0055'
January 1992
«y
FINAL
DRINKING WATER C3UTERIA DOCUMENT0
FOR
SIMAZINE
Health and Ecological Criteria Division
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC 20460
I-
CM
HEADQUARTERS LIBRARY
ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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Simazine Criteria Document
CONTENTS
LIST OF TABLES ui
LIST OF FIGURES iii
FOREWORD iv
L SUMMARY M
IL PHYSICAL AND CHEMICAL PROPERTIES H-l
A. GENERAL PROPERTIES DM
B. MANUFACTURE AND USES n-1
C. ENVIRONMENTAL FATE .' H-3
D. SUMMARY n-4
m. ToxicoioNEncs ni-i
A. ABSORPTION EM
B. DISTRIBUTION ffl-1
C METABOLISM IH-3
D. EXCRETION ffl-5
E. BIOACCUMULATION AND RETENTION ID-6
F. SUMMARY HI-6
IV. HUMAN EXPOSURE IV-1
V. HEALTH EFFECTS IN ANIMALS V-l
A. SHORT-TERM EXPOSURE V-l
1. Lethality V-l
2. Subacute Toxicity V-3
B. LONG-TERM EXPOSURE V^
1. Subchronic Toxicity V-4
2. Chronic Toxicity ". V-7
C REPRODUCnVE/TERATOGENIC EFFECTS . . . .' V-17
D. MUTAGENICITY .. V-23
1. Gene Mutation Assays (Category 1) V-23
2. Chromosome Aberration Assays (Category 2) V-25
3. Other Mutagenic Mechanisms (Category 3) I V-25
E. CARdNOGENICITY V-26
1. Female Rats V-27
2. Male Rats V-33
F. SUMMARY V-39
VL HEALTH EFFECTS IN'HUMANS VI-1
A. CLINICAL CASE STUDIES . . . . . VI-1
B. EPIDEMIOLOGICAL STUDIES VI-1
C HIGH-RISK POPULATIONS VI-1
D. SUMMARY VI-1
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Simazine Criteria Document
C' HIGH-RISK POPULATIONS VI-1
D. SUMMARY VI-1
Vn. MECHANISMS OF TOXTCITY VH-l
Vm. QUANTTHCATTON OF TOXICOLOGICAL EFFECTS vTH-l
A. PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS VEI-1
1. Noncarcinogenic Effects VET-1
2. Carcinogenic Effects '. , . . . . vm-3
B. QUANTIFICATION OF NONCARCINOGENIC EFFECTS FOR SIMAZINE VEI-5
1. One-day Health Advisory ' ".. VUJ-5
2. Ten-day Health Advisory ' '. VEI-5
3. Longer-term Health Advisory ' VHI-8
4. Reference Dose and DrinJdng Water Equivalent Level VHI-9
C. QUANTIFICATION OF CARCINOGENIC EFFECTS FOR SIMAZINE . VDI-12
I. Categorization of Carcinogenic Potential vni-12
2. Quantitative Carcinogenic Risk Estimates -. VttI-13
D. EXISTING GUIDELINES AND STANDARDS VHI-15
E. SUMMARY ; , VTH-15
DC REFERENCES K-li
APPENDIX: HUMAN EXPOSURE
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Simazine Cr/.eria Document
LIST OF TABLES
Table E-l. Physical and Chemical Properties of Simazine n-2
Table ffl-l. :*C Residue Levels in Tissues of Sprague-Dawley Rats 7
Days After Receiving Single Oral Doses of '"C-Simazine ^ . m-2
Table V-l. Toxicological Effects of Single Doses of
Commercial Simazine Administered to Sheep V-2
Table V-2.- Orai Toxicicy of Simazine in Sheep'Following ' .
Administration of Various Dosing Regimens. . V-8
. Table V-3. Experimental Design for the Chronic/Carcinogenicity Study With Rats V-ll
Table \M. Schedule for Hematology, Blood Chemistry, and Urinalyses for the
Chronic/Carcinogenicity Study With Rats V-13
"£, Table V-5. Summary of Histopathological Lesions in Male Rats Fed Diets
*" Containing Simazine for 2 Years V-28
Table V-6. Summary of Histopathological Lesions in Female Rats Fed Diets
Containing Simazine for 2 Years V-29
Table V-7. Incidence of Mammary Gland Tumors in Female Rats Fed Diets
Containing Simazine for 2 Years* : V-30
Table V-8. Incidence of Mammary Gland Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsFemale Mammary Gland Tumor Rates and Peto Prevalence Test Results .. . V-31
Table V-9. Incidence of Pituitary Tumors in Sprague-Dawley Rats Fed Simazine f
for 2 YearsFemale Pituitary Gland Tumor Rate, Fatal Tumor
Analysis, and Generalized K/W Test Results V-34
Table V-10. Incidence of Kidney Tumors in Sprague-Dawley Rats Fed Simazine ..
for 2 YearsFemale Kidney Tubule Tumor Rate, Cochran-Armitage ||
Trend Test, and Fisher's Exact Test Results V-35
Table V-ll. Incidence of Liver Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsMale Liver Tumor Rate, Cochran-Armitage Trend Test,
and Fisher's Exact Test Results V-36
Table V-l2. Incidence of Thyroid Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsMale Thyroid C-Cell Tumor Rates and Peto Prevalence Test Results V-37
Table V-13, Incidence of Kidney Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsMale Kidney Tubule Tumor Rates and Peto Prevalence Test Results V-38
Table VTH-1, Summary of Candidate Studies for Derivation of the Ten-day
Health Advisory for Simazine Vm-6
Table VIE-2. Summary of Candidate Studies for Derivation of the DWEL for Simazine .. VHI-11
Table VHI-3. Summary of Candidate Studies Considered for Derivation of the
Carcinogenic Risk Estimates for Simazine Vffl-14
Table VTJI-4. Summary of Quantification of Toxicoiogical Effects for Simazine Vffl-16
LIST OF FIGURES
Figure ffi-1. Proposed In Vivo Metabolism of Simazine in Rats IH-4
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Simazine Criteria Document
FOREWORD
Section 1412 (b)(3)(A) of the Safe Drinking Water Act, as amended in 1986, requires the
Administrator of the Environmental Protection Agency to publish Maximum Contaminant Level Goals
(MCLGs) and promulgate National Primary Drinking Water Regulations for each contaminant, which,
in the judgment of the Administrator, may have an adverse effect on public health and which is known
or anticipated to occur in public water systems. The MCLG is nonenforceable and is set at a level at
which no known or anticipated adverse health effects in humans occur and which allows for an adequate
margin of safety. Factors considered in setting the MCLG include health effects data and sources of
exposure other than drinking water.
This document'provides the health effects basis to be considered in establishing the MCLG. To
achieve this objective, data on pharmacokinetics, human exposure, acute and chronic toxicity to animals
and humans, epidemiology, and mechanisms of toxicity were evaluated. Specific emphasis is placed on
literature data providing dose-response information. Thus, while the literature search and evaluation
performed in support of this document was comprehensive, only the reports considered most pertinent
in the derivation of the MCLG are cited in the document The comprehensive literature data base in
support of this document includes information published up to July 1989; however, more recent data may
have been added during the review process.
i.
When adequate health effects data exist. Health Advisory values for less-than-lifetime exposures
(One-day, Ten-day, and Longer-term, approximately 10% of an individual's lifetime) are included in this
document. These values are not used in-setting the MCLG, but serve as informal guidance to
municipalities and other organizations when emergency spills or contamination situations occur.
James R. Elder
Director
Office of Ground Water and Drinking Water
Tudor T. Davies
Director
Office of Science and Technology
IV
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Simazine Criteria Document
I. SUMMARY
Simazine (CAS No. 122-34-9) is the common name for 2-chloro-4,6-bi5(ethylamino)-l,3,5-niazine.
It is a herbicide belonging to the triazine family of pesticides. It is a noncorrosive, nonflammable,
colorless, crystalline solid with low water solubility (3.f mg/L at 20°C). It is formulated as a powder
and marketed under the trade names Aquazine, Gesatop, Primatol S, or Princep.
Simazine is produced by the reaction of cyanuric chloride with two equivalents of ethylamine in the
presence of an acid acceptor. It is used at a rate of 0.5 to 4 kg/hectare (ha) as a selective preemergent
herbicide for the control of annual grasses and broadleaf weeds, in deep-rooted crops, and at higher rates
(5 to 20 kg/ha) for nonselective control of herbaceous weeds on noncropland. Simazine is also approved
for selective control of algae and submerged weeds in ponds and small bodies of water. Forestry uses,
all uses on alfalfa, and uses on drainage ditch banks, forage Bermuda grass and hay, and grass grown
for seed in the Pacific Northwest were canceled prior to January 1989.
i
Simazine is reported to have relatively low mobility in soil, mostly remaining in the upper 5 cm of
the soil profile for several months after application. Degradation is reported to occur via chemical
hydrolysis and microbial breakdown. The half-life of simazine in soil has been estimated to be 4 to 6
months. The half-life in water has been reported to be 50 to 70 days, with 99% loss in 12 months.
Based on its physicochemical properties, its persistence in water and soil, and the mobility of the
pesticide and its degradates, simazine can potentially contaminate ground and surface water. In fact, its
presence has been detected in these waters.
Little information on the toxicokinetics of simazine in animals was located in the available literature.
. Data for goats, sheep, and rats suggest that about 70 to 74% of an oral dose may be absorbed. Simazine
was metabolized by rats, rabbits, and ruminants to yield the mono- and di-N-dealkylated metabolites,
without disruption of the triazine ring. Limited data suggest that the principal route of excretion is the
urine, with peak urinary levels occurring several days after exposure.
The acute oral LDio estimates are 5,000 mg/kg or higher in rats, mice, rabbits, and birds, but a dose
of 500 mg/kg has been reported to be lethal in sheep. Pharmacotoxic signs in sheep included
incoordination. tremors, weakness, cyanosis, and clonic convulsions. A dose of 4,200 mg/kg caused
anorexia, weight loss, and some lethality in rats.
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Simazine Criteria Document
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In rats, short-term oral administration of 500 mg/kg/day caused death in 11 to 20 days. A dose level
of 15 mg/kg/day was found to produce mild hepatic degeneration in 3 days, but this condition did not
progress with repeated dosing. The validity of these data is questionable.'
Simazine orally administered to albino mice at dose levels ranging from 0 to 4,500 mg/kg/day
showed no discernible adverse effects in gross pathology, food consumption, and body weight at levels
up to 450 mg/kg/day at the end of 28 days. A NOAEL of 450 mg/kg/day has been identified from this
study. . .
Daily oral administration of simazine at 50, 100, or 400 mg/kg/day for 31, 14, or 9 days, respect-
ively, produced death in Delaine sheep. Toxic symptoms consisted of muscular spasms, fasiculation,
stiff gait, and increased breathing.
Simazine applied dermaily to rabbits at doses up to 1 g/kg for 21 days produced neither-systemic
toxicity, dermal irritation, nor dermal sensitization. . ,
0
No treatment-related deaths were observed in rats fed simazine at dose levels up to 343 mg/kg/day
(4.000 ppm in females for 13 weeks), but decreases in body weight gain and changes in hematological
parameters were noted. Histopathology revealed dose-related increased incidences of renal calculi and
renal epithelial hyperplasia in males, which was significant at the highest dose. Based on these findings,
a NOAEL. of less than 10 mg/kg/day was identified. The same protocol was used to study the effects
of simazine in dogs, and a NOAEL of approximately 7 mg/kg/day was identified based on reduced
serum albumin and increased serum globulin, and elevated urinary ketone bodies at 64 to 65 mg/kg/day.
A 6-month study in rats and guinea pigs indicated that a dose of 20 mg/kg/day had no effect, but a dose
of 100 mg/kg/day suppressed normal weight gain and caused an increase in leukocyte count Lower
doses (1.4 to 25 mg/kg/day) have been reported to cause hypothyroidism in sheep following daily doses
for 63 to 142 days.
A detailed 95-week chronic feeding study in Crl:CDl(lCR)BR mice revealed a NOAEL of 6 mg/kg'
day and a LOAEL of 150 mg/kg/day based on decreased body weight gain. The body weight reductions
were significant (p <0.0l) at dose levels of 150 and 600 mg/kg/day. Hematocrit and hemoglobin values
tended to be lower in high-dose mice than in controls. Amyloidosis was more pronounced in all dose
groups than in controls; this and other incidental effects were not considered to be compound related.
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Simazine Criteria Document
Another chronic feeding toxicity study (17 to 22 months) with Charles River CD-I mice receiving dose
levels ranging from 0 to 300 mg/kg/day was determined to be invalid.
A recent 2-year chronic feeding study in Sprague-Dawley rats established a NOAH, of 0.52 mg/kg/
day and a LOAEL of 5.3 mg/kg/day based on decreased body weights and hematological indices (red
blood cell count, hemoglobin concentration, and hematocrit in females). In an earlier 2-year feeding
study in rats, doses up to 100 ppm in the diet (about 5 mg/kg/day) did not produce apparent systemic
toxicity. '
f.
A 1-year chronic feeding study in beagles also revealed a NOAEL of 0.72/mg/kg/day (0.76 and 0.68
mg/kg/day for females and males, respectively) and a LOAEL of 3.6 mg/kg/day based on decreased
body weight gain, erythrocyte count, and hemoglobin concentration, and a nominal increase in platelets
in females. In an earlier 2-year feeding study in beagles, doses up to 150 ppm (about 3.5 mg/kg/day)
were without effect. However, a dose of 1,500 ppm (about 35 mg/kg/day) resulted in slight thyroid
hyperplasia and a slight increase in serum alkaline phosphatase and serum glutamic-oxaloacetic
transaminase activities. However, neither chronic toxicity nor oncogenic potential could be determined
from this study.
A two-generation reproductive toxicology study in rats fed simazine technical (96.9% pure) in the
diet at 10, 100, and 500 ppm levels produced no adverse health effects at 10 ppm and a transient
treatment-related reduction in weight gain at 100 ppm. At 500 ppm, observed adverse effects included
reduced weight gain and increased mean relative testicular and ovarian weights. No effect on reproduc-
tive parameters, pup survival weights, sex ratios, or malformation at any dose level was produced.
Additionally, remarkable gross or histopathological findings were absent in any of the examined**-
generations. This study suggested a reproductive NOAEL of 500 ppm and a parental NOAEL of-
10 ppm for simazine technical. . - . '
In a three-generation reproduction study with Charles River rats fed simazine SOW in the diet at 50
or 100 ppm, a parental toxicity NOAEL of less than 50 ppm and a LOAEL of 50 ppm were identified
based on reduced weight gains in males during the premating periods. The reproductive toxicity
NOAEL/LOAEL could not be detected in this study because the apparent sterility in FH, generation
males was not evaluated.
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Sirnazine Criteria Document
In a teratology study with rats, simazine administered at high doses (78 and 2,500 mg/kg/day) during
gestation days 6 through 15 delayed fetal development and was embryotoxic but not teratogenic.
Another teratology study in CrkCOBS CD SD BR rats administered simazine by gavage at doses of 30,
300, and 600 mg/kg/day on gestation days 6 through 15 revealed developmental and maternal toxicity
NOAELs of 30 mg/kg/day and LOAELs of 300 mg/kg/day based on skeletal variations (incomplete
ossification) in fetuses and decreased weight gain in dams. However, the U.S. EPA has raised some
questions and has requested additional information for this study. Similarly, maternal tpxicity was
observed in New Zealand rabbits given oral doses of 75 or 200 mg simazine/kg on gestation days 7-19.
The maternal toxicity NOAEL was 5 mg/kg/day based on decreased body weight gain, tremors, and
abortions at higher levels. The teratogenic NOAEL was 200 mg/kg/day, and this dose produced reduc-
tions in fetal body weight and fetal skeletal variations. The fetotoxic NOAEL was 75 mg/kg/day. Doses
of 6 'or 25 mg/kg/day administered to sheep for 142 days or 37 to 111 days, respectively, caused
decreased spermatogenesis.
* *.
Most tests of mutagenic potential for simazine have .been negative, both in procaryotic and
i
eucaryotic systems. The herbicide was nonmutagenic in the S<2/m0ne//o/rnicrosome assay, mitotic
recombination assay in Saccharomyces, and unscheduled DNA synthesis assay in human fibroblasts.
However, it induced sex-linked recessive lethal mutations in Drosophila and sister chromatid exchanges
in human lymphocytes.
No increase in tumor frequency and/or neoplastic lesions was observed in C57BL/6 x C3H/Anf and
C57BL/6 x AKR mice dosed with simazine at 215 mg/kg/day by stomach tube for 18 months. A 95-
week feeding toxicity/oncogenicity study in CrhCDl mice fed diets containing 40, 1,000, or 4,000 ppm
simazine revealed no evidence suggestive of oncogenic activity. A chronic 2-year oncogenicity
i
with Sprague-Dawley rats fed simazine at dietary levels of 10, 100. and 1,000 ppm revealed the
occurrence of mammary rumors at 100 ppm (5.3 mg/kg/day) and 1,000 ppm (63.1 mg/kg/day) in
females; in males, simazine appeared to induce the formation of liver tumors at 1,000 ppm (45.8 mg/kg/
day).
Almost no information is available regarding simazine toxicity in humans. One study reported acute
and subacute dermatitis in workers at plants manufacturing simazine.
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Simazine Criteria Document
The mechanism of simazine toxicity in animals is not known. Simazine has been reported to inhibit
the activity of plant, animal, and yeast alcohol dehydrogenases. When tested with HeLa cells, simazine
had no effect on the incorporation of labeled amino acids into protein or labeled uridine into RNA.
No suitable studies were found to permit calculation of the One-day and Ten-day Health Advisories
(HAs). Consequently, the Longer-term HA value for a child is used as a conservative estimate of the
One-day and Ten-day HA values. The Longer-term HA value for simazine was calculated to be 70 ug/L
for a child and 300 ug/L for an adult. However, it is advisable that the Longer-term HA value of
70 ug/L for a 10-kg child also be used as the Longer-term HA value for a 70-kg adult because the
relative source contribution for Longer-term dietary exposure for adults could not be determined at this
time from the available data. A 2-year chronic toxicity study in rats is used as the basis for calculation
of a Reference Dose (RfD) of 5 ug/kg/day, and for a DWEL of 180 ug/L for simazine.
Based on available data, simazine was found to produce mammary tumors in female rats and liver
tumors in male rats. Simazine was determined to be a Category C oncogen. The excess cancer risk has
been determined for simazine. The Q!* was estimated to be 1.2 x 10"l (mg/kg/day)"1 in human equiva-
lents. The oncogenic risk of exposure to 1 ppb simazine in drinking water is 3.4 x 10"6, assuming that
a 70-kg man consumes 2 liters of water per day.
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n. PHYSICAL AND CHEMICAL PROPERTIES
A. GENERAL PROPERTIES
Simazine (CAS No. 122-34-9) is the common name for the compound known alternatively as 2-
cnloro-4,6-bis(ethylamino)-l,3,5-aiazine (International Union of Pure and Applied Chemistry) or 6-
chloro-N,N'-diethyl-l,3,5-triazine-2,4-diamine (Chemical Abstracts). It is a herbicide belonging to the
triazine family of pesticides. It is a noncorrosive, nonflammable, colorless, crystalline solid (Worming,
1979; Weed Science Society of America, 1983). The physical and chemical properties of simazine are
shown in Table n-1.
B. MANUFACTURE AND USES
Simazine is produced by the reaction of cyanuric chloride and two equivalents of ethylamine in the
presence of an acid acceptor (Sittig, 1980). Simazine may be applied preemergence, preplan!
incorporated, at planting, or postemergence. Application rates as high as 40 pounds of active ingredient
per acre have been used in noncrop sites such as rights-of-way. Simazine is used at
0.5 to 4 kg/hectare (ha) as a selective preemergent herbicide to control annual grasses and broadleaf
weeds in deep-rooted crops (e.g., citrus, alfalfa, deciduous fruits, olives, asparagus, corn, certain nuts,
grapevines, and various ornamental and tree nursery stock), and in turf grass sod production. It is used
at 5 to 20 kg/ha as a nonseiective herbicide to control herbaceous weeds in noncropiand (Meister, 1983;
Worthing, 1979). Simazine is also approved for selective control of algae and submerged weeds in
ponds, and is used to control algae in swimming pools, large aquaria, ornamental fish ponds, fountains,^
and recirculating water-cooling towers (Weed Science Society'of America, 1983).
The estimated uses for simazine are as follows: 30% on com (field); 10% on alfalfa (prior to the
voluntary cancellation by the registrant in 1987); less than 22% on fruits and nuts; 27% on water
treatment sites; 3% on noncrop sites; 10% on tree nurseries (cancelled); and 9% on other nonagricultural
sites. Currently, simazine is registered for uses on terrestrial food crops, terrestrial
nonfood crops, noncrop sites, and aquatic nonfood sites. Forestry uses, all uses on alfalfa, and uses on
drainage ditch banks, forage Bermuda grass and hay, and grass grown for seed in the Pacific Northwest
were canceled prior to January 1989.
