TECHNICAL REPORT DATA
(fiettt rttd Instruction* on the reverse btfort completing)
1. REPORT NO.
2.
3. RECIPIENTS ACCESSION NO
PB88-182878/AS
4. TITLE AND SUBTITLE
5. REPORT DATE
Health Effects Assessment for Parathion
6. PERFORMING ORGANIZATION CODE
7. AUTMOR(S)
I. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
15 SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and- carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD5 or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS C. COSAT1 Field/Group
18. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (Thu Report)
Unclassified
21. NO. Of PAGES
20. SECURITY CLASS (Thupagt)
Unclassified
22. PRICE
EPA F««* 2220-1 ((*•». 4-77) PMKVIOU* COITION i* OMOLCTC
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EPA/600/8-88/047
July, 1987
HEALTH EFFECTS ASSESSMENT
FOR PARATHION
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed In accordance wHh the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with parathlon.
All estimates of acceptable Intakes and carcinogenic potency presented 1n
this document should be considered as preliminary and reflect limited re-
sources allocated to this project. Pertinent toxlcologlc and environmental
data were located through on-Hne literature searches of the TOXLINE and the
CHEMFATE/OATALOG data bases. The basic literature searched supporting this
document 1s current up to May, 1986. Secondary sources of Information have
also been relied upon In the preparation of this report and represent large-
scale health assessment efforts that entail extensive peer and Agency
review. The following Office of Health and Environmental Assessment (OHEA.)
sources have been extensively utilized:
U.S. EPA. 1984b. Reportable Quantity Document for Parathlon.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Emergency and Remedial Response,
Washington, DC.
U.S. EPA. 1986a. Reference Doses (RfOs) for Oral Exposure.
Parathlon CAS# 56-38-2. Prepared by the Environmental Criteria and
Assessment Office, Cincinnati, OH.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$o)
exposures.
111
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The RfO (formerly AIC) Is similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980) for a discussion of this concept]. The
RfO Is route-specific and estimates acceptable exposure for either oral
(RfDfj) or Inhalation (RfOj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1984a).
For compounds for which there 1s sufficient evidence of cardnogenldty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Inhalation data were not available for parathlon; therefore, Inhalation
risk assessment values could not be calculated. RfDg and RfQ$o values
of 0.006 mg/kg/day or 0.4 mg/day for a 70 kg human were derived based on a
human study In the CBI files showing a NOAEL for erythrocyte chollnesterase
Inhibition. Whether this value 1s protective against the reproductive and
carcinogenic effects of parathlon Is uncertain. A CS of 36, based on
reduced survival at weaning at 30 ppm 1n the diet of rats 1n a 3-generat1on
study located In the CBI files (U.S. EPA, 1986b), was the highest CS calcu-
lated for parathlon.
The available data on cardnogenlclty places parathlon In EPA Group C.
This category Is for the agents with limited evidence of cardnogenlclty In
animals, and no or Inadequate data on humans (U.S. EPA, 1986c).
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
. 3.3.1. Oral
3.4., TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfOs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfOcr)
Page
. . . 1
. . . 3
. . . 3
. . . 3
4
4'
. . . 4
7
. . . 7
. . . 7
. . . 9
. . . 9
. . . 9
. . . 10
. . . 13
. . . 13
13
. . . 13
. . . 14
. . . 14
15
. . . 17
... 18
18
... 18
... 18
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TABLE OF CONTENTS
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfD0) 18
6.2.2. Inhalation (RfDi) 19
6.3. CARCINOGENIC POTENCY (q-|*) 19
6.3.1. Oral 19
6.3.2. Inhalation 21
7. REFERENCES 22"
APPENDIX: Summary Table for Parathlon 33
vlll
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LIST OF ABBREVIATIONS
ATP Adenoslne trlphosphate
AUC Area under the curve
BCF B1oconcentrat1on factor
bw Body weight
CBI Confidential business Information
CHO Chinese hamster ovary
CNS Central nervous system
CS Composite score
ODC 01ethyld1th1ocarbamate
DNA Oeoxyr1bonucle1c acid
EEG Electroencephalogram
HA Health advisory
ID Median lethal dose
MED Minimum effective dose
MFO Mixed function oxldase
MTD Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
PEL Permissible exposure limit
ppm Parts per million
RBC Red blood cell
RfD Reference dose
RfDT Inhalation reference dose
RfDQ Oral reference dose
RfD_ Subchronlc reference dose
o
RfD_T Subchronlc Inhalation reference dose
Subchronlc oral reference dose
RQ Repor table quantity
SCE Sister chromatld exchange
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
parathlon are presented In Table 1-1. Synonyms for parathlon are: phos-
phorothlolc add; 0,0-d1ethyl-0-(4-n1trophenyl)ester; 0,0-d1ethyl-0-p-n1tro-
phenyl phosphorothloate; d1ethyl-p-n1trophenyl monothlophosphate and DNTP.
Trade names are: S.N.P.; E605; AC3422; ENT 15108; Alkron; Aileron;
Aphamlte; Etllon; Folldol; Fosferno; N1ran; Paraphos; Rhodlatox and Thlophos".
The half-life of parathlon In the atmosphere could not be located In the
available literature. Monitoring data Indicate that parathlon and Us
Initial transformation product, paraoxon, may exist In the atmosphere In
vapor form and adsorbed onto airborne partlculate matter (Sanborn et al.,
1977).
