August, 1987
820K88109
PROPAZINE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the one-hit, Weibull, logit or probit models. There is no 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 another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
-------
Propazine August, 1987
? -2-
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 139-40-2
Structural Formula p.
V i 5 "
/ru \ r-N^*^fcj*^N
vurij^^ , N i
H H
6-Chloro-N,N'-bis(1-methylethyl)-1-3,5-triazine-2,4-diamine
Synonyms
0 Geigy 30,028; Gesomil; Milogard; Plantulin; Primatol P; Propasin;
Prozinex (Meister, 1983).
Uses
0 Selective preemergence and preplant herbicide used for the control of
most annual broadleaf weeds and annual grasses in milo and sweet
sorghum (Meister, 1983).
Properties (Meister, 1983; IPC, 1984; CHEMLAB, 1985; TDB, 1985)
Chemical Formula CgHig^Cl
Molecular Weight 230.09
Physical State (25°C) Colorless crystals
Boiling Point —
Melting Point 212 to 214°C
Density —
Vapor Pressure (20°C) 2.9 x 10~8 mm Hg
Water Solubility (29°C) 8.6 mg/L
Octanol/Water Partition -1.21
Coefficient
Taste Threshold ~
Odor Threshold —
Conversion Factor —
Occurrence
0 Propazine has been found in 132 of 1,231 surface water samples
analyzed and in 20 of 1,056 ground water samples (STORET, 1987).
Samples were collected at 253 surface water locations and 639 ground
water locations, and propazine was found in 8 states. The 85th
percentile of all nonzero samples was 2.3 ug/L in surface water and
0.2 ug/L in ground water sources. The maximum concentration found
was 20 ug/L in surface water and 300 ug/L in ground water
0 Propazine was detected in ground water in California at trace levels
(<0.1 ppb) (U.S.G.S., 1935).
-------
Propazine August, 1987
1
-3-
Environmental Fate
The following data were submitted by Ciba-Geigy and reviewed by the Agency
(U.S. EPA, 1987):
0 Hydrolysis studies show propazine to be resistant to hydrolysis.
After 28 days, at pH 5, 60% remains; at pH 7, 92% remains; and at pH 9,
100% remains. Hydroxypropazine ( 2-hydroxy-4,6-bis-isopropylamino)-s-
triazine) is the hydrolysis product.
0 Propazine at 2.5 ppm in aqueous solution was exposed to natural
sunlight for 17 days. In that time, 5% degraded to hydroxy-propazine.
0 Under aerobic conditions, 10 ppm propazine was applied to a loamy
sand (German) soil with 2.2% organic carbon. The soil was incubated
at 25°C in the dark and kept at 70% of field capacity. Propazine
degraded with a half-life of 15 weeks. Hydroxypropazine was the
major degradate from aerobic soil metabolism; its concentration
increased from 14% at 12 weeks to a maximum of 31% after 52 weeks of
incubation. Trapped volatiles identified as C02 accounted for 1% of
the applied propazine after 52 weeks. Bound residues increased up to
35% after 12 weeks of incubation.
0 Under anaerobic conditions, further degradation of propazine was
slight.
0 Freundlich soil-water partition coefficient (Kd) values for propazine
and hydroxypropazine were determined for four soils: a sand loam
(0.7% OM), a sand loam (1.4% OM), a loam soil (2.9% OM) and a clay
loam (8.3% OM). The Kd values were: 0.34, 1.13, 2.69 and 3.19,
respectively, for propazine. On the same four soils the Kd values
for hydroxypropazine were: 1.13, 2.94, 31.8 and 10.6, respectively.
All Kd values have units of ml/gm.
0 Leaching studies for propazine performed on four soils under worst-case
conditions (30-cm columns leached with 20 inches of water) for
propazine indicate propazine's mobility in soil-water systems. In a
loamy sand (0.7% OM), a sandy loam (1.4% OM), a loam (1.7% OM), and a
silt loam (2.4% OM), 82.5%, 18%, 69.5%, and 23.6% leached, respectively.
0 In column studies using aged propazine, degradation products leached
from a loamy sand soil with 2.2% OM. About 25% of the aged propazine
added to the columns leached. In a loam soil with 3.6% OM, <0.05% of
the aged propazine added to the columns leached.
