the
phthalate esters in either freshwater or marine environments (U.S. EPA,
1979).
TABLE 2
CALCULATED ALLOWABLE DAILY INTAKE IN WATER AND
FISH FOR VARIOUS PHTHALATE ESTERS (U.S. EPA, 1979)
Ester NO Effect Species Days
Dose
(mg/kg/day)
Dimethyl
Oiethyl
Oibutyl
Dicyclohexyl
Methyl phthayl
ethyl glycolate
Ethyl phthayl
ethyl glycolate
Butyl phthayl
ethyl glycolate
Oi-2-ethyhexyl
1000
625
13
14
750
250
140
60
Rat
Dog
Dog
Dog
Rat
Rat
Dog
Dog
104
52
52
52
104
104
104
52
ADI** F**_* Recommended
(mg/day) Criteria
(mg/1)
700
438
12.6
9.8
525
175
98
42
130
270
26
Not
Established
Not
Established
Not
Established
Not
Established
95
160
60'
5
10
**Allowable Daily Intake for 70 kg person (100 safety factor)
***F = Biomagnification factor
XT
-------
PKTHALATE ESTERS
REFERENCES
Albro, P.W., et al. 1973. Metabolism of diethhexyil phtha-
late by rats. Isolation and characterization of the urinary
raetabolies. Jour. Chromatogr. 76: 321.
Autian, J. 1973. Toxicity and health threats of phthalate
esters: Review of the literature. Environ. Health Perspect.
June 3.
Sower, R.K., et al. 1970. Teratogenic effects in the chick
embryo caused by esters of phthalic acid. Jour. Pharmacol.
Exp. Therap. 171: 314.
Carter, B.R., et al. 1977. Studies on dibutyl phthalate-
induced testicular atrophy in the rat: Effect on zinc metabo-
lism. Toxicol. Appl. Pharmacol. 41: 609.
Daniel, J.W., and H. Bratt. 1974. The absorption, metabo-
lism and tissue distribution of di(2-ethylhexyl) phthalate
in rats. Toxicology 2: 51.
Draize, J.H., et al. 1948. Toxicological investigations
of compounds proposed for use as insect repellents. Jour.
Pharmacol. Exp. Ther. 93: 26.
Sngelhardt, G. et al. 1975. The microbial metabolism of
di-n-butyl phthalate and related dialkyl phthalates. Bull.
Environ. Contam. Toxicol. 13: 342.
Gilioli, R. et al. 1978. A neurological electromyographic
and electroneurographic study in subjects working at the
production of phthalate plasticizers: Preliminary results.
Med. Law. 6£: 631.
Industrial Bio-Test. 1978. Three generation reproduction
study with di-2-ethyl hexyl phthalate in albino rats. Plas-
tic Industry News, 24, 201-203.
Jaeger, R.J., and R.J. Rubin. 1970. Plasticizers from
plastic devices: Extraction, metabolism, and accumulation
by biological .systems.' Science 170: 460.
Kevy, S.V., et al. 1978. Toxicology of plastic devices
having contact with blood. Rep. NO1 HB 5-2906, Natl. Heart,
Lung and Blood Inst. Bethesda, Md.
Lake, 3.G., et al. 1975. Studies on the hepatic effects .
of orally administered di-(2-ethylhexyl) phthalate in the
rat. Toxicol. Appl. Pharmacol. 32: 355.
-1750-
-------
Lake, 3.G., et al. 1977. The in vitro hydrolysis of some
phthalate diesters by hepatic and intestinal preparations
from various species. Toxicol. Appl. Pharmacol. 39: 239.
Mallette, F.S., and E. Von Haam. 1952. The toxicity and
skin effects of compounds used in the rubber and plastics
industries. II. Plasticizers. Arch. Ind. Hyg. Occup.
Med. 5: 231.
Mayer, F.L. Jr., and H.O. Sanders. 1973. Toxicology of
phthalic acid esters in aquatic organisms. Environ. Health
Perspect. 3: 153. . . . .
Mehrle, P.M., and F.L. Mayer. 1976. Di-2-ethylhexylphtha-
late: Residue dynamics and biological effects in rainbow
trout and fathead minnows. Pages 519-524. I_n Trace sub-
stances in environmental health. University of Missouri
Press, Columbia.
Milkov, L.E., et al. 1973. Health status of workers ex-
posed to phthalate plasticizers in the manufacture of artifi-
cial leather and films based on PVC resins. Environ. Health
Perspect. Jan.. 175.
Nikonorow, M. , et al. 1973. Effect of orally ••-^'minister ed
plasticizers and polyvinyl chloride stabilizers in the rat.
Toxicol. Appl. Pharmacol. 26: 253.
Peakail, D.B. 1975. Phthalate esters: Occurrence and
biological'effects. Residue Rev. 54: 1.
Peters, J.W. , and R.M. Cook. 1973. Effects q*--,phthalate
esters on reproduction of rats. Environ. Heal"u.i Perspect.
Jan. 91.
Rock, G. et al. 1978. The accumulation of mo't.^-2-ethyl
hexyl phthalate (MEHP) during storage of whole blood and
plasm. Transfusion ].£ 553.
Rubin, R.J., and R.J. Jaeger. 1973. Some pharmacologic
and toxicologic effects of di-2-ethylhexyl phthalate (DEHP)
and other plasticizers. Environ. Health Perspect. Jan. 53.
Rubin, R.J., et al. 1979. Ames mutagenic assay of a series
of phthalic acid esters: positive response of the dimethyl
and diethyl esters in TA 100. Abstract. 3oc. Toxicol. Annu.
Meet. New Orleans, March 11.
Schulz, C.O., and R.J. Rubin. 1973. Distribution, metabo-
lism and excretion of di-2-ethylhexyl phthalate in the rat.
Environ. Health Perspect. Jan."123.
-------
Seth, P.K., et al. 1976. Biochemical changes induced by
di-2-ethylhexyl phthalate in rat liver. Page 423 in Environ-
mental biology. Interprint Publications, New DelhTT India.
Shaffer, C.B., et al. 1945. Acute and subacute toxicity
of di(2-ethyhexyl) phthalate with note upon its metabolism.
Jour. Ind. Hyg. Toxicol. 27: 130.
Singh, A. et al. 1972. Teratogenicity of phthalate esters
in rats. J. Pharm. Sci. 61, 51 (1972).
Singh, A.R., et al. 1974. Mutagenic and antifertility
sensitivities of mice to di-2-ethylhexyl phthalate (DEHP)
and dimethoxyethyl phthalate (DMEP). Toxicol. Appl. Pharm-
acol. 29: 35.
Singh, A.R., et al. 1975. Maternal-fetal transfer of 14C-
di-2-ethylhexyl phthalate and C-diethyl phthalate in rats.
Jour. Pharm. Sci. 64: 1347.
Swinyard,. E.A., et al. 1976. Nonspecific effect of bis(2-
ethylhexvl) phthalate on hexobarbital sleep time. J. Pharm.
Sci. 65": 733.
Tomita, I., et al. 1977. Phthalic acid esters in various
foodstuffs anmd biological materials. Ecotoxicology and
Environmental Safety. 1: 275.
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. Phthalate Esters: Ambient Water Quality
Criteria Document. (Draft).
U.S. International Trade Commission. 1978. Synthetic or-
ganic chemicals, U.S. production and sales. Washington,
D.C.
Waddell, W.M., et al. 1977. The distribution in mice of
intravenously administered C-di-2-ethylhexyl phthalate
determined by whole-body autoradiography. Toxicol. Appl.
Pharmacol. 39: 339.
Wallin, R.F., et al. 1974. Di (2-ethylhexyl) phthalate
(DEHP) metabolism in animals and post-transfusion tissue
levels in man. Bull. Parenteral Drug Assoc/ 28: 278.