The persistence and fate of parathlon residues In environmental media
depend on such factors as temperature, humidity, light, pH, the presence of
organic matter, and micro- and macroflora and fauna prevailing 1n a given
environment. These parameters Influence activation or chemical/biological
degradation of the parent molecule to nontoxlc products (Felsot and Dahm,
1979).
In water and soil, parathlon 1s decomposed primarily by biologically
mediated hydrolysis. Mechanisms of decomposition also Include other
biological processes, oxidation and sunlight. Laboratory and field studies
of the persistence of parathlon show half-lives of the parent compound,
resulting from normal usage concentrations, to be on the order of days In
ambient waters. In soils, the half-life of parathlon ranges from a few
weeks to a few months, depending on soil characteristics and the climate.
OlOlh -1- 07/15/87
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TABLE 1-1
Selected Chemical and Physical Properties
and Environmental Fate of Parathlon
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Chemical formula:
Melting point:
Boiling point:
(760 mm Hg)
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
Bloconcentratlon factor:
Soil adsorption
coefficient:
Half-lives:
A1r
Water
Soil
56-38-2
organophosphorus
pesticide
291.27
-
C2H50/ \—
-N02
6°C
375°C
3.78xlO"5 mm Hg at 20°C
24 mg/i at 25°C
3.83
103-480 (estimated)
1038-1388
965-1724
Sanborn et al., 1977
Sanborn et al., 1977
Hansch and Leo, 1985
Lyman et. al., 1982
Felsot and Oahm, 1979
Sharon et al., 1984
NA
days
a few weeks to a few months
NA = Not available
OlOlh
-2-
02/04/87
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Parathlon 1s readily absorbed from the gastrointestinal tract. This Is
Indicated In a study by Morgan et al. (1977) where volunteers were given 2
mg parathlon orally. Within 48 hours, 30-40X of the administered dose of
parathlon was excreted In the urine as metabolites (paranltrophenol, alkyl
phosphates and thlophosphates). Braeckman et al. (1983) studied the
absorption of parathlon 1n ethanol-propylene glycol following gavage
administration to mongrel dogs of either sex. They found that radio-
labeled parathlon appeared to be well absorbed since urinary excretion of
radioactivity following oral dosing at 5 mg/kg was nearly as complete and as
rapid as following Intravenous dosing with a dose of the same size. Orally
administered parathlon appeared to have very low bloavallablllty (<30X),
compared with Intravenous dosing, evaluated by comparing the AUCs for serum
concentration, as a result of first-pass extraction In the liver. Addi-
tional quantitative data regarding the absorption of parathlon following
oral administration could not be located In the available literature.
2.2. INHALATION
Parathlon Is absorbed during Inhalation exposure (Simpson and Beck,
1960; Wolfe et al., 1967). To prevent dermal exposure, Durham et al. (1972)
exposed an Individual completely covered with rubber and plastic clothing to
mist from an alrblast spray machine during parathlon application In
orchards, and collected tissue for several days. p-NltrophenoT, a major
metabolite of parathlon, was excreted 1n urine collected within 24 hours
after exposure. More quantitative data regarding the Inhalation absorption
of parathlon could not be located In the available literature. Absorbtlon
from dermal exposure may exceed respiratory Intake (Cohen et al., 1977;
Malbach et al., 1971).
OlOlh -3- 07/15/87
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Moeller and Rider (1961) gave parathlon In corn oil 1n
gelatin capsules at doses of 3-4.5 mg/day for 28 days and 6.0 mg/day for 43
days to volunteers. Plasma and RBC chollnesterase activities were depressed
by 10-15% at 6 mg/day, but not at lower doses.
In a study by Rider et al. (1969), groups of volunteers (five test
subjects and two controls/dose level) were given capsules containing 3.0,
4.5, 6.0 or 7.5 mg parath1on/day. Controls received capsules containing
corn oil. Before treatment, baseline measurements of plasma and RBC cholln-
esterase activities were made. Depression of plasma or RBC chollnesterase
activity was not observed at doses <6.0 mg/day. At 6.0 mg/day, there was a
slight but not significant depression of plasma chollnesterase activity. In
subjects receiving 7.5 mg/day, average plasma chollnesterase activity was
depressed by -15% from days 4-35 as compared with baseline values.
Individual variability was fairly large, with three subjects at 7.5 mg/day
showing a decreased plasma chollnesterase activity of 50-55X. At 7.5
mg/day, a 7-10X depression In baseline RBC chollnesterase activity was also
observed.
Edson et al. (1964) exposed humans orally to parathlon at 0 or 0.6
mg/day, which was Increased to 4.8 mg/day during weeks 4-13 (TWA = 4.0
mg/day) or to 1.2 or 2.4 mg/day for <70 days. Four females received 7.2 mg
parath1on/day, 5 days/week for 6 weeks. RBC and plasma chollnesterase
activity levels were 84 and 63X of control levels, respectively, In females
treated at 7.2 mg/day. No changes In chollnesterase activities were
observed at lower dose levels.