0 In field dissipation studies, propazine was found at 18 inches the
deepest depth in the soil sampled. Hydroxypropazine was found at
all depths and sites up to 3 years after application. Field half-
lives for propazine were 5 to 33 weeks in the 0- to 6-inch depth,
and 17 to 51 weeks at the 6 to 12 inch depth.
-------
Propazine August, 1987
, «
-4-
III. PHARMACOKINETICS
Absorption
0 Bakke et al. (1967) administered single oral doses of ring-labeled
14c-propazine to Sprague-Dawley rats. After 72 hours, about 23% of
the label was recovered in the feces and about 66% was excreted in
the urine. This indicates that gastrointestinal absorption was at
least 77% complete.
Distribution
0 Bakke et al. (1967) administered ring-labeled 14C-propazine (41 to
56 mg/kg) to rats by gastric intubation. Radioactivity in a variety
of tissues was observed to decrease from an average of 46.7 ppm 2 days
posttreatment to 22.3 ppm after 8 days. Radioactivity was detected
in the lung (30 ppm), spleen (25 ppm) heart (27 ppm), kidney (17 ppm)
and brain (13 ppm) for up to 8 days. After 12 days, the only detectable
quantities were in hide and hair (3.35% of administered dose), viscera
(0.1%) and carcass (2.22%).
Metabolism
0 Eighteen metabolites of propazine have been identified in the urine of
rats given single oral doses of 1^c-propazine (Bakke et al., 1967).
No other details were provided. Based on metabolites found in urine,
Bakke et al. (1967) reported that dealkylation is one reaction in the
metabolism of propazine. No other details were provided.
Excretion
0 Bakke et al. (1967) administered single oral doses of 1 Boring-labeled
propazine to rats. Most of the radioactivity was excreted in the
urine (65.8%) and feces (23%) within 72 hours. Excretion of propazine
and/or metabolites was most rapid during the first 24 hours after
administration, decreasing to smaller amounts at 72 hours.
IV. HEALTH EFFECTS
Humans
0 Contact dermatitis was reported in workers involved in propazine
manufacturing (Hayes, 1982). No other information on the health
effects of propazine in humans was found in the available literature.
Animals
Short-term Exposure
0 The reported acute oral LD5r) values for propazine (puritv not specified)
were >5,000 mg/kg in rats (Stenger and Kindler, 1963a). >5,000 mq/kq
in mice (Stenqer and Kindler. 1963b) and 1.200 mq/kq in quinea oiqs
(NIOSH. 1985).
-------
Propazine August, 1987
-5-
0 Stenger and Kindler (1963a) reported that dietary administration of
propazine (purity not specified) to rats (five/sex/dose) at doses of
1,250 or 2,500 mg/kg for 4 weeks resulted in a decrease in body
weight, but there were no pathological alterations in organs or
tissues. No other details were provided.
Dermal/Ocular Effects
0 The acute dermal LD5Q value in rabbits for propazine (90% water dis-
persible granules) was reported as >2,000 mg/kg (Cannelongo et al.,
1979).
0 Stenger and Huber (1961) reported that rats were unaffected when
a 5% gum arabic suspension of propazine (0.4 mL/animal) was applied
to shaved and intact skin of five rats then washed away 3 hours
later.
0 Palazzolo (1964) reported that propazine (1 or 2 g/kg/day) applied to
intact or abraded skin of albino rabbits (five/sex/dose) for 7 hours
produced mild erythema, drying, desquamation and thickening of the
skin. Body weights, mortality, behavior, hematology, clinical chemistry
and pathology of the treated and untreated groups were similar.
Long-term Exposure
0 In 90-day feeding studies by Wazeter et al. (1967a), beagle dogs
(12/sex/dose) were fed propazine (80 WP) in the diet at 0, 50, 200
or 1,000 ppm active ingredient. Based on the assumption that 1 ppm
in the diet of dogs is equivalent to 0.025 mg/kg/day (Lehman, 1959)
these doses correspond to 0, 1.25, 5.0 or 25 mg/kg/day. No compound-
related changes were observed in general appearance, behavior,
hematology, urinalysis, clinical chemistry, gross pathology or histo-
pathology at any dose tested. In the 1,000 ppm dose group, four
dogs lost 0.3 to 1.1 kg in body weight, which the author suggested
may have been compound-related (no p value reported). Based on these
results, a No-Observed-Adverse-Effect-Level (NOAEL) of 200 ppm
(5 mg/kg/day) and a LOAEL of 1,000 ppm (25 mg/kg/day) were identified.