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Simazine Criteria Document
Table n-1. Physical and Chemical Properties of Simazine
Property
Value
Reference
Chemical Abstracts
(CAS) Registry Number
Registry of Toxic
Effects of Chemical
Substances (RTECS)
Number
Simazine products
Chemical formula
Structure
122-34-9
XY5250000
Aquazine, Gesatop,
Primatol S, Princep
C,H,2C1NS
Lewis and Tatken (1980)
Lewis and Tatken (1980)
Worthing (1979)
Windholz (1983)
Weed Science Society of America
(1983)
Molecular weight
Melting point
Vapor pressure
Density
Stability in water
Solubility in water
201.7
226-227°C
6.1 x 10-' mmHg (20°C)
1.302 g/cm3
Little or no hydrolysis
in water
2.0 mg/L at 0°C
3.5 mg/L at 20°C
84,0 mg/L at 85eC
Windholz (1983)
Windholz (1983)
Meister (1984)
Esser et al. (1969)
Freed (1976)
Weed Science Society of
America (1983)
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Simazine Crksna Document
C ENVIRONMENTAL FATC
Simazine has relatively low mobility in soil (Ghassemi et aL, 1981). Several investigators have
reported that the greatest concentration of simazine remains in the upper 5 cm of the soil profile for
several months after application (Marriage et aL, 1975; Hance et aL, 1976). The depth to which
simazine penetrates increases with the amount of water applied (Bumside et aL, 1961; Kozlowski and
Kuntz, 1962), up to a maximum of about 18 cm (Haque and Freed, 1974). Leaching and desorption of
simazine are lowest in soils high in clay or organic matter (Harris and Warren, 1964; Helling, 1970).
Absorption of simazine onto soil colloids decreases with increasing pH and increasing temperature
(Talbert, 1963). Simazine has little lateral movement in soil but can be washed along with soil particles
(Weed Science Society of America, 1983).
Degradation of simazine in soil occurs via chemical hydrolysis and microbial breakdown (Ghassemi
et aL, 1981). Degradation follows first-order reaction kinetics with no lag period (Zimdahl et aL, 1970).
The half-life of simazine in soil has been estimated to be 4 to 6 months (Ghassemi et aL, 1981). The
major soil metabolite is hydroxysimazine (2-hydroxy-4,6bis(ethylamino)-s-triazine) (Khan and Marriage,
1979). The annual rate of degradation of hydroxysimazine is 80 to 85% compared with an annual
simazine degradation of over 95% (Khan and Marriage, 1979). Degradation of simazine from soil by
photodecomposition and/or volatilization is considered to be insignificant (Weed Science Society of
America, 1983).
The half-life of simazine in water is 50 to 70 days, with 99% loss in 12 months (Ghassemi at aL,
1981). The average half-life of simazine in pond water was reported to be 30 days (Weed Science
Society of America, 1983). According to the manufacturer, water from treated ponds may not be used
for irrigation, for watering animals, or for human consumption until 12 months following treatment
(Ciba-Geigy Corporation, 1976).
Based on simazine's physiochemical properties, its persistence in water and soil, and the mobility of
simazine and its degradates, there is potential for contamination of ground and surface water with the
herbicide and its degradates. In fact, detection of simazine has been reported in ground and surface
water.
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Simazine Criteria Dce-mer.t
D. SUMMARY
Simazine (2-cMoro-4,6-bis(ethylamino)-i,3,5-triazine; CAS No. 122-34-9) is a herbicide belonging
to the triazine family of pesticides. It is a noncorrosive, nonflammable, colorless, crystalline solid with
low water solubility (3.5 mg/L at 20°C). Simazine is formulated as a powder and is marketed under the
trade names of Aquazine, Gesatop, Primatol S, and Princep. It is currently registered for uses on
terrestrial food crops,, and nonfood crops, noncrop sites, and aquatic nonfood sites. Forestry uses, all
uses on alfalfa, and uses on drainage ditch banks, forage Bermuda grass and hay, and grass grown for
seed in the Pacific Northwest were canceled prior to January 1989.
Simazine is produced by the reaction of cyanuric chloride with two equivalents of ethylamine in the
»
presence of an acid acceptor. It is used at a rate of 0.5 to 4 kg/ha as a selective preemergent herbicide
for the control of annual grasses and broadleaf weeds in deep-rooted crops, and at higher rates (5 to 20
kg/ha) for nonselective control of herbaceous weeds on noncropland. Simazine is also approved for
selective control of algae and submerged weeds in ponds and small bodies of water. ^
(
"Simazine is reported to have relatively low mobility in soil, with most remaining in the upper 5 cm
"-''',-'. .-*- .-... fe
of the soil profile for several months after application. Degradation is reported to occur via chemical
.hydrolysis and microbialbreakdown. The half-life in soil has been estimated to be 4 to 6 months. The
half-life of simazine in water has been reported to be 50 to 70 days, with 99% loss in 12 months. Based
*
on its physicochemical properties, its persistence in both water and soil, and the mobility of the herbicide
and its degradates, there is potential for contamination of ground and surface water. Detection of
simazine in ground and surface has been reported.
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Simazine Criteria Document
HI. TOXICOKINEnCS
A. ABSORPTION
Orr and Simoneaux (1986) studied the metabolism of uC-simazine (uniformly labeled in the niazine
ring), in groups of five male and five female. SpragueDawley rats following oral administration in single
doses at 0.5 or 200 mg/kg. At the low dose, 51 to 62% of the dose was eliminated in the urine and about
-12% was found in the tissues, suggesting that about 63 to 74% (Le., 0.315 to 0.37 mg/kg) of the dose
was absorbed. At the high dose, only about 22% (i.e., 44 mg/kg) of the dose was found in urine and
2% (4 mg/kg) in the tissues of males or females. A third group of animals received daily single oral
doses of unlabeled simazine at 0.5 mg/kg/day for 14 days followed .by a single 14C dose. Elimination
of 14C in urine ranged from 59 to 66% of the dose, and 8% was found in the tissues. Bakke and
Robbins (1968) reported that in goats and sheep, from 67 to 77% of a dose (the dose was not reported
in this abstract) of 14C-simazine (given orally in gelatin capsules) was excreted in urine. This suggests
absorption was around 70%. ' (
B. DISTRIBUTION
Orr and Simoneaux (1986) reported that 7 days following oral administration of l*C-simazine to male
and female Sprague-Dawley rats at 0.5 or 200 ug/kg, the highest 14C residue levels were found in the
red blood cells, accounting for 16.3 to 19.9 ppm at the high dose and 0.18 to 0.23 ppm at the low dose.
Residue levels in red blood cells were slightly higher in males than in females. The data are
summarized in Table DI-1 and expressed as percent of dose found in individual tissues. Lower
concentrations were found in the other tissues, ranging from 0.0 to 0.16 ppm at the low dose and from
0.78 to 5.2 ppm at the high dose. Relatively higher residues were found in the liver and kidney of rats
receiving the low dose (0.1 to 0.16 ppm), with lower levels found in fat, plasma, and bone (0.0 to 0.03
ppm). A similar pattern was observed in rats receiving the high dose, except that the spleen contained
higher MC residues (4.1 to 5.2 ppm) than the liver and kidney (2.9 to 4.0 ppm).
Residue levels in tissues of animals receiving the low 14C dose following 14 days of repeated dosing
were generally lower than those observed in rats receiving a single low dose, except in red blood cells
(see Table ffi-1). The authors suggested that repeated dosing with unlabeled simazine significantly
reduced the number of available binding sites in all tissues, except the red blood cells.
m-i
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Sraazine Chreria Document
Table ffl-1. 14C Residue Levels in Tissues of Sprague-Dawley Rats 7
. Days After Receiving Single Oral Doses of t4C-Simazine
14C Residues expressed as % of dose
Tissue
Heart
Lung
Spleen
Kidney
Liver
Fat
Testes/Uteius
Muscle
Brain
Carcass
Plasma
RBC
Bone
Total
0.5 me/kg Csinele')
Males Females
0.04 '
0.06
0.02
0.23
1.08
0.19
0.11
2.76 .
0.09
5.40
0.16
1.13
0.01
11.79
0.04
0.05
0.03
0.15
1.26
0.09
0.01
3.28
0.10
6.34
0.07
0.83
0.01
12.26
0,5 mg/kg
Males
0.08
0:03
0.02
0.10
0.88
0.29
0.05
1.61
0.04
3.99
0.04
1.13
0.01
8.21
(repeated*)*
Females
0.03
0.04
0.02
0.10
0.90
-0.26
0.01
1.54
0.05
3.63
0.03
1.10
0.01
7.73
200 mg/kg Csingle)
Males Females
0.01
0.01 '
o.or '
0.01
0.09
0.05
0.01
0.44
0.01
1.13
0.03
0.27
0.00
2.05
0.01
0.01
0.01
0.02
0.08
0.05
0.00
0.45
0.01
1.00
0.03 1
0.23
0.00 '
1.89
Animals received daily single oral doses of unlabeled simazine followed by a single 14C dose.
SOURCE: Adapted from Orr and Simoneaux (1986).
m-2
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Simazine Criteria Document " - .
In rats receivi g the high dose, UC residue levels, expressed as ppm, were 29-fold (kidney) to 516-
fold (spleen) higher than those in animals receiving the low dose (Orr and Sirnoneaux, 1976).
C. METABOLISM
Simoneaux and Sy (1971) conducted a preliminary investigation on the metabolites of UC ring-
Jabeled simazine found in the urine of female white rats. The rats were orally dosed once at 1.5 mg/kg,
and the urine eliminated within 24 hours was collected and analyzed by thin-layer chromatography and
thin-layer elecuophoresis. The metabolites identified by. comparison to authentic compounds were
hydroxysimazine, 2-hydroxy4-amind-6-ethylamino-s-triazine, and 2-hydroxy-4,6-diamino-s-oriazine.
These metabolites accounted for 6:8, 6.1, and 14.0% of the administered radioactivity, respectively.
i ' -'
When the urine was hydrolyzed with performic acid to cleave sulfur-carbon bonds prior to thin-layer
. chrorrtatography, about 8.1, 7.7, and 31.3% of the radiolabel were detected as the. three identified
metabolites, respectively. Approximately half of the radioactivity in the urine was not identified. J
i
Based on these findings, Orr (1985) proposed the metabolic pathway for simazine depicted in Figure
m-L
Bradway and Moseman (1982) investigated the metabolism of rimazine in rats. Male Charles River
rats averaging 300 g were given simazine (suspended in peanut oil) by gavage. Two doses of 1 mL,
containing 0, 0.005, 0.5, 5, or 50 mg/mL, were given 24 hours apart. This corresponds to doses of 0,
0.017, 1.7, 17, or 167 mg/kg/day, respectively. Urine samples (24-hour intervals) were extracted and
analyzed by gas cinematography for the presence of the mono- and di-N-dealkylated metabolites. The
percent of the dose excreted as these metabolites depended somewhat on the dose level, with higher
doses yielding higher percent excretion of the metabolites. The di-N-deaikylated metabolite (2-chloro-
4,6-diamino-s-triazine) appeared to be the major product, ranging from 1.6% at the 0.5-mg dose to
18.2% at the 50-mg dose, while the mono-N-dealkylated metabolite ranged from 0.35% at the 0.5-mg
dose to 2.8% at the 50-mg dose.
Similar results were obtained by Bohme and Bar (1967). Albino rats (200 to 300 g) or rabbits (2
to 3 kg) were fed simazine at levels of 50 to 200 mg/rat (200 to 800 mg/kg) or 600 to 1,000 mg/rabbit
(240 to 400 mg/kg). Several metabolites wen: isolated and identified, all of which retained the triazine
ring intact. The principal metabolites were the mono- and di-N-dealkylated metabolites.
m-3
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Simazine Criteria Document
SlMAZlHf
A.
"^
M
1*
OM
A,
an
A *l
'r^'-^»
a
i
!
Figiue ffl-1. Proposed /n Wvo Metabolism of Simazine in Rats
SOURCE: Adapted from Orr (1985).
ffl-4
-------
Simazine Criteria Document
Bohme and Bar (1967) and Larsen and Bakke (1975) observed that rat and rabbit urinary metabolites
from the 2-chloro-s-triazines were all 2-chloro analogs of their respective parent molecules, and none
of the metabolites contained the 2-hydroxy moiety. Total N-dealkylation, partial N-dealkylarion, and
N-dealkylation with N-alkyl oxidation were suggested as the major routes of the metabolism of 2 chloro-
s-triazines in rats and rabbits. a
Guddewar and Dauterman (1979) purified glutathione-s-transferase 61-fold from mouse liver. This
enzyme conjugates chloro-s-triazine herbicides. A chloro group at the C2-position was found to be
-itf- *
necessary for conjugation to occur. When this 2-chloro was replaced by a methylmercapto group, no
conjugation occurred. The reaction rate decreased with triazine analogs lacking the alkyl side-chains.
Atrazine was conjugated faster than either simazine or propazine.
Bakke and Robbins (1968) investigated the metabolism of simazine in goats and sheep. Animals
were orally dosed (the dose was not reported in this abstract) using gelatin capsules. The sheep were
given l4C-simazine labeled on the triazine ring or on the ethylamino side-chain, while goats were given
- 0
the ring-labeled compound only. ,No 14C02 was detected from animals receiving ring-labeled herbicides,
~i.-~ "'"«.
which suggested that the triazine 'ting was not metabolized. In sheep that received chain-labeled
triazines, at least 40% of the ethylamino side-chains were removed. Using ion-exchange
chromatography, 18 labeled metabolites were found in urine.
D. EXCRETION
Orr and Simoneaux (1986) studied the metabolism of 14C-simazine in Sprague-Dawley rats following
oral administration in single doses. Male and females receiving 0.5 mg/kg eliminated 50.5 and 62.1%
of the dose, respectively, in the urine, and 19.1 and 13.3% of the dose in the feces, 7 days after dosing.
In animals receiving a single dose of 14C-simazine following repeated dosing at 0.5 mg/kg/day for 14
days with unlabeled simazine, males eliminated 58.5 and 24.5% of the dose in urine and feces,
respectively, whereas females eliminated 66.0 and 17.8% of the dose. A third group of males and
females receiving a single dose of 200 mg/kg eliminated about 21% of the dose in the urine and about
2.0% in the feces.
The elimination pattern with time after dosing was biphasic with rates being faster in females than
males. Most of the radioactivity was eliminated in 72 hours with a half-life of 9 to 15 hours.
DI-5
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Simazir.e Criteria Document
Elimination of the remaining radioactivity followed slower kinetics with half-life values ranging from
21 to 32 hours. In a preliminary study with two female white rats dosed orally at 1.5 mg/kg, Simoneaux
and Sy (1971) found less than 0.05% of the dose being eliminated as uC-carbon dioxide 96 hours after
dosing. Approximately 49.3% of the dose was eliminated in the urine and 40.8% in the feces.
»
Bakke and Robbins (1968) studied the excretion of simazine in lactating goats and sheep using
triazines labeled with !*C on the ring or on the ethylamino side-chains. No '*C02 was detected from
animals that received the ring-labeled compounds, which suggested thai the triazine ring was not
V ' '
metabolized. Approximately 67 to 77% of the administered ring-labeled activity was found in the urine,
and }3 to-25% was found in the feces. About 0.1-6 ppm of 14C residues were present in the milk
immediately after dosing, but the level decreased to 0.04 ppm within 48 hours.
St. John et al. (1965) fed unlabeled simazine (5 ppm) to a lactating cow.for 3 days. Urine and milk
were collected and analyzed during the feeding period and'for 3-days .thereafter. 'No simazine was;
detected .in the milk (sensitivity of method approximately 0.1 ppm), and.only'about,1% of the
administered simazine was excreted in the urine as the. parent -compound. Milk, excreta, and body
* ' ' . -.-*
. tissues were not analyzed for simazine metabolites.
* . * " .
Hapke (1968) reported that simazine residues were present in the urine of sheep for up to" 12 days
after administration of single oral doses of 250, 500, 630, 700, and l-.OOO mg simazine (50% active
ingredient)/kg. The maximum concentrations (from 6 ppm in the low dose to 70 ppm in the high dose)
in the urine occurred from 2 to 10 days after administration.
>.
E. BIOACCUMULATION AND RETENTION '
No studies providing quantitative information on simazine bioaccumulation or retention in mammals
were located.
F. SUMMARY
Little information is available on the toxicokinetics of simazine in animals. Up to 74% of an oral
dose was absorbed in Sprague-Dawley rats following a single administration of 0.5 mg "C-simazine./kg.
The highest !4C residue levels were found in the red blood cells 7 days following administration. Data
m-6
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Simazine Criteria Document
on goats and sheep suggest that about 70% of an oral dose may be absorbed. Simazine was
metabohzed, without hydrolysis of the triazine ring, by rats and rabbits to yield the mono- and di-N-'
dealkylated metabolites and the corresponding 2-hydroxy derivatives resulting from dechlohnation of
S1mazine. Similar results have been reported in ruminants. Limited data suggest that the principal route
ol excretion is the urine, with r*ak urinary levels occurring several days after exposure. No data are
available on tissue distribution, bioaccumulation, and retention of simazine.
ra-7
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Slimline Criteria Document
IV. HUMAN EXPOSURE
Information on human exposure is presented in the appendix portion of this document.
IV-1
-------
Simazine Catena Document
V. HEALTH EFFECTS IN .ANIMALS
A. SHORT-TERM EXPOSURE
1. Lethality . ,
. a
The acute oral LDJO of simazine in rats, mice, rabbits, chickens, and pigeons has been reported to
'be greater than 5,000 mg/kg (Dalgaard-Mikkelsen and Poulsen, 1962; Martin and Worthington, 1977;
.USDA, 1984; Cosmopolitan Safety Evaluation, 1985). The acute dermal'LD50 in rabbits is more than
10,200 mg/kg (We.ed Science Society of America, 1983).
Cosmopolitan Safety -Evaluation (1985) conducted an acute oraUoxicity study with five female and
five male Sprague-Dawley albino rats given ,a Single oral dose of simazine in com oil at 5,000 mg/kg
body weight (bw). .One male and two females';died qri day '6 or 7'following administration of
herbicide:- No additional deaths occurred during the 2-week observation period.'
The animals lost a significant amount of weight during the first week after dosing. OfTdays 3
through 10 or 11, several signs of poisoning were observed, including chromorhinorrhea,
*
chromodacryorrhea, perinea! and/or abdominal staining, reduced activity, emaciation, and ataxia before
death. Necropsy of the three rats that died during the study showed congestion of the gastrointestinal
tract, which contained a reddish-brown fluid. Survivors had no pathognomonic signs at necropsy.
Mazaev (1965) studied the effect of a single oral dose of simazine administered to rats at 4,200
mg/kg. Anorexia and a loss of weight were observed, with some of the animals dying in 4 to 10 days.
When Mazaev (1965) administered 500 mg/kg daily, all of the animals died in the period between days
11 and 20. The time of death was correlated with loss of weight. No other data on acute toxicity were
reported in this abstract.
Hapke (1968) administered, by oral intubation, single doses of commercial simazine (50% active
ingredient) to sheep (merino meat sheep, blackheaded sheep, or milk sheep) at dose levels of 200, 250,
500, 600, 630, 790, and 6,000 mg/kg. The numbers of deaths and effects at various dose levels are
shown in Table V-l. No discernible effects were noted at the 200-mg/kg dose level, although minor
toxicity was observed at 250 mg/kg. The lowest dose at which deaths were observed was 500 mg/kg.
V-l
-------
Simazine Criteria Document
Table V-l. Toxicological Effects of Single Doses of
Commercial Simazine Administered to Sheep
Dose
mg/kg
(50% a.i.)'
200
" 250 ' .
No. of
animals
5
2
No. of deaths
0"
0
Effects
No discernible effects.
Slight reduction in feed uptake,
500
600
630* *' "
790
6,000
6 .
Four on days
6, 7, 8, and
25
One on day 6
0
Three on days
10, 12, and 16
One on day 4
'polydipsia, apathy for 3 to 8
days.
Slight reduction in feed uptake,
polydipsia, ataxia, trembling,
salivation.
Same as above plus slight . «;_
paralysis of the hind-legs. : *
i
Reduction in feed uptake, difficulty
in standing, ataxia, motor inactivity.
Difficulty in moving, paralysis of
hindquarters, pale mucous membranes,
urination and defecation impeded.
Trembling muscles, ataxia, clonic cramps,
paralysis of rear extremities, bleeding in
stomach mucous membrane.
"a.i. - Active ingredient.
The animals were under observation for at least 4 weeks.
SOURCE: Adapted from Hapke (1968).
V-2
-------
Simazine Criteria Document
The toxic signs in affected animals included reduction in feed uptake, pblydipsia, ataxia, paralysis .of
extremities, and finally death. Although the types of sheep used foE each dose were not identified, the
authors indicated that the milk sheep, and merino sheep were more susceptible to simazine than the
blackheaded sheep. A N'OAEL of 200 mg simazine (50<&)/kg and a LOAEt of 250 mg simazine
(50%)/kg have been identified from this study.