OlOlh -4- 10/21/86
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Edson et al. (1964) also studied the effects of parathlon In female rats
(20/dose level) and female pigs (2/dose level). The rats received parathlon
In the diet at 0, 0.05, 0.5 and 5 ppm for 84 days. The pigs were fed diets
containing parathlon at 0, 0.2, 1.0 and 5 ppm for -89 days. The 0.2 and 1.0
ppm levels 1n pigs were Increased to 25 and 100 ppm on days 33-72 and
73-114, respectively. No effects on general health, growth, food consump-
tion and gross organ appearance were observed In either rats or pigs. In
rats fed diets containing parathlon at 0.5 and 5 ppm, RBC chollnesterase
activity was 46 and 20% of levels In controls after 12 weeks. In rats, RBC
chollnesterase activity appeared to be Inhibited more than plasma chollnes-
terase activity. In pigs fed 100 ppm, RBC chollnesterase activity was 20%
of controls after 7 weeks of treatment.
Edson and Noakes (1960) fed female Hlstar rats diets containing
parathlon at 1, 5, 25 and 125 ppm for 16 weeks. The high-dose group showed
reduced weight gain, cardiac fibrillations, nervousness and mortality of
7/10 rats. In rats fed 25 ppm, slight fibrillations were observed. At 5,
25 and 125 ppm, dose-related depressions of RBC. plasma and brain chollnes-
terase activities were observed. RBC chollnesterase activity was 28, 8 and
4% of control levels at 5, 25 and 125 ppm, respectively. Plasma chollnes-
terase activities were 44 and 10% of control levels at 25 and 125 ppm, and
brain chollnesterase activities were 89 and 9% of control levels at 25 and
125 ppm, respectively.
In a 90-day study by Olkshlth et al. (1978), a group of 12 adult male
white rats were treated by gavage with parathlon 1n peanut oil at 2.6
mg/kg/day. Controls received peanut oil. Four of the treated rats died,
but no gross abnormalities were observed In any organ. A significant
decrease In activity of sucdnlc dehydrogenase In the liver (p<0.0011) and
OlOlh -5- 10/21/86
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kidney (p<0.001) was observed. There was also a significant decrease In
ATPase activity of the liver and kidney (p<0.0011}. In the testes, the
activities of most enzymes remained unchanged except for Increased (p<0.011)
ATPase activity. A significant (p<0.001) Inhibition of acetylchollnesterase
activity In the blood and brain was observed.
Frawley and Fuyat (1957) fed groups of one male and one female mixed
breed dogs diets containing parathlon at 1, 2 and 5 ppm (0.021, 0.047 and
0.117 mg/kg/day) for 24 weeks. Controls received parathlon-free diets. In
dogs fed 0.047 and 0.117 mg/kg/day, plasma chollnesterase was reduced by
30-50% compared with controls. At 0.021 mg/kg/day, plasma chollnesterase
was reduced 20%. RBC chollnesterase was reduced 20-40% 1n dogs treated at
the highest dose. Dogs recovered from these effects 6-8 weeks posttreatment.
In a study by Hassan and Cueto (1970), two groups of New Zealand white
rabbits were dosed by gavage with parathlon 1n peanut oil at 0.5 or 1.0
mg/kg/day for 222 days. After 100 days of treatment, urinary excretion of
4-hydroxy-3-methoxymandel1c acid (vanniylmandellc acid) and 5-hydroxy-3-
Indoleacetlc add was higher In treated rabbits than In controls. These
Increases were considered by the Investigators to be a result of the
Increased metabolism rates of catecholamlnes and serotonin, respectively.
Analysis of blood and urine levels of amlno adds showed no significant
differences between control and treated groups.
In a study by Barnes and Denz (1951), groups of 36 male and 36 female
albino rats were fed diets containing parathlon (76.8% pure) at 10, 20, 50,
75 or 100 ppm, 6 days/week for 1 year; 30 rats/sex fed diets without
parathlon served as controls. Treatment of rats fed 100 ppm was terminated
after 19 days as a result of excessive mortality; 58/72 rats died and most
only consumed 5 g of food/day. Treatment of rats fed 75 ppm was terminated
OlOlh -6- 10/21/86
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after 27 days; 53/72 rats died. Pathological changes In the submaxlllary
gland, pancreas, spleen and thymus were observed 1n these two high-dose
groups. Survivors of these groups recovered after treatment termination and
showed no permanent effects when examined after 1 year. In rats fed diets
containing 50 ppm, mortality was -61% with most deaths occurring before week
4. Body weight gains were reduced In both males and females at 50 ppm; this
effect was not attributed to decreased food consumption. Moribund an1mal,s
showed changes 1n the submaxlllary gland, pancreas, spleen or thymus with no
hlstologlcal changes noted 1n survivors. Rats fed 10 or 20 ppm gained
weight comparably with controls, and chemical-Induced mortality was not
Indicated. No treatment-related pathological changes 1n rats fed 10 or 20
ppm were observed. Chollnesterase activities apparently were not monitored.
3.1.2. Inhalation. Kay et al. (1982) studied the effects of exposure to
parathlon spray on blood Chollnesterase activities of apple growers.
Sprayers were exposed for -2 days at 10-day Intervals for 2 months; airborne
concentrations 1n the breathing zone ranged from 2-15 mg/m3. Depression
of RBC Chollnesterase activity averaged 21% for all sprayers. No signifi-
cant difference In RBC Chollnesterase activity levels were noted between
sprayers reporting symptoms and those apparently symptom-free; symptoms
Included nausea and headaches. The relative Importance of Inhalation
exposure versus dermal exposure was not determined.
3.2. CHRONIC
3.2.1. Oral. In an NCI (1979) bloassay, groups of 50 Osborne-Mendel
rats/sex and 50 B6C3F1 mice/sex were fed diets containing parathlon.