0 Wazeter et al. (1967b) supplied CD rats (80/sex/dose) with propazine
(80 WP) in the diet for 90 days at dose levels of 0, 50, 200 or
1,000 ppm active ingredient. Based on th? assumption that 1 ppm in
the diet is equivalent to 0.05 mg/kg/day iLehman, 1959), these doses
correspond to 0, 2.5, 10 or 50 mg/kg/day. No compound-related changes
were observed in appearance, general behavior, hematology, clinical
chemistry, urinalysis, gross pathology and histopathology. There was
a 12% reduction (p <0.01) in body weight of females at 1,000 ppm (50
ing/kg/day) at the end of the study. Based on body weight loss, a
NOAEL of 200 ppm (10 mg/kg/day) and a Lowest-Observed-Adverse-Effect-
Level (LOAEL) of 1,000 ppm (50 mg/kg/day) were identified.
0 Geigy (1960) dosed rats (12/sex/dose) of an unspecified strain with
propazine (50% a.i.) by stomach tube for 90 days at 0, 250 or 2,500
nig/kg/day (a.i.) or for 180 days at 0 or 250 mg/kg/day (a.i.). In the
-------
Propazine August, 1987
-6-
90-day study, a reduction in body weight (30%, no p value given) and
feed consumption were reported at 2,500 mg/kg/day, but no effects
were seen at 250 mg/kg/day. No histopathological evaluations were
performed at the high-dose level. After 180 days, rats administered
propazine at 250 mg/kg/day were similar to untreated controls in
growth rates, daily food consumption, gross appearance and behavior,
mortality, gross pathology and histopathology. This study identified
a NOAEL of 250 mg/kg/day and a LOAEL of 2,500 mg/kg/day.
Jessup et al. (1980a) fed CD mice (60/sex/dose) technical propazine
(purity not specified) for 2 years at dose levels of 0, 3, 1,000 or
3,000 pptn. Based on the assumption that 1 ppm in the diet of mice is
equivalent to 0.15 mg/kg/day (Lehman, 1959), these doses correspond
to 0, 0.45, 150 or 450 mg/kg/day. The general appearance, behavior,
survival rate, body weights, organ weights, food consumption and
incidence of inflammatory, degenerative or proliferative alterations
in various tissues and organs did not differ significantly from
untreated controls. The author identified a NOAEL of 3,000 ppm (450
the highest dose tested).
0 Jessup et al. (1980b) fed CD rats (60 to 70/sex/dose) technical
propazine (purity not specified) in the diet for 2 years at dose
levels of 0, 3, 100 or 1,000 ppm. Based on the assumption that 1 ppm
in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959),
this corresponds to doses of 0, 0.15, 5 or 50 mg/kg/day. No compound-
related effects were observed in behavior, appearance, survival, feed
consumption, hematology, urinalysis and in nonneoplastic alterations
in various tissues and organs. Mean body weight gains appeared to be
lower in the treatment groups than the control groups. Body weights
at 104 weeks were lower than controls at all dose levels. The percent
decreases in males and females were as follows: -6.3 and -3.9% (3
ppm); -4.6 and -5.6% (100 ppm); -13.1 and -11.4% (1,000 ppm). These
decreases were statistically significant in males at 3 and 1,000 ppm,
and in females at 100 and 1,000 ppm. The decreases at 3 or 1 00 ppm
appeared to be so small that they may not be considered biologically
significant; a NOAEL was identified at 100 ppm (5 mg/kg/day).
Reproductive Effects
0 Jessup et al. (1979) conducted a three-generation study in which CD
rats (20 females and 10 males/dose) were administered technical
propazine in the diet at 0, 3, 100 or 1,000 ppm. Based on the
assumption that 1 ppm in the diet is equivalent to 0.05 mg/kg/day
(Lehman, 1959), this corresponds to doses of 0, 0.15, 5 or 50 mg/kg/day.
No compound -re la ted effects were observed in any dose group in
general behavior, appearance or survival of parental rats or pups.