Yagi, Y. et al. 1978. Smbryotoxicity of phthalate. esters
in mouse. In: Proceedings of the First International Con- •
gress on Toxicology. Plaa, G. and Duncan. W. (eds.)
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No. 147
Phthalic Anhydride
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.
-/75V-
-------
• PHTHALIC ANHYDRIDE '
Summary
Phthalic anhydride failed to produce carcinogenic effects in rats or
mice in a long term National Cancer Institute (NCI) feeding study (7,500
ppm; 15,000 ppm).
Information on the mutagenic effects of phthalic anhydride was not
found in the available literature.
The hydrolysis product of phthalic anhydride, phthalic acid, has shown
teratogenic effects in the developing chick embryo, but not in any mammalian
tests. Phthalic anhydride inhalation at high levels may produce repro-
ductive impairment in male rats.
»
Chronic occupational exposure to phthalic anhydride has been reported
to produce progressive respiratory damage in workers, including marked
fibrosis of the lungs.
Data concerning the effects of phthalic anhydride to aquatic organisms
was not found in the available literature.
-------
PHTHALIC ANHYDRIDE
I. INTRODUCTION
This profile is based on the Preliminary Environmental Hazard Assess-
ment of Chlorinated Naphthalenes, Silicones, Fluorocarbons, Benzene-
polycarboxylates, and Chlorophenols (U.S. EPA, 1973).
Phthalic anhydride (molecular weight - 148.1) is a white, crystalline
solid that melts (sublimes) at 131°C, has a boiling point of 284.5°C, a
density of 1.527, and a solubility of 0.62 gms/100 gms water at 25°C
(Towle, et al. 1963). This compound is soluble in alcohol and sparingly
soluble in ether.
The major uses of phthalic anhydride are in the synthesis of plasti-
cizers, alkyd resins, unsaturated polyester resins, and in the preparation
of various classes of chemical dyes (U.S. EPA, 1973). 4
Production of phthalic anhydride in 1971 was 4 x 10 tons (Blackford,
1970).
Phthalic anhydride is in equilibrium with phthalic acid in aqueous sys-
tems. Under dry conditions, phthalic anhydride is relatively stable at am-
bient temperature (U.S. EPA,.1973). Elevated temperatures will produce oxi-
dative degradation of phthalic anhydride.
Phthalic anhydride is biodegraded by microorganisms (Ribbons and Evans,
1960; Saegar and Tucker, 1973).
II. EXPOSURE
Phthalic anhydride is used in large quantities and therefore has poten-
tial for industrial release and environmental contamination. No monitoring
data are available to indicate ambient air or water levels of the compound.
Fawcett (1970) has determined 40-200 ppm by volume in phthalic anhydride
y
-------
off-gas process. Phthalic acid wastes have been noted in waste waters from
paint and varnish industries (Mirland and Sporykhina, 1963) and alkyd resin
plants (Minkovich, 1960).
Human exposure to phthalic anhydride from foods cannot be assessed, due
to a lack of monitoring data.
Release of phthalic acid from parenterally-used plastic medical devices
(blood bags, plastic tubings, catheters, etc.) may occur since these mater-
ials have been treated with phthalate plasticizers; however, no data on this
type of release are available (U.S. EPA, 1973).
Bioaccumulation data on phthalic anhydride were not found in the avail-
able literature.
III. PHARMACOKINETICS
Specific information on the metabolism, distribution, absorption, ox
elimination of phthalic anhydride was not found in the available literature.
IV. EFFECTS
A. Carcinogenicity
A long-term carcinogenesis bioassay in rats and mice fed phthalic
anhydride (7,500 ppm; 15,000 ppm) has been conducted by the NCI (1979). The
results indicate that oral administration of these levels of the compound
produced no carcinogenic effects in either of the species used.
B. Mutagenicity
Information on the mutagenic effects of phthalic anhydride was not
found in the available literature.
C. Teratogenicity
Phthalic acid was shown to produce an increase in teratogenic
«
effects in the developing chick embryo following injection (Verrett, et al.
-------
1969). Mammalian testing of phthalic acid for teratogenicity failed to show
effects in mice (Koehler, et al. 1971).
D. Reproductive Effects
Inhalation exposure of rats to phthalic anhydride at high levels
(100-200 mg/1) has been reported to cause testicular changes and impaired
reproductive capability (Protsenko, 1970).
E. Chronic Toxicity
Markman and Savinkina (1964) have reported progressive respiratory
damage in workers exposed to phthalic anhydride for two years or more.
Workers exposed for six years evidenced marked fibfosis of the lungs.
F. Other Relevant Information
Phthalic anhydride has been implicated as a skin sensitizing agent
in some individuals exposed for prolonged periods of time (Amer. Ind. Hygi
Assoc., 1967).
V. AQUATIC TOXICITY
Data concerning the effects of phthalic anhydride to aquatic organisms
were not found in the available literature.
VI. EXISTING GUIDELINES
The 8-hour, TWA occupational exposure limit established for phthalic
anhydride is 1 ppm (ACGIH, 1977).
-------
PHTHALIC ANHYDRIDE
References
American Industrial Hygiene Association. 1967. Phthalic anhydride: Human
toxicity. Amer. Ind. Hyg. Assoc. J. 28: 395.
ACGIH. 1977. Threshold limit values for chemical substances in workroom
air.
Slackford, ••- J-.L. 1970. Isophthalic acid. Chemical economics handbook,
Stanford Research Institute.
Fawcett, R.L. 1970. Air pollution potential of phthalic anhydride. J. Air
Pollut. Contr. Assoc. 20: 461.
Koehler, F., et al. 1971. Teratogenicity of thalidomide metabolites.
Experientia. 27: 1149.
Markman, G.I", and R.A. Savinkina. 1964. The condition of the lungs of
workers in phthalic anhydride production (an x-ray study). Kemerovo. 35.
Mirland, L.A. and V.A. Sporykhina. 1968. Polarographic determination of
phthalic acid in waste waters from the paint and varnish industry.
Lakokrasch.. Mater. Ikh. Primen. 1: 49.
Minkovich, O.A. 1960. The recovery of phthalic anhydride wastes in the
manufacture of alkyd resins. Lakokra. Mater, i ikh Primen. 1: 83.
NCI. 1979. Bioassay of phthalic anhydride for possible carcinogenicity.
NCI-CG-TR-159.
Protsenko, E.I. 1970. Gonadotropic action of phthalic anhydride. Gig.
Sanit. 35: 105.
Ribbons, D.W. and W.C. Evans. 1960. Oxidative metabolism of phthalic acid
by soil pseudomonads. Biochem. J. 76: 310.
Saegar, V.W. and E.S. Tucker. . 1973. Biodegradation of phthalate esters.
In: Flexible vinyls and human safety: An objective analysis. Conference
or the Society of Plastics Engineers, Inc., March 20-22. Kiamesha Lake, N.Y.
Towle, P.H., et al. 1968. Phthalic acids and other benzenepolycarboxylic
acids. Vol. 15, p. 444. In: A Stauden (ed.), Encyclopedia of chemical
technology. 2nd ed. J. Wiley 4 Sons, New York.
U.S. EPA. 1973. Preliminary hazard assessment of chlorinated naphthalenes,
silicones, fluorocarbons, benzenecarboxylates, and chlorophenols.
Verrett, M.J., et al. 1969. Teratogenic effects of captan and related com-
pounds in the developing chick embryo. Ann. N.Y. Acad. Sci. 160: 334.
•mi-
-------
No. 148
2-Picoline
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.
-------
2-PICOLINE
Summary
Pertinent data could not be found that defined 2-picoline as
a carcinogen or a mutagen. Studies on rats indicated that the
structure and composition of the liver and the structure and growth
pattern of the- skin were disrupted in the offspring of tested rats
who were given 157 mg per kg body weight daily during their pregnancy.
