820K88112 August, 1987
PROMETON
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.
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Prometon
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 1610-18-0
Structural Formula
OCH,
H
u
*•
H
H
3)3
2,4-bis(isopropylamino)-6-methoxy-s-triazine
Synonyms
Uses
Gesafram 50; Ontracic 800; Primatol 25E; Pramitol; Methoxypropazine
(Meister, 1983).
A nonselective herbicide that controls most perennial broadleaf weeds
and grasses (Meister, 1983).
Properties (Meister, 1983; TDB, 1985; CHEMLAB, 1985)
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density
Vapor Pressure (20°C)
Specific Gravity
Water Solubility (20°C)
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
C10H19N50
225.34
White crystals
91 to 92°C
1 .088 g/cm3
2.3 x 10~6 mm Hg
750 mg/L
-1.06 (calculated)
Occurrence
Prometon has been found in 385 of 1,459 surface water samples analyzed
and in 40 of 757 ground water samples (STORET, 1987). Samples were
collected at 240 surface water locations and 650 ground water locations,
and prometon was found in 12 states. The 85th percentile of all
nonzero samples was 0.6 ug/L in surface water and 50 ug/L in ground
water sources. The maximum concentration found was 8.5 ug/L in
surface water and 250 ug/L in ground water.
Prometon residues resulting from agricultural practice have been detected
in California ground waters at 0.21 - 80 ppb (Eiden, 1987).
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Environmental Fate
0 Prometon is stable to hydrolysis at pH 5, 7, and 9 at 25°C for 40
days (Ciba-Geigy Corporation, 1985a).
0 Prometon in aqueous solution was stable to natural sunlight for 2
weete (Ciba-Geigy, 1985b).
0 Prometon has the potential to leach through soil, based on adsorption/
desorption tests and soil thin-layer chromatography (TLC). K^'s for
five soils were: sandy loam (2.61), silt loam (2.90), silty clay
loam (2.40), silt loam (1.20) and sand (0.398); organic matter content
ranged from 0.8 to 5% (Ciba-Geigy, 1985c).
0 Rf values for soil Thin Layer Chromatography (TLC) plates of five
soils put prometon in Class 4 (Very Mobile), Class 3 (Intermediate
Mobile), and Class 2 (Low Mobility). Prometon was very mobile in a
Mississippi silt loam and Plainfield sand, intermediately mobile in a
Hagerstown silty clay loam and Dubuque silt loam, and had low mobility
in a California sandy loam (Ciba-Geigy, 1985d).
0 In field dissipation studies, prometon was shown to have a half-life
>459 to 1,123 days at 3 different sites. Residues were found at all
depths sampled, down to 18 inches. There was no deeper sampling.
At 2 out of 3 sites, deal kylated prometon was found at the 0- to
18-inch depth (Ciba-Geigy, 1986)
III. PHARMACOKINETICS
Absorption
0 Prometon is rapidly absorbed from the gastrointestinal tract. Based
on the radioactivity recovered in the urine and feces, prometon is
completely absorbed within 72 hours in the rat (BakJe et al., 1967).
Distribution
0 Seventy-two hours after intragastric intubation of 14C-prometon in
rats, no detectable levels of radioactivity were detected in any of
the tissues examined (BakJe et al., 1967).
Metabolism
0 Eleven metabolites of prometon have been identified in the urine of
rats treated with 14C-prometon. 2-Methoxy-4,6-diamino-S triazine and
ammeline represented 14% and 31%, respectively, of the radiolabel
excreted in the urine (Ciba-Geigy Corp., 1971).
0 Based on the metabolites formed, triazine ring cleavage apparently
does not occur during prometon metabolism (Ciba Geigy-Corp., 1971).
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Prometon August, 1987
Excretion
0 Excretion of prometon and/or its metabolites in rats was most rapid
during the first 24 hours after administration of 1 4c-prometon and
decreased to trace amounts at 72 hours. The radioactivity was quanti-
tatively excreted in the urine (91%) and feces (9%) within 72 hours
after dosing with 14C-prometon (Bakke et al., 1967).
IV. HEALTH EFFECTS
Humans
No information on the health effects of prometon in humans was found
in the available literature.
Animals
Short-term Exposure
0 The acute oral LDgg value for prometon ranges from 1,750 to 2,980 mg/kg
in rats and is 2,160 mg/kg in mice (Meister, 1983; NIOSH, 1985).
0 The acute inhalation LC50 value in rats is >3.6 mg/L for 4 hours
(Meister, 1983).