The mean parental body weights were statistically lower at 1,000 ppm
(50 mg/kg/day). No differences were reported in feed consumption
for treated and control animals. No treatment-related effects were
observed in fertility, length of gestation or viability and -surivival
of the pups through weaning. Mean pup weights at lactation were not
adversely affected at 3 or 1 00 ppm (0.15 or 5 mg/kg/day). However,
at 1,000 ppm (50 mg/kg/day), there was a statistically significant
-------
Propazine August, 1987
-7-
decrease in mean pup weights for all generations except ?ia. Based
on these data, a NOAEL of 100 ppm (5 mg/kg/day) was identified.
Developmental Effects
0 Fritz (1976) administered technical propazine (0, 30, 100, 300 or
600 mg/kg/bw) orally by intubation to pregnant Sprague-Dawley rats
(25/dose) on days 6 through 15 of gestation. No maternal toxicity,
fetotoxicity or teratogenic effects were observed at 100 mg/kg/day
or lower. Maternal body weight and feed consumption were reduced at
300 mg/kg/day or higher. Fetal body weight was reduced, and there
was delayed skeletal ossification (of calcanei) at 300 mg/kg/day or
higher. Based on body weights, a maternal NOAEL of 100 mg/kg/day
and a fetal NOAEL of 100 mg/kg/day were identified.
0 Salamon (1985) dosed pregnant CD rats (21 to 23 animals per dose
group) with technical propazine (99.1% pure) by gavage at dose levels
of 0, 10, 100 or 500 mg/kg/day on days 6 through 15 of gestation.
Maternal body weight and feed consumption were statistically signifi-
cantly (p <0.05) decreased at doses of 100 mg/kg/day or higher.
Fetal body weight was reduced, and ossification of cranial structures
was delayed at 500 mg/kg/day. Based on maternal toxicity, a NOAEL of
100 mg/kg/day was identified.
Mutagenicity
0 Puri (1984a) reported that propazine (0, 0.4, 20, 100 or 500 ug/mL)
did not produce DNA damage in human fibroblasts in vitro.
0 Puri (1984b) reported that propazine (0, 0.50, 2.5, 12.5 or 62.5
ug/mL) did not cause DNA damage in rat hepatocytes in vitro.
0 Strasser (1984) reported that propazine administered to Chinese
hamsters by gavage (0, 1,250, 2,500 or 5,000 mg/kg) did not cause
anomalies in nuclei of somatic interphase cells.
Carcinogenicity
0 Innes et al. (1969) fed propazine in the diet to 72 mice (C57BL/6
x AKRF1, C57BL/6 x C3H/ANF1) for 18 months at a dose level of 46.4
mg/kg/day. Based on histopathological examination of tissues (no data
reportec), the authors stated that propazine, at the one dose tested,
did not cause a statistically significant increase in the frequency
of any tumor type in any sex-strain subgroup or combination of groups.
0 Jessup et al. (1980b) fed CD rats (60 to 70/sex/dose) technical
propazine (purity not specified) in the diet for 2 years at dose
levels of 0, 3, 100 or 1,000 ppm. Based on the assumption that 1 ppm
in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman, 1959),
this corresponds to doses of 0, 0.15, 5 or 50 mg/kg/day. Tumor inci-
dence was evaluated for a variety of organs and tissues. The most
commonly occurring tumors were mammary gland tumors in female rats.
At the highest dose tested (1,000 ppm, 50 mg/kg/day), the authors
-------
Propazine August, 1987
-8-
reported an increase in adenomas (10/55, 18%), adenocarcinomas (9/55,
16%) and papillary carcinomas (8/55, 15%) compared to corresponding
tumor levels in untreated controls (3/55, 5%), (6/55, 11%) and
(4/55, 7%), respectively. Also, it was reported that the percentage
of tumor-bearing rats was 73% in the high-dose treated group compared
to 50% in corresponding untreated controls. The authors did not
consider these increases to be statistically significant. However,
in 1981, Somers reported historical control values of 122/1,248 (10%)
for adenomas and of 769/1,528 (50%) for percentage of tumor-bearing
animals. Further evaluations by Somers (1981) of the above data
(control and treated) and historical control data indicated that the
increase in mammary gland adenomas and the number of rats bearing one
or more tumor was statistically significant (p <0.02).