2-picoline has been shown to produce biochemical and physical
changes in the liver, spleen, bone marrow, and lymph nodes.
-I76-3L-
-------
I. INTRODUCTION
2-picoline (alpha-picoline, 2-methylpyridine; CAS No.
109-06-8) is a colorless liquid possessing a strong unpleasant
odor. It has the following physical properties:
Formula: CgHyN
Molecular Weight: 93.12
Melting Point: -70°C
Boiling Point: 129°C
Vapor Pressure: 8 mm Hg at 20°C
Vapor Density: 3.21
2-picoline is freely soluble in water and miscible with alcohol
and ether (Windholz, 1976). 2-picoline is used as an organic
solvent and intermediate in the dye and resins industries.
II. EXPOSURE
A. Water
Pertinent data could not be located in the available
11terature.
B. Food
Pertinent data could not be located in the available
1 i terature.
C. Inhalation
2-picoline occurs in the working environment of coke oven
workers (Naizer and Mashek, 1974) and is present in cigarette smoke
(Brennemann et. al., 1979).
D. Dermal
»
Pertinent data could not be located in the available
li terature.
'1763-
-------
III. PHARMACOKINETICS
A. Absorption
In rats, 2-picoline is rapidly absorbed and taken up by
the liver, heart, spleen, lungs, brain, and muscles during the
first 10 to 20 minutes after oral administration (Kupor, 1972).
B. Distribution
Pertinent data could not be located in the available
1 i terature.
C. Metabolism and Excretion
Most of an administered dose in an acute toxicity study
was excreted in the urine within 48 hours (Kuper, 1972).
IV EFFECTS
A. Carcinogenic! t y "• '
Pertinent data could not be found in the available
li terature. .
B. Mutagenicity
,-'X
Pertinent data could not be found in the available •-'
li terature. "j
C. Teratogenicity
The structure and composition of the liver and the
structure and growth pattern of the skin were disrupted in the
offspring of treated rats who were administered 157 mg per kg body
weight of 2-picoLine throughout their pregnancy (Nikiforova and
Taskaev, 1974).
D. Other Reproductive Effects
»
Glycolytic processes and protein formation in the liver
was disturbed during the pregnancy of rats inhaling 2-picoline at
-------
Che maximum permissable concentration for 4 months. The pregnancy
complicated toxicosis which without pregnancy was successfully
compensated by the liver (Taskaev, 1979).
E. Chronic Toxicity
The following biochemical and physical changes have been
observed in rats after the administration of 2-picoline; changes
occurred in the liver carbohydrate metabolism (Taskaev, 1979; Kuper
and Gruzdeva, 1974) and changes occurred in protein synthesis of the
liver.noted after chronic oral (Kuper and Gruzdeva, 1974) and
inhalation (Taskaev, 1979) exposure. Administration of low doses
results in changes in LDH isoenzyme distribution and activity
(Gruzdeva, 1976). The major chronic effects of 2-picoline are
injury to the liver (Ovchinnikova, 1978; Taskaev, 1979; Ovchinnikova,
1977) and spleen, bone marrow, and lymph nodes (Semchenko, 1973 and
1972).
F. Other Relevant Information
Pertinent data could not be found in the available
literature.
V. AQUATIC TOXICITY
A. Acute Toxicity
Pertinent information could not be found in the available
li terature.
B. Chronic Toxicity, Plant Effects and Residues
Pertinent information could no-t be f'bund in the available
1i terature.
»
C. Other Relevant Information
Pertinent information could not be found in the available
1i terature.
/
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The 8-hour, time-weighted average occupational exposure
limit for alpha-picoline has been set .in Russia at 5 mg/m^
(Verschueren, 1977). Maximum allowable concentration in Class I
waters for the production of drinking waters has been set in the
Netherlands at 0.05 mg/1 (Verschueren, 1977).
B. Aquatic
Pertinent information could not be found in the available
li terature.
-------
REFERENCES
Brunnemann, K.D., and at. al. , 1978. Chemical Studies on
Smoke: LXI. Volatile Pyridines: Quantitative Analysis in
and Sidestream Smoke of Cigarettes and Cigars. Anal
545-560.
Tobacco
Mains t rearn
Lett. 11(7):
Gruzdeva. K.N., et. al. 1976. Use of Electrophoretic Methods for
Determining Lactate Dehydrogenase Isoenzymes in Studying Chronic
Poisoning with Pyridine Derivatives. Khromatogr. Elektroforeticheakia
Metody Issled. Biol. Aktiv. Soedin. 44-7.
Kuper, V.G. Distribution of alpha-Picoline in Rat Tissue During
Acute alpha-Picoline Intoxication. Vop. Patokhimii Biokhim.
Belkov. Drugikh Biol. Aktiv. Soedin. 51-2.
Kuper, V.G., and K.N. Gruzdeva. 1974. Concerning the Question of
Carbohydrate Metabolism After Chronic Poisoning with alpha-Picoline.
Narusheniya Metab., Tr. Naucha. Konf. Med. Inst. Zapadn., Sib.,
1st, 261-5.
Naizer , Y. , and
Its
(5)
Homologs
76-78.
in
V. Mashek. 1974.
the Environment of
Determination of Pyridine and
Coke Plant Workers. Gig. Sanit
Niklforova, A.A., and I.I. Taskaev. 1974. Liver and Skin Morpho-
genesis in Some Laboratory Animal Embryos Following Poisoning with
Pyridine Bases. Reakt. Plast. Epiteliya Soedin. Tkani Norm, Eksp.
Patol. Usloviyakh, Dokl. Mezhvuz, Gistol. Konf. 196-9.
Ovchinnikova , L.S. 1977. Morpholgical and Histochemical Changes
in White Rats Liver After Acute Poisoning with alpha-Picoline and
2,5-Lutidine. Gig. Aspekty Okhr. Zdorov'ya Naseleniya. 124-5.
Ovchinnikova , L.S,
and Lambina
1978. Morphohistochemical
Changes in Liver of White Rats with Subacute Poisoning with Products
of Synthetic Rubber Production. Deposited Doc., ISS. Vinitl 2667-
78, 101-2.
Semchenko, V.V. 1972. Regenerative Processes in Blood-Forming
Organs of Experimental Animals During and After Chronic Intoxica-
tion by Methylpyridine. Mater. Nauch. Sess., Posvyashch. 50-
•Letiyu Obrazov. SSSR, Omsk, Gos. Med. Inst. 896-8.
Semchenko, V.V. 1973. Histological and Hi st o-chemical Characteristics
of Spleen and Lymph Nodes of Rats During Chronic Intoxication with
alpha-Picoline and 2,5-Lutidine. Hezenkhima Tkanevya Proizvod. Evol.
Ontog., 56-8.
-rra-
-------
REFERENCES
Taskaev, I.T. 1979. Histological and Cytological Changes in Rat
Liver During Experimental Poisoning and Subsequent Pregnancy.
Arkh. Anat.. Gistol. Embriol. Vol. 76, ISS. 2, 49-54.
Verschueren, K. 1977. Handbook of Environmental Data on Organic
Chemicals. Van Nostrand Reinhold Company. New York.
Windholz, Martha et. al. (editors). 1976. The Merck Index. Merck
& Co., Inc. Rahway, N.J.
-------
No. 149
Polynuclear Aromatic Hydrocarbons (PAH)
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
•I76J-
-------
DISCLAIMER
This report represents a survey of. the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-uracy.
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
polynuclear aromatic hydrocarbons and has found sufficient
evidence to indicate that this compound is carcinogenic.
-/7/V-
-------
POLYNUCLEAR AROMATIC HYDROCARBONS (PAH)
SUMMARY
The first chemicals ever shown to be involved in the development of
cancer belong to the polycyclic aromatic hydrocarbon (PAH) class. Several
PAH are well-known as animal carcinogens by all routes of administration.