»
In primary irritation studies in rabbits (USDA, 1984), simazine caused transient Inflammation of the
conjunctiva. . ' ft
" *
*2. Subacute Toxicitv .. .
v .
* 1
' No lethality was.observed in rats fed 1,250 or 2,500 mg simazine/kg six times/week for 4 weeks
(Gysin and Knusli, 1960). Oledza-Slotwinska (1974) gave simazine via stomach tube to male albino
rats at a dose of 15 mg/kg/day for 3 or 28 days. Histologic examination of the livef showed a few focai
lesions in hepatic parenchyma after the first 3 days.'but the condition.did not progress. The hepatocyies
-------
Simazine Criteria Document
Palmer and Radeieff (1964) found that repeated oral administration of simazine, at daily doses of
50 mg/kg for 31 days, 100 mg/kg for 14 days, or 400 mg/kg for 9 days,'was fatal to Delaine sheep.
One sheep and one dairy cow receiving daily oral doses of 250 mg/kg for 3 days survived but showed
toxic effects after one dose. Muscular spasms and fasciculation. stiff gait, and increased respiratory rates
were observed. Simazine was also lethal when administered at 100 mg/day for 14 days by drench
(Palmer and Radeieff, 1969). . . '
° »
In a 21-day subacute dermal toxicity. study in rabbits, Ciba-Geigy <198jOa) reported, that dermal
. o
applications of technical simazine at doses up to 1 g/kg produced no systemic toxicity and no dose-
related alterations of the sldrh '.
B. LONG-TERM EXPOSURE
,
P a
1. Subchrontc Toxicitv i
* . *
0
A subchronic toxicity study was carried out in 10-week-old Sprague-Dawley Cri:COB CD (SD) BR
rats (Tai et aL. 1985a). This study was reviewed by'the O.S: EPA (Robinson et aL, 1985). Animals
were randomly assigned to one of four groups, each consisting of 10 rats/sex, and were fed technical
simazine (97.5% pure) in a powdered feed ad libitum for 13 consecutive weeks (7 days/week). The .
concentrations of simazine were 0 (control), 200, 2,000, and 4,000 ppm. Hematological and clinical '
chemistry studies and urinalyses were performed on blood and urine samples collected from the animals
prior to study termination. All surviving animals at the end of the dosing period (91 days) were
necropsied, and tissues were examined histopathologically.
r
Significant dose-related reductions in mean body weights and mean body weight gains occurred in-
both sexes in all treated groups. This paralleled dose-related reductions in mean feed intake. The
average feed intake was reduced by 52.5 and 46.4% in males and females receiving 4,000 ppm, by 37.2
and 32.1% in males and females receiving 2,000 ppm, and by 6.5 and 7.9% in males and females
receiving 200 ppm, respectively. Based on actual feed consumption, the average doses of simazine for
the 200-, 2,000-, and 4,000-ppm diets in males ranged from 9.6 to 17.4, 104.6 to 151.8, and 199.3 to
289.7 mg/kg/day, and in females from 13.8 to 18.8, 143.3 to 186.4, and 239.2 to 343 mg/kg/day,
respectively. Dose-related reductions were detected in mean erythrocyte counts in both sexes in all
treated groups. Decreased hematocrit was detected in females dosed at 2,000 and 4,000 ppm and in
V-4
-------
Simazine Criteria Document
males receiving 4,000 ppm. Mean leukocyte counts were significantly lower in males at ail doses.
Neutrophil and platelet counts were significantly higher in females at the 2,000- and 4,000-ppm dose
levels. Several differences in clinical chemistry and urinalysis indices occurred in treated rats compared
with controls, including lowered blood glucose, sodium, and calcium in males; increased cholesterol and
inorgan:c phosphorus levels in both sexes; and decreased levels of blood urea nitrogen, lactic acid
dehydrogenase, serum glutamic-oxaloacetic acid transaminase (SCOT), and creatinine in females.
Elevated urinary ketone levels were seen in males, and decreased urinary protein was seen in females
«SSt
when compared with controls.
Reduced absolute organ weights and increased relative organ weights were observed for the brain,
heart, kidney, liver, and lestes in males, and for the brain and spleen in females. Other effects consisted
of increased relative adrenal weights for both sexes, reduced absolute weight for trie spleen in males,
and reduced absolute weights of the ovary and heart in females receiving 2,000 and 4.000 ppm. Relative
ovarian weight was also reduced in females receiving 4,000 ppm. Histological examination revealed
.a flose-related increase, in the incidences of renal calculi but no gross lesions. The incidence of calculi,
^ '" ' '
renal epithelial hyperplasia, and tissue reaction to calculi were significant in males receiving 4,000 ppm.
* >
The effects were most pronounced in the high-dose groups. Most of these effects were considered to
represent secondary changes that occurred as a result of reduced dietary intake and reduced growth rate.
This study suggested a NOAEL of less than 200 ppm (10 mg simazine/kg/day) based on adverse
hematological and clinical chemistry indices and dose-related incidence of renal calculi The results of
this study were, however, considered to be of limited value because the reduction in food intake
associated with the addition of simazine to the diet seriously affected the nutritional status of treated rats.
A subchronic toxicity study for simazine was carried out in dogs (Tai et aL, 1985b) using a protocol
similar to that described above and was also reviewed by the U.S. EPA (Robinson et aL, 1985)^
Purebred 7- to 8-month-old beagle dogs (body weight ranging from 8.0 to 10.0 kg for males and 7.0 to,:
8.6 kg for females) were assigned to one of four groups, each consisting of four/sex, and were fed diets
containing technical grade simazine (97.5% pure) at concentrations of 0, 200,2,000, and 4,000 ppm for
at least 91 consecutive days. All dogs were observed daily for mortality and signs of toxiciry. Blood
and urine were collected from all dogs at predose and at study days 44 and 92 for hematologicai, clinical
chemistry, and urinalysis determinations. All dogs were sacrificed and necropsied between 93 and 98
days of study for gross and histopathological investigation.
V-5
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Simazine Catena Document
Treaimem-related clinical signs observed in dogs receiving 4,000 ppm included alopecia, tremors,
dermatitis (males), and emesis (females). Mean daily feed consumption was significantly reduced in the
2,000- and 4,000-ppm dose groups compared with controls in both sexes throughout the 13-week feeding
period. Males in the 4,000-ppm dose group and females in the 2,000- and 4,000-ppm dose groups lost
weight during the 13-week feeding. Based on actual feed consumption, the average dose of simazine
for the 200-, 2,000-, and 4,000-ppm groups was 6.9, 65.2, and 133.6 mg/kg/day for males and 8.2, 64.3,
and 136.7 mg/kg/day for females, respectively. Erythrocyte counts, hemoglobin, and hematocrit were
reduced in. both sexes dosed, at 4,000 ppm during weeks 7 and 13; lieutrophils were higher and
lymphocytes were lower compared with controls in males dosed at 4,000 ppm at week 13; platelet count
was increased in males receiving 400 ppm during weeks 7 and 13; eosinophils were reduced in males
at all doses at'week 7 and in males receiving 4,000 ppm at week 13; and prothrombin time was
significantly less in females at all doses at week 13,when compared with controls. Significantly lowered
serum albumin/increased serum globulin, and decreased albumin/globulin ratio were observed in males
receiving 2,000 and 4;000 ppm at week 13. Serum SCOT and creatinine levels were high in males
receiving 4,000 ppm at week. 13, and calcium ions (divalent) were increased in males receiving 2,000
and 4,000 ppm at week 13 when compared with controls. Urinary ketone levels were increased in males
and females in the mid- and high-dose groups at week 7, and in males receiving the high dose at week
* i *
13 when compared with controls. Although differences were found in the organ weights (especially the
&
heart, brain, and liver compared with controls), no gross or microscopic lesions attributable to simazine
were revealed. «
This study suggested a NOAEL of 200 ppm (7 mg/kg/day) based on reduced serum albumin levels,
increased serum globulin, and elevated urinary ketone at 2,000 ppm (maximum tolerated dose of
simazine). The study authors commented that 200 ppm simazine in the diet for 1 year might result in
a decreased weight gain. However, as with the previous study in rats, the results of this study are of
limited value because the reduced feed consumption seriously affected the nutritional status of test
animals.
Mazaev (1965) administered daily oral doses of 20 or 100 mg simazine/kg in a starch solution to
rats and guinea pigs for 6 months. The higher level suppressed the weight gain of the animals and
caused an increase in the number of leukocytes and a decrease in cholinesterase activity in blood during
the first 2 months of the study. No changes in the blood protein fractions, hemoglobin content, number
of erythrocytes, or liver carbohydrate metabolism were evident. However, some dystrophic changes of
V-6
-------
Simazine Criteria Document
»
the kidneys and atrophic gastritis were found. This study is of minimal value because the details of
experimental design (including number of animals) were not reported in this abstract.
Dshurov (1979) studied histological changes in the organs of 21 sheep (29 to 48 kg, 1.5 to 6 years
old) following oral administration of various dosing regimens of sinuzine (50% active ingredient) (Table
V-2). Fatty and granular liver degeneration, diffuse granular kidney degeneration, neuronophagia, diffuse
glial proliferation, and degeneration of ganglion cells 'in the cerebrum and medulla, were found. Sheep
that died showed spongy degeneration, hyperemia, and edema in the cerebrum; the de"gree of change
varied with the dose of simazine and the period of dosing. The thyroid showed hypofunction after
repeated daily doses of 1.4 to 6.0 mg/kg administered for periods varying ffom 63 to 142 days. The
' ' :>
greatest antithyroid effect followed one or two doses at 250 mg/kg, which produced parenchymatous
goiter and a papillary adenoma in one of the three dosed sheep. This type of goiter was also seen in
Sheep administered 50 or 100 mg simazine/kg once each week for approximately 22 weeks. The report
does not provide sufficient details on dose/duration effects on which to base determination of the
NOAEL or LOAEL. ' -f :
t
«
2. Chronic Toxicitv . -,,<--.
A chronic toxicity study with Swiss white, Charles River CD-I mice fed diets containing simazine
herbicide for 17 to 22 months was reported by-Ciba-Geigy (1980a). The study was conducted by
Industrial Bio-Test Laboratories/Inc. (JBT).-..The EPA has declared this study invalid owing to
-------
Simazine Criteria Document
Table V-2. Oral Toxicity of Simazine in Sheep Following
Administration of Various Dosing Regimens
No. of sheep
2
2
2
2
8
2
- .'-* .'"" i
.2-
. -3-- ,- .
Dose (mg/kg)
(50% a.i.)'
0
1.4
3.0
6.0 '
25
50
100
. -*- *_y ?. * '. ' ,i
250
Exposure duration
b
9 '
90 and 129 days
63 and 65 -days
;-.'. "141 and- 142, days
37, 49, 63. 69, 90, and 111 days
,% . Every. 7'days for 133 days. . . '
* -. ' -"
Every 7 days for -15 3 days '' '"
4
i^.- " " *
One or two doses with a 20- to :
30-day interval between doses
*a.L = Active ingredient.
bNot reported.
SOURCE: Adapted from Dshurov (1979).
V-8
-------
Simaz-re Criteria Document
higher incidence of enlarged seminal vesicles in males fed the 3,000-ppm diet and a greater number of
enlarged spleens in females fed the 15- or 1,000-ppm diets when compared with all other groups of the
same sex. Antemortem observations such as skin irritation, hair loss, and skin lesions reportedly were
not compound related. No histopathological lesions were found in any of the animals. However, this
study is inadequate for evaluating the chronic toxicity of simazine owing to the questionable laboratory
practices adopted by IBT. . ,
A 95-week chronic feeding toxicity/oncogenicity study ire Crl:CDl(ICR)BR mice was .recently
reported by Hazelette and Green (1988 for Ciba-Geigy). Simazjne of undefined purity (the same batch
of simazine was reported to be 97.5% pure in a subchronic oral study with rats) was mixed in the diet
at concentrations of 0,40,1,000, or 4,000 ppm and fed to.5-week-old mice (males weighing 19.1 to 32.1
g and females weighing 14.4 to 26.3 g). These dietary levels correspond to simazine doses of 0, 6,150,
'and 600 mg/kg/day.. However, based on actual food intake, the mean compound intake for the entire
study was 0,5.3,131.5, and 542 mg/kg/day for males and 0, 6.2,160, and 652.1 mg/kg/day for females.
Body weights and food consumption were determined weekly up to week 13 and monthly thereafter.
Water "consumption was measure
-------
Simazine Criteria Document
groups, the' feed consumption also correlated with body weight gains. Water consumption tended to be
decreased in males and females receiving 1,000 and 4,000'ppm.
Hematocrit (HCT) and hemoglobin (HGB) values in high-dose mice tended to be lower than those
of controls. He wever, HCT was statistically significant (p <0.05) only in males at day 184, and HGB
was significant in females at day 365. The changes in erythroid indices, mean corpuscular volume, and
me^n corpuscular HGB concentration did not correlate with changes in red blood cells. HCT, and HGB.
C tt *
Slight alterations in other hematologic indices were considered to be of no biologic" significance.
Urinary indices were normal in dosed ^groups. No significant changes were noted'in absolute and
£ *
relative .organ weights and organ-to-brain weight ratios in males after 26 weeks, 52 weeks, or at the .
. «
terminal sacrifice. There were several significant (p = 0.05 or 0.01) increases in organ-to-body weight
ratios in females receiving 1,000 and 4,000 ppm simazine. However, these changes generally correlated
with reductions of body weights and were not accompanied by increases in absolute organ weights or
organ-to-brain weight ratios. -There were no dose-related incidences of gross pathology. Histologicallv,
amyloidosis was significantly increased in dosed groups compared with controls. The incidence was
fairly high as early as'the 52-week sacrifice (62% of males and 20% of females in all groups combined)/ '
When "the numbers of mice from each group with amyloidosis at any site were compared, no increase
was related to dosing. Amyloidosis was not considered to be related to dosing with simazine. This
study suggested a LOAEL of 1,000 ppm (150 mg simazine/kg/day) based on decreased weight gain and
a NOAEL of 40 ppm (6 mg simazine/kg/day).
The U.S. EPA (loannou and Copley, 1988) has reviewed and evaluated an oral 2-year chronic
toxicity/oncogenicity study (McCormick et al., 1988, for Ciba-Geigy) in 6-week-old Sprague-Dawley
albino rats (males weighing 126 to 189 g, females weighing 101 to 167 g). Groups of randoml^***"
assigned animals (40 rats/sex in the control and 1,000-ppm groups, and 30 rats/sex in the 10- and 100-
ppm groups) were fed diets containing 0 (control), 10, 100, or 1,000 ppm technical grade simazine
(96.9% pure), which corresponds to simazine doses of 0, 0.5, 5.0, and 50 mg/kg/day, respectively, for
104 weeks (7 days/week) according to the schedule in Table V-3.
V-10
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Simazine Criteria Document
Table V-3. Experimental Design for the Chronic/Carcinogenicity Study With Rais
Dose group
(ppmVphase
Control
",
' 10
100
1,000
-
Chronic
Carcinogenicity
Chronic
Carcinogenicity
Chronic
Carcinogenicity
Chronic
Carcinogenicity
No. rats
Males
10
10
20
50
10
20
50
10
20
50
10
' 10"
20
50
Females
10
10
20
50
.10
20
50
10 " :
20
50
10
10b
20
50
Time of sacrifice '
(52 weeks) Least number '
Males Females Of dose weeks
10 10 . 52
52 + 52-week recovery
104
104
10* 10 52 :'
104 i;
3 ' '
'.104 l
1.0 101 52 '' . A
' ' .104 ' M
i
104
10 101 52
52 + 52-week recovery
104
104
>***;
Only nine animals were actually sacrificed in these dose groups.
These 10 animals were excluded from analysis.
SOURCE: Adapted from McCormick et al. (1988).
V-ll
-------
Simarine Criieria Document
All animals were observed daily for clinical signs of toxiciiy and mortality. Food consumption and
body weights were determined weekly for study weeks 1 through 13, biweekly for smdy weeks 14
through 25, and monthly thereafter. Water consumption was measured at study weeks 1, 2,' 53 'through
64, and 102. Hematological, blood biochemistry, and urinalysis determinations were carried out as
indicated in Table V-4.
, The mortality rate was' high (40-79%) between study weeks 53 and 106 (terminal sacrifice) for all
groups. The survival rate in females in the 1,000-ppm group was 20% as .compared with 34% in
controls; for males, the survival rate was higher than that of controls (60% versus 39%). Mean body
weights for males and females in the 1,000-ppm group were significantly (p <0.0l) lower than those of
controls from day 7 through termination of the study (day 728). For the 100-ppm group, female rats
had significantly (p
-------
inff Criteria Document
Table V^t. Schedule for Hematology, Blood Chemistry, and Urinalyses for the
Chronic/Carcinogenicity Study With Rats
No. nu used for clinical
lab determinations!
Dose
group (ppts)
Baseline*
Control
10 .'
100
1.000
- NO;
M
20
to
20
.20
. 20
io
20
nil
WaBt
F
20
10
20
20°
20
10
20
Week of
ucnfice
1
105-106
105-106
105-106
105-106
105-106
105-106
Haruiolog
M
10
10
to .
10
. 10
-to
10 . .
r1
F -
10
10
to *
,10' -
aio
to ':
10
|iocfl
M
' 10
10
10
10
10*
. - -
* 10'
10
on.*
F
10
10
10
10
10
a
10
10
Uriaalyserit
M
10
10
10
. 10
10
> .
' 10
10
F
to
10
10
10
10
<7
80'
10
Aaimaii from the caicissf enicity pluat were wed Tor Qtett deiennioaaoDi u tin flnai sunpUng pehod ia
order io luve lO/ieVgrovp. ' ' ' :
*AMlyiet wen conducted pradoM (lest weel^ -1) on baeline taiouto: al weeki 25 and M. T7 aad 78. ud 104
on tainuli Jitigoed to toe 104-week chronic phue; and u week! 52, 65 ud 66, and 78 and 104 on tntmaU
anigoed to (be recovery pbaie. .
Bueline aniroalt included tO/sex for hentiology ud 10/iez for b|oebeau»ry ud wiaalyiu.
SOURCE: Adapted £rom McCormidc ei aL (1988).
V-13
-------
Simazir.e Criteria Document
group males, significantly lower valuestwere seen on day 537 for MCV and on days 537 and 725 for'
MCHB.
The only changes in clinical chemistry indices attributable to simazine treatment were the depression
of glucose levels in females at all time points of sampling. The lower glucose values, however, might
. be the indirect result of depressed body weights in this group. Glucose depression was also seen with
the recovery group females at all time points tested except day 725. Most of the urinalysis indices were
comparable in the control and treated groups in both sexes.
Significant (p <0.05 to 0.01) decreases in absolute organ weight were observed for the brain in males
receiving 1,000 ppm at the 52-week sacrifice, for the heart in males receiving 1,000 ppm at the terminal
sacrifice, and for the liver in females'receiving 1.000 ppm at the 52-week sacrifice. In male rats
receiving 1,000 ppm,'the relative weights for the brain, liver, and testes were significantly (p <0.05)
higher than those of controls at the.52- and 104-week sacrifices. In females receiving' 1,000 ppm,.tH&
relative weights of the brain, heart, adrenal, kidney, liver, and ovaries at the 52-week interim sacrifice/
were significantly higher than those of controls; for kidneys, a significant difference was also seen at
the 100-ppm dose. Additionally, the relative weights of the heart, kidney, and liver were significantly
higher than controls in the 1,000-ppm group at the 104-week terminal sacrifice. Significantly lower
organ-to-brain weight ratios were observed for the heart in males receiving 1,000 ppm at the 104-week
sacrifice and for the liver in females receiving 1,000 ppm at the 52-week sacrifice. The organ weight
changes mentioned above were not thought to indicate a major lexicological concern, since such changes
-
were .not. associated with concomitant clinical chemistry changes or changes in macroscopic or
9 '
" { / fpticroscopic.pathology in the same organs. In this study, the LOAEL of 5.3 mg simazine/kg/day in rats
»'-' --.**. »
Vas based on body_weight depression and depression of hematology indices (RBC, HGB, and HCT) in
female rats.,.,TheTICi^Hrwas found to be'0.52 mg simazine/kg/day. .4^.,-.-
Gysin and Knusli (1960) reported that simazine, fed to rats for 2 years' at 1,10, or 100 ppm in the
diet, produced no apparent signs of systemic toxicity (no details given). These diets correspond to doses
of about 0.05, 0.5, or 5 mg/kg/day, assuming daily consumption of 40 g feed/kg bw.