0 Jessup et al. (1980a) fed CD mice (60/sex/dose) technical propazine
(purity not stated) for 2 years at dose levels of 0, 3, 1,000 or
3,000 ppm. Assuming that 1 ppm in the diet of mice is equivalent
to 0.15 mg/kg/day (Lehman, 1959), this corresponds to doses of 0,
0.45, 150 or 450 mg/kg/day. The incidence of proliferative and
neoplastic alterations in the treated groups did not differ signifi-
cantly from the control group at any dose level.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS x
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW ) = /L ( « ,
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effeet-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No information was found in the available literature that was suitable
for determination of the One-day HA value for propazine. It is, therefore,
recommended that the Ten-day HA value for a 10-kg child, 1.0 mg/L (1,000 ug/L,
calculated below), be used at this time as a conservative estimate of the
One-day HA value.
-------
Propazine August, 1987
«
-9-
Ten-day Health Advisory
The study by Salamon (1985) has been selected to serve as the basis for
the determination of Ten-day HA value for propazine. In this teratogenicity
study in rats, body weight was decreased in dams dosed on days 6 to 15 of
gestation with 100 mg/kg/day or greater. No adverse effects were observed
in either dams or fetuses at 100 mg/kg/day. The rat study by Fritz (1976)
reported maternal and fetal toxicity at 300 mg/kg/day, but not at 100 mg/kg/day.
This NOAEL was not selected, since maternal weight loss was noted at this dose
by Salamon (1985).
Using a NOAEL of 10 mg/kg/day, the Ten-day HA for a 10-kg child is
calculated as follows:
Ten-day HA = (10 mg/kg/day) (10 kg) „ K0 m /L {1 000 ug/L) '
(100) (1 L/day)
where:
10 mg/kg/day = NOAEL, based on absence of maternal and developmental
toxicity in rats exposed to propazine by gavage on
days 6 through 15 of gestation.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Longer-term Health Advisory
The 90-day feeding study in dogs by Wazeter et al. (1967a) has been
selected to serve as the basis for the Longer-term HA for propazine. In this
study, body weight loss occurred at 1,000 ppm (25 mg/kg). A NOAEL of 200 ppm
(5 mg/kg/day) was identified. This is supported by the 90-day rat feeding
study by Wazeter et al. (1967b), which identified a NOAEL of 10 mg/kg/day and
a LOAEL of 50 mg/kg/day. The 90-day study in rats by Geigy (1960) has not
been selected, since the NOAEL (250 mg/kg/day) is higher than the LOAEL
values reported above.
Using a NOAEL of 5 mg/kg/day, the Longer-term HA for the 10-kg child is
calculated as follows:
Longer-term HA = (5 mg/kg/day) (10 kg) = 0.5 mg/L (500 ug/L)
(100) (1 L/day)
where:
5 mg/kg/day = NOAEL, based on absence of effects on appearance,
behavior, hematology, urinalysis, clinical chemistry,
gross pathology, histopathology and body weight gain
in dogs exposed to propazine via the diet for 90 days.
-------
Propazine August, 1987
-10-
10 kg = assumed body weight of a child.
100 - uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day « assumed daily water consumption of a child.
The Longer-term HA for a 70-kg adult is calculated as follows:
Longer-term HA = (5 mg/kg/day) (70 kg) . U75 mg/L (1,750 ug/L)
(100) (2 L/day)
where:
5 mg/kg/day = NOAEL, based on absence of effects on appearance,
behavior, hematology, urinalysis, clinical chemistry,
gross pathology, histopathology and body weight gain
in dogs exposed to propazine via the diet for 90 days.
70 kg = assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three-step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classifed as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised
in assessing the risks associated with lifetime exposure to this chemical.
The 2-year feeding study in rats by Jessup et al. (1980b) has been
selected to serve as the basis for determination of the Lifetime HA for
-------
Propazine August, 1987
-11-
propazine. No effects were detected on behavior, appearance, mortality, food
consumption, hematology, urinalysis or body weight gain at doses of 5 mg/kg/day.
At 50 mg/kg/day, decreased weight gain was noted, and there was evidence of
increased tumor frequency in the mammary gland. This NOAEL value (5 mg/kg/day)
is supported by the NOAEL of 5 mg/kg/day in the three-generation reproduction
study in rats by Jessup et al. (1979). The 2-year feeding study in mice by
Jessup et al. (1980a) has not been selected, since the data suggest that the
mouse is less sensitive than the rat.
The Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (5 mg/kg/day) = 0.02 mg/kg/day
(100) (3)
where:
5 mg/kg/day * NOAEL, based on absence of effects on behavior,
appearance, mortality, hematology, urinalysis or
body weight gain in rats exposed to propazine via
the diet for 2 years.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
3 = additional uncertainity factor to account for data gaps
(chronic feeding dog study) in the propazine database.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DW^L = (0*02 mg/kg/day) (70 kg) _ 0.70 mg/L (700 ug/L)
(2 L/day)
where:
0.02 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day.= assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (0-70 m?/L > (20%) = 0.014 mg/L (14 ug/L)
(10)
where:
0.70 mg/L = DWEL.
20% = assumed relative source contribution, from wa-ter.
10 = additional uncertainty factor per ODW policy to account
for possible carcinogenicity.
-------
Propazine August, 1987
-12-
Evaluation of Carcinogenic Potential
0 No evidence of increased tumor frequency was detected in a 2-year
feeding study in mice at doses up to 450 mg/kg/day (Jessup et al.,
1980a) or in an 18-month feeding study in mice at a dose of 46.4
n>9Ag/day (Innes et al., 1969).
0 Jessup et al. (1980b) reported that the occurrence of mammary gland
tumors in female rats administered technical propazine in the diet for
2 years at 1,000 ppm (50 mg/kg/day) was increased but did not differ
significantly from concurrent controls. However, a reevaluation of
the data by Somers (1981) that considered historical control data
indicated that the increase in mammary gland adenomas and the number o<
rats bearing one or more tumors was statistically significant (p <0.02)
0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of propazine.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986a), propazine may be classified in
Group C: possible human carcinogen. This category is for substances
with limited evidence of carcinogenicity in animals in the absence of
human data.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The U.S. EPA (1986c) has established residue tolerances for propazine
in or on various agricultural commodities of 0.25 ppm (negligible)
based on a Provisionary Acceptable Daily Intake (PADI) of 0.005 mg/kg/day,
0 NAS (1977) determined an Acceptable Daily Intake (ADI) of 0.464
ing/kg/day, based on a NOAEL of 46.4 mg/kg identified in an 80-week
feeding study in mice with an uncertainty factor of 1,000.
8 NAS (1977) calculated a chronic Suggested-No-Adverse-Effeet-Level
(SNARL) of 0.32 mg/L, based on an ADI of 0.0464 mg/kg/day and a
relative source contribution factor of 20%.
VII. ANALYTICAL METHODS
Analysis of propazine is by a gas chromatographic (GC) method appli-
cable to the determination of certain nitrogen-phosphorus containing
pesticides in water samples (U.S. EPA, 1986b). In this method,
approximately 1 liter of sample is extracted with methylene chloride.
The extract is concentrated and the compounds are separated using
capillary column GC. Measurement is made using a nitrogen-phosphorus
detector. The method detection limit has not been determined for
propazine, but it is estimated that the detection limits for analytes
included in this method are in the range of 0.1 to 2 ug/L.
VIII. TREATMENT TECHNOLOGIES
No information regarding treatment technologies applicable to the
removal of propazine from contaminated water was found in the available
literature.
-------
Propazine August, 1987
-13-
IX. REFERENCES
Bakke, J.E., J.D. Robbins and V.J. Fell. 1967. Metabolism of 2-chloro-4,6-
bis(isopropylamine), S-triazine (propazine) and 2-methoxy-4,6-bis (isopro-
pylamino)-s-triazine (prometone) in the rat. Balance study and urinary
metabolite separation. J. Agr. Food Chem. 15(4):628-631.
Cannelongo/ B., E. Sabol, R. Sabol et al.* 1979. Rabbit acute dermal toxicity.
Project No. 1132-79. Unpublished study. MRID 00111700.
CHEMLAB. 1985. The Chemical Information System, CIS, Inc., Bethesda, MD.
Fritz, H.* 1976. Reproduction study. G 30028 technical rat study. Segment II.
Test for teratogenic or embryotoxic effects. Experiment No. 227642.
Unpublished study. MRID 00087879.
Geigy, S.A.* 1960. Chronic toxicity of propazine 50 WP. Unpublished study.
MRID 00111671.
Hayes, W.J. 1982. Pesticides studied in man. Baltimore, MD: Williams and
Wilkins.
IPC.* 1984. Industria Prodotti Chimici. Atrazine product chemistry data.