0 Long-Evans rats of both sexes (five/sex/dose) were fed a diet containing
0, 10, 30, 100, 300, 600, 1,000, 3,000, 6,000 or 10,000 ppm prometon
[technical, 97% active ingredient (a.i.)] for 4 weeks (Kileen et al.,
1976a). This corresponds to doses of 0, 0.5, 1.5, 5, 15, 30, 50,
150, 300, or 500 mg/kg/day, assuming 1 ppm in the diet corresponds to
0.05 mg/kg/day (Lehman, 1959). Rats fed 3,000 or more ppm prometon
showed a reduction in body weight during the treatment period; at
6,000 or 10,000 ppm (300 or 500 mg/kg/day) the reduction in body
weight was statistically significant (p <0.05 and 0.01, respectively).
At 1,000 ppm or less, mean body weight of both males and females were
comparable to controls. Gross pathology performed at the time of
sacrifice did not show any compound-related effects. The No-Observed-
Adverse-Effect-Level (NOAEL) and Lowest-Observed-Adverse-Effect-Level
(LOAEL) identified in this study are 3,000 and 6,000 ppm (150 and
300 mg/kg/day), respectively.
0 Beagle dogs (one/sex/dose) were administered 100, 300 or 3,000 ppm
prometon (technical) in the diet (2.5, 7.5 or 75 mg/kg/day, assuming
1 ppm in the diet is equivalent to 0.025 mg/kg/day; Lehman, 1959) for
2 weeks after which the 100- and 300-ppm doses were changed to 1,000
and 2,000 ppm (25 and 50 mg/kg/day) for the next 2 weeks (Killeen
et al., 1976b). Dogs that consumed 3,000 ppm showed a decrease in body
weight and food consumption. The body weight of the females receiving
1,000 or 2,000 ppm (25 or 50 mg/kg/day) was also decreased slightly;
food consumption was also slightly lower for the females receiving
2,000 ppm prometon (50 mg/kg/day). At 300 ppm and less, the body
weight and food consumption for both males and females were comparable
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Prometon August, 1987
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to those of the controls. The NOAEL and LOAEL identified in this
study are 300 and 600 ppm (7.5 and 25 mg/kg/day), respectively.
Dermal/Ocular Effects
0 Prometon is a minimal dermal irritant (Meister, 1983). Barely
perceptible erythema was observed in rabbits exposed to 500 mg
prometon (97%) applied to one abraided and one intact site for 24 hours.
At 2,000 mg/kg, mild edema and slight desquamation was also observed
(Ciba-Giegy, 1977).
Long-term Exposure
0 Sprague-Dawley rats (30/sex/group) were fed a diet containing technical
prometon (98% active ingredient) at levels of 0, 10, 50, 100 or 300
ppm for 90 days (Johnson and Becci, 1982). Based on the assumption
that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman,
1959), these doses correspond to approximately 0, 0.5, 2.5, 5 or 15
mg/kg/day. Although female rats exposed to 300 ppm showed an increase
in mean absolute weight of the kidneys, this was considered of no
toxicological significance, since the relative kidney to body weight
ratios were not changed (U.S. EPA, 1985). The NOAEL identified in
this study is, therefore, 300 ppm (15.0 mg/kg/day, the highest dose
tested).
Reproductive Effects
0 Prometon (technical, 98% a.i.) in corn oil was administered to Charles
River rats (25/dose) via gavage at levels of 0, 36, 120 or 360 mg/kg/day
from days 6 through 15 of gestation (Florek et al., 1981). Rats treated
with 120 or 360 mg/kg/day gained less body weight than the controls
during treatment; body weight gain in the 36-mg/kg/day group was
similar to that of the controls. Rats in all dosage groups exhibited
excessive salivation. Increased respiratory rate and lacrimation
were also seen in the 360-mg/kg/day group. No effects on implantation,
litter size, fetal viability, resorption, average fetal body weight
or gross external, soft tissue or skeletal variation in the fetuses
were observed at any dose level. This study identified a maternal
NOAEL of 36 mg/kg/day and a maternal LOAEL of 120 mg/kg/day.
0 New Zealand White rabbits (16/dose) administered prometon at dose levels
of 0, 0.5, 3.5 or 24.5 mg/kg/day (98* a.i.) from days 6 through 30 of
gestation showed reduced pregnancy rates at all dosage levels (Lightkep
et al., 1982). Pregnancy occurred in 16, 13, 13 and 11 rabbits given
0, 0.5, 3.5 and 24.5 mg/kg/day, respectively. Anorexia and excess
lacrimation were observed more frequently in the high-dose group.
Maternal body weight was significantly retarded during treatment in
the 24.5-mg/kg/day group. The maternal NOAEL identified in this study
is 3.5 mg/kg/day and the maternal LOAEL is 24.5 mg/kg/day.