The U.S. EPA (Anderson and Copley, 1988) evaluated a 1-year chronic feeding study (McCormick
and Green, 1988, for Cifaa-Geigy) in beagle dogs approximately 6 months old (males weighing 7.5 to
9.1 kg, females weighing 6.5 to 8.2 kg). Technical grade simazine of unspecified purity (the same batch
V-14
-------
Simazine Criteria Document
of simazine was reported to b^ ?/.5% pure in a previous study) was included in the diet at 0, 20, 100,
and 1,250 ppm, which corresponds to simazine doses of 0, 0.76, 3.6, and 45 mg/kg/day for females 'and
0,0.68, 3.4, and 43 mg/kg/day for males. The diet with or without (control) simazine was'administered
to randomly grouped (four per group) animals for 52 weeks (7 days/week). Animals were inspected
daily for signs of toxicity and mortality. The animals were weighed weekly for the first 12 weeks and
monthly thereafter. Mean daily dietary consumption was determined. Efficiency and compound intake
were calculated from the food consumption and the body weight gain data. Hematology and clinical
chemistry analyses were carried out on blood samples collected from.all animals before treatment and
at days §6,177, and 359. Urinalyses were carried out on usually catheterized urine from predosing and
at 86,177, and 359 days. All animals were sacrificed ori schedule and-subjected to gross pathology and
histopathology. ' ..' . .
Apparent dose-related fecal changes such as diarrhea, discoloration and presence of blood, and
infrequent emesis were observed: Cachexia* was noted in one male/and one female dog receiving 1.25Q
ppm from study'weeks 14 through 22. No deaths occurred during the study period. Male body weigh;.
gain was depressed at the 1,250-ppm dose level during most of the study but not at the end of the study.
i .
Body weight gain in females dosed at 1,250 ppm was depressed through study week -36, when females
appeared to begin gaining body weight. Almost all animals gained a normal amount of weight at the
100-ppm dose level. Food consumption was reduced in females receiving 1,250 ppm during the first
20 .weeks of study; otherwise, no reductions in food intake were observed for males and females. Food-
efficiency appeared to be compromised only in females receiving 1,250 ppm during the first 12 weeks *
of the study.
In males receiving 1,250 ppm, a transient nominal decrease was observed in RBC and HGB at study
days 86 and 177, and a significant (p <0.05) depression in.HCT was observed at study day 86 when
compared with controls. The platelet counts were significantly (p <0.05-0.01) elevated in the 1,250-ppm
males at the end of 86 (142%), 177 (170%), and 359 (155%) days of dosing. In the 1,250-ppm females,
a significant (p <0.05) transient decrease in RBC, HGB, and HCT occurred at study days 86 and 177.
MCHB was slightly but significantly elevated after 359 days of dosing, but MCV, MCHB, and MCHC
values were within the control range. The study indicated that the hematologic effects were secondary
to body weight decrements, but additional data were not provided as evidence.
V.-1S
-------
Sinmir.e Criteria Document
Random changes occurred in clinical chemistry indices at the 1,250-ppm dose level, but they
appeared to be neither consistent nor dose related. This was true for elevation in serum sodium in male
dose groups at 177 days and for decreases in serum calcium in all female dose groups at 86 days.
Urinalyses did not reveal any treatment-related changes. No dose-related effects occurred in organ
weights, organ-to-brain weight ratios, and organ-to-body weight ratios despite some observed nominal
increases" in adrenal (130%), kidney (111%), and livet (108%) weights, and decreases in the
. thyroid/parathyroid (60%) and spleen (69%) weights in males dosed at 1,250 ppm. Similarly, in females
.. dosed at l;250 ppm, some nominal weight increases were noted in the adrenal (129%), liver (104%),
and thyroid/parathyroid (114%), and weight decreases were noted in the spleen (81%). Neither gross
nor microscopic dose-related effects were observed in the above organs and tissues.
3
, This' study indicated a NOAEL of 20 ppm or 0.76 mg simazine/kg/day for females or 0.68 mg
simazine/kg/day for males. These Values are quite close,.and, therefpre, a mean of 0.72 rhg
simazine/kg/day can t>e considered as the NOAEL. Based on decreased body weight gain, and decrease?
. in RBG, HGB, HCT, and a nominal increase in platelet counts in tcmales, idO ppm or 3.6 mg
simazine/kg/day is indicated .as the LOAEL. .
In a 2-year chronic feeding study in beagles, simazine SOW (80%) was administered in the diet at
15,150, and 1,500 ppm (Woodard Research Corporation, 1965b, as cited in NAS, 1977). These levels
correspond to doses of about 0.35, 3.5, or 35 mg/kg/day, assuming 1 ppm is. equivalent to 0.025
mg/kg/day (Lehman, 1959). Animals receiving the high dose (1,500 ppm) developed a slight thyroid
hyperplasia, and several dogs fed 1,500 ppm had slight increases in serum alkaline phosphatase and
serum glutamic-oxaloacetic transaminase activities. Minimal data were reported on which to base an
evaluation of a dose-response relationship. U.S. EPA (1985) evaluated this study (submitted by Ciba-
Geigy Chemical Corp. for registration), in which all dogs survived the 2-year period with no signs of
toxieity due to dietary administration of simazine at 15,150. and 1,500 ppm, except for a net weight loss
of 6% at 1,500 ppm and reduced weight gain at 150 ppm during the first year of the study. These
differences could not be accounted for, since the reports lacked individual feeding records. Neither
chronic toxieity nor oncogenic potential could be determined from this study.
Clayton and Clayton (1981) reported that when simazine was fed to dogs for 2 years, no adverse
effects were seen at the 12- and 120-ppm dietary concentrations; however, slight signs of toxieity were
noted at the 1,200-ppm dietary concentration. Other data were not presented.
V-16
-------
EFFECTS
i
A two-generation reproductive toxicity study (Ciba-Geigy Corp., 1992) was carried out in Sprague-
Dawley rats (CRL: COBS CD (SD) BR) using simazine technical (96.5% pure) in the die:. Two
,l
successive generations (F0 and F.) of rats (30/sex/group) were fed continuously throughout
premating/rest, mating, gestation, and lactation periods with the herbicide at 10,100, and 500 ppm levels
in the diet: a control group received the diet without simazine. The F, generation of all four groups fijad
two matings, which produced F^ and Fa offspring. In the 10 ppm groups, neither adverse clinical signs,
;i
toxicologic effects nor mortality were observed. Treatment-related transient reductions in body weight
gains (about 6-13%} but no mortality were observed in the 100 ppm F0 and F, parental animals. In die
500 ppm groups, significant reductions in mean body weight gains were noted during the feeding periocs
in parental males (approximately 27% for F0, and 8-51% for F: generations) and in parental females
(approximately 38% for F0? and 32-75% for F. generations). A comparison between treated (F0 and F»
progeny)^ and control groups revealed no treatment-related effects on mating, duration of gestation,;
fertility, and mating and gestation indices. Similarly, no differences in die treatment-related effects, were;,
i ,'
noted in any of the measured reproductive parameters (the mean number of implantation sites and viable i:
* ' i !
rjeonates, the mean number and percentage post-implantation loss and the-mean number and percentage ij
of still births) between treated and control groups. There were no treatment-related effects on F, and f
Ffc pup survival, weights, sex ratios, or malformations at any feeding level.
A significant increase (approximately 11 %) in mean relative testicuiar weight in F0 males was related
to a treatment-related decrease in body weight gain in these animals since meari absolute testicular
weights were unaffected. Mean absolute and relative ovarian weights in F0 females were not affected
by treatment. Also, slight increases in F, relative testicular weight and Fl mean relative ovarian weights
were attributed to treatment-related decreases in mean terminal body weights. Treatment-related effects
were not noted following gross necropsy or histopathological examination of tissues in any of the created
groups. Based on the results of this study, simazine technical was not considered t^ffecr reproductive
performance in rats. The-reproductive NOAEL was suggested as 500 ppm and the parental NOAEL as
10 ppm. The dietary level of 500 ppm simazine was considered equal to or greater than the maximum
tolerated dose, based on die significant reduction in body weights observed at this level.
Woodard Research Corporation (1965a) conducted a mree-generation reproduction study in rats and
found no adverse effects on the development or reproductive performance of the animals, A group of
V-17
-------
Simazine Criteria Document
40 weanling Charles River albino rats (20 males, 20 females; F, generation) were fed simazine SOW
(80%) in the diet at 100 ppm (approximately 5-mg/kg/day, assuming a daily consumption of 50 g
feed/kg bw). Another group of 20 males and '20 females served as controls. After exposure to the test
compound for 74 days, the two sexes were paired and allowed to mate for 10 days. The Fu generation
and litters were examined for the number of live pups and the mean litter weights, number of stillborn,
and physical condition of test animals. After weaning the first litters, parents were remated as different
pairs and F,b litters were obtained and examined. The Ft animals were divided into two test groups.
One group was. fed simazine at 50 ppm (approximately 2.5 mg/kg/day), and the other group was fed
simazine at 100 ppm (approximately 5 mg/kg/day). After 81 days of dosing, the animals were mated,
and Fi and Fa litters 'were produced. Fa"rats were mated to produce Fj, and F3b litters. At weaning,
the F3, litters were sacrificed and the F3b Utters were necropsied, Liver, kidney, and heart weights were
determined for two animals/sex/litter at weaning. These tissues plus the spleen, adrenal, thyroid, gonad,
and bone marrow were preserved. Tissues from one animal/sex/litter were examined histologically.
0 ,
Data from this. 1965 study were reevaluated by the U.S. EPA in 1989 (Spencer and Copley, 1989).,
It was pointed out that the purity of simazine used in this study was 8(5%. The test diets were not
<>.
assayed for homogeneity orjpj the actual amount of simazine present in the diet. No statistical analyses
..'." «
of the data were performed.. Food and "water consumption data were not compiled. Daily observation
^>c°.':- rf .parental -afl&fiB&^alled no clinical signs of toxicity. However, body weight gains were reduced
---' " £ _r. '""''' '
teJ^ generation in males but not in females. Reduced gains were observed as early as the second
. " ° °
'jpek of, exposure to 100 ppra,simazine. A 9.5% reduction in weight gain was seen by week 14 when
compared with controls.
In the Fls males, 7.7 and 15.6% reductions in weight were observed by weeks 16 and 26,
respectively, in the 100-ppm group as compared with controls. At 16 weeks, however, a greater change
was observed in the 50-ppm group than in the 100-ppm group, in that the percentage of weight loss was
18.7 and 22.7, respectively, as compared with controls. In Ftb females, the weight loss was about 7.5%
by study week 8 in both the 50- and 100-ppm groups. Males in the Fa generation appeared to be more
affected by the 50-ppm dose diet than by the 100-ppm dose diet. About 10% weight loss occurred at
50 ppm by week 17 of the study! F^ females exhibited weight losses of about 10% by week 11 of the
study at both dosages. The adult animals were not weighed during gestation or lactation.
V-18
-------
Simazine Criteria Document
Absolute organ weights and organ-to-body weight ratios were similar to those of treated animals and
controls. However, a dose-related increasing trend in absolute liver weights was noted in the F3b
weanling males. No gross lesions relating to dietary exposure to simazine were observed, although
necropsy results were sparsely reported. No histopathqlogy wa.> reported in adult males, including 3/10
in the iOO-ppm Fib group that appeared to have been sterile in their mating efforts. No histopaihologic
changes were observed in one male and one female examined in each litter of the F3b pups as^compared
with controls. Treated pup mean weights (g/pup/litter) a: birth did not vary significantly from controls
in any generation.
The Agency concluded (Spencer and Copley, 1989) that this study suggests a parental toxicity
NOAEL of <50 ppm and a LOAEL of 50 ppm based on reduced weight gains in males during the
premating periods. A reproductive toxicity NOAEL/LOAEL could not be determined based on lack of
evaluation of apparent sterility in the F,b generation males. Up to 33% of the'potential parental stock
f
at 100 ppm did not produce a pregnant female in two successive breeding sessions. '; . l
. " ' * *
Chen (1981) studied the teratogenic effects of simazine in rats. The herbicide was administered by
gastric intubation to pregnant rats from gestation days 6 through 15 at dose levels of 78,312,1,250, and
2,500 mg/kg bw/day. Ossification of the sternum and cranium was delayed at all four dose levels. At
doses of 312-mg/kg and above, body weight gain was inhibited in the dams, the number of live fetuses
wa°s reduced, and the rate of fetal resorptions increased. At the higher dose level (2,500 mg/kg),
simazine caused delayed fetal development. The author concluded that simazine was toxic to rat
embryos but was not teratogenic.
The U.S. EPA (Anderson and Copley, 1988) evaluated a maternal and developmental (embryo/fetal)
*
toxicity study carried out in Crl: COBS CD SD BR rats (Mainiero.et.al., 1986). The age of die animals
at mating was not specified, but weights were in the range of 200 to 350 g. Technical grade simazine
of unspecified purity (the same batch was specified as 97.5% pure in a previous subchronic study in
dogs) was administered by gavage in 2% carboxymethylcellulose in a volume of 10 mL/kg. Simazine
was administered on gestation days 6 through 15 in doses of 30, 300, and 600 mg/kg/day. Animals were
observed twice daily for signs of toxicity and mortality, and weighed on gestation days 0 (the day sperm
were detected), 6, 10, 14, 18, and 20; carcass weights (body:weight minus uterus and contents) were
determined on gestation day 20. Feed consumption was reported between gestation days 0 and 5, from
gestation days 6 through 15, on days 16/17, and days 18/19. Relative efficiency of feed utilization was
V-19
-------
Simazir.e Criteria Document
calculated as mean daily body weight gain (kg) divided by mean daily feed consumption (g). Dams
.were killed on gestation day 20 by carbon dioxide asphyxiation and subjected to gross pathology. Fetal
- examination consisted of evaluation of viable litter size, live and dead fetuses, and postimplantation loss.
Significant (p <0.5-0.1) reduction in body weights compared with vehicle-created controls occurred
on gestation days 10 (93%), 14 (89%), and 18 (94%) in rats dosed at 300 mg/kg/day; at 600 mg/kg/day,
the corresponding values were 90, 86, and 94%, respectively. The carcass weight was decreased 93 and
91% in the 300- and 600-mg/kg/day dose groups. Body weight gains were significantly less (p <0.05)
than controls from gestation days 6 to 10 and 10 to 14, and greater (p <0.05) than controls from
a
gestation days 14 to 18 and 18 to 20 in animals dosed at 300 and 600.mg/kg/day. Food consumption
was significantly (p <0.05-0.01) decreased from gestation days 6 through 15, and increased during
gestation days 15 through 19 at both the mid and high doses. The relative efficiency of food utilization
apparently decreased at the mid and high doses for gestation days 7 to 10, and a nominal decrease
occurred for days 7 to 10 at .the 30-mg/kg/day dose level, and for days 11 to 14 at the 600-mg/kg/day"
dose level. Treated and control rats gained the least body weight and consumed -the least food during
gestation days 6 through 10.
Gross pathology of dams demonstrated no dose-related effects. No dose-related effects were noted
for mean fetal weights, viable litter size, live and dead fetuses, .postimplantation loss, and visceral
*
malformations or variations. Some random variations occurred, including short or absent renal papillae,
dilated uterus, dilated trachea, and mottled livers. Skeletal effects that occurred in fetuses on a litter
basis in a dose-related manner but that were reported as not significant were unossified presphenoid at
600 mg/kg/day and additional lumbar vertebrae/centra at 300 and 600 mg/kg/day. Additionally, the total
number of variations were* nominally increased and appeared to be dose-related in fetuses at all dose
levels. Significant
(p <0.05-0.01) fetal skeletal variations that occurred at 300 and 600 mg/kg/day were as follows: head
incompletely ossified, unossified teeth, unossified centra/vertebrae and/or additional, rudimentary ribs,
and unossified stemebrae. These results suggested a NOAEL of 30 mg/kg/day for developmental
(embryo/fetal) toxicity and a LOAEL of 300 mg/kg/day. No malformations were reported. A maternal
toxicity NOAEL of 30 mg/kg/day and a LOAEL of 300 mg/kg/day and higher for decreased maternal
body weight and body weight gain, food consumption, and efficiency of food utilization were also
identified in this study.
V-20
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Simazine Criteria Document
In evaluating this study, the U.S. EPA (Anderson and Copley, 1988) pointed out that most of the
parameters associated with fetal toxicity frequently occur in association with maternal toxicity and some
might disappear if the fetuses were followed after birth. The statistically significant increase in fetuses
but not in litters for unossified stemebrae at all dose levels may not be real, especially at 30 mg/kg/day.
* o .
The increase in unossified stemebrae at 30 mg/kg/day resulted from a high non-dose-related incidence
of unossified stemebrae 5 and 6 in all groups, and a low incidence for stemebrae 1, 2, 3, and 4. A
comparatively higher incidence of unossified stemebrae 2 and 3 resulted in a doss-related manner at 300
' '
and 600 mg/kg/day and in the apparent dose-related response seen at the 30-mg/kg/day dose. For this
.study, the high incidence in historical controls, the failure of the effects to be statistically significant in
i
litters, and the interaction of the incidence of the"six stemebrae and the unossified stemebrae in animals
* *
dosed at 30 mg/kg/day are not considered to be an effect. The Agency has requested additional
information related to the mode of preparation of the test material, the appropriate particle sizes and the
distribution of panicle sizes of the test material suspended in the vehicle, the analyses data on samples
of dosing suspensions, the purity .of the test material, and the source of the test animals in the study}.
The study was graded as being supplementary because of the additional information requested. -
» " . ^ * . -.
»
«
iSimazins (technical grade), was administered by gavage to a group of 19 New Zealand White rabbits
(2.5 to 4;5 kg) at daily doses of 5,75, or ?00 mg/kg for days 7 through 19 of presumed gestation (Ciba-
Geigy, 1984). The herbicide was delivered as.a suspension in 3% comstarch containing 0.5% Tween-80.
A control group was given the vehicle only. One death was observed in each group; however, death
of the low-dose dam was assumed to be due to a dosing accident and not to the compound-related drug.
Maternal toxicity at 75 and 200 mg/kg was indicated by abortions, tremors, decreased motor control and
activity, ataxia (in one high-dose animal), few or no stools, anorexia, weight loss, and decreased body
weight gain, Embryotoxicity was not observed, but fetal toxicity, which was believed to be the
consequence of maternal toxicity, was evident in the intermediate and high-dose groups as indicated by
decreased numbers of viable fetuses. Fetal toxicity at 200 mg/kg also was reflected by reduced fetal
body weights, increased occurrence of floating and fully formed ribs, and decreased ossification of the
patellae. No malformations were associated with any dose level of simazine, and at 5 mg/kg the
herbicide exerted neither toxic nor teratogenic effects. The authors concluded that at doses of 75
mg/kg/day and higher, simazine was very toxic to fetuses and dams but was neither embryotoxic nor
teratogenic.
V-21
-------
SLmazine Criteria Docu.-r.ent
Tnis teratology study has been reviewed by the U.S. EPA (Mount/on et al., 1986, for Ciba-Geigy),
and adequate explanations for some of the issues were sought. Ciba-Geigy has responded to these issues
by supplying additional information and satisfactorily addressing the issues raised in the review. First.
while the study reported statistically significant decreases in the mean number of live fetuses at the 75-
and 1100-mg/Tcg dose levels, the data presented for the groups dosed at 0 (control), 5,75, and 200 mg/kg
were 7.9, 8.4, 6.8, and 7.8, respectively. The mean of 7.8 in the 200-mg/kg group was not significantly
different from the mean of 7.9 for the control group. Furthermore, the differences between the control
group and the 75- and 200-mg/kg groups were demonstrated only, in a nonparametric analysis of
covariance with the number of implantation sites as a covariant. Thus, no significant differences were
found to exist between controls and treated groups jor this reproductive index. Second, the EPA
reviewers questioned the validity 'of calculating the pre- artd postimplamation loss rates. They
determined that instead of calculating loss percentages per dam and .then deriving mean group loss
percentages, the investigators should have calculated group percentages of pre- and postimplantation
losses 'using the total .numbers of corpora lutea, implantations, and viable fetuses per dose group.1
a »
However, the Ciba-Geigy group explained to the satisfaction of the Agency'that if one failed to use the
' - line/-as. the excsrimental unit, the latter procedure would lead to the incorrecj assumption that there can
c
be no influence of litter ifize upon fetal and embryonic viability, and that the fetus, instead of the, liner.
5 .
is the experimental-unit.
ft
The Agency concluded that based on this study, the teratogenic NOAEL for simazine in rabbits was
up to and including 200 mg/kg when administered by gavage on days 7 through 19 of gestation. At 200
mg/kg, a significant reduction in mean fetal weight and a significant increase in the incidence of skeletal
variations in fetuses were observed. The fetotoxic NOAEL was 75 mg/kg. The maternal NOAEL was
5 mg/kg based on decreased body weight gain, tremors, and increased abortions at 75 and 200 mg/kg.
Dshurov (1979) reported that repeated oral administration of simazine to sheep (6.0 mg/kg for 142
days or 25 mg/kg for 37 to 111 days) caused necrosis and dystrophy in the germinal epithelium of the
testes and disturbances of spermatogenesis.