Low-dose male rats were fed at 40 ppm for 13 weeks then at 30 ppm for 67
weeks for a TWA of 32 ppm. High-dose males received diets containing 80 ppm
for 13 weeks then 60 ppm for 67 weeks for a TVIA of 63 ppm. TWA doses for
female rats were 23 and 45 ppm for low- and high-dose rats, respectively.
OlOlh -7- 01/27/87
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Low-dose females received diets containing 20 ppm for 13 weeks, 30 ppm for
21 weeks and 20 ppm for 46 weeks, high-dose females received diets contain-
ing 40 ppm for 13 weeks, 60 ppm for 21 weeks and 40 ppm for 46 weeks. All
rats were treated for a total of 80 weeks followed by a 32-week observation
period. Matched controls from the parathlon bloassay were pooled with
controls from other bloassays for a total of 90 male and 90 female rats,
which were observed for 112 weeks. Low-dose male mice were fed parathlon In
«
the diet at 80 ppm for 71 weeks with an 18-week observation period.
High-dose male mice received 160 ppm 1n the diet for 62 weeks with a 28-week
observation period. Low- and high-dose female mice received 80 or 160 ppm,
respectively for 80 weeks followed by a 9-week observation period for
low-dose mice and 10 weeks for high-dose female mice. Hatched controls were
pooled with controls from other bloassays for a total of 140 males and 130
females, which were observed for 90 weeks.
Rats showed lower mean body weights. 1n the high-dose groups during the
treatment period as compared with controls. This effect was particularly
pronounced In females from weeks 14-35. Body tremors and diarrhea were
observed In all treated rats; these effects were particularly pronounced 1n
the high-dose females. No significant positive dose-related trend 1n
mortality was observed In either sex. H1stopatholog1cal examination showed
no effect on the Incidence of nonneoplastlc lesions.
Mortality was not affected In female mice, but a positive dose-related
trend was observed 1n males. Reduced mean body weight, body tremors and
diarrhea were observed 1n all treated groups. H1stopatholog1cal examination
Indicated that nonneoplastlc lesions were not affected by parathlon
treatment.
OlOlh -8- 10/21/86
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3.2.2. Inhalation. Pertinent data regarding the effects of parathlon
following chronic Inhalation exposure could not be located In the available
literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. In a study by Deskln et al. (1979), pregnant CO mice were
treated by gavage with parathlon 1n peanut oil at 0.01, 0.10 and 1.00
mg/kg/day from day 2 of gestation to day 15 of lactation. Control mice
received peanut oil. Ten offspring at each dose were observed for toxic
effects on day 24 postpartum. Male offspring showed no significant change
(p<0.05) 1n RBC and plasma chollnesterase. Female offspring from dams dosed
at >0.01 mg/kg/day showed significant reduction of plasma chollnesterase
activity, but not RBC chollnesterase activity. Electrocardiographs of male
and female offspring showed significant changes, but these are difficult to
evaluate without hlstopathologlcal examinations of the heart.
In a study by Barnes and Denz (1951), rats were fed diets containing 50,
20 or 10 mg/parath1on/kg diet {50, 20 or 10 ppm, 76.8% pure) before mating
through to parturition. Utter sizes of the 50 ppm diet rats were
decreased. Survival of neonates was Inversely dose-related; there were no
survivors at 50 ppm, 43% survived at 20 ppm and 100% survived In the 10 ppm
group and controls. Offspring of the group treated at 10 ppm were fed a
similar diet and mated after 178 days. Five of six mated females produced
Utters, but only 7/37 neonates born survived more than a few days. Cross
mating of six exposed females with control males resulted 1n only 2 Utters.
The number of offspring was normal In these Utters, but only 38% survived.
Mating an exposed F, male with control dams resulted 1n fertility and
survival of young that were comparable with control matings.
OlOlh -9- 01/27/87
-------
Studies 1n the CBI files (U.S. EPA, 1986b) conflict with the findings of
Barnes and Denz (1951). In a 3-generat1on study In rats, effects on pups
were observed at a higher dietary concentration but not at 10 ppm.
3.4. TOXICANT INTERACTIONS
The ability of many agents to alter the toxldty of parathlon has been
Investigated. One of the most significant ways to alter the toxldty of
parathlon Is by the Induction or Inhibition of drug-metabol'izlng enzymes.
Hale rats have been found to be less susceptible to the toxldty of
parathlon than female rats, perhaps as a result of the Inducing effects of
testosterone (Newell and Ollley, 1978).
Rats pretreated with ethylestrenol gained some protection from the toxic
effects of parathlon (Robinson et al., 1976). Norbolethan and splrono-
lactone, two other steroids, also provided some protection.
In a study with rats, carbon monoxide exposure prolonged time until
death caused by an Intraperltoneal Injection of parathlon (Baeza et al.,
1972). Pretreatment with turpentine (Omlrov and Aberkulov, 1972), ovex
(Black et al., 1975), halogenated benzenes (Townsend and Carlson, 1981) and
trl-o-tolyl phosphate (Lynch and Coon, 1972) also provided some protection
against parathlon toxldty. In a study by Murphy (1980), phenobarbltal
pretreatment was found to protect against the antlchoHnesterase activity of
parathlon In an unspecified species. Pretreatment with d1-2-ethylhexyl
phthalate also reduced the degree of chollnesterase Inhibition In rats
caused by parathlon (Srlvastava et al., 1976).