Others are not carcinogenic alone, but in certain cases can enhance or in-
hibit the tumorigenic response of carcinogenic PAH. Numerous studies of
workers exposed to coal gas, coal tars, and coke oven emissions, all of
which have large amounts of PAH, have demonstrated a positive association
between their exposures and lung cancer development. The carcinogenic risk
of ingested PAH in humans, however, has not been extensively studied.
NO standard toxicity data for aquatic organisms are available for
freshwater or marine life. Limited information concerning toxic responses
•*
of freshwater fish reveals that concentrations of 1,000/jg/1 for six months
produced an 87% mortality in one warm water species.
-------
I. INTRODUCTION
This profile is based primarily upon the Ambient Water Quality Criteria
Document for Polynuclear Aromatic Hydrocarbons (U.S. EPA, 1979a) and the
Multi-media Health Assessment Document for Polycyclic Organic Matter (U.S.
EPA, 1979b).
Polycyclic aromatic hydrocarbons (PAH) are a diverse class of compounds
consisting of substituted and unsubstituted polycyclic and heterocyclic aro-
matic rings. PAH are formed as a result of incomplete combustion of organic
material (e.g., fossil fuels, wood, etc.). This leads to formation of C-H
free radicals which can polymerize to form various PAH. Among these PAH are
compounds such as benzo(a)pyrene (BaP) and benz(a)anthracene (BaA), which
are ubiquitous in the environment and well-known for their carcinogenic
activity. The presence in ambient air of over one hundred individual PAH
has been reported, but quantitative data on only 26 PAH are available thus
far.
Most of the PAH are high melting-point, high boiling-point solids that
are very insoluble in water. As the ring size increases, the volatility de-
creases significantly. The PAH are strong absorbers of ultraviolet light,
and PAH fluoresce strongly; .both of these properties lead to analytical
methods for detection of trace quantities. Because of their high melting
points and low water solubilities and vapor pressures, most PAH are gener-
ally associated with particulate matter. In air, they are adsorbed on small
diameter particles that can be easily inhaled. In water, PAH appear to also
be primarily associated with particulate matter. Based upon water treat-
ability of PAH, the compounds appear to exist in equal proportions in three
forms; bound to large suspended particles; bound to finely dispersed par-
ticles, and as the dissolved form (U.S. EPA, 1979a).
-------
PAH adsorbed to airborne particulate matter appear to be fairly stable
in the environment. Nevertheless, some photooxidation occurs with atmos-
pheric PAH since quinone derivatives have been detected in the atmosphere,
and their concentrations increase during the summer when the light intensity
is greatest.
Considerable study on the microbial and chemical stability and degra-
dation of PAH in the aquatic environment has been conducted. In general,
the low .molecular weight molecules appear to biodegrade relatively rapidly
while PAH containing more than three rings appear to be extremely stable.
The first step in the microbial degradation process appears to be the forma-
tion of ortho-dihydrodiols which rapidly react to open the ring. PAH also
appear to be light sensitive in aquatic systems, but the rate of degradation
is difficult to determine experimentally since the vast majority of the corrs-
pounds are adsorbed to particulate matter. Recent studies have shown that
adsorption of many PAH compounds to sediments is a major transport process
in aqueous systems. Studies in water treatment of municioal and industrial
• . V
sewage indicate that about two-thirds of the PAH can be eliminated by sedi-
mentation and biodegrac )ion. If this secondary effluent is subjected to
chemical treatment (chlorination or ozonation) the remaining PAH ' can be
degraded.
II. EXPOSURE
A. water
Based upon work by Basu and Saxena (1978) the average concentra-
tions of BaP, carcinogenic PAH (BaP, benzoCj)fluoranthene, indeno(l,2,3-cd)-
pyrene), and total PAH (above 3 compounds plus benzo(g,h.i)perylene, benzo-
(b)fluoranthene, and fluoranthene) in U.S. drinking water are 0.55 ng/1, 2.1
ng/1, and 13.5 ng/1, respectively. NO drinking water monitoring data on
-------
other PAH compounds are available. The low con- centrations are somewhat a
reflection of the extremely low water sclu- biiities of PAH compounds.
Slightly higher drinking water values have been reported in Europe (e.g. 3-5
ng/1 carcinogenic PAH and 40-60 ng/1 total PAH), but these differences will
have relatively negligible effects on the calculated daily intake values
through drinking water compared to other sources (U.S. EPA, 1979a).
Assuming that a human consumes approximately 2 liters of water per day, the
daily intake of PAH via drinking water would be:
0.55 ng/1 x 2 liters/day = 0.0011 jug/day (8aP)
2.1 ng/1 x 2 liters/day = 0.0042 ^g/day (carcinoaenic PAH)
13.5 ng/1 x 2 liters/day = 0.0270 jug/day (total PAH)
9. food
It is difficult to evaluate the human dietary intake of PAH through
foods since the amount not only depends on the food habits of the individual
and the style of cooking, but it also depends upon the origin of the foods.
In order to provide a reasonably accurate estimate of the PAH dietary in-
take, average concentrations of RAH in representative food items would have
to be available. Unfortunately, as of this date, these data have not been
generated. However, examination of the available food monitoring data does
suggest that a typical range of concentrations for PAH and 8aP are 1.0-10.0
ppb and 0.1-1.0 ppb, respectively (U.S. EPA, 1979a). Combining these ranges
with average .total daily food consumption by man from all types of foods of
1600 g/day, the following estimates of dietary PAH and BaP intake are poss-
ible:
0.1 - 1.0 ppb x 1600 g/day = 0.16 - 1.6 jug/day (3aP)
1.0 - 10 ppb x 1600 g/day = 1.6 - 16^ug/day"(PAH)
-------
The U.S. EPA (1979a) has estimated the weighted average bioconcen-
tration factors for the edible portion of all aquatic organisms consumed by
Americans. These range from 120 to 24,000, and are based on the octanol-
/water partition coefficients for each compound.
C. Ambient Air
It is not possible to determine the average intake of PAH from in-
halation of ambient air in the United States because the monitoring data
have focused mostly on BaP concentrations. However, by making some assump-
tions, it is possible to provide estimates that are reasonably close to
probable actual values. Using the 1974-1975 Los Angeles monitoring data
from Gordon (1976), the relative amounts to carcinogenic PAH and total PAH
compared to the average BaP concentration .are presented below.
Ambient cone, ng/m^
Inhalation intake,
'•• micrograms/daya
BaP
0.5-2.9
0.0095-0.0435
Carcinogenic
PAH
. 2.0
0.038
Total
.PAH
10.9
0.207
aAssumed average air breathed per day was 19 m-5
III. PHARMACOKINETICS
There are no data available concerning the pharmacokinetics of PAH in
humans. Nevertheless, it is possible to make limited assumptions based on
the results of animal studies conducted with several PAH, particularly BaP.
The metabolism of PAH in human and animal tissues has been especially well-
studied, and has .contributed significantly to an , understanding of the
mechanisms of PAH-induced cancer.
-------
A. Absorption
Regardless of the route of exposure, it can be demonstrated in
laboratory animals that PAH are readily absorbed across all epitnelia which
are in contact with the external environment (Rees, et al. 1971; Kotin, et
al. 1969; Vainio, et al. 1976). The fact that PAH are generallly high
lipid-soluble neutral molecules greatly facilitates their passage through
the predominantly lipid-like cell membranes of animals, including man.
3. Distribution
Upon reaching the bloodstream, PAH are rapidly distributed to most
internal body organs (Kotin, et al. 1969; Sock and Oao, 1961: Dao, et al.