No treatment-related developmental effects were observed by Newell and Dilley (1978) in the
offspring of pregnant rats exposed to simazine at 0, 17, 77, and 317 mg/mj via inhalation for 1 to 3
hours/day on days 7 through 14 of gestation.
V-22
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Simazir.e Criteria Document
Dunachie and Fletcher (1970) tested 25 herbicides, including simazine, for their toxiciry to chicken
embryos, using an egg-injection technique. Except for feather blanching caused by some of the substitute
phenoxy-acids, no teratogenic effects were found. According to the authors, simazine was difficult to
dissolve and to keep in solution; concentrations up to 300 ppm (in 75% acetone) did not produce any
significant toxic effect.
i' ." . ' *
The effect of simazine on the gonads of chick and quail embryos in in vitro culture has been studied
by Didier (1974). In these studies, gonads of 9-day-old embryos were explanted on a medium
containing simazine. After 5 days, the male gonads of the chick embryos displayed sterility or reduced
fertility, while the ovaries reacted by a Joss of cortex. In the quail embryos, the germinal material of
the testes was destroyed and the gonocytes of the ovary degenerated.
D. MUTAGENIC1TY .
n. ' ' '
. ^
«.
Relatively few studies investigating the genotoxic potential of simazine have appeared in the
published literature. This section includes the published experiments as well as a series of unpublished
assays that were performed to meet U.S. EPA registration requirements. These are categorized into gene
*
mutation assays (Category 1), chromosome aberration assays (Category 2), and studies thar assess other
mutagenic mechanisms (Category 3), The findings are discussed below.
o
1. Gene Mutation Assays (Category I)
a. Microorganisms, reverse and forward mutations
Anderson et aL (1972) evaluated the mutagenicity of 110 herbicides including simazine by measuring
reversion frequency of histidine independence in eight unidentified mutant strains of Salmonella
typhimurium. Small crystals of simazine were applied directly to the surface of each plate after the top
agar layer (containing the bacteria) had solidified. Further details were not reported. Simazine did not
cause a measurable increase in reversion frequency in comparison with controls.
Simmons et al. (1979) evaluated the mutagenicity of 18 pesticides including simazine by measuring
reverse mutation frequencies in S. rfphimurium and Escherichia colL Simazine was negative in both
tests. Experimental details were not reported. Simazine also elicited negative responses when tested
V-23
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Simazir.e Criierla Document
for mutagenicity in 5. yphimurium (Commoner, 1976), E. coli, mdSerratia marcescens (Fahrig, 1974).
Details of the experiments were not reported. ' ' '
Eisenbeis y. al. (1981) tested the mutagenic" activity of 20 herbicides including simazine in five
mutant strains of S. typhimurium (TA 1535, 1537, 1538, 98, and 100) with and without a rat liver
microsomal preparation. Simazine (tested at full strength, details hot reported) did not produce an
increase in the number of revenant colonies per plate in comparison with controls.
Nishimura et al. (1982) evaluated the mutagenic activities of 25 pesticides, including simazine, in
the Ames Salmonella microsome assay. S.ryphimurium strains TA98 and. TA 100 were tested both with
i
and without S-9.mix prepared from phenobarbital-induced rat livers. Simazine'did not elicit mutagenic
' *
responses in TA98 or TA100, either with or without the S-9 mix, over a wide dose range up to the fatal
dose. The results were reported for only one dose level, i.e., 1.0 umoVplate. . ' " ' .
Plewa et al. (1979) repotted moderate positive mutagenic responses withjriazine herbicides in tests'
with 5. typhimurium. and Saccharomyces cerevislae, but no details were provided. .
(3. Gene mutations in mammalian cells
Waters et al. (1982) reported positive results for simazine in a mouse lymphoma assay. Other
information was not available.
Murnick and Nash (1977) employed three assays to test simazine for mutagenicity in Drosophila
melanogaster, Assays for dominant lethal mutations, sex-linked recessive lethal (SLRL) mutations, and
chromosomal nondisjunction, loss, and breakage were .performed on male flies treated by injection or
by larval feeding of the herbicide simazine as Princep SOW (80% simazine, 20% inert ingredients). The
feeding experiments used the highest concentrations of simazine (0.4 and 0.6%) found to be nonfatal to
larvae. The average dose given to adults by injection was 0.074 mg simazine solution (5.9 x 10"* g
simazine). Simazine significantly increased the rate of dominant iethals; however, the reduction in egg
hatch was probably due to physiological toxicity to sperm. The herbicide did not significantly increase
sex-linked recessive Iethals, X or Y loss, XY nondisjunction, or partial loss of the Y chromosome when
administered by larval feeding. However, when administered by injection in the adult males, simazine
V-24
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Simazins Criteria Document
induced SLRL at a rate of 0.34%. which differed significantly from the control (p
-------
Simnzine Criteria Document
c. Sister chromatid exchange ("SCE1
*
Ghiazza et al. -(1984) investigated the induction of sister chromatid exchange in cultured human
lymphocytes exposed to simazine concentrations of 0.001, 0.01, and 1 ppm. An increase in 5CE per
cell was found in cultures treated' with 1 ppm simazine (5.09 ± 1.19) as compared with the control (3.51
+ 1.14). 'The authors stated that these differences were statistically significant (p = 0.001). .
Waters et ai. 0982) reported that simazine was negative in a sister chromatid exchange study. Other
information was not available.
d. Cell transformation»
The U.S. EPA Gene-Tox Program reported that simazine was positive in cell transformation assay
** * « *.
with hamster embryo cells. Other data were not available.
E. CARdNOGENICITY '
Innes et al. (1969) performed a screening study on the tumorigenicity of 130 pesticides and industrial
compounds, including simazine. Beginning at 7 days of age, two hybrid strains of mice (C57BL/6 x
C3H/Anf and C57BL/6 x AKR) were administered simazine by stomach tube at 215 mg/kg/day. After
weaning. 18 mice of each sex of each strain (total of 72) were fed 603 ppm simazine in the diet (215
mg/kg/day for 4-week-old mice) ad libitum for 18 months. The tumor incidence in mice treated with
simazine was not significantly higher than that of controls (p <0.01) for any type of tumor.
Simazine did not produce inflammatory, degenerative, proliferative, orneoplastic lesions in male and
female Swiss Charles River mice fed simazine at dietary levels of 15,1,000, or 3,000 ppm for 17 to 22
months (Ciba-Geigy, 1980a). This corresponds to average daily doses of 1.5, 100, and 300 mg
simazine/kg/day, assuming daily consumption of 100 g feed/kg bw. Gross pathological examinations
performed on all 480 animals (including 120 controls) showed no dose-related or compound-related
effects of simazine. However, this study was performed by IBT and is considered to be invalid.
An oncogenicity study in Crl:CDl(ICR)BR mice fed technical grade simazine in the diet at
concentrations of 40,1,000, or 4,000 ppm for 95 weeks (Hazelette and Green, 1988) did not reveal any
V-26 -
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Simazine Criteria Document ~
evidence of carcinogenicity, suggesting that the compound was not oncogenic in mice. In fact, the
incidence of malignant lymphomas was higher in control females than in dosed groups. However, all
values were within the range of incidence found in other laboratories. There were several nononcogenic
effects; these effe'cts and^exgenmental details were discussed in Section V.B.2 of this document. . -
* %
Low-level carcinogenicity was noted in white rats and CC57 mice following chronic feeding or
dermal application of simazine (Pliss and Zabezhinsky, 1977). Simazine also produced sarcomas at the "
site of subcutaneous, injection in both rats arid mice. Tumors occurred in 30% of the experimental
animals following an 18-month latency period. Details as to "tumor types and«control incidences were
not presented in this abstract. Thus, the study has no value in assessing carcinogenicity.
o '
»
' * .
. The U.S. EPA.(Ioannou and Copley, 1988) has evaluated the histopathological data from a 2-year
# .
feedlng/oncogenicity study in Sprague-Dawley albino rats (McCormick et al., 1988, for Ciba-Geigy).
The experimental details and results of hematology, clinical chemistry, urinalysis. and gross and
histopathology as related to nononcogenic responses .for technical simazine were presented in Section
o
V.B.2 of this repprt Neoplastic and nonneoplastic lesions encountered in male and female rats are
O , i
summarized in Tables. V-5 and V-6, respectively. Based on the statistical evaluation of the neoplastic
findings described below, simazine technical was considered to be onogenic in female Sprague-Dawley
rats receiving 100 and 1,000 ppm (including the formation of mammary gland carcinomas). Simazine
technical also appears to increase the induction of liver tumors in male rats receiving 1,000 ppm.
Tumor incidences presented in Tables V-7 to V-13 in the following section are for the number of
tumor-bearing animals/number of animals at risk (excluding animals that died before the observation of
the first tumor or animals not examined), and the percent incidence is denoted in parentheses. The
significance of trend is denoted in the "control" columns, and the significance of pairwise comparison
with contro4is denoted in the "dose level" columns.
1. Female Rats
* Mammarv gland - In female rats in the main study, there was a statistically significant
increase in the incidence of mammary carcinomas in the mid- and high-dose groups
compared with controls. A statistically significantly higher incidence of fibroadenomas
was seen in the high-dose group. Table V-7 summarizes the incidence of these lesions
when calculated separately for female animals that died (or were sacrificed moribund) or
animals that survived to terminal sacrifice.
V-27
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Suukzine Criteria Document
Table V-5. Summary of Histopaihological Lesions in Male, Rats Fed Diets
Containing Simazine for 2 Years
Dose (com)
Histopathological observation1
c
Neooiastic lesions
t t , ,
.Adrenal - Cortical adenoma .
.
Kidney -.Adenoma
- Carcinoma (primary) _ .
Liver - Hepatocellular adenoma
- Hepatocarcinoma
- Combined adendma and/or
carcinoma
thyroid - C-cell adenoma
- C-cell carcinoma
- Combined adenoma and/or
carcinoma
Pituitary Adenoma
Nonneoolastic lesions
*
Adrenal Cortical hypertrophy/
cystic degeneration
- Focal cortical
hyperplasia
Liver - Hyperplasia
Pituitary - Hyperplasia
Skin - Chronic lymphocytic
inflammation
Testis - Focal interstitial
cell hyperplasia
Thyroid - Focal interstitial
cell hyperplasia
0
0/69b -
' 0/70 *
.0/70. ; /
'""1/70
0/70
1/70
0
. 2/70
2/70-
4/70
42/69 -
7/69
2/69
2/70
12/69
1/70
6/70
7/70
10
0/70
0/70
0/70.
1/70
2/70
3/70 . .
7/69
1/69
8/69
47/70
4/70
2/70
0/70
14/70
0/68
2/70
3/69
100
»
1/69 '
o
0/70
0/70
0/70
4/70
4/70'
. 5/69
1/69
6/69
47/70
6/69
3/69
0/70
10/70
1/69
8/70
5/69
1,000
' 2/69 '
1/70 ..
. 2/ZO
3/70
3/70
6/70
6/70
3/70 l
9/70
.38/70
13/69
.7/69
0/70
15/70
5/70
11/70
9/70
Main study only (interim sacrifice and recovery groups not included).
"Number of rats* were specified observation/total number of tissues examined.
SOURCE: loannou and Copley (1988).
V-28
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Simazine Criteria Document
Table V-6. Summaiy of Histopathological Lesions in Female Rats Fed Diets
Containing Simazine for 2 Years
0
Histopathological observation* '
Neoplastic lesions
Mammary - Adenoma
- Carcinoma
- Fibroadenoma
Pituitary - Adenoma
" - Carcinoma
Kidney - Adenoma (tubular)
Nonneoplasric lesions
Mammary - Cystic glandular
hyperplasia
Pituitary - Hyperplasia
o
Kidney - Hydronephrosis
Epithelial hyperplasia
pelvic
Adrenal Focal medul hyperplasia
Liver - Hematopoiesis
Spleen - Hematopoiesis
Thyroid - Focal interstitial
cell hyperplasia
0
2/70" '
14/70 -'
22/70'
62/70
1/70
e?
0/70
51/70
2/70
3/70
0/70
0/70
0/70
3/70
0/70
Dose
10
4/70 .
13/70 '
27/70
57/70
3/70
0/70 '
50/70 .
6/70
0/70
0/70
4/70
1/70
1/70
2/70
(ppm)
100
1/70
19/70*
19/70
60/70
0/70
0/70
53/70 ..
- 3/69
0/70
0/70
3/70
1/70
1/70
2/70
1,000
5/70
35/70***
40/70** '
57/70
6/70
2/70 i
i
65/70***
2/70
6/70
3/70
3/70
5/70*
10/70*
4/70
"Main study only (interim sacrifice and recovery groups not included).
"Number of rats were specified observation/total number of tissues examined.
*, **, ***rndicate significance at p <0.05, p <0.01, and p <0.001, respectively.
SOURCE: loannou and Copley (1988).
V-29
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Simazine Criteria .Document
, Table V-7. Incidence of Mammary Gland Tumors in Female Rats Fed Diets
Containing Simazine for 2 Years
Dose (ppm)
Sacrifice schedule .
Early deaths (prior to
terminal sacrifice)
Scheduled sacrifice.
(104 weeks)
Combined incidence
*
,
Lesion
Adenoma*
Carcinoma
Fibroadenoma
Adenoma
Carcinoma
Fibroadenoma
Adenoma
Carcinoma
Fibroadenoma
0
2/46"'
10/46
14/46
0/24
4/24
8/24
2/70
14/70
22/70
10
. 3/47
9/47
17/47 3
1/23-
4/23
10/23
4/70 '
13/70
27/70
100
1/53
12/53 .
. 11/53
0/17
7/17
8/17
1/70
19/70*
19/70
1,000
4/56
28/56**
28/56**
1/14
7/14* .
12/14*
5/70.
. 35/70** "
40/70** *
"Number of animals .with specified observation/total number of tissues examined.
*,**Indicate significance at p <0.05 and p <0.01, respectively.
SOURCE: loannou and Copley (1988).
0 '
V-30
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Sirnazine Criteria Document
Table V-8. Incidence of Mammary Gland Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsFemale Mammarv Gland Tumor Rates and Peto Prevalence Test Results
Tumor type
-^Adenoma/
fibroadenoma
.~;
.* ..
j
Carcinoma.
*
Adenoma/
carcinoma
0
23/89
(26)
p = 0.0689
. «
16/89-
(18)
p <0.0001**
39/89
(44) .
p <0.0001**
a
10
20/78'
'(26)
p= 0.302 :
13/80'-
(16)
p = 0.4740
33/80
(41)
p = 0.4064
j
Dose (ppm)
100
*
'- .
11/71
(15)
' p m 0.177
. . ,
. 0
4
. 20/75b. '
(27)
p = 0.0392*
31/75
(41)
p = 0.2229
i,odb '
0
21/75
0 (28)
p = 0.123
a '
40/78
(51)
. p<0.0001*
i
61/78
(78)
p<0.0001**
'First adenoma observed at 48 weeks at the 10-ppm dose level. First
fibroadenoma observed at 52 weeks at the 0-, 10-, and 1,000-ppm dose levels.
bFirst carcinoma observed at 48 weeks at the 100-ppm dose level.
*, **Indicate significance at p <0.05 and p <0.01, respectively.
SOURCE: loannou and Copley (1988).
V-31
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Simazine Criteria Document
As the statistical analyses carried out by the authors for different tumors in male and
female rats were determined to be inadequate, further statistical, evaluation for the major
rumors listed in Tables V-5 and V-6 was conducted by the Agency. Data presented in all
tables following are the combined tumor incidences from the 52-week' interim sacrifice and
the 104-week study. The incidence of mammary tumors in- female rats is presented in
Table V-8.
." These results indicated a statistically significant dose-related trend in mammary carcinomas
and in combined adenomas and carcinomas. The incidence of mammary carcinomas was
statistically significantly increased in the mid- and5 high-dose groups -cempared with
controls; also the incidence of combined adenomas and,carcinomas was significantly higher
in the highest dose tested (HOT) compared.-with controls. Mammary carcinomas {in the
main study^104-week sacrifice) contributed, according to the authors, to the increased
mortality in the high-dose group animals (1,000 ppm). A higher incidence of mammary .
carcinomas was also seen in the recovery study (52 weeks of treatment, wish 1,000 ppm
followed by 52 weeks of recovery), 1/10 versus 4/10, for the control and HDT,
respectively.
1 * * .
In female rats, the incidence of hyperplastic changes (cystic glandular hyperplasia) in the
mammary gland was very statistically significantly higher than controls in the HDT-. TM§
finding corroborates the observed high incidence of tumors in the HDT. It'.is generally
understood that the higher tumor incidence correlates directly with a higher incidence of
* hyperplastic changes.' , »
a-
b. Pituitary gland - In female rats, the incidence of pituitary (pars distalis) carcinoma was
found to be higher than controls in the HTD. The authors reported that this incidence was
.statistically significant with the Peto life-table method of analysis used. The incidence of
adenomas was found to be extremely high in all groups, but the authors reported that the
incidence in the mid* and high-dose groups was statistically significantly increased when
Peto's method was used for analysis (when contribution to death is considered). Further
statistical analysis of these tumors (total tumor analysis) indicated, as shown in Table V-9,
that the incidence of combined adenomas/carcinomas in the mid- and high-dose groups was
o statistically significantly higher than controls with a significant dose-related trend.
>.
The authors reported that these tumors (adenomas and carcinomas) were considered to tfc
fatal "by virtue of their size and compression of the mid-brain," and thus contributed to the
decreased survivability of the mid- and high-dose group females. Although these tumors
(adenomas/carcinomas) were of approximately the same numerical incidence in all groups
(treated and control), examination of the Kaplan-Meier survival curves indicates that the
onset of these tumors is 4 to 15 weeks earlier in the mid- and high-dose groups as
compared with the control and low-dose groups.
For further evaluation of these rumor data, the Agency requested historical control data and
the results of the immunocytochemical staining of the pituitary for identification of
prolactin. . <&
c. Kidney - A very low incidence of tubular adenomas was seen in female rats receiving the
high dose (Table V-10). The low incidence of this tumor does not appear to be
biologically significant.
V-32
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Simazine Criteria Document
2. Male Rais
c.
* « .
Liver - In male rats, the incidence of hepatocellular adenomas or carcinomas was very low
in ail treated and control groups (0-5%). As shown in Table V-ll, the incidence of
combined adenomas and carcinomas was* statistically significantly higher in the high-cose
group compared with controls, possibly suggesting oncogenic potential of simazine to male
rats.
The incidence of hyperplastic changes, however, was very low in the control (2/70) and
nonexistent in the treated groups (0/70, see Table V-5)
Thvroid - Although the incidence of combined thyroid £-cell adenomas and carcinomas
was numerically higher in .all treated groups as compared with controls, as shown in Table
V-12, there was no significant dose-related tren,d or statistical significance between treated
and control groups. The incidence of hyperplastic changes was comparable to the
. incidence"of tumors for each group.
»
Kidnev - A very low incidence of tubular adenomas and carcinomas was seen in male rats
(Table V-13). A statistically significant dose-related trend was observed for the incidence
of carcinomas as well as the incidence of combined adenomas and carcinomas. As in
female rats, the very low incidence of this rare rumor in male rats does not appear to be
of biological significance.
V-33
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Simazir.e Criteria Dccumeni
Table V-9. .Incidence of Pituitary Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsFemale Pituitary Gland Tumor Rate, Fatal Tumor
. . Analysis, and Generalized K/W Test Results
Tumor type
Adenoma
Carcinoma
Adenoma/.
carcinoma
a
0
73/89
(82.0)
. p = 0.0033**
1/73
-.. -0-4)
p = 0.0010**
74/89
(83.1)
p = 0.0005**
10 . .
0
57/80
(71,2) .
p =» 0.9944
3/61
(4.9)
p = 0.2351
' 60/80
' (75.0)
p = 0.8351 -
Dose (ppm)
100
63/771 " ' '
(81.8)
p = 0.020.6*
0/52 '
-(0.0) '
- p = 0.4545
63/77.
(81.8)
p..= 0.025,1*
*
1,000
61/79
(77.2)
p = 0.0033**
6/53b
(11-3)
p = 0.0153*
67/79
(84.8)
p = 0.0005**
'First adenoma observed at 35 weeks at the 100-ppm dose level
bFirst carcinoma observed at 72 weeks at the 1,000-ppm dose level
*, **Indicate significance at p <0.05 and p <0.0l, respectively.
SOURCE: loannou and Copley (1988).
. .
"*
' V-34
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Sirrozine Criteria Document
Table V-10. Incidence of Kidney Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsFemale Kidney Tubule Tumor Rate, Cochran-Armitage
Trend Test, and Fisher's Exact Test Results
Dose (ppm)
Tumor type
10
100
1,000
Adenoma
0/74
' (0.0)
p * 0.0042**
0/62 -
(0.0)
p = 1.0000
0/54
. .(0.0)'
' p = 1.0000
2/551
(3.6)
p = 0.1799
'First adenoma observed at 71 we.eks at the 1,000-ppm dose level No
carcinomas were noted.