Homann et al. (1985) studied the effect of DDC, a known Inhibitor of
mixed-function oxldase activity, on the toxldty of parathlon to male rats.
DOC, when Injected Into rats 45 minutes before or 10 minutes after parathlon
Intoxication, had no effect on the survival rate. DOC administered simul-
taneously with parathlon resulted 1n the rate of survival rising 53%.
OlOlh -10- 10/21/86
-------
Mirer et al. (1977) studied the effects of plperonyl butoxlde pretreat-
ment on parathlon toxldty In mice. An Injection of plperonyl butoxlde 1
hour before parathlon treatment resulted In a 2-fold potentlatlon of
parathlon toxldty.
A study by Vukovlch et al. (1971) examined the effects of IntraperHo-
neal Injections of chlorpromazlne on the oral toxldty of parathlon to mice.
Chlorpromazlne Injected 1 or 6 hours before parathlon treatment Increased
the oral toxldty of parathlon. The toxldty was decreased when chlorproma-
zlne was administered 1 day before parathlon treatment. Weiss and Orzel
(1967) found that an Intraperltoneal Injection of reserplne, chlordl-
azepox1de-HCl, hexobarbltal sodium or phenobarbltal sodium enhanced the
toxldty of rats to 1ntraper1toneally Injected parathlon at 2 and 4 mg/kg.
Chlorpromaz1ne-HCl and meprobamate only Increased the toxic effect of
parathlon at 4 mg/kg.
To determine If parathlon alters hepatic mlcrosomal drug metabolism, the
effect of the pesticide on hexobarbltal sleeping times In mice was studied
(Hart and Fouts, 1963). An 1ntraper1toneal Injection of parathlon (2.5
mg/kg) was administered to CF No. 1 white mice. Significant prolongation of
sleeping times was observed 1 and 3 days following parathlon Injection.
A number of studies have Investigated the Interaction of parathlon with
other pesticides. Scheln and Thomas (1975) found that oral doses of
parathlon and dleldrln caused a greater disturbance In testosterone dynamics
1n male mice than either compound alone. The acute toxldty was found to be
greater than additive when parathlon was administered with chlorbufam
(Nledner and von Oettlngen, 1976), fenltrotlon (Kawal et al., 1973) and
chlordane plus malathlon (KepHnger and Delchmann, 1967).
OlOlh -11- 10/21/86
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Trlolo and Coon (1966) studied the effects of orally administered aldMn
on the toxic effects of oral parathlon 1n mice. They found that 1 hour
after aldrln administration parathlon toxlclty was Increased. Aldrln admin-
istered 16 hours to 12 days before parathlon resulted 1n protection from
parathlon toxlclty. This protection reached a maximum when parathlon was
given 4 days after aldrln administration.
Malathlon, when administered with parathlon subcutaneously Into male
mice, has been shown to have a less than additive effect (Kawal et al.,
1973). Pretreatment with carbaryl In the diet (Neskovlc, 1979) or Undane
(Chadwlck et al., 1984) has also been shown to reduce parathlon toxlclty 1n
rats.
The state of the animal has also been shown to affect parathlon toxlc-
lty. Parathlon Is more toxic to rats under 35 days of age (Harbison, 1973;
Benke and Murphy, 1975) and more toxic to pregnant than nonpregnant mice
(Heltman et al., 1983). Food restriction (Vllleneuve et al., 1978) and low
protein diets (Casterllne and Williams, 1971; Boyd, 1969; Bulusu and Chak-
ravarty, 1986) have also been shown to Increase parathlon toxlclty 1n rats.
OlOlh -12- 10/21/86
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the carcinogenic potential of parathlon In
humans following oral or Inhalation exposure could not be located 1n the
available literature.
4.2. BIOASSAYS
4.2.1. Oral. Hazelton and Holland (1950) conducted a cancer bloassay
using groups of 8-20 male and female albino rats (strain unspecified).
Males were fed diets containing parathlon at 50 or 100 ppm for 100 weeks or
10 or 25 ppm for 88 weeks. Females were fed diets containing parathlon at
10 or 50 ppm for 64 weeks. Another group of females was fed 100 ppm In the
diet for an unspecified length of time. Ten males observed for 104 weeks,
20 males observed for 88 weeks and 6 females observed for 64 weeks served as
controls. No dose-related effect on mortality was noted. Hlstologlcal
examination of a limited number of tissues from high-dose group survivors
showed no tumors.
In the NCI (1979) bloassay, groups of 50 male and 50 female Osborne-
Mendel rats and B6C3F1 Charles River mice were fed parathlon 1n the diet
(see Section 3.2.1.). Male rats received TWA doses of 32 or 63 ppm, female
rats 23 or 45 ppm. Rats were treated for 80 weeks and observed for 32
weeks. Male mice were fed diets containing 80 or 160 ppm for 71 or 62
weeks, respectively, and female mice were fed at 80 or 160 ppm for 80 weeks.
Mice were observed for 9-28 weeks.
In rats, the Incidence of adrenal cortical adenomas and carcinomas was
Increased; the Incidence 1n low-dose males was 7/49, In high-dose males was
11/46, In low-dose females was 6/47 and 1n high-dose females was 13/42.