1959; Flesher, 1967). Under experimental conditions with laboratory
animals, the route of exposure has little apparent influence on the tissue
\
- localization of PAH. Extensive localization in the fat and fatty tissues
(e.g., breast) is observed (Bock and Oao, 1961; Schlede, et al. 1970 a,b)
and suggests that these tissues may act as a chemical trap, creating a situ-
ation for sustained release of the unchanged substance. In pregnant rats,
'''%
it is apparent that 8aP and 7,12-dimethylbenz(a)anthracene, but probably not
3-methylchnlanthrene, are capable of transplacental passage and localization
__ /
in the fetus (Shendrikova and Aleksandrov, 1974).
C. Metabolism
PAH are metabolized by the microsomal mixed-function oxidase
system, also known as aryl hydrocarbon hydroxylase. This enzyme system is
readily inducible and is found in most mammalian tissues, although pre-
dominantly in the liver. In conjunction with various P-450 type cyto-
chromes, this enzyme complex is involved in detoxification of manv xeno-
-1777-
-------
biotics, but may also catalyze the formation of reactive epoxide metab-
olites, themselves leading to carcinogenesis. A. second microsomal enzyme,
epoxide hydrase, converts epoxide metabolites of PAH to vicinal glycols, a
process which may also be of critical importance in the process of
carcinogenesis.
Because of the importance of metabolic activation for the ex-
pression of carcinogenic effects by PAH, the chemical fate of many repre-
sentative compounds in mammalian cells has been extensively explored (U.S.
EPA, 1979a). By far the most widely studied of the PAH has been 8aP, one of
the principal carcinogenic products from the combustion of organic
material. The metabolites of BaP (and . all PAH) can be divided into a
water-soluble and an organic solvent-soluble fraction. Components of the
latter fraction are- primarily ring-hydroxylated products, quinones, and
.labile epoxide intermediates, "or BaP there'are at. least three dihydro-
diols, three quinones, and four phenols which can be detected as positional
isomers. The- K-region (4,5-) and non-K-region (7,3-; 9,10-) epoxides are
precursors of the corresponding vicinal diols, which are formed by the
action of the epoxide hydrase enzyme. A subsequent oxidative attack by aryl
hydrocarbon hydroxylase may convert the non-K-region diols to vicinal diol
epoxides, one of which (7,8-diol-9,10-epoxide) is an ultimate carcinogenic
form of BaP.
In the water-soluble fraction containing BaP metabolites are mainly
conjugates of hydroxylated products with glutathione, glucuronic acid, -and
sulfate. This group of metabolies is tentatively regarded to be composed of
non-toxic excretion products.
-------
The aeneral scheme of metabolism for unsubstitutsd PAH closely
parallels that for BaP, although several other major environmental PAH have
not been studied. It is also evident that K-region derivatives of PAH may
be preferred targets for conjugation and excretion, whereas non-K- region
epoxides undergo further reductions and oxidative attack to form
toxicologically important molecules. For PAH bearing alkyl substituents
(e.g., DM8A, MCA), the primary metabolites formed are hydroxymethyl
derivatives. Nevertheless, epoxidation reactions at '<- region and
non-K-region aromatic double bonds occur which are catalyzed by aryl
hydrocarbon hydroxylase. Removal of activated intermediates occurs by
conjugation with glutathione or glucuronic acid, or by further metabolism to
tetrahydrotetrols.
0. Excretion .
Over forty years ago, researchers recognized that various PAH were
excreted primarily through the hepatobiliary system and the feces (Peacock.
1936; Chalmers and Kirby, 1940). However, the rate of disappearance of
various PAH from the body, and the principal routes of excretion are influ-
enced both by structure of the parent compound and the route of adminis-
tration (Heidelberger and Weiss, 1959; Aitio, 1974a,b). Moreover, the rate
of disappearance of a PAH (i.e., benzo(a)pyrene) from body tissues can be
stimulated markedly by prior treatment with inducers of microsomal enzymes
(e.g., benzo(a)pyrene, 7, 12-dimethylbenz( a) anthracene, 3-methylcholanthrene,
chrysene) (Schlede, et a!. 1970a,b). Likewise, it has been shown that in-
hibitors of microsomal enzyme activity, such as parathion and paraoxon, can
decrease the rate of 8aP metabolism in certain animal tissues (Weber, et ai.
t
1976). From the available data concerning excretion of PAH in animals, it
is apparent extensive bioaccumulation is not likely to occur.
177?-
-------
IV. EFFECTS
A. Carcinogenicity
PAH were the first compounds ever shown to be associated with car-
cinogenesis. As of this date, carcinogenic PAH are still distinguished by
several unique features: (1) several of the PAH are among the most potent
carcinogens known to exist, producing tumors by single exposures to
microgram quantities; (2) they act both at the site of application and at
organs distant to the site of absorption; and (3) their effects have been
demonstrated in nearly every tissue and species tested, regardless of the
route of administration (U.S. EPA, 1979a). Among the more common PAH, at
least one, BaP, is ubiquitous in the environment. In animals, PAH produce
tumors which resemble human carcinomas. T' v -demonstration that organic
. s
extracts of particulate air pollutants are carcinogenic to animals has
raised concern over the involvement of PAH in human cancer formation
(Hoffmann and Wynder, 1976).
Oral administration of PAH to rodent •'-> can result in tumors of the
fore-stomach, mammary gland, ovary, lung, liver, and lymphoid and hemato-
poietic tissues (U.S. EPA,. 1979a). Exposure \v very small doses of PAH by
inhalation or intratracheal instillation can also be an effective means of
producing tumors of the respiratory tract. However, for both oral and in-
tratracheal routes of administration, BaP is less effective than other PAH
(e.g., OMBA, MCA) in producing carcinomas. However, BaP has a remarkable
potency for the induction of skin tumors in mice that cannot be matched by
any other environmental PAH. Therefore, caution must be exercised in con-
sidering the carcinogenicity of PAH as a class, or in using BaP as a repre-
»
se.ntative example in evaluating the carcinogenic risk of PAH.
-------
The presence of PAH in the air, or as components of soot, tars, and
oils, have long been associated with an excess incidence of cancer in human
populations (U.S. EPA, 1979a,b). However, it has never been possible to
study a population having exposure to PAH in the absence of other potential
carcinogens, cocarcinogens, tumor initiators, or tumor promoters.
Convincing evidence from air pollution studies indicates an excess
of lund cancer mortality among workers exposed to large amounts of PAH-
containing materials such as coal gas, tars, soot, and coke-oven emissions
(Kennaway, 1925; Kennaway and Kennaway, 1936, 1947; Henry, et al. 1931;
Kuroda, 1937; Reid and Buck, 1956; Doll, 1952; Doll, et al. 1965, 1972;
Redmond, et al. 1972, 1976; Mazumdar, et al. 1975; Hammond, et al. 1976;
Kawai, et al. 1967). However, no definite proof exists that the PAH present
in these materials are responsible for the cancers observed. Nevertheless,
our understanding of the characteristics of PAH-induced tumors in animals,
and their close resemblance to human carcinomas of the same target organs,
suggests PAH pose a carcinogenic threat to man, regardless of the route of
exposure.
3. Mutagenicity
The demonstration of mutagenicity in bacterial and mammalian cells
by exposure to PAH is generally equated with the capability to induce tumor
formation. This assumption is based on the participation of a common elec-
trophilic metabolite in producing the carcinogenic/mutagenic event, and the
common target site in the cell (i.e., DNA or other components of the genome)
for -the effect to be produced.
In recent years, considerable research effort has been directed at
determining the mutagenicity of various PAH derivatives as a means of 'ident-
ifying structural features associated with the biological effect produced.