**Indicates significance at p <0.01.
SOURCE:' loannou and Copley (1988).
V-35
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Simazins Criteria Document
Table V-ll. Incidence of Liver Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YeanMale Liver Tumor Rate, Cochran-Armitage Trend Test,
and Fisher's Exact Test Results
. .& -
Tumor type "
» .
Adenoma
Carcinoma
.*
Adenoma/
carcinoma
0 .
1/88
(1.1)
p = 0.0824
0/88
(0.0)
p. = 0.2169
1/88
(1.1)
p = 0.0643
10 .
2/79" '
. (2.5)
p .0.4594
* m
2/79
(2.5)
p = 0.2223
4/79
(5.1)
p = 0.1519
Dose (ppm)
100
0/80
(0.0)
p = 0.5238/
4/80"
(5.0)
p = 0.0494*
4/80
(5.0) .
p = 0.1554
+ ,
1,000
a ...
3/80 ' ' .
" C3.8J
p- 0.2752
3/80
(3.8) .
p = <0.1058
i.
6/80
(7.5)
p = 0,0449*
"First adenoma observed at 52 weeks at the 10-ppm dose level.
"First carcinoma observed at 99 weeks at the 100-ppm dose level.
*Indicates significance at p <0.05.
SOURCE: loannou and Copley (1988).
V-36
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Simazine Criteria Document
Table V-12. Incidence of Thyroid Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsMale Thyroid C-Cell Tumor Rates and Peto Prevalence Test Results
9
Tumor type
Adenoma
Carcinoma
Adenoma/
carcinoma
-
0
2/52
(4)
p = 0.3355
2/34
' (6)
p = 0.1762
4/52 ' -
(8)
p = 0.1924
10
7/52* '
(13)
p = 0.0606
1/31
(3)
p = 0.1082
8/52
(15)
p = 0.1965
Dose (ppm)
100
5/51
(10)
p F 0.1082
1/36
(3)
p = 0.2881*
6/51
(12)
p = 0.2261 .
1,000
'6/58
(10)>.
p = 0.0870
3/45"
'(7)
p = 0.4183
i
9/58 i
(16)
p = 0.1505
"First adenoma observed at 89 weeks at theJO-ppm dose level.
"First carcinoma observed at 102 weeks at the 1,000-ppm dose level
*Indicates significance at p <0.05.
SOURCE: loannou and Copley (1988).
V-37
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Simazine Criteria Document
Table V-13. Incidence of Kidney Tumors in Sprague-Dawley Rats Fed Simazine
for 2 YearsMale Kidney Tubule Tumor Rates and Peto Prevalence Test Results
Dose (ppm)
Tumor type
Adenoma
Carcinoma
Adenoma/
carcinoma
0
0/51
(0)
p = 0.0543
1/66
(2)
p = 0.0332**
1/66
(2)
p - 0.0056**
'' 10
0/46
(0)
p = 1.0000
0/62
(0)
p = 0.1660
0/62
(0)
p = 0.1410
100
0/48
(0)
p= 1.0000
0/64
(0)
p = 0.1821
0/64
(0)
p = 0.1721
1,000
1/57'
(2)
p = 0.5278"
2/656
(3)
p = 0.2091
3/65
(5)
p = 0.1087
'First adenoma observed at 92 weeks at the 1,000-ppm dose level.
The p values for adenomas were calculated using the Cochran-Armitage Trend
test and Fisher's Exact test, since the Peto Prevalence method collapsed to
one interval.
**Indicates significance at p <0.01.
SOURCE: loannou and Copley (1988).
V-38
-------
In a 2-year dietary study (Hazleton Laboratories, 1960; NAS, 1977), simazine SOW (49.9% active
ingredient) was administered in the diet to Charles River rats at 0, 1, 10, and 100 ppm (expressed on
the basis of 100% active ingredient). These doses correspond to 0,0.05,0.5, and 5 mg/kg/day, assuming
daily consumption of 50 g feed/kg bw (Lehman, 1959). Thyroid and mammary tumois were observed
in high-dose females. Complete histopathological details were not provided, and statistical significance
was not evaluated. This study was not considered to be adequate for evaluation of carcinogenic potential
owing to high incidence of respiratory and ear infections in all groups.
F.- SUMMARY
'£
'$-
The acute oral LD50 estimates in rats, mice, rabbits, and birds are 5,000 mg/kg or higher, but a dose
of 500 mg/kg has been reported to be lethal in sheep. Pharmacotoxic signs in sheep included
incoordination, tremors, weakness, cyanosis, and clonic convulsions. A single dose of 4,200 mg/kg
caused anorexia, weight loss, and some lethality in rats.
Short-term oral administration of 500 mg/kg/day in rats resulted in lethality within 20 days. Doses
of 15 mg/kg/day in rats produced mild hepatic degeneration in 3 days, but this condition did not progress
with repeated dosing.
In a 28-day oral toxicity study, simazine was fed to albino mice at dose levels ranging from 0 to
4,500 mg/kg/day. The animals were examined for gross pathology, food consumption, and body weight
at the end of 28 days. No discernible toxicologic effects were noted in mice fed simazine up to 450
mg/kg/day. A NOAEL of 450 mg/kg/day has been identified from this study.
Death occurred in Delaine sheep administered daily oral doses of simazine at 50, 100, or 400
mg/kg/day for 31,14, or 9 days, respectively. Toxic symptoms produced consisted of muscular spasms,
fasciculations, stiff gait, and increased breathing.
Dermal application of simazine to rabbits at doses up to 1 g/kg/day for 21 days did not show
systemic toxicity, dermal irritation, or dermal sensitization.
No treatment-related deaths were observed in rats fed simazine at dose levels up to 343 mg/kg/day
for 13 weeks, but significant reduction in body weight and organ weight were observed in both males
V-39
-------
Simazir.e C.-:er.j Document
and females at ail dose levels. Other parameters affected included decreased erythrocyte and leukocyte
counts and other hematology indices in all treated groups, lowered blood glucose, sodium and calcium,
high cholesterol, and low liver function. Histology revealed a dose^related increase in the incidences
of renal calculi and renal epithelial hyperplasia, which was significant in the 4,000-ppm males. Based
on these findings, a NOAEL of less than 10 mg/kg/day was identified.
The- same protocol was used to study the effects of simazine in dogs, and a NOAEL of.
a .
' 9 , . ' -
approximately 7 mg/kg/day was obtained based on reduced serum albumin levels, increased serum
B
globulin, and elevated urinary ketone bodies at the 2,000-ppni dose level (64 to 65 mg/kg/day). A 6-
month study in rats and guinea pigs indicated .that a dose of 20 mg/kg/day was without effect, but a dose
of 100 mg/kg/day suppressed normal weight gain and caused an increase in leukocyte count. Lower
. *
doses (1.4 to 25 mg/kg/day) have been reported to cause hyppthyroidism in sheep following daily doses
for 63 to 142 days. '.:.''
' . " »
' ' a .
In a chronic oral toxicity study, simazine was fed to Charles River CD-I mice for 17 to 22 months
c ' ° . '
at dose.levels ranpng from 0 to 300 mg/kg/day. A decline HI survival rate and body weight was
observed in animals receiving the high dose (300 mg/kg/day). No treatment-related effects were noted '
with regard to gross pathology. However, this study was determined to be invalid. A detailed 95-week
f
chronic feeding study in Crl:CDl(ICR)BR mice revealed a NOAEL of 6 mg simazine/kg/day and a
LOAEL of 150 mg/kg/day based on decreased body weight gain. The body weight reductions were
significant (p <0.01) at dose levels of 150 and 600 mg/kg/day. Hematocrit and hemoglobin values
tended to be lower in the high-dose animals than in controls. Amyloidosis was more pronounced in all
dose groups than in controls; this and other incidental effects were not considered to be compound
related. :
In a 2-year feeding study with rats, doses up to 100 ppm in the diet (about 5 mg/kg/day) did not
produce apparent systemic toxicity. A recent 2-year chronic feeding study in Sprague-Dawley rats
revealed a NOAEL of 0.52 mg simazine/kg/day and a LOAEL of 5.3 mg/kg/day based on decreased
body weights and on hematology indices (red blood cells, hemoglobin concentration, and hematocrit in
females).
A 1-year chronic feeding study in beagles revealed a NOAEL of 0.72 mg/kg/day (0.76 and 0.68 mg
simazine/kg/day for female and male dogs, respectively) and a LOAEL of 3.6 mg/kg/day based on
V-40
-------
Simazine Criteria Document
and females at all dose levels. Other parameters affected included decreased erythrocyte and leukocyte
* -i *
.counts and other hematology indices in all treated groups,.lowered blood glucose,'sodium and calcium.
high cholesterol, and low liver function. Histology revealed a dose-related increase in the incidences
of renal calculi and renal epithelial" hyperplasia, which was significant in the 4,000-ppm males. Based
on these findings, a NOAEL of less than 10 mg/kg/day was identified.
The same protocol was used to study the effects of simazine in dogs, -and a NOAEL of
approximately 7 mg/kg/day was obtained based on reduced serum> albumin levels, increased serum
« . " ' *
globulin, and elevated urinary ketone bodies at the 2,000-ppm dose level (64 to 65, mg/kg/day), A 6-
month study in rats' and guinea pigs indicated that a dose of 20 mg/kg/day was without effect, but a dose
of 100 mg/kg/day suppressed notrrial weight gain-and caused an increase in> leukocyte count. Lower
doses (-1.4 to 25 mg/kg/day) have been reported to cause hypothyroidism in sheep following daily doses
for 63 to 142 days. . '' ."-,'
°
In a chronic oral toxicity study, simazine' was fed to Charles River CD-I mice for 17 to 22 months
6 ' * ' - '
at dose levels ranging from 0 to 300 mg/kg/day. A decline in survival rate and body .weight was
observed, in animals receiving the high dose- (300 mg/kg/day). No treatment-related effects were noted
with regard to gross pathology. However, this study was determined to be invalid, A detailed ^5-week
a
chronic feeding study in Crl:CDl(ICR)BR mice revealed a NOAEL of 6 mg simazine/kg/day and a
LOAEL of 150 mg/kg/day based on decreased body weight gain. The body weight reductions were
significant (p <0.01) at dose levels of 150 and 600 mg/kg/day. Hematocrit and hemoglobin values
tended to be lower in the high-dose animals than in controls. Amyloidosis was more pronounced in all
dose groups than in controls; this and other incidental effects were not considered to be compound
related.
In a 2-year feeding study with rats, doses up to 100 ppm in the diet (about 5 mg/kg/day) did not
produce apparent systemic toxicity. A recent 2-year chronic feeding study in Sprague-Dawley rats
revealed a NOAEL of 0.52 mg simazine/kg/day and a LOAEL of 5.3 mg/kg/day based on decreased
body weights and on hematology indices (red blood cells, hemoglobin concentration, and hematocrit in
females).
A 1-year chronic feeding study in beagles revealed a NOAEL of 0.72 mg/kg/day (0.76 and 0.68 mg
simazine/kg/day for female and male dogs, respectively) and a LOAEL of 3.6 mg/kg/day based on
V-40
-------
Sirnazine Criceria Document
decreased body weight gain, erythrocyte count, and hemoglobin concentration, and a nominal increase
in platelets in females. In a 2-year feeding study in dogs, doses up to 150 pprn'(about 3.5 mg/Tsg/day)
were without effect. However, a dose 'of 1,500 ppm (about 35 mg/kg/day) resulted in a slight thyroid
hyperplasia and a slight increase in serum alkaline phosphatase and serum glutamic-oxaloacetic
transaminase activities. . '
A two-generation reproductive toxicology study in rats fed simazine technical in the diet at 10, 100,
and 5QO ppm revealed no. adverse-clinical signs, treatment-related toxic effects, or mortality at the
10 ppm level. A transient treatment-related decrease in body weight gain was observed in the parental
animals at the 100 ppm level. However, at 500 ppm, treatment-related adverse effects were noted in
. 0
FO and F! parental animals and included reduced body, weight gain, slightly ingreased mean relative
testicular weights as well as mean relative ovarian weights in F; females. No treatment-related effects '
'- t *
were observed on reproductive parameters, F, and.F^ pup survival, weights, sex ratios,'or malformations
* t »' * ',
at any 'dose level Remarkable gross or hi|topathoiogical effects were not observed in any of the
" ° . '
examined generations at any dietary level. Based on significant weight gain reductions at 500 ppnvthis
a
dose was considered equal to or greater than the maximal tolerated dose. This study suggested a
reproductive NOAEL of 500 ppm and a- parental NOAEL of 10 ppm.
In a three-generation reproduction study with Charles River rats continuously fed simazine SOW in
the diet at 50 (2.5 mg/kg/day) or 100 ppm (5 mg/kg/day), a parental NOAEL of less than 50 ppm and
a LOAEL of 50 ppm were identified based on reduced weight gain in males during the premating
periods. The reproductive toxicity NOAEL/LOAEL could not be determined in this study because of
the lack of evaluation of apparent sterility in FIb generation males.
In a teratology study with rats, simazine administered in high doses (78 to 2,500 mg/kg/day) during
gestation days 6 through 15 delayed fetal development and was embryotoxic but not teratogenic.
Another teratology study in Crl:COBS CD SD BR rats administered simazine by gavage in doses of 30,
300, and 600 mg/kg/day on gestation days 6 through 15 revealed developmental and maternal toxicity
NOAELs of 30 mg/kg/day and LOAELs of 300 mg/kg/day based on skeletal variations (incomplete
ossification) in fetuses and decreased body weight gain in dams. At the LOAEL, several developmental
variations were observed, but the U.S. EPA has not considered them to be a compound-related effect.
The study was graded as supplementary because additional information was requested. Similarly,
maternal and fetal toxicity were observed in rabbits given oral doses of 75 or 200 mg simazine/kg on
V-41
-------
Criteria Document
gestation days 7 through 19. The teratogenic .N'OAEL was 200 mg simazine/kg. At this dose, a
significant reduction in mean fetal weight and a significant increase in the incidence of skeletal
variations in fetuses were observed. The fetotoxic NOAEL was 75 mg/kg. The maternal N'OAEL was
5 mg/kg, which was based on decreased body weight gain, tremors, and increased abortions at 75 and
200 mg/kg. Doses of 6 or 25 mg/kg/day for 142 diiys or 37 to 111 days, respectively, caused decreased
6-spermatogenesis in sheep. -' ". "...."
Most tests of mutagenic potential for simazine have been negative, both in procaryotic and
eucaryotic systems. The herbicide was nonmutagenic in the Ames Salmonelia/micTOsomt assay,' mitotic
* ...
recombination assay in Stocpharomyces, and unscheduled DNA synthesis assay in human fibroblasts.
However, it induced sex-linked recessive lethal mutations in Drpsophila and sister chromatid exchanges
' in human lymphocytes. . ' ' -
« . i . *
' ' ' v "
No increases in tumor frequency and/or neoplastic lesions were observed in C57BL/6 x C3H/An£
t ' '
and C57BL/6 x AKR mice dosed with simazine at 215 mg/kg/day. by stomach tube for 18 months. A
. 17- to 22-month feeding study IH Swiss Charles River mice (Ciba-Geigy, I980a) indicated no dose-
;elated adverse effects for simazine, but this study, performed by 1ST, is considered to be invalid. A
95-week oral toxicity/oncogenicity study in Crl:CDl mice receiving diets containing 40,1,000, or 4.000
ppm simazine revealed no evidence suggestive of oncogenic activity. In the 2-year carcinogenicity study
in Sprague-Dawley rats fed dietary simazine at 10, 100, and 1,000 ppm for 104 weeks, simazine was
found to be oncogenic in female rats, inducing mammary tumors at dose levels of 100 ppm (5.3
mg/kg/day) and 1,000 ppm (63.1 mg/kg/day). In male rats, simazine appears to induce the formation
of liver tumors at the 1,000-ppm dose level (45.8 mg/kg/day).
V-42
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Siraazine Criteria Document
VI. HEALTH EFFECTS IN HUMANS'
A. CLINICAL CASE STUDIES "
No reports of toxicity resulting from oral ingestion of simazine by humans were located. Yelizarov
(1977) reported that simazine and propazirie caused acute and subacute dermatitis in 124 workers who
had" close contact with the herbicides in the U.S.S.R. In subacute cases, pale pink erytherna and slight
edema of the skin, lasting 3 to 4 days, Were observed. Symptoms of acute cases usually lasted 7 to 10
days and included erytherna and edema as well as a number of small vesiculopapular elements that
sometimes produced dermatitis bullosa.
B-. EPIDEMIOLOGICAL STUDIES
No epidemiological studies of simazine exposure were located in the literature. . ' .l
« *.'"'''
. C. HIGH-RISK POPULATIONS . . . ' '
o
No data were located regarding differential sensitivity of different human subpopulations.
D. SUMMARY
Almost no information is available regarding simazine toxicity in humans. One study reported acute
and subacute dermatitis in wo±ers at plants manufacturing simazine. ^
VI-1
-------
Simazine Criteria Document
.VH. MECHANISMS OF TOXIQIY
Very little infonnation was found on the mechanism of simazine-induced toxicity in animals.
Lefalova et al. (1983) reported that terbutylazine and simazine inhibited the activity of plant, animal, and
yeast alcohol dehydrogenases in vitro. The character 6f inhibition for both herbicides studied in the
reaction catalyzed by pea, liver, and yeast alcohol dehydrogenase was always noncompetitive toward
ethanol and competitive with respect to nicotinamide adenine .dinucleotide. Inhibition constants were
about KT'to 10'5 M. . ...
Myhr (1973). measured the toxic effect of eight pesticides on protein and RNA synthesis in HeLa
cells. -The effect of a 30-minute exposure to pesticides on the incorporation rates of labeled amino acids
into protein and labeled undine into RNA in HeLa cells was examined; Simazine (0.35 mg/mL) had
' . < .' «
no effect on the incorporation rates. . .
. « . - * *
i
8
Atrazine, a structural analog of simazine, has been found to interfere'with nucleic acid synthesis both,
in vivo in BALB/c mice and in vitro in ascites tumor cells (Walker et al., 1979). Similarly, arrazine has
been found to inhibit glycogen synthesis following intraperitoneal injection 'in adult- female Sprague-
Dawley rats in vivo and in isolated hepatocytes in vitro (Messner, 1979).
VH-1
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Simazine Criteria Document
. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
The quantification of toxicological effects of a chemical consists of an assessment of
noncarcinogenic and carcinogenic effects. Chemicals that do not produce carcinogenic effects are
believed to have a threshold dose below which no adverse, noncarcinogenic health effects. occur.' whereas
carcinogens are assumed to act without a threshold. . .
i»
A. PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS ' .
L Noncarcinogenic Effects . ----
In the quantification of noncarcinogenic effects, a Reference Dose (RfD), formerly called the
Acceptable Daily Intake (ADI), is calculated. The RfD is. an estimate of a daily exposure of the human
population that .is likely to be without appreciable risk of deleterious health effects, even if exposure}
occurs over a lifetime. The RfD is derived from a No Observed Adverse Effect Level (NOAEL) or
Lowest Observed Adverse Effect Level (LOAEL), identified from a subchronic or chronic study, and
divided by an uncertainty factor (UF). The RfD is calculated as follows:
RfD . (NOAEL or LOAEL) , _ mg/kg/day
UncenimyFactors
Selection of the uncertainty factor to be employed in the calculation of the RfD is based on
professional judgment while considering the entire data base of toxicological effects for the chemical
To ensure that uncertainty factors are selected and applied in-a consistent manner, the Office of Science
and Technology (OST), formerly Office of.Drinking Water (OD W), employs a modification to the guide-
lines proposed t>y" the National Academy of Sciences (NAS, 1977, 1980), as follows:
a
* An uncertainty factor of 10 is generally used when good chronic or subchronic human exposure data
identifying a NOAEL are available and are supported by good chronic or subchronic toxicity data
in other species.
vni-i
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Simazine Criteria Document
An uncertainty factor of 100 is generally used when good chronic toxicity data identifying a NOAEL
are available for one or more animal species (and human data are not available), or when good
chronic or subchronic toxicity data identifying a LOAEL in humans are available.
An uncertainty factor of 1,000 is generally, used when limited or incomplete chronic or subchronic
toxicity data are available, or when good chronic or subchronic toxicity data identifying a LOAEL.
but not a NOAEL, for one or more animal species are available.
The uncertainty factor used for a specific risk assessment is based principally on scientific judgment,
.-"-.'.' . ' .
rather than scientific fact, and accounts for possible intra- -and intejrspecies differences. Additional
considerations not incorpprated in the NAS/OST guidelines for selection of an uncertainty factor include
the use of a less-than-lifetime study for deriving an RfD, the significance of the adverse health effect,
and the counterbalancing of beneficial effects, .
4 «.