OlOlh -13- 10/21/86
-------
Incidences In controls were 0/9 1n matched control males, 3/80 In pooled
control males, 1/10 1n matched control females and 4/78 In pooled control
females. Using pooled controls, these results are significant by the
Cochran-Armltage test for positive trend (p<0.001), and high-dose results 1n
both sexes are significant In the Fisher Exact test (p<0.002). The biologi-
cal significance of these results 1s uncertain. IARC (1983) states that
"the significance of adrenal cortical adenomas In aged rats Is not well
understood, and that adrenal cortical carcinomas occurred only 1n two rats
of each sex and treatment group." NCI (1979) reported that under the condi-
tions of the bloassay, parathlon appears to be carcinogenic 1n Osborne-
Mendel rats.
In mice, no Increased Incidences of neoplastlc lesions were observed.
NCI (1979) reported that parathlon was noncarclnogenlc In mice.
Welsburger (1982) reviewed the NCI (1979) study and concluded that
parathlon was not carcinogenic 1n mice, but was suggestive of neoplasla In
rats. After review of one mouse and three rat studies, IARC judged the rat
adenomas to be of uncertain significance, and overall evaluated the data
base to be Inadequate for evaluation of human carcinogenic potential.
4.2.2. Inhalation. Pertinent data regarding the carcinogenic potential
of parathlon following Inhalation exposure could not be located In the
available literature.
4.3. OTHER RELEVANT DATA
IARC (1983) has reviewed mutagenlclty and other short-term studies of
parathlon. Portions of that review are reproduced as follows:
"Parathlon was negative In the rec-assay (differential killing
assay utilizing H17 rec* and M45 rec~ strains of Bacillus
sub* 1 Us) and the Escherlchla coll Pol-assay without exogenous
metabolic activation (Simmon et al., 1977). In a large number of
tests 1t did not Induce gene mutations In E_. coll. Salmonella
OlOlh -14- 03/30/87
-------
typhlmurlum. Serratla marcescens. Saccharomyces c.ervlslae or
Schlzosaccharomyces pombe, with or without exogenous metabolic
activation (Mohn, 1973; Fahrlg, 1974; Simmon et al., 1977; Bartsch
et al., 1980; Degraeve et al., 1980)."
"No excess of sex-linked recessive lethal mutations was Induced In
Drosophlla melanoqaster by parathlon (99X pure) (Valencia, 1977;
Waters et al., 1982). Negative results have also been reported for
the Induction of unscheduled DNA synthesis by parathlon (99% pure)
In W138 human flbroblasts, with or without unlnduced mouse liver
mlcrosomal fractions (Jones et al., 1982; Waters et al., 1982). No
dominant lethal mutation was Induced 1n mice fed parathlon (99%
pure) for seven weeks at dose levels of 62.5, 125 or 250 mg/kg of
diet (Simmon et al., 1977) or following a single IntrapeMtoneal
Injection (Degraeve et al., 1980)."
In a study not reviewed by IARC (1983), parathlon was found to Induce
statistically significant Increases 1n SCE 1n CHO cells (Nlshlo and Uyekl,
1981).
Maronpot et al. (1983) tested parathlon In the Strain A mouse pulmonary
tumor-Induction bloassay model. Groups of 20 or 30 Strain A mice of both
sexes were Injected 1ntraper1toneally with parathlon 3 times/week for 8
weeks. The doses used were the MTD, MTD/2, MTD/4 and MTD/5. The doses 1n
mg were not specified. Vehicle, untreated and positive urethane controls
were Included as part of the experiment. The mice were killed 16 weeks
after the last Injection and grossly visible pulmonary tumors were counted.
Parathlon treatment resulted In a significant (p<0.05) Increase In the
number of mice with tumors and the multiplicity of tumors compared with
negative controls. Positive controls responded appropriately.
4.4. WEIGHT OF EVIDENCE
IARC (1983) reviewed the weight of evidence of the cardnogenlclty of
parathlon to humans and concluded that data are Insufficient for evaluation.
The NCI (1979) study resulted 1n suggestive evidence for cardnogenldty
1n rats. Male and female rats treated with parathlon had an Increased Inci-
dence of combined adrenal cortical adenomas and carcinomas. The biological
OlOlh -15- 03/30/87
-------
significance of these tumors In aged rats 1s -uncertain. Since the IARC
(1983) evaluation, parathlon has tested positive In the Strain A mouse
pulmonary tumor bloassay model (Maronpot et al., 1983) and this evidence
together with suggestive but uncertain response 1n rats 1s sufficient to,
place parathlon 1n EPA Group C, a possible human carcinogen. This category
1s for the agents for which there Is no evidence or no data on cardnogen-
IcHy In humans and only limited evidence In animals (U.S. EPA,, 1986c).
OlOlh -16- 03/30/87
-------
5. REGULATORY STANDARDS AND CRITERIA
NAS (1977) calculated 4.3 ug/kg/day as an RfD for parathlon from the
study by Rider et al. (1969). This value was obtained by applying an uncer-
tainty factor of 10 to the dose of 3.0 mg/day that was the lower NOEL. From
this level NAS (1977) calculated or suggested a NOA£L In drinking water of
0.03 mg/i, assuming 70 kg as an average body weight and an average dally
water Intake of 2 l, and that 20X of the total Intake 1s from water.
An RfD of 5xlO~3 mg/kg/day can be derived by applying an uncertainty
factor of 10 to the NOEL of -50 mg/kg/day In the Edson et al. (1964) study.