Developmental Effects
0 In a teratogenicity study, prometon (technical) was administered to
albino rats at dose levels of 25 or 50 mg/kg/day on days 6 through
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Prometon August, 1987
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15 of gestation (Haley, 1972). No significant differences between test
and control groups were seen in the maternal body weight, resorption
sites, viable fetuses, fetal external abnormalities, fetal skeletal
development or fetal internal development (details of the protocol
and individual data were not provided). Based on this information,
a NOAEL of 50 mg/kg/day (the highest dose tested) was identified.
e Florek et al. (1981) reported no effects on fetal viability, resorp-
tion, average fetal body weight or gross external, soft tissue or
skeletal variations in the fetuses of Charles River rats (25/dose)
administered prometon via gavage at levels of 0, 36, 120 or 360
mg/kg/day (98% a.i.) in corn oil. A teratogenic NOAEL of 360 mg/kg/dsy
(the highest dose tested) and a maternal-toxicity NOAEL of 36 mg/kg/day
were identified.
0 Lightkep et al. (1982) observed no gross, soft tissue or skeletal
variations in fetuses of New Zealand White rabbits (16/dose) administered
prometon at dose levels of 0, 0.5, 3.5 or 24,5 mg/kg/day (98% a.i.) on
days 6 through 30 of gestation. A teratogenic NOAEL of 24.5 mg/kg/day
(the highest dose tested) and a maternal-toxicity NOAEL of 3.5 mg/kg/day
were identified.
Mutagenicity
0 No information on the mutagenicity of prometon was found in the
available literature.
Carcinogenicity
0 No information on the carcinogenicity of prometon was found in the
available literature.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
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) . mg/L ( ug/L)
(UP) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-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.
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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 prometon. It is therefore
recommended that the DWEL value adjusted for the 10-Jcg child (0.15 mg/L,
calculated below) be used at this time as a conservative estimate of the
One-day HA value.
Ten-day Health Advisory
Reduced body weight compared to controls has been observed in acute
and subchronic toxicity studies in the rat, dog and rabbit. Male and female
rats fed diets containing 3,000 ppm prometon for 4 weeks (300 mg/kg/day;
Killeen et al., 1976a) and pregnant rats administered 120 and 360 mg/kg/day
on days 6 through 15 of gestation (Florek et al., 1981) exhibited lower body
weights compared to controls. Dogs exhibited decreased body weight in a
4-week feeding study with dosing regimens as low as 2 weeks of initial dosing
at 100 ppm followed by 2 weeks at 1,000 ppm (25 mg/kg/day) (Killeen et al.,
1976b). Lightkep et al. (1982) treated rabbits via gavage with doses of 0.5,
3.5 and 24.5 mg/kg/day on days 6 through 15 of gestation and observed decreased
weights in animals exposed to the highest dose. From these studies, it can
be concluded that the rat is less sensitive to the effects of prometon on
weight gain than the dog. The rabbit appeared to exhibit a similar sensitivity
to the dog, but the method of oral dosing differed (gavage vs. feed). The
NOAEL identified from the rabbit study (3.5 mg/kg/day) is lower than that
identified in the dog study (7.5 mg/kg/day) and provides a more conservative
estimate of prometon toxicity.
Prometon, toxicity is not well characterized, and fluctuations in weight
gain may not be an appropriately sensitive end point of toxicity. For this
reason, it is recommended that the DWEL, adjusted for a 10-kg child (0.15 mg/L,
calculated below) be used as a conservative estimate of the Ten-day HA value
for prometon.
Longer-term Health Advisory
The only species to be tested in subchronic studies of prometon toxicity
was the rat. In the study by Johnson and Becci (1982), rats were fed a diet
containing 0, 10, 50, 100 or 300 ppm prometon (0, 0.5, 2.5 or 15 mg/kg/day)
for 90 days. A NOAEL of 15 mg/kg/day (the highest dose tested) was identified.
A NOAEL of 100 mg/kg and a LOAEL of 300 mg/kg/day were identified from the
4-week rat feeding study by Killeen et al. (1976a). More conservative NOAEL
values can be identified from acute studies of other species (3.5 mg/kg/day,
rabbit, Lightkep et al., 1982; 7.5 mg/kg/day, dog, Killeen et al, 1976b).
The toxicity of prometon is not well characterized. It is therefore recommended
that the DWEL adjusted for a 10-kg child (0.15 mg/L, calculated below) be used
as a conservative estimate of the Longer-term HA value for prometon.
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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). Prom 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 classified 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.
No suitable chronic or lifetime studies were available for the calculation
of a Lifetime HA for prometon. The available studies all reported on acute
health effects except that of Johnson and Becci (1982). In this study, rats
were fed diets containing 0, 10, 50, 100, or 300 ppm prometon for 90 days.