-m/-
y
-------
Working with bacterial mutants which can be reverted to histidine inde-
pendence by a chemically-induced mutation, epoxides of carcinogenic PAH were
shown to possess significant mutagenicity (U.S. EPA, 1979a). Further work
with cultured mammalian cells established that carcinogenic PAH can produce
forward mutations when a drug metabolizing enzyme system is available
(Huberman and Sachs, 1974, 1976).
Numerous attempts have been made to correlate exposure to PAH with
the induction of chromosomal aberrations. Although variations in chromosome
number and structure accompany PAH-induced tumors in rodents, it is not
clear whether these changes are consistently observable (U.S. EPA,
1979a,b). NO evidence in the published literature has been found to in-
dicate that PAH may produce somatic mutations in the absence of neoplastic
transformation. ^
• C. . Teratogenicity
PAH are not generally regarded to have significant teratogenic
activity. BaP showed no effect on the developing embryo in several mam-
malian and non-mammalian species (Rigdon and Rennels, 196A; Rigdon and Meal,
1965). In contrast, DMBA and its hydroxymethyl derivatives apparently are
teratogenic in the rat, but~ only at high doses (Currie, et al. 1970; Bird,
et al. 1970).
D. Other Reproductive Effects
Little additional, information is presently available to indicate
whether PAH present a significant hazard to reproductive success. Further-
more, effects on'the fetus which may be due to maternal toxicity or experi-
mental conditions (e.g., injection vehicle, stress) have not been adequately
»
dissociated from true embryotoxicity or teratogenesis.
-/7SSI-
-------
t. Chronic Toxicity
Little attsntion has been paid to the non-carcinogenic effects of
exposure to PAH. Nevertheless, it is known that tissues of the rapidly pro-
liferating type (e.g., intestinal epithelium, bone marrow, lymphoid organs,
testis) seem to be the preferred targets for PAH-induced cytotoxicity (U.S.
EPA, 1979). This action is probably due to a specific attack on ONA of
cells in the S phase of the mitotic cycle (Philips, et al. 1972).
Acute and chronic exposure to various carcinogenic PAH has resulted
in selective destruction of hematopoietic and lymphoid elements, ovotoxicity
and anti-spermatogenic effects, adrenal necrosis, and changes in the intes-
tinal and respiratory epithelia (U.S. EPA, 1979a). For the most part, how-
ever, tissue damage occurs at dose levels that would also be expected to in-
duce carcinomas, and thus the threat of malignancy predominates in evalu-
ating PAH toxicity. For the non-carcinogenic PAH, there is a shortage of
available data concerning their involvement in toxic responses.
V. AQUATIC TOXICITY
A. Acute Toxicity
Standard toxicity determinations for freshwater or marine organisms
have not been conducted for any PAH. The marine worm, Neanther
arenaceodenta, was exposed to crude oil extracts, and LC5Q values for
various PAH ranged from 300 to l,000^g/l (Neff, et al. 1976a,b). A 90 per-
cent lethality, determined from photodynamic response, was obtained for the
protozoa, Paramecium caudatum at an for anthracene concentration of 0-1 /jg/1
in one-hour exposures (Epstein, 1963). Bluegill sunfish (Lepomis
macrochirus) displayed an 87% mortality at concentration of 1,000 ug/1
benzo-a-anthracene.
A
-------
8. Chronic
Standard toxicity studies using either freshwater or marine organ-
isms have not been conducted on any PAH. A six-month study of benzo-
(a)pyrene on the bluegill sunfish (Leaomis macrochirus) produced 87 percent
mortality at a concentration of 1,000 ug/1 (Brown, et al. 1975).
C. Plants
Studies of the effects of PAH on freshwater or marine plants could
not be located in the available literature.
D. Residues
In short-term modeling of freshwater ecosystem studies, three-day
bioconcsntration factors for benzo(a)pyrene of 930, 5,258, 11,536, 82,231,
and 134,248 were obtained for the mosquito-fish (Gambusia affinis), the
algae Oedoqonium cardiacum, the mosquito Gulex pipiens quinouefasciatus, the
snail Phvsa sp.?. and cladocsran Dapnia pulex, respectively (Lu, et al.
1977). For anthracene, a i-nour bioconcentration factor of 200,was obtained
.for Osohnia maona (Herbes, •1976). .. For . marine molluscs, bioconcentration
factor values ranged from 8.2 for the clam (Ranqia cuneata) (Neff, et al.
1976a) to 242 for the eastern oyster (Crassostrea virqinica) (Couch, et al.,
in press).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health and aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have not gone through the process of
public review; therefore, there is a possibility that these criteria may be
changed.
-------
A. Human
To date, one recommended standard for PAH as a class has been
developed. The World Health Organization (1970) recommends a concentration
of PAH in water not to exceed 0.2/jg/l. This recommended standard is based
on the composite analysis of six PAH in drinking water: (1) fluoranthene,
(2) benzo(a)pyrene, (3) benzo(g,h,i)perylene, (4) benzo(b)-fluoranthene, (5)
benzo(k)fluoranthene, and (6) indeno(l,2,3-cd)pyrene.
In the occupational environment, a Federal standard has been pro-
mulgated for coke oven emissions, based primarily on the presumed effects of
the carcinogenic PAH contained in the mixture as measured by the benzene
soluble fraction of total particulate matter. Similarly, the American Con-
ference of Governmental Industrial Hygiensists recommends a workplace expo-
sure limit for coal tar pitch volatiles, based on the benzene-soluble frac-
tion containing carcinogenic PAH. The National Institute for Occupational
Safety and Health has also recommended a workplace criterion for coal tar
products (coal tar, creosote, and coal tar pitch), based on.measurements of
the cyclohexane extractable fraction. These criteria are summarized below:
Substance Exposure Limit Agency
Coke Oven Emissions 0.150 mg/m3, 8-hr. U.S. Occupational Safety
time-weighted average and Health Administration
Coal Tar Products 0.1 mg/m^, 10-hr. U.S. National Institute for
time-weighted average Occupational Safety and
Health
Coal Tar Pitch 0.2 mg/m^, (benzene American Conference of
Volatiles soluble fraction) 8-hr. Governmental Industrial
time-weighted average Hygienists
Based on animal bioassay data, and using the "one-hit" model, the
U.S. EPA (I9.79a) has .set draft ambient water quality criteria for 3aP and
#
dibenz(a,h)anthracene (DBA) which will result in specified risk levels of
human cancer as shown in the table below.
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Exposure Assumptions
(per day)
2 liters of drinking water
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and
shellfish only.
Exposure Assumptions
--- (per day)
2 liters of drinking water
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and
shellfish onlv.
SaP
Risk Levels and Corresponding Draft Criteria
ng/1
0
0
10-7
0.275
•1.25
2.75
12.5
10-5
27.5
125
DBA
Risk-Levels and Corresponding Draft Criteria
ng/1
0
0
10-7
0.43
1.96
10-6
4.3
19.6
10-5
43
196
8. Aquatic
Criteria have not been proposed for the protection of aquatic
organisms (U.S. EPA, 1979a).
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POLYNUCLEAR AROMATIC HYDROCARBONS
REFERENCES
Aitio, A. 1974a Different elimination and effect on mixed function oxidase
of 20-methylcholanthrene after intragastric and intraperitoneal adminis-
tration. Res. Commun. Chem. Path. Phamacol. 9: 701.
Aitio, A. 1974b. Effect of chrysene and carbon tetracnloride adminis-
tration on rat hepatic microsomal monoxygenase and udglucuronsyltransferase
activity. FE3S Lett. 42: 46.
3asu O.K. and J. Saxena. 1978. Polynuclear aromatic hydrocarbons in selec-
ted U.S. drinking waters and their raw water sources. Environ. Sci.
Technol. 12: 75.