This dosage appears to be calculated as the TWA of 0.6 mg/day for 4 weeks
raised to 4.8 mg/day for an additional 9 weeks, assuming a human body weight
of 70 kg. Using 2 l as the average water Intake for an average 70 kg
human, and a fish Intake of 0.0065 kg/day with a BCF of 347, 0.1 mg/i can
be recommended as the water criterion.
The most recent RfD calculated for parathlon Is 0.4 mg/day for a 70 kg
man (U.S. EPA, 1986a). This value was based on a human NOEL of 4.5 mg/day
located In the CBI files (U.S. EPA, 1986b). Higher doses were associated
with blood chollnesterase Inhibition.
The AC6IH (1986) TLV-TWA based on skin exposure Is 0.1 mg/m3. The
OSHA (1985) PEL based on skin exposure has also been set at 0.1 mg/m3. A
tolerance of 1.0 ppm parathlon has been established for most agricultural
commodities (U.S. EPA, 1983).
OlOlh -17- 07/15/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfOc)
d
6.1.1. Oral (RfDSQ). Risk assessment of parathlon Is based on Us
action as a chollnesterase Inhibitor. The threshold for chollnesterase
Inhibition varies between species, Indicating that human data would be most
appropriate for risk assessment.
A number of RfDs have been calculated from human data (see Chapter 5).
The most recent RfO, 0.006 mg/kg/day (U.S. EPA, 1986a,d), was derived from a
human study found In the CBI files, which Identifies a human NOAEL for
erythrocyte chollnesterase Inhibition. The value calculated from this
study, 0.006 mg/kg/day or 0.4 mg/day for a 70 kg human, will be recommended
as the RfO-0 for the purpose of this document.
6.1.2. Inhalation (RfO..). Pertinent data regarding the toxldty of
parathlon following Inhalation exposure could not be located 1n the
available literature; therefore, an RfOSI cannot be derived.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). No chronic human oral studies of parathlon are
available. Subchronlc studies have been used to calculate an RfO. The most
recent RfO, derived from a human NOAEL for erythrocyte chollnesterase
activity found In a CBI study, and an uncertainty factor of 10, Is 0.006
mg/kg/day or 0.4 mg/day for a 70 kg human (U.S. EPA, 1986a,d). For the
purpose of this document, these values will be recommended as the RfDQ for
parathlon. Whether this level will be protective against the
carclnogenldty or reproductive effects of parathlon Is uncertain.
In deriving an RQ for parathlon, CSs have been calculated (U.S. EPA,
1984b). The largest CS value In this document was derived from the study by
Barnes and Oenz (1951). This 3-generat1on study, however, used parathlon
OlOlh -18- 07/15/87
-------
that was only 76,8% pure and only six rats were used. Because of these
deficiencies and because better studies are available, CS values from the
Barnes and Denz (1951) study will not be presented In this document.
Human MEOs derived In U.S. EPA (1984b) are higher than the values
reported 1n this document because 1t appears that the cube root of the body
weight ratio was not used to convert from animal exposure to the human MEO.
CSs for parathlon from a number of studies are presented In Table 6-1.
Data In the CBI files Indicate that the MEO for blood chollnesterase
Inhibition In humans Is 0.079 mg/kg/day or 5.53 mg/day, assuming a human
reference body weight of 70 kg. This dose 1s associated with an RV. of
4.4. Inhibition of blood chollnesterase activity Is assigned an RV of 1.
A CS of 4.4 results. The highest value, 36, was obtained from a 3-genera-
tlon rat study found In the CBI file (U.S. EPA, 1986b).
6.2.2. Inhalation (RfD,). Pertinent data regarding the toxic effects
of parathlon following Inhalation exposure could not be located 1n the
available literature; therefore, an RfD, cannot be derived.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. The NCI (1979) bloassay showed an Increase In the combined
Incidences of adenomas and carcinomas of the adrenal cortex 1n rats of both
sexes. Adenomas predominated 1n the study, and the significance of these
tumors 1n aged rats Is uncertain. Because of the weakness In the specific
animal cancer data for parathlon, a q,* value will not be calculated for
this document.
In a report 1n the CBI files (U.S. EPA, 1986b), the OPP reinterpreted
the results of the NCI (1979) bloassay. Using the Incidence of adrenal
cortical tumors In female rats, OPP estimated "virtually safe" exposures.
OlOlh -19- 07/15/87
-------
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Applying the linear extrapolation model, the dose corresponding to a risk of
10~5 Is almost an order of magnitude smaller than the RfDSQ and RfOQ
value presented 1n this document. The less conservative log-problt model
estimates a dose corresponding to a risk of 10"5 that 1s of the same order
of magnitude as the RfDSQ and RfDQ value. The U.S. EPA uses the
multistage, model of Crump (U.S. EPA, 1980) to estimate risk for
carcinogens. At low risk levels, this model usually results In values
closer to the linear model (Park and Snee, 1983). Therefore, If adrenal
adenomas and carcinomas 1n rats are a biologically significant tumorlgenlc
response to parathlon exposure, the RfDSQ/RfDQ value of 6.4xlO~3
mg/kg/day may not be protective from the carcinogenic potential of parathlon
at the risk level of 10"5.
6.3.2. Inhalation. Data regarding the carcinogenic potential of para-
thlon following Inhalation exposure could not be located In the available
literature; therefore, an Inhalation q * cannot be calculated.