From the RfD, a Drinking Water Equivalent Level (DWEL) can be calculated. The DWEL represents,
a medium-specific (i.e., drinking water) lifetime exposure at which adverse, noncarcinogenic health
effects are not expected to occur. The DWEL assumes 100% exposure from drinking water. The DWEL
provides the noncarcinogenic health effects basis for establishing a drinking water standard. From'
ingestion data, the DWEL is derived as follows:
DWEL
RfD x (body weight in kg)
Drinking water volume in L/day
,_. mg/L
where: ^
Body weight = assumed to be 70 kg for an adult.
Drinking water volume = assumed to be 2 L per day for an adult.
In addition to the RfD and the DWEL, Health Advisories (HAs) for exposures of shorter duration
(One-day, Ten-day, and Longer-term HAs) are determined. The HA values are used as informal guidance
to municipalities and other organizations when emergency spills or contamination situations occur. The
HAs are calculated using a similar equation to the RfD and DWEL; however, the NOAELs or LOAELs
are identified from acute or subchronic studies. The HAs are derived as follows:
vm-2
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Simazi-.c Criteria Document
(NOAEL or LOAEL) x (BW)
" L/day) '
Using the above equation, the following drinking water HAs ire developed for noncaicinogenic
effects:
o
1. One-day HA for a 10-kg child ingesting 1- L water per day.
2. Ten-day HA for a 10-kg child ingesting 1 L water per day,
. 3. Longer-term HA for a 10-kg child .ingesting 1 L water per day.
4. Longer-term HA.for a 70.-kg adult'ingesting 2 L water per day.' .
" * *
. " . » - '
The One-day HA calculated for a 10-kg child assumes a single acute.exposure to the criemical and
is generally derived from a.study of less than 7'days' duration. The Ten-day HA assumes a limited^
o a ,
exposure period of 1 to 2 weeks and is generally derived from a study of less than 30 days'-duration.
' ' « . *
The Longer-term HA is calculated for both a 10-kg child and a 70-kg adult and assumes an exposure
» ^
period of approximately 7 years (or 10% of an individual's lifetime). The Longer-term HA is generally
.
derived from a study of subchronic duration (exposure for 10% of an animal's lifetime).
2. Carcinogenic Effects
The EPA categorizes the carcinogenic potential of a chemical, based on the overall weight of
evidence, according to the following scheme:
Group A: Known Human Carcinogen. Sufficient evidence exists from epidemiology studies to-
support a causal association between exposure to the chemical and human cancer.
Group B: Probable Human Carcinogen. Sufficient evidence of carcinogenicity in animals with
limited (Group Bl) or inadequate (Group B2) evidence in humans.
Group C: Possible Human Carcinogen. Limited evidence of carcinogenicity in animals in the
absence of human data.
vni-3
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Simazir.e Criteria Document
-
Group D: Not Classified as to Human Carcinogenicitv. Inadequate human and animal evidence
of carcinogenicity or for which no data are available.
Group E: Evidencejjf Noncarcinogenfcity for Humans. .No evidence pf carcinogenicity in at least
two adequa:e animal tests in different species or in both adequate epidemioiogic and
animal studies.
If toxicological evidence leads to the classification of the contaminant as a known, probable, or
possible human carcinogen, mathematical models are used to calculate .the estimate of excess cancer risk
associated with the ingestion of the contaminant in drinking water. The data used in these estimates
o .
usually come from lifetime exposure studies in animals. To predict the risk for humans from animal
data, animal doses must Jje convened to equivalent human doses. This conversion includes correctipn
for noncontinuous exposure, less-than-lifetime studies, and for differences in size. The factor that
« . ' * '
compensates for the size difference is the cube root of the ratio of the animal. and human bod/ weightsC
It is assumed that the average adult human body weight is 70 kg and that the average water consumption
a " «
'of an adult human is 2 liters per day. ',-.,''
For contaminants with a carcinogenic potential, chemical levels are correlated with a carcinogenic
risk estimate by employing a cancer potency (unit risk) value together with the assumption for lifetime
exposure via ingestion of water. The cancer unit risk is usually derived from a linearized multistage
model, with a 95% upper confidence limit providing a low-dose estimate; that is, the true risk to
humans, while nc£. identifiable", is not likely to exceed the upper limit estimate and, in fact, may be
lower. . Excess cancer,risk estimates may also be calculated using other models such as the one-hit,
Weibull, logit, and probit. There is little basis in the current understanding of the biological mechanisms
_ involved in cancer to suggest that any one of these models is able to predict risk more accurately than
any other. Because each model is based on differing assumptions, the estimates that were derived for
each model can differ by several orders of magnitude.
The scientific data base used to calculate and support the setting of cancer risk rate levels has an
inherent uncertainty due to the systematic and random errors in scientific measurement. In most cases,
only studies using laboratory animals have been performed. Thus, there is uncertainty when the data
are extrapolated to humans. When developing cancer risk rate levels, several other areas of uncertainty
exist, such as the incomplete knowledge concerning the health effects of contaminants in drinking water.
vm-4
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iive Criteria Document
the 'impact of the laboratory animal's age, sex, and species; the nature of the target organ system(s)
examined; and the.acruai rate of exposure of the internal targets in laboratory animals or humans. Dose-
response data usually are available only for high1 levels of exposure, not for the lower levels of exposure
closer to where a standard may be set. When there is exposure to more than one contaminant, additional ,
uncertainty results from a lack of information about possible synergistic or antagonistic effects.
B. QUANTIFICATION OF NONCARCINOGENIC EFFECTS FOR SIMAZJNE ' .
1. One-dav Health Advisory
The only study (except for LDJO/lethality studies) considered to be of possible use in ..the calculation
* * ' - a
of a One-day HA value for simazine was a single-dose oral toxicity study in sheep (Hapke, 1968). The
sheep were administered a single dose of commercial simazine (50% active ingredient), by oral
c
incubation, at dose levels of 200, 250, 500, 600, 630, 790, and 6,000 mg/Kg and observed for toxic
.effects for at least 4 weeks. No discernible effects were noted in the 200-mg/kg dose group. Slight
*
reduction in feed uptake," polydipsia, and apathy were observed in the 250-mg/kg dose group. A dose
of 500 mg/kg was fatal to four 'out of six sheep. A NOAEL of 200 mg simazine (50%)/kg and a
LOAEL of 250 mg simazine (50%)/kg have been identified from this study. These NOAEL and
LOAEL values would correspond to 400 and 500 mg/kg, respectively, if the active ingredients were
100% simazine. These are conservative estimates, since Hapke found sheep to be more susceptible to
simazine than rats and mice. This study, however, was not considered to be adequate for derivation of
the One-day HA value because the number of animals used was low (two to six/dose), and no
histopathology was performed. ...,
,\
Since no studies found in the literature were suitable for determination of the One-day or Ten-day.
HA values for simazine, it is recommended that the Longer-term HA value of 70 ug/L be used as a
conservative estimate of the One-day HA and Ten-day HA values.
2. Ten-dav Health Advisory
Of several studies considered for calculation of the Ten-day Health Advisory, none was found to be'
adequate. Table VIII- 1 summarizes the studies considered for calculation of the Ten-day HA for
simazine. The teratology study carried out by Ciba-Geigy (1984) in New Zealand rabbits was described
vrn-5
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Simazine Criteria Document
Table Vm-1. Summary of Candidate Studies for Derivation of the Ten-day
Health Advisory for Simazine
Specie)
Rabbit
'. .
.
Rat
'
' '
&
Rat
Mouse
Route
Gsvige
in 3%
com-
lurch
* 0.5*
Tweea-.
SO
Gavage
in 2%
carbony
methyi-
eeliu-
lose
Oral
Oral
Exposure
Duration
Oayi 7
through
19 of
gestation
Days 6
through
15 of
gestation o
3 or 28
day*
28 days
Endpoinu
Reduced
mean body
weight.
increased
itcefetal
variations
at LOAEL
Reduced body
weight, in-
creased in-
cidences of
incompletely
ossified
head, urfoj-
itfled teeth.
unoisified
. ' centra/
vertebrae.
pnsphenoid.
and siemebrae.
and/o; addi-
tional rudi-
mentary ribs
Liver
histopaihuiujiy
Body weight
' gross
pathology
NOAEL o LOAEL
(rag/kg/day) (mg*g/day) Reference
i 200 Ciba-Ceigy
(maumai) (matemaj (1984)
75 and fetal) . '
(fetal)
"-''
' ." '"'.'.
30 300.' Mauuero
(fetal) (fetal) eial. (19*6)
30 300- « '
(maternal) (mtumai) 3
a
.
,
» ^
to .
' f
' '
OledM-
Sloiwinska
<1?74)
450 Ciba-deigy
(1976)
"Hn determined.
vm-6
-------
Sinazir.e Criteria Document
in Section V.C of this document. Pregnant rabbits were given, by gavage, simazine in doses, ranging
from 5 to 200 mg/kg over days 7 through 19 of gestation. Maternal toxicity was observe'd at 75 mg/kg
as indicated by. increased abortions, tremors, decreased motor control activity, and decreased weight gain.
' Fetal toxicity was noticed at 200 mg/kg and was associated with reduced body- weights, increased occur-
rence of floating and fully formed ribs, and decreased ossification of the patellae. aAt the 5-mg/kg dose
.level, simazine did not exert a toxic or teratogenic effect. No malformations were associated with any
dose level of simazine. The maternal toxicity NOAEL of 5 'iflg/kg/day is, however, higher than- the
fl a
NOAEL of 0.72' mg/kg/day suggested in the 1-year study with dogs (McCormick et al., 1988) chosen
for deriving the Longer-term HA.
"> * .
o
"n the teratology study described by Mainiero et al. (1986), rats were dosed by gavage with simazine
in 2% carboxyrhethylcellulose vehicle on gestation days 6 through 15 at doses of 30, 300, or 600
mg/kg/day. This study suggested a NOAEL and LOAEL of 30 and 300 mg/kg/day, respectively, for
fetal toxicity based on increased incidence of developmental indices such as head incompletely ossified^
.teeth unossified, central vertebrae unossified and/or additional, rudimentary ribs, presphenoid unossified,,
and stemebrae unossified. As mentioned in Section V.C, the U.S. EPA raised several issues such as
those concerning the role of maternal toxicity and its influence on fetuses, the non-dose-related nature
of the incidence of unossified stemebrae 5 and 6, the higher incidence of dose-related unossified
stemebrae 2 and 3 at higher doses, the high incidence of unossified stemebrae in historical controls, the
mode of preparation of the test materials, and the source of test animals. For these reasons, and until
more information becomes available on the concerns raised, the NOAEL and LOAEL suggested in this
study have not been considered for development of the Ten-day HA value.
The 3- to 28-day oral toxicity study in rats by Oiedza-Slotwinska (1974) was not selected for
calculation of die Ten-day HA value because the animals were exposed to only one dose (15 mg/kg/day)
for 3 or 28 days/ Focal lesions were observed in hepatic parenchyma after the first 3 days, but the
condition did not progress. Since a wide range of doses was not employed, a NOAEL or LOAEL could
not be identified.
A 28-day oral toxicity study in albino mice (Ciba-Geigy, 1976), which was described in detail in
Section V.A.2, was not considered for calculation of the Ten-day HA value for a child because this was
a range-finding study and did not include adequate histopathological evaluations.
VHI-7
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Sumzine Criteria Document
3. Longer-term Health Advisory
« ' A
The l^ear feeding study in dogs (McCormick and Green, 1988), described in Section V.B.2, was1
considered suitable for calculating a Longer-term HA. In this smdy, beagle dogs were fed simazine in.
the diet at dose levels corresponding to (£76,. 3.6, and 45 mg/kg/day for females, and 0.68, 3:4, and 43
' *« . »
mg/kg/day for males, for 52 weeks. Detailed monitoring of food consumption, body weight, hema'tdlogy, .
clinical chemistry, urinalysis, and gross and histopathology of organs/tissues was carried out. This study
indicated a NOAEL of 0.76 mg/kg/day for females and 0.68 mg/kg/day for males.. These values are
-close to each other, and the mean of 0.72 mg/kg/day is considered to be the NOAEL. The NOAEL is
based on decreases in body weight gain, red blood cells (RBQ, hemoglobin (HGB), hematocrit (HCT),
and a nominal increase in platelet counts noted in females 'at the LOAEL of 3.6 mg/kg/day and in males
ai 43 mg/kg/day. ,
Two other studies were also considered. The 13-week oral toxicity study in rats (Tai.et al., 1985a^
i
did not determine a NOAEL. The 13-week- oral toxicity smdy in dogs (Tal et aL, 1985b), which
indicated a NOAEL of 200 ppm, was considered less appropriate than the 1-year oral toxicity study in
dogs (McConnick and Green. 1988). The latter study was chosen for deriving a Longer-term HA.
The NOAEL of 0.72 mg/kg/day in the dog is selected for use as the basis for calculating the Longer-
term HA. This value is also close to the NOAEL of 0.52 mg/kg/day suggested in the 2-year chronic
toxicity study with rats (McCormick et aL, 1988) described in Section V.B.2. The latter study, which
has been verified by the U.S. EPA, is considered to be more appropriate for calculating the RfD.
The Longer-term HA for a 10-kg child is calculated as follows:
Longer-tern HA -
(OJ2
*? - 0.072 mg/L (rounded to 70 ug/L)
where:
0.72 mg/kg/day = NOAEL, based on adverse effects such as decreases in body weight gain, RBC,
HGB, and HCT, and a nominal increase in platelet counts at the 3.6-mg/kg/day
dose level in female dogs.
This NOAEL is also supported by the NOAEL of 0.52 mg/kg/day developed
in the 2-year chronic toxicity study in rats.
vm-8
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Simazine Criteria Document
10 kg = assumed weight of a child.-
* ' " . ' .
. 100 = uncertainty factor, chosen in accordance with NAS/OST guidelines for use with
a NOAEL from an animal study.
I L/day = assumed water consumption of a 10-kg child.
The Longer-term HA for a 70-kg adult is calculated as follows: '
Longer-tern HA . (b'72 *&***> <70 ^ . 0.252 mg/L (rounded to 300 ug/L)
. ' ' (100H2 L/day) *
- ' ' .
where:- " . .o * .
0.72 rag/kg/day = NOAEL, based on adverse effects in -female dogs such as decreases in body,
' ' weight gain, RBC, HGB, and HCT, and a nominal increase in platele; counts
at the 3.6-mg/kg/day dose level. . '
* * * *
This NOAEL is also supported by the NOAEL of 0.52 mg/kg/day developed.
in the '2-year chronic toxicity study in rats. '
. " * o *
70 kg = assumed weight of an adult.
* a
a
. v-V 100 = uncertainty^actor, chosen in accordance with NAS/CST guidelines for use with
a NOAEL from ^n animal study.
2 L/day = assumed water consumption of a 70-kg adult.
However, it is advisable that the Longer-term HA value of 70 ug/L for a 10-kg child also be used
as the Longer-term HA for value for a 70-kg adult, because the relative source contribution for longer-
term dietary exposure for adults could not be determined from the available data at this time.
4. Reference Dose and Drinking Water Equivalent Level
A carefully controlled and executed 2-year chronic toxicity study (McCormick et al., 1988) in rats
was described in detail in Section V.B.2. This study has been verified by the U.S. EPA for
determination of the RfD, and was considered to be most suitable for calculation of the DWEL. In this
study, the LOAEL was 5.3 mg simazine/kg/day, and at this level, depressed body weight gain and
adverse effects on several hematological parameters were observed. The NOAEL was 0.52 mg/kg/day.
This NOAEL is also supported by the NOAEL of 0.72 mg/kg/day obtained in the 1-year chronic toxicity
study in dogs (McCormick and Green, 1988), described in detail in Section V.B.2.
vm-9
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Simazine Criteria Document
o
Table VDI-2 summarizes the studies considered for calculation of the Rfl>and DWEL for simazine.
* ' ">
Ciba-Geigy (1980) reported a 17- to 22-month orii toxicity study with mice. This study was not
'" "'»"
selected for calculation- of the DWEL because it was declared invalid by EPA owing to inadequate.
»
laboratory performance by Industrial Bio-Test Laboratories, Inc. ? " '
* *
A 95-week oral chronic .toxicity study in Cri:CDl(ICR)BR mice (Hazelette and Green, 1988) was
« ,
also considered For developing the DWEL. The LOAEL for this study was 150 rag simazine/kg/day
based on depressed weight gain, and the NOAEL was 6 mg/kg/day. 10 this study the irigestion period
was less, and the NOAEL is much higher than that obtained in the 2-year chronic study with rats. The
2-year oral chronic toxicity studies in rats (Gysin and Knusli, 1960) and dogs (Woodard Research
Corporation, I965b) were not selected because they lacked sufficient documentation on which to base
4 " " *
evaluation of dose-response. The 1-year chronic feeding study with dogs (McCormick and Green, 1988)
was considered more useful for calculating the Longer-term HA than for determination of the RfD, since
the study did not involve lifetime exposure to simazine. This study suggested a NOAEL of 0.76 mg/kg4
day for females and 0.68 mg/kg/day for males, and supports the NOAEL determined in the 2-year study,
with rats.
The three-generation reproduction study with rats by Woodard Research Corporation (1965a) was
considered and evaluated by the U.S. EPA (Spencer and Copley, 1989) for derivation of the RfD and
DWEL for simazine. Although this study suggested a parental NOAEL of less than 50 ppm,
reproductive toxicity could not be assessed owing to lack of histologic evaluations in apparently sterile
males in the Flfc generation. Up to 33% of the potential parental stock at 100 ppm (5 mg/kg/day) did
not produce a pregnant female in two successive breeding sessions. Additionally, tissues from the male
and female parents were not examined histologically in any generation. The parental NOAEL of
<50 ppm (<2.5 mg/kg/day) indicated in this study is higher than the NOAEL of 0.52 mg/kg/day
suggested in the 2-year chronic toxicity study in rats (McCormick et aL, 1988).
Therefore, a NOAEL of 0.52 mg/kg/day observed in toe 2-year chronic study in rats is used for
calculation of the RfD.
vm-io
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Simazine Criteria Document
Table Vin-2. Summary of Candidate Studies for Derivation of the DWEL for Simazine
Specie*
Mouie
Mouse
R«
Rat
Rat
Dog
Dog
Exposure
Route duniioD
Diet 17 to 22
months
Diet 93 weeks
Diet 2 yean
Diet 74 days
(jea.1);
81 days
(lea. 2);
uadeier-
mined
Diet 2 yean
Diet 2 yean
Diet 1 year
Eadpointt
Food con-
sumption.
gross
pathology.
Oisto-
patbolojy
Body weigbi
Systaltic
toxieiiy
Three-
generation
reproduction
winy
Body weigbL
denuulogy
Thyroid
byperplasia
Body weigol.
hematology
NOAH. LOAEL
(mg/kg/day) ' (mg/kg/day) Refemce
« ^ Ciba-Oeiw
(1980-b)
6 ISO Hizelene and
Green (1988)
>5 Gysin and
Knuiii (i960)
<2J 12 Woodatd
(puoittl KesearcB
uxieicy} Careontion
(1965a)
Q-S2 S.3 MeCormidc
etit
(1988)
3J Woodart
Reseaieb
ogTsb)
cued in
NAS. 1977)
0.76 3.6 MeComiek and
Green (1988)
4ot deiorained.
vm-n
-------
ounazme
d. L>ocumeni
Using this study, the DWEL is derived as follows:
Step 1: Determination of the Reference Dose (RfD)
= (0.52 mg/kg/day) =
(rounded to 5 u/kg/day)
where:
0.52 rag/kg/day = NOAEL, based on depression in body weight and several hematological
parameters in the 2-year chronic toxicity study at 5.3 mg/kg/day.
100 = uncertainty factor of 100 was chosen in accordance with NAS/OST guidelines
for use with a NOAEL from an animal study of lifetime duration.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
D n (0.005 mR/kg/day) (70 kg) = ^ g
(2 L/day)
where:
0.005 mg/kg/day = RfD (after rounding). '
70 kg = assumed body weight of an adult
2 L/day = assumed daily water consumption of an adult
The proposed DWEL reflects the assumption that 100% exposure to simazine is from drinking water.
Since this chemical is used on food crops, the potential dietary exposure should be assessed. When the
percentage contribution in the diet is determined, the DWEL should be adjusted to accommodate this
factor in the determination of the MCLG. *
C QUANTIFICATION OF CARCINOGENIC EFFECTS FOR SIMAZINE
1. Categorization of Carcinogenic Potential
Based on the available data, there is evidence (McCormick et al., 1988) to show that simazine is
carcinogenic in female Sprague-Dawley rats, inducing mammary tumors at dose levels of 100 ppm (5.3
VEI-12
-------
Simazine Criteria Document
mg/kg/day) and 1,000 ppm (63.1 mg/kg/day). In male rats, the formation of liver tumors (hepatocellular
adenomas/carcinomas) was observed at 1,000 ppm (45.8 mg/kg/day). Table Vffi-3 summarizes the
studies considered for the calculation of the carcinogenic risk estimates for simazine. No evidence of
carcinogenicity was found in an 18-monrh study with mice (Innes et al., 1969) or a 95-week mouse
oncogenicity study (Hazelette and Green, 1988). The 2-year study with rats by Hazleton Laboratories
(1960) was not considered adequate to assess the carcinogenicity of simazine because of the high
incidence of respiratory and ear infections. Similarly, the 17- to 22-month study in mice by Ciba-Geigy
(1980t)yas invalid.