Bird, C.C., et al. 1970. Protection from the embryopathic effects of
7-hydroxymethyl-12-methylbenz(a) anthracene by 2-methyl-l,2-bis-(3
pyridyl)-l-propanone(metopirone ciba) and B-diethyl-amincethyl-
diphenyl-n-propyl acetate (SKR 525-A). Br. Jour. Cancer 24: 548.
Bock, F.G., and T.L. Dao. 1961. Factors affecting ..a polynuclear hydro-
carbon level in rat mammary glands. Cancer Res. 21: 1024. ,i
Brown, E.R., et al. 1975. Tumors in fish caught in polluted waters: poss-
ible explanations. Comparative Leukemia Res. 1973, Leukemogenesis. Univ.
Tokyo PressAarger, Basel, pp. 47-57.
Chalmers, J.G., and A.H.M. Kirby. 1940. The elimination of 3,4-benzpyrene
from the animal body after subcutaneous injection.) I. Unchanged benz-
pyrene. Biochem. Jour. 34: 1191.
Couch, J.A. et ai. The American oyster as an indie ."br of carcinogens in
the aquatic environment. In: Pathobiology of environmental pollutants -
animal models and wildlife of monitors. Storrs, Conn. National Academy of
Sciences. (In press).
Currie, A.R., et al. 1970. Embryopathic effects of 7,12-dimethyl-
benz(a)anthracene and its hydroxymethyl derivatives in the Sprague-Oawley
rat. Nature 226: 911.
Oao. T.L., et al. 1959. Level of 3-methylcholanthrene in mammary glands
of rats after intragastric instillation of carcinogen. Proc. Soc. Exptl.
Biol. Med. 102: 635.
Doll. R. 1952. The causes of death among gas workers with special refer-
ence to cancer of the lung. Br. Jour. Ind. Med. 9: 180.
Doll. R., et al. 1965. Mortality of gas workers with special reference to
cancers of the lung and bladder, chronic bronchitis, and pneumoconiosis.
3r. Jour. Ind. Med. 22: 1.
Doll R. et al. 1972. Mortality of gas workers - final report of a pros-
pective study. Br. Jour. Ind. Med. 29: 394.
Epstein, S.S., et al. 1963. The photodynamic effect of the carcinogen,
3,4-benzpryene, on Paramecium caudatum. Cancer Res. 23: 35.
-------
Flesher, J.S. 1967. Distribution of radioactivity in the tissues of rats
after oral administration of 7,12-dimethyl-benz(a)anthracene—*H. Biochem.
Pharmacol. 16: 1821.
Gordon, R.J. 1976. Distribution of airborne polycyclic aromatic hydro-
carbons throughout Los Angeles. Environ. Sci. Technol. 10: 370.
Hammond, E.G., et al. 1976. Inhalation of benzpyrene and cancer in man.
Ann. N.Y. Acad. Sci. 271: 116.
Heidelberger, C., and S.M. Weiss. 1959. The distribution of radioactivity
in mice following administration of 3,4-benzpyrene-5Ci4 and 1,2,5,6-di-
benzanthracene-9, 10-C14. Cancer Res. 11: 885.
Henry, S.A. et al. 1931. The incidence of cancer of the bladder and pros-
tate in certain occupations. Jour. Hyg. 31: 125.
Herbes, S.E. 1976. Transport and bioaccumulation of polycyclic aromatic
hydrocarbons. (PAH) in aquatic systems. In: Coal technology program
quarterly progress report for the period ending December 31, 1975. Oak
Ridge National Lab., Oak Ridge, TN. ORNL-5120. pp. 65-71.
Hoffmann D. and E.L. Wynder. 1976. Re.spiratory carcinogenesis. In: chem-
ical carcinogens C.E. Searle (ed.) ACS Monograph 173, Amer. Chem. Soc'.-
Washington, D.C. ^
Huberman, E., and L. Sachs. 1974. Cell-mediated mutagenesis of mammalian
cells with chemical carcinogens. Int. Jour. Cancer 13: 32.
Huberman, E., -and L. Sachs. 1976. Mutability of different genetic loci in
mammalian cells by metabolically activated carcinogenic polycyclic hydro-
carbons. Proc. Natl. Acad. Sci. 73: 188.
Kawai, M., et al. 1967. Epidemiologic study of occupational lung cancer.
Arch. Environ. Health.14: 859.
Kennaway, E.L. 1925. The anatomical distribution of the occupational
cancers. Jour. Ind. Hyg. 7: 69.
Kennaway, E.L., and N.M. Kennaway. 1947. A further study of the incidence
of cancer of the lung and larynx. Br. Jour. Cancer. 1: 26'o.
Kennaway, N.M., and E.L. Kennaway. 1936. A study of the incidence of can-
cer of the lung and larynx. Jour. Hyg. 36: 236.
Kotin, P., et al. 1969. Distribution, retention, and elimination of
C^-3,4 benzpyrene after administration to mice and rats. Jour. Natl.
Cancer Inst. 23: 541.
Kuroda, S. 1937. Occupational pulmonary cancer of Generator gas workers.
Ind. Med. Surg. 6: 304.
Lu, P. et al. 1977. The environmental fate of three carcinogens;- benzo-
• (a)-pyrene, benzidine, and vinyl chloride evaluated in laboratory moqel eco-
systems. Arch. Environ. Contam. Toxicol. 6: 129.
Mazumdar, S., et al. 1975. An epidemiologicai. study of exposure to coal
tar pitch volatiles among coke oven workers. APCA Jour. 25: 382.
-------
Neff, J.M., et ai. 1976s. Effects of petroleum on survival, respiration
and growth of marine animals. In: Sources, Effects and Sinks of Hydro-
carbons in the Aquatic Environment. Proceedings of a symposium, American
University, Washington, O.C., American Institute of Biological Sciences, p.
520.
Neff, J.M., et al. 1976b. Accumulation and release of petroleum-derived
aromatic hydrocarbons by four species of marine animals. Mar. 8ioi.
38: 279.
Peacock, P.R., 1936. Evidence regarding the mechanism of elimination of
1,2-benzpyrene, 1,2,5,6-dibenzanthracene, and anthracene from the blood-
stream of injected animals. Br. Jour. Exptl. Path. 17: 164.
Philips, E.F., et al. 1972. In vivo cytotoxicity of polycyclic hydro-
carbons., Vol. 2. p. 75 In: Pharmacology and the Future of Man. Proc. 5th
Intl. Congr. Pharmacology, 1972, San Francisco.
Redmond, C.K., et al. 1972. Long term mortaility study of steelworkers.
Jour. Occup. Med. 14: 621.
Redmond, C.K., et al. 1976. Cancer experience among coke by-product
workers. Ann. N.Y. Acad. Sci. p.102.
Rees, E.O., et al. 1971. A study of the mechanism of intestinal absorption
of benzo(a)pyrene. Biochem. Biophys. Act. 225: 96.
Reid, O.O., and C. Buck, 1956. Cancer in coking plant workers. Br. Jour.
Ind. Med. 13: 265.
Rigdon, R.H., and J. Neal. 1965. Effects of feeding benzo(a)pyrene on fer-
tility, embryos, and young mice. Jour. Natl. Cancer Inst. 34: 297.
Rigdon, R.H., and E.G. Rennels. 1964. Effect of feeding benzpyrene on re-
production in the rat. Experientia 20: 1291.
Schlede, E., et al. 1970a. Stimulatory effect of benzo(a)pyrene and pheno-
barbital 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.
Shendrikova, I.A., and V.A. Aleksandrov. 1974. Comparative characteristics
of penetration of polycyclic hydrocarbons through the placenta into the
fetus in rats. -Byull. Eksperiment. Biol. i Medit. 77: 169.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient Water Quality
Criteria (Draft).
•
U.S. EPA. 1979b. Multi-media Health Assessment of Polycyclic Organic
Matter. (Draft) prepared under contract to U.S. EPA by J. 'Santoa'onato, et
al., Syracuse Research Coro.