No toxic effects were observed at any of the dose levels tested, and a NOAEL
of 15 mg/kg/day was identified. This value may be a conservative estimate
of the NOAEL for rats; a NOAEL of 100 mg/kg was identified from the study
by Killeen et al. (1976a). In contrast, lower NOAELs were identified from
studies of acute exposure via gavage in other species (3.5 mg/kg/day, rabbit,
Lightkep et al., 1982; 7.5 mg/kg/day, dog, Killeen et al., 1976b). Taking
into consideration both the acute and subchronic test results, the study
of Johnson and Becci (1982) has been selected to serve as the basis for
determination of the RfD.
Step 1: Determination of the Reference Dose (RfD)
where:
RfD = mggay = 0>015 mg/kg/day
(1,000)
15 mg/kg/day = NOAEL, based on the absence of effects on the absolute
weight of the kidneys and on the mean kidney-to-brain
ratios in rats exposed to prometon in the diet for
90 days.
1,000 « uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
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Prometon August, 1987
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Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.015 mg/kg/day) (70 kg) = 0>525 ffl /L (525 ug/L)
(2 L/day)
where:
0.015 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 = 0.525 mg/L x 20% = 0.1 mg/L (100 ug/L)
where:
0.525 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 No carcinogenicity studies were found in the literature searched.
0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of prometon.
0 Applying the criteria described in EPA's final guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986a), prometon may be classified in
Group D: not classified. This category is for substances with
inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 No information was found'in the available literature on other existing
criteria, guidelines and standards pertaining to prometon.
VII. ANALYTICAL METHODS
0 Analysis of prometon 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
prometon, 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.
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VIII. TREATMENT TECHNOLOGIES
0 Whittaker (1980) experimentally determined the adsorption isotherms
for prometon on granular activated carbon (GAC).
0 One study (Rees and Au, 1979) reported 95% removal efficiency when
prometon-contaminated water was passed over a 1 x 20 cm column packed
with resin.
0 Available data indicate that GAC adsorption and resin adsorption will
remove prometon from water (Whittaker, 1980; Rees and Au, 1979).
However, selection of individual or combinations of technologies to
attempt prometon removal from water must be based on a case-by-case
technical evaluation, and an assessment of the economics involved.
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IX. REFERENCES
Bakke, J.E., J.D. Robbins and V.J. Fell. 1967. Metabolism of 2-chloro-4,6-
bis(isopropylami.no)-s-triazine(propazine) and 2-methoxy-4,6-bis(isopro-
pylamino)-s-triazine (prometon) in the rat. Balance study and urinary
metabolite separation. J. Agr. Food Chem. 15(4): 628-631.
CHEMLAB. 1985. The Chemical Information System, CIS, Inc. Cited in U.S. EPA.
1985. Pesticide survey chemical profile. Final report. Contract no.
68-01-6750. Office of Drinking Water, Washington, DC.
Ciba-Geigy Chemical Corporation.* 1971. Metabolism of s-triazine herbicides.
Unpublished study. EPA Accession No. 55672.
Ciba-Geigy Corporation.* 1977. Acute toxicity studies with prometon tech-
nical (97%). Industrial Bio-Text Laboratories, Inc. IBT No. 8530-09308.
Unpublished study. EPA Accession No. 231815.
Ciba-Geigy Corporation. 1985a. Hydrolysis of prometon (Hazleton Study
6015-165). In: Environmental fate data required by special ground water
data call-in, May 30, 1985. Greensboro, NC.
Ciba-Geigy Corporation. 1985b. Photolysis of prometon in aqueous solution
under natural sunlight and artifical sunlight conditions (1972), Ciba-
Geigy Report No. 72127. In: Environmental fate data required by special
ground water data call-in, May 30, 1985. Greensboro, NC.
Ciba-Geigy Corporation. 1985c. The adsorption/desorption of radiolabeled
prometon on representative agricultural soils (Hazleton Study 6015-164).
In: Environmental fate data required by special ground water data call-in,
May 30, 1985. Greensboro, NC.
Ciba-Geigy Corporation. 1985d. Mobility determination of prometon in soils
by TLC (Hazleton Study No. 6015-167). In: Environmental fate data
required by special ground water data call-in, May 30, 1985. Greensboro,
NC.
Ciba-Geigy Corporation. 1986*. Field disposition studies in California,
Nebraska and New York. Preprared by Daniel Sumner. August 21, 1986.
Eiden, C. 1987. Assessing the leeching potential of pesticides: national
perspectives. Draft report prepared by the U.S. Environmental Protection
Agency, Office of Pesticide Programs, Washington, DC.
Florek, C., G. Christian et al.* 1981. Teratogenicity study of prometon
technical in pregnant rats. Argus Project 203-003. Unpublished study.
EPA Accession No. 129983.
Haley, S.* 1972. Report to Geigy Agricultural Chemicals, Division of Ciba-
Geigy Corporation. Teratogenic study with prometon technical in albino
rats. IBT No. B904. Unpublished study.
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