Applying the criteria described in EPA's guidelines for the assessment of carcinogenic risk (U.S.
EPA, 1986), simazine may be classified in Group C: Possible Human Carcinogen. This category is
use'd for substances with limited evidence of carcinogenesis in animals in the absence of human data.
2. Quantitative Carcinogenic Risk Estimates
Quantitative carcinogenic risk estimates of simazine have been developed ( Fisher , 1989). "The
Agency's peer review committee recommended (Fisher, 1989) the use of rat mammary gland carcinomas
for the estiamtion of Qt*. The females had a statistically significant incidence of mammary carcinomas
(40/78) and adenomas/carcinomas (61/78) at the high dose (1,000 ppm) and in carcinomas (20/75) at the
mid dose (100 ppm) as compared to controls (16/89 for carcinomas, 39/89 for adenomas/carcinomas).
There was also a significantly increasing trend in mortality in females with dose increments of simazine
from 100 to 1,000 ppm, as compared to controls (for details see Section V.B.2 and Section VS.,
Carcinogenicity). The calculation of the unit risk was made by the use of Weibull 83 (time to death
with tumor multistage mode by K. Crump). The unit risk calculated from the female data in ppm doses
was converted to rat mg/kg/day by the use of Lehman's tables and then to human equivalents by the use
of interspecies surface area adjustments as recommended by EPA cancer guidelines (U.S. EPA, 1986).
The unit risk, Qt*. of simazine is 1.2 x 10'1 (mg/kg/day)'1 in human equivalents. The oncogenic risk
of exposure to drinking water is 3.4 x 10"* assuming that a 70-kg man consumes 2 liters of water per
day with a Maximum Contaminant Level Goal of 1 ppb (1 ug/L) for simazine. It is to be noted that
Qt* is an estimate of the upper-bound (95%) on risk and that as stated in the EPA guidelines (U.S. EPA,
1986), the true value of the risk is unknown and the lower limit of the risk may be as low as zero.
Vm-13
-------
Simazine Criteria Document
Table Vffl-3. Summary of Candidate Studies Considered for Derivation of the
Carcinogenic Risk Estimates for Simazine
Species
Mouse
Mouse
Mouse
Rai
RM
Exposure Dote
Route duration (mg/Xg/day) Results
liionjich 18 months 215 Treatment did noi increase tumor
tube incidence.
Diet 17 to 22 1.5 to 300 Invtlid IBT study.
months
Diet 95 weeks 6 to 600 No evidence of oeopiastic
lesions.
Diet 2 yeas 0.05 to 5 Tumors in high-dose females:
btitopainological details.
not provided
Diet 2 yean 0.52 to 50 At doses of 100 and 1.000 ppro
(5.3 tod 63.1 mgAg/day).
incidence of micusary gland
catcinoma is female no. la mile
rats, hepaiocellultr idenomas/
caicinomaf wen observed at 1,000
ppra (45.8 mg/kg/dty).
Reference
innes et aL (1969)
Ciba-Geigy <1980b)
Htzeteae and Green
Green (1988)
(1960)
McCormick et al.
(1988)
vm-H
-------
Simazine Criteria Document
D. EXISTING GUIDELINES AND STANDARDS
A tolerance level of 10 }ig/L has been established for simazine and its metabolites in potable water
when present as a result of application to growing aquatic weeds (U.S. FDA, 1979).
Residue tolerances for simazine in or on raw agricultural commodities ranged between 20 and 15,000
mg/kg (U.S. EPA, 1986b).
E. SUMMARY
Table Vin-4 summarizes the HA and DWEL values (calculated on the basis of noncarcinogenic
endpoints). Since no studies found in the literature were suitable for determination of the One-day and
Ten-day HA values for simazine, the Longer-term HA of 0.072 mg/L for a 10-kg child is used as a
conservative estimate for the One-day and Ten-day HA values. A. DWEL of 0.175 mg/L (rounded to
180 ug/L) was calculated for a 70-kg adult. Simazine is classified as a Category C carcinogen. Excess
cancer risk has been determined for simazine. The Qt* = 1.2 x 10*' (mg/kg/day)'1 in human equivalents.
The oncogenic risk of exposure to 1 ppb simazine in drinking water is 3.4 x 10"*, assuming that a 70-kg
man consumes 2 liters of water per day.
VHI-15
-------
Simazine Crusru; Document
Table vni-4. Summary of Quantificadon of Toxicological Effects for Simazine
Value
Drinking Water
Concentration
(ug simazine/L)
Reference
One-day HA for 10-kg child '
'^Ten-day HA for 10-kg child '
..Longer-term HA for 10-kg child 70
Longer-term HA for 70-kg adult 300"
DWEL for 70-kg adult 180
Excess cancer risk (3.4 x 10"6) le
McCormick and Green (1988)
McCormick and Green (1988)
McCormick and Green (1988)
McCormick and Green (1988)
McCormick et al. (1988)
The Longer-term HA value for a 10-kg child is recommended as a conservative estimate of the One-day
and Ten-day HA values.
"It is advisable that the Longer-term HA value of 70 ug/L for a 10-kg child also be used as the Longer-
term HA value for a 70-kg adult, because the relative source contribution for Longer-term dietary
exposure for adults could not be determined at this time from the available data.
The unit drinking water risk is the risk associated with exposure to 1 ug/L simazine; this is 3.4 x 10*
excess cancer risk per year.
VHI-16
-------
Simazine Criteria Document
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* * * .
* .
Anderson KJ, Leighty EG, Takahashi MT. 1972. Evaluation of herbicides for possible mutagenic .,
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i
Bumside OC, Schmidt EL, Behrens R. 1961. Dissipation of simazine from the soil. Weeds 9:477-484.
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Chen BQ. 1981. Experimental studies on toxicity and teratogenicity of simazine. Chung Hua Fang I
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IX-1
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Simazine Criteria Document
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*
Dollenrneier P. 1988. Structural chromosomal aberration test-Chromosome studies on human
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. »
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.' . . % '
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.» . ' '
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"' "**- ;
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IX-2
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Simazine Criteria Document
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>
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o
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* * «
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-'' *
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IX-3
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Simazine Criteria Document
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t ^ i
<"
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» ' *
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.
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» *
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<
MyhrBC 1973. A screen for pesticide toxicity to protein and RNA synthesis in HeLa cells. J.'Agric.
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*
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Palmer J3, Radeleff RD. 1964. The toxicologic effects of certain fungicides and herbicides on sheep
and canfe. Ann. N.Y. Acad. Sci 111:729-736.
Palmer JS, Radeleff RD. 1969. The toxicity of some organic herbicides to cattle, sheep, and chickens.
Production Research Report No. 106, U.S. Department of Agriculture, Agricultural Research Service.
1-26.
IX-4
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Simazine Criteria Document
Plewa MJ, Wagner ED, Gentile JM. 1979. Analysis of the mutagenic properties of pesticides
incorporating animal and plant activation. Environ. Mutagen. 1:142.
Pliss GB, Zabezhinsky MA. 1977. Carcinogenicity of symmetric triazine derivatives. Pest. Abstr. 5:72-
1017.
Robinson GW, Mountfort R, Jaeger RB. 1985. ID No. 100-541. Simazine Registration Standard:
Recent Toxicity Studies, Ace. Nos. 257692,257694, and 244268. Caswell No. 740. U.S. Environmental
Protection Agency, Office of Pesticides and Toxic Substances.
Simmons VF, Poole DC, Riccio ES, Robinson DE, Mitchell AD, Waters MD. 1979. In vitro
mutagenicity and genotoxicity assays of 38 pesticides. Environ. Mutagen. 1:142-143.
Simoneaux BJ. Sy A. 1971. Metabolism of Simazine and Its Metabolites in Female Rats. MRID No.
262646.
Sittig M. 1980. Simazine. In: Pesticide Manufacturing and Toxic Materials Control Encyclopedia.
Park Ridge, NJ: Noyes Data Corp., p. 673.
Spencer HW, Copley MP. 1989. U.S. EPA Data Evaluation Report on Simazine: Three-Generation
Reproduction Study in the Rat by Johnston CD. Woodard Research Corporation. Study sponsored by
Ciba-Geigy Research Laboratories. MRID Nos. 0023365, 00080631.
St. John LE, Ammering JW, Wagner DG, Warner RG, Lisk DJ. 1965. Fate of 4,6-dinitro-2-
isobutylphenol, 2-chloro-4,6-bis-(ethylamino)-s-triazine, and pentachloronitrobenzene in the dairy cow.
J. Dairy Sci. 48:502-503.
Tai CN, Breckenridge C, Green JD. 1985a. Simazine Technical Subacute Oral 13-Week Toxicity
Study in Rats. MRID No. 143265. Accession No. 257693.
Tai CN, Breckenridge C, Green JD. 1985b. Simazine Technical. Subacute Oral 13-Week Toxicity
Study in Dogs. MRID No. 146655. Accession No. 257693.
Talbert RE. 1963. Studies of the behavior of some triazine herbicides in soils. Diss. Abstr. 24:923.
USDA. 1984. United States Department of Agriculture. Forest Service. Pesticide Background
Statements. Vol. 1. Herbicides.
U.S. EPA. 1985. U.S. Environmental Protection Agency. U.S. EPA Data Evaluation Report 01
Simazine SOW: Two-Year Dietary Feeding Study in Dogs. Study conducted by Woodard Research
Corporation for Ciba-Geigy Corporation. MRID Nos. 00023364, 00080627.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for carcinogen risk assessment.
Fed. Reg. 51(185)33992-34003. September 24.
IX-5
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Simazine Criteria Document
U.S. FDA. 1979. U.S. Food and Drug Administration. Code of Federal Regulations. 21 CFR
193.400. April 1.
Valencia R. 1981. Mutagenesis screening of pesticides using Drosophila. Project Summary.
Research Triangle Park, NC: U.S. Environmental Protection Agency, Health Effects Research
Laboratory. EPA-600/S1-81-017.
Walker EM Jr., Gale GR, Atkins LM, Gadsden RH. 1979. Some effects of atrazine on Ehrlich
ascites tumor cells in vitro and in vivo. Bull. Environ. Contain. Toxicol. 22:95-102.
Waters MD, Saindhu S, Simmon ZS. 1982. Study of pesticide genotoxicity. In: Fleck RA,
Nollaender A, eds. Gen. Toxicol. Agric. Persp. 21:275-326. Basic Life Sciences Series.
Weed Science Society of America. 1983. Herbicide Handbook. 5th Ed. Champaign, IL: Weed
Science Society of America, pp. 433-437.
Windholz M, ed. 1983. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals.
10th Ed. Rahway, NJ: Merck and Co.. p. 1225.
Woodard Research Corporation. 1965a. Three-generation reproduction study of simazine in the diet
of rats. MRID Nos. 23365, 80631.
Woodard Research Corporation. 1965b. Two-year dietary study in dogs. MRID Nos. 00023364,
00080627.
Worthing CR. 1979. The Pesticide Manual: A World Compendium. 6th Ed. Croydon: British
Crop Protection Council, p. 474.
Yelizarov GP. 1977. Occupational skin diseases caused by simazine and propazine. Pest. Abstr.
6:73-0352.
Zimdahl RL, Freed VH, Montgomery ML, Furtick WR. 1970, The degradation of ttiazine and
uracil herbicides in soil. Weed Res. 10:18-26.
IX-6
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APPENDIX
HUMAN EXPOSURE
-------
Human Exposure to Simazine
CONTENTS
HUMAN. EXPOSURE
A. EXPOSURE ESTIMATION
.. 1. Drinking Water
2. Diet.::...;
_1 ' 3. Air ...'
B. SUMMARY
~ ' C REFERENCES
A-l
A-2'
A-2
A-2
A-4
A-4
A-8
' LIST OF TABLES
Table A-l. Estimated Daily Intake of Sinffiine From Drinking Water
'Table A-2. Tolerances for Simazine .' '.
A-3
A-5
-------
H.-oosure to Simazine
HUMAN EXPOSURE
Humans may be exposed to chemicals such as simazine from a variety of sources, including
surface water, groundwater, drinking water, food, ambient air, and consumer products.
o
Simazine has. been found in 877 of 5,067 surface water samples analyzed and in 229 of 2,282
groundwater samples. Samples were collected at 472 surface water locations and 1,730 groundwater'
locations, and simazine was found in 22 States.* The- 85th perceiitile of all non-zero samples was
2.18 ug/L in surface water and 1.60 ug/L in groundwater sources. The maximum concentrations
found in ground and surface water were 800 ug/L and 1,300 ug/L, respecfively, Simazine has been
found .in groundwater in California, Pennsylvania, and Maryland; typical positives were 0.2 to 3.0
ppb (Cqhen et al., 1986). EPA documented findings of simazine in groundwater in several States,
0 q. o -
including California, .Connecticut, Maryland, "Nebraska, and Pennsylvania (U.S. EPA, 1989). 'Several
detections have approached or exceeded the Maximum Contaminant Level goal of 1 ppb. Additional
o ' «
" . *
' ' available data provided by the registrant indicated that simazine is present at the level of 0.25 ppb of
t
above in groundwater in 6 of 11 states studied across the country. However, nationwide assessment
is not possible from these data in view of the limited scope of the study and the low intensity of
sampling. There is evidence for the detection of simazine in surface waters, and maximum
detections are found in Pennsylvania, Ohio, Michigan, Wisconsin, Texas, and Nebraska. The
validity of. these data has not been confirmed.
The following analysis of human exposure to simazine is limited to drinking water, food, and
ambient air because those media are considered to be sources common to all individuals. Even in
limiting the analysis to these three sources, it must be recognized that individual exposure will vary
widely based on many personal choices and on several factors over which little control exists. Daily
exposure and intafee are profoundly affected by the area in which an individual lives, works, and
travels;.by an individual's diet; and by physiologic characteristics related to age, sex, and health
status. Individuals living in the same neighborhood or even yi the same household can experience
vastly different exposure patterns.
Human exposure to simazine, through close contact with the herbicide, has been documented in
124 workers from the U.S.S.R. (Yelizarov, 1977). The workers suffered from acute and subacute
dermatitis (for details, see Section VLA). Detailed information concerning the occurrence of and
A-l
-------
Human Exposure to Simazine
exposure to simazine in the environment is presented in a report by Borum (1984). Section A of this
appendix summarizes the pertinent information presented in that document to assess the relative
»
source contribution from drinking "water, food, and air. Available information is presented on the
, e
range of human exposure to and intake of simazine from drinking water, food, and ambient air for a
70-kg aciuir male; It is not possible, to provide an estimate of the number of individuals experiencing
specific combined exposures from these three sources. '
A. EXPOSURE ESTIMATION ' . . - ' - ' :
1. Prinking Water . ?
*- " *
Levels of simazine in drinking water vary from one location to another. The highest
concentration of simazine reported in the National Screening Program (NSP) for Organics in
Drinking Water was 4.4 pg/L (Borum, 1984). However, concentrations of simazine in drinking
i
water typically appear to be somewhat lower than this level. Analysis of the data in the NSP
suggests that median levels of simazine in drinking water systems are below 0.1 pg/L, since only 1
of the 12 groundwater systems and 13 of the 104 surface water systems sampled contained levels of
simazine above the quantification limit of 0.1 ug/L (Boland, 1981). Some areas may not contain
simazine in drinking water. Sufficient monitoring data are not available to determine regional
variations in levels of exposure to simazine.
The estimated daily intake of simazine from drinking water of a 70-kg adult m?.le consuming 2
L/day ranges from 0.0 to 0.126 pg/kg/day (Table A-l). However, the values presented do not account
for variances in individual exposure or uncertainties in the assumptions used to estimate exposure >
i
levels.
A tolerance level of 10 pg/L has been established for simazine and its metabolites in potable
water when present as the result of application to growing aquatic weeds (U.S. EPA, 1986).
2. Diet
Data obtained on levels of simazine in foods in the United States were insufficient for use in
determining typical dietary intake levels. Tolerances for residues of simazine and combined residues
3
A-2
-------
Human exposure to Simazine
4 " Table A-l. Estimated Daily Intake of Simazine From Drinking Water*
Drinking water concentration (pg/L) * Intake (pg/kg/day)
° » '
o.o -... . o.o
1
- 0.1 0.003
4.4 " . 0.126
0
'Assumed consumption of a 70-kg adult male is 2 L water/day.
A-3
-------
Human Exposure to Simazine
of simazine and its metabolites, in and on raw agricultural commodities, and in foods are listed in
Table A-2. These data cannot be used, however, to estimate typical dietary intake.
3. Air
No data were qbtained on levels of simazine in ambient air. Therefore, the intake of simazine
from ambient air could not be estimated. . . .
n
* 6
B. SUMMARY '
' e»
Sufficient dataware available to indicate that simazine can leach into groundwater although a
nationwide assessment is not possible at this time because of the limited scope of the study and the
low intensity of sampling. Simazine has been found in surface water samples, but the validity of
these findings remains to be confirmed. Data are being developed on the maximum concentrations
of simazine in these waters as well as on the major source contributor to total intake of simazine.
A-4
-------
Human Exposure to Simazine
Table A-2. Tolerances for Simazine
Commodity
Food
Sugarc'ane syiup
Sugarcane molasses
o
Raw agricultural commodity
Tolerance (mg/kg)
1,000
«
1,000
Alfalfa
forage
hay
Almonds
hulls-
' Apples
Artichokes
Asparagus
Avocados
Bananas
Bermuda grass
forage
hay
Blackberries
Blueberries
Boysenbenies
Cattle
fat
meat by-products
meat
15,000
15,000-
15,000
250
250 i
250
500
10,000
250
200*
15,000
15,000
15,000
250
250
250
20
20
20
(continued)
A-5
-------
Human Exposure to Simazine
v
. o Commodity . '
A '
. - : -Cherries
- Com
; fodder ' '
forage
fresh (including sweet)"
grain
Cranberries
Currants
° » 3
Dewberries
Eggs t
Filberts-
Fish
Goats
fat
meat by-products
meat
Grapefruit
Grapes
Grass
forage
hay
Hogs
fat
meat by-products
Horses
fat
meat by-products
meat
Table A-2. (contiqued)
Tolerance (mg/kg)
250
0
.3 *
250
250 ...
.250 ....
250-
250 ' ,
. . 250 - - '
250
20
i,
250 \
12,000*
20
20
20
250
250
15,000
15,000
15,000
20
20
20
20
20
(continued)
i
A-6
-------
Human Exposure to Simazine
p '
Commodity
Lemons . '
Loganberries
Macadarnia nuts
Milk
Olives
Oranges 0
Peaches
t
Pears
Pecans
Plums .
Poultry
fat
meat by-products
meat
Raspberries
Sheep
fat
meat by-products
meat
Strawberries
Sugarcane
Table A-2. (continued) .
Tolerance (mg/kg)
250
.250 .
.250 .-.-
20
. ' . , 250
250
. 250 .
250 - ' - i
'""' ' 100
a
250
20
20
20
250
20
20
20
250
250
Tor combined residues of simazine and its metabolites.
''Kernels plus cob with husk removed.
SOURCE: Adapted from U.S. EPA (1986).
A-7
-------
>
Human Exposure to Simazine
C. REFERENCES . '-
o i . .
Borurn D. JRB Associates. 1984. Pesticide Occurrence in Drinking Wate/, Food and Air. Vol. n.
Draft prepared by JRB Associates, McLean, VA, for Office of Drinking Water, U.S. Environmental
' Protection-Agency, Washington, DC. EPA Contract No. 68-01-6388.
' . * ' '
Boland PA. SRI International. 1981. National screening program for organics in drinking water.
Pan n. Data. Prepared by SRI International, $lenlo park, CA, for Office of Drinking Water, U.S.
Environmental Protection Agenqy, Washington, DC. EPA Contract No. 68-01-4666.
.'*-.'»''* ' . ' ' '
Cohen SZ, Eiden C, Lorber MN. 1986. Monitoring ground water for pesticides in the U.S.A. In:-
American Chemical Society Symposium Series titled Evaluation'of Pesticides in Ground Water (in
press).'
U.S. EPA. 1986. U.S. Environmental Protection Agency. Code of Federal Regulations, 40 CFR
180.213." July 1. '
9 »
U.S. EPA. 1989. Guidance for the Registration of Pesticide Products Containing Simazine as the
Active Ingredient. Internal/External Review Draft. August 1989.
rt
YeJizarov GP. 1977. Occupational skin diseases caused by simazine and propazine. Pest, Abstr. ,
6:73-0352.
A-8
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