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Vainio, H., et al. 1976. The fate of intratracheally installed benzo-
(a)pyrene in the isolated perfused rat lung of both control and 20-
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No. 150
Pyridine
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.
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PYRIDINE
Summary
Pyridine has not shown carcinogenic effects following repeated subcuta-
neous administration to rats; the compound did not show mutagenic activity
in the Ames Salmonella assay.
A single study has indicated that pyridine produced developmental ab-
normalities when administered to chicken embryos.
Chronic exposure to pyridine produces CMS disturbances and may produce
adverse hepatic and renal effects.
Pyridine has been shown to be toxic to freshwater fish at concentra-
tions ranging from 100,000 to 1,580,000 ;ug/l. For freshwater invertebrates,
toxic concentrations of pyridine range from 575,000 to 2,470,000 jug/1.
-------
I. INTRODUCTION
Pyridine (CAS number 110-86-1) is a colorless " liquid possessing a
sharp, penetrating odor. It has the following physical properties:
Formula: C-H-N
Molecular Weight: 79.1
Melting Point: -42°C
Boiling Point: 115.3°C
. Density: 0.982
Vapor Pressure: 10 mm Hg at 13.2°C
(Sax, 1975)
Solubility: miscible with water, alcohol,
ether, and other organic
solvents (Windholz, 1976)
Pyridine is a weak base and forms salts with strong acids. It .is used
as a solvent for anhydrous mineral salts, in various organic synthetic pre-
parations, and in analytical chemistry (Windholz, 1976). The estimated an-
nual production of pyridine is in excess of 60 million pounds (Federal Reg-
ister 43:16638, April 19, 1978).
II. EXPOSURE
A. Water
Pertinent data could not be located in the available literature.
8. Food
Reported levels of pyridine in foods include: from O.G2 tc 0.12
ppm, ice cream; 0.4 ppm, baked goods; 1.0 ppm, non-alcoholic beverages; 0.4
ppm, candy. Pyridine has also been found to occur naturally in coffee and
tobacco (Furia, 1975).
C. Inhalation
Pyridine may be produced and released during the combustion of
coke and as a combustion product in cigarette smoke (Graedel, 1978). •
-------
The major release of pyridine is from emissions from manufacturing
and chemical processes. Based on total annual production, the U.S. EPA
(1976) has estimated a significant potential emission of pyridine during
manufacture.
0. ' Dermal
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
A. Absorption
Absorption of pyridine occurs through the respiratory and gastro-
intestinal tracts, but probably not through the skin (Gosselin, et al. 1976).
B. Distribution
Pertinent data could not be located in the available literature.
C. Metabolism and Excretion
Pyridine may be partly excreted unchanged or may be methylated at
the N-position (Patty, 1963) and excreted as N-methyl pyridinium hydroxide,
its chief metabolite (Browning, 1965). Methylation occurs in mice but not
in rats, and it may occur to some extent in man The fate of the majority
.of absorbed pyridine is not known (Browning, 1965).
IV. EFFECTS
A. Carcinogenicity
Subcutaneous injection of pyridine at levels of 3 to 100 mg/kg
twice weekly for a year did not produce tumors in rats (Mason, et al. 1971).
B. Mutagenicity
Pyridine did not show mutagenic effects with activation in the
Ames Salmonella assay (Commoner, 1976).
C. Teratogenicity
Pyridine caused chick embryo abnormalities in one limited study
(Federal Register 43:16688, April 19, 1978).
-/rtf-
-------
D. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
Prolonged daily exposure to pyridine at levels from 6 to 12 ppm
causes mild central nervous system (CNS) disturbances in workers, while ex-
posure from 15 to 330 ppm causes insomnia, nervousness, and low-back or ab-
dominal pain accompanied by frequent urination (Gosselin, et al. 1976).
In animals, the major effects of repeated feeding of pyridine are
hepatic and renal injury (Patty, 1963). Chronic exposure to 10 or 50 ppm
pyridine vapors causes increased liver/body weight ratios in rats (ILO,
1971).
F. Other Relevant Information
Symptoms in humans associated with inhalation or ingestion of
pyridine are CNS depression, and liver and kidney damage (Federal -Register
4:16688, April 19, 1978; Gosselin, et al. 1976; Sax, 1975; ILO, 1971).
Vapors are also irritating to eyes, skin, and- nasal membranes (ACGIH, 1977;
Sax, 1975). Skin eruptions induced by pyridine may be provoked by exposure
to light (Arena, 1974). Ingestion of pyridine causes CNS depression, heart
and gastrointestinal distress, fever, and, at high doses, death; and may
stimulate bone marrow production of platelets in low doses (ACGIH, 1977;
Gosselin, et al. 1976). Death may be due .to- either hepatic or renal damage,
or from pulmonary injury (Gosselin, et al. 1976; ACGIH, 1977).
Exposure to vapors of .pyridine from 1,250 to 10,000 ppm for 1 to 7
hours did not cause mortality in rats, but a 0.1 percent diet of pyridine
induced rapid weight loss and death in two weeks.(ILO, 1971).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
McKee and Wolf (1963) have reviewed the effects of pyridine on
several aquatic organisms. The freshwater minnow, bleak (Alburnus lucidus),
was the most sensitive species tested with threshold toxicities ranging from
100,000 to 160,000.pg/1. Tests with the freshwater mosquitofish (Gambusia
affinis) revealed a 96-hour LC5Q value of 1,3.00,000 pg of pyridine per
liter of turbid water. Orange-spotted sunfish .(Lepomis humilis) were killed
in one hour from exposure to. pyridine at concentrations ranging from
1,480,000 to 1,580,000 pg/1, while goldfish (Carassius auratus) were killed
after 10 to 30 hours' exposure to pyridine. Verschueren (1979) has reported
a 24-hour LC50 value of 1,350,000 jug/1 for mosquitofish exposed to pyri-
dine.
Dowden and Bennett (1965) demonstrated a 48-hour LC5Q value of
2,114,000 jug/1 for Daphnia magna exposed to pyridine. McKee and Wolf (1963)
reported a threshold effect of 40,000 ug/1 for Daphnia sp. Canton and Adema
(1978). determined 48-hour LC5Q values ranging from 1,130,000 to 1,755,000
ug/1 for Daphnia magna, and 48-hour LC5Q values of 575,000 and 2,470,000
pg/1 for Daphnia pulex and Daphnia cucullata, respectively.
8. Chronic Toxicity, Plant Effects and Residues
Pertinent data could not be located in the available literature.
C. Other Relevant Information
Thomas (1973) reports that pyridine exposure levels of 5,000 pg/1
impart an off-flavor to fish flesh.
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VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The 8-hour, time-weighted-average occupational exposure limit for
pyridine recommended by the American Conference of Governmental Industrial
Hygienists is 5 ppm (ACGIH, 1977).
B. Aquatic
Based on 96-hour LC5Q data, Hahn and Jensen (1974) have assigned
pyridine an aquatic toxicity rating of from 100,000 to 1,000,000 ug/1.
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Agency of California. State Water Quality Control Board Publication 3-A.
Patty, F. 1963. Industrial Hygiene -and Toxicology: Volume 2, Toxicology.
2nd ed. John Wiley and Sons, New York.
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Sax, N.I. 1975. Dangerous Properties of Industrial Materials. 4th ed.
Van Nostrand Reinhold Co., New York.
Thomas, N.A. 1973. Assessment of fish tainting substances. In: Biological
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U.S. EPA. 1976. Preliminary scoring of selected organic air pollutants.
U.S. Environ. Prot. Agency, EPA 450/3-77-008a.
Verschueren, K. 1979. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Co., New York. /
Windholz, M. (ed.) 1976. Merck Index. 9th ed. Merck and Co., Rahway, New
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