OlOlh -21- 07/15/87
-------
7. REFERENCES
ACGIH (American Conference of Government Industrial Hyglenlsts). 1986.
Documentation of the Threshold L1mH Values and Biological Exposure Indices,
5th ed. Cincinnati. OH. p. 458.
Baeza, C., A. Goldberg and R.J. Rubin. 1972. Effect of carbon monoxide on
response to parathlon and paraoxon. Toxlcol. Appl. Pharmacol. 22(2): 288.
Barnes, J.M. and F.A. Denz. 1951. The chronic toxldty of p-n1trophenyl
dlethyl thlophosphate (E:605): A long-term feeding experiment with rats. J.
Hyg. 49: 430-441.
Bartsch, H., C. Malavellle, A.M. Camus, et al. 1980. Validation and
comparltlve studies on 180 chemicals with S. typh.1mu.r1um strains and V79
Chinese hamster cells In the presence of various metabolizing systems.
Mutat. Res. 76: 1-50.
Benke, G,M. and S.O. Murphy. 1975. Influence of age on the toxldty and
metabolism of methyl parathlon and parathlon In male and female rats.
Toxlcol. Appl. Pharmacol. 31: 254-269.
Black, W.D., R.B. Talbot and A.E. Wade. 1975. A study of the effect of
ovex on parathlon and paraoxon toxldty In rats. Toxlcol. Appl. Pharmacol.
33(3): 393-400.
OlOlh -22- 02/04/87
-------
Boyd, E.M. 1969. Dietary protein and pesticide toxldty 1n male weanling
rats. Bull. WHO. 40(5): 801-805.
Braeckman, R.A., F. Audenaert, J.L. Williams, P.M. Belpalre and M.G. Bogaert.
1983. Tox1cok1net1cs of methyl parathlon and parathlon In the dog after
Intravenous and oral administration. Arch. Toxlcol. 54(1): 71-82.
Bulusu, S. and I. Chakravarty. 1986. Subacute administration of organo-
phosphorus pesticides and hepatic drug metabolizing enzyme activity In
normal and malnourished rats. Bull. Environ. Contam. Toxlcol. 36(1): 73-80.
Casterllne, J.L., Jr. and C.H. Williams. 1971. The effect of 28-day
pesticide feeding on serum and tissue enzyme activities of rats fed diets of
varying casein content. Toxlcol. Appl. Pharmacol. 18: 607-618.
Chadwlck, R.W., M.F. Copeland, R. FroehUch, N. Cooke and D.A. WhHehouse.
1984. Interaction between ^-nexachlorocyclohexane and the gastrointesti-
nal mlcroflora and their effect on the absorption blotransformatlon, and
excretion of parathlon by the rat. NTIS/PB84-246438. 8 p.
Cohen, B., E. Rlchter, E. Welsenberg, J. Schoenberg and M. Lurla. 1977.
Sources of parathlon exposure for Israeli aerial spray workers, 1977.
Pestle. MonH. J. 13: 81-86.
Oegraeve, N., J. Gllot-Oelhalle, J. Moutschen, et al. 1980. Comparison of
the mutagenlc activity of organophosphorus Insecticides 1n mouse and 1n the
yeast Schlzosarcharomyces pombe (Abstract No. 65). Mutat. Res. 74: 201-202.
OlOlh -23- 07/15/87
-------
Oeskln, R., L. Rosensteln, N. Rogers and B. Westbrook. 1979. Parathlon
toxlclty In perinatal rats exposed In utero. Toxlcol. Lett. 3(1): 11-14.
DlkshHh, T.S.S., S.K. Tandon, K.K. Datta, P.K. Gupta and 3.R. Beharl. 1978.
Comparative response of male rats to parathlon and Undane: Hlstopathologlcal
and biochemical studies. Environ. Res. 17(1): 1-9.
Durham, W.F., H.R. Wolfe and 3.W. Elliott. 1972. Absorption and excretion
of parathlon by spraymen. Arch. Environ. Health. 24(6): 381-387.
Edson, E.F. and D.N. Noakes. 1960. The comparative toxlclty of six organo-
phosphorus Insecticides In the rat. Toxlcol. Appl. Pharmacol. 2: 523-539.
Edson, E.F., et al. 1964. Summaries of toxlcologlcal data: No effect
levels of three organophosphates In rat, pig and man. Food Cosmet. Toxlcol.
2: 311-316.
Fahrlg, R. 1974. Comparative mutagenlcHy studies with pesticides, in:
Chemical Cardnogenesls Essays. IARC Sc1. Pub!. 10: 161-181.
Felsot, A. and P.A. Oahm. 1979. Sorptlon of organophosphorus and carbamate
Insecticides by soil. 3, Agrlc. Food Chem. 27: 557-563.
Frawley, 3.P. and H.3. Fuyat. 1957. Effect of low dietary levels of
parathlon and systov on blood chollnesterase of dogs. 3. Agrlc. Food Chem.
5: 346.
OlOlh -24- 07/15/87
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Hansch, C. and A.J. Leo. 1985. MedChem Project Issue #26. Pomona College,
Claremont, CA. CAS #56-38-2.
Hart, L.G. and J.R. Fouts. 1963. Effects of acute and chronic DDT adminis-
tration on hepatic mlcrosomal drug metabolism In the rat. Proc. Soc. Exper.
B1ol. Med. 114: 388-392.
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OlOlh -32- 07/15/87
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