Unpublished compilation. MRID 00141156. v
Innes, J., B. Ulland, M.G. Valerio, L. Petrucelli, L. Fishbein, E. Hart and
A. Pallotta. 1969. Bioassay of pesticides and industrial chemicals for
tumorigenicity in mice. A preliminary note. J. Natl. Can. Inst.
42(6):1101-1114.
Jessup, D.C., R.J. Arceo and J.E. Lowry.* 1980a. Two-year carcinogenicity
study in mice. IRDC No. 382-004. Unpublished study. MRID 00044335.
Jessup, D.C., G. Gunderson, L.J. Ackerman et al.* 1980b. Two-year chronic
oral toxicity study in rats. IRDC No. 382-007. Unpublished
study. MRID 00041408.
Jessup, D.C., C. Schwartz, R.J. Arceo et al.* 1979. Three generation study
in rat. IRDC NO. 382-010. Unpublished study. MRID 00041409.
Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs and
cosmetics. Assoc. Food Drug Off.
Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister
Publishing Company.
NAS. 1977. National Academy of Sciences. Drinking water and health.
Washington, DC: National Academy Press.
NIOSH. 1985. National Institute for Occupational Safety and Health. Registry
of Toxic Effects of Chemical Substances (RTECS). National Library of
Medicine Online File.
-------
Propazine August, 1987
-14-
Palazzolo, R.* 1964. Report to Geigy Research Laboratories. Repeated dermal
toxicity of propazine 80 W. Unpublished study. MRID 00111670.
Puri, E.* 1984a. Autoradiographic DNA repair test on human fibroblasts with
G30028 technical. Test No. 831373. Unpublished study. MRID 00150024.
Puri, E.* 1984b. Autoradiographic DNA repair test on rat hepatocytes with
G30028 technical. Test Report No. 831371. Unpublished study. MRID
00150623.
Salamon, C.* 1985. Teratology study in albino rats with technical propazine.
Report No. 450-1788. Unpublished study. American Biogenics Corporation.
MRID 00150242.
Somers, J.A.* 1981. Letter sent to Robert J. Taylor dated April 14, 1981.
Propazine herbicide chemical no. 080808, 6(a)(2): submission of treated
vs. control data involving mammary tumors in rats in IRDC study no.
382-007; response to November 18, 1980. MRID 00076955.
Stenger and Kindler.* 1963a. Subchronic oral toxicity in the rat. A trans*
lation ofs subchronische toxizitat--ratte p.o. Unpublished study.
MRID 00111678.
Stenger and Kindler.* 1963b. Acute toxicity - mouse, oral. Translation of
akute toxizitat—maus per OS. Unpublished study. MRID 00111675.
Stenger and Huber.* 1961. Subchronic toxicity—rat skin, A translation of:
subchronic toxizitat—ratte, haut. Unpublished study, including German
text. MRID 00111677.
Strasser, F.* 1984.' Nucleus anomaly test in somatic interphase nuclei of
Chinese hamster. Test Report No. 831372. Unpublished study. MRID
00150622.
TDB. 1985. Toxicology Data Bank. MEDLARS II. National Library of Medicine's
National Interactive Retrieval Service.
U.S. EPA. 1986a. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Fed. Reg. 51(185):33992-34003. September 24.
U.S. EPA. 1986b. U.S. Environmental Protection Agency. U.S. EPA Method #1
- Determination of nitrogen and phosphorus containing pesticides in
ground water by GC/NPD, January 1986 draft. Available from U.S. EPA's
Environmental Monitoring and Support Laboratory, Cincinnati, OH.
U.S. EPA. I986c. U.S. Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 180.243. July 1, 1985. p. 296.
U.S. EPA. 1987. U.S. Environmental Protection Agency. Environmental fate
of propazine. Memo from C. Eiden to D. Tarkas, June 9.
U.S.G.S. 1985. U.S. Geological Survey. Regional assessment project. C. EidenJ
-------
Propazine August, 1987
-15-
Wazeter, F., R. Buller, R. Geil et al.* 1967a. Ninety-day feeding study in
the beagle dog. Propazine SOW. Report No. 248-002. Unpublished study.
MRID 00111680.
Wazeter, F., R. Buller, R. Geil et al.* 1967b. Ninety-day feeding study in
albino rats. Propazine 80W. Report No. 248-001. Unpublished study.
MRID 00111681.
Confidential Business Information submitted to the Office of Pesticide
Programs.
------- |