820K88105 AU9USt- 1987
AMETRYN DRAFT
•^•1^%I B
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 accuratel> 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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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 834-12-8
Structural Formula
SCH3
H
2-(Ethylamino)-4-(isopropylamino)-6-(methylthio)-s-triazine
Synonyms
0 N-ethyl-Nt-(1-methylethyl)-6-(methylthio)-1,3,5-triazine-2,4-diamine;
Ametrex; Ametryne; Cemerin; Crisatine; Evik SOW; Gesapax (WSSA, 1983;
Meister, 1983).
Uses
0 A selective herbicide for control of broadleaf and grass weeds in
pineapple, sugarcane, bananas and plantains. Also used as a post-
directed spray in corn, as a potato vine dessicant and for total
vegetation control (WSSA, 1983).
Properties (WSSA, 1983)
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure
Specific Gravity
Water Solubility
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor — •
Occurrence
0 Ametryn has been found in 3 of 1,246 surface water samples analyzed
and in 27 of 653 ground water samples (STORET, 1987). Samples were
collected at 211 surface water locations and 544 ground water
locations, and ametryn was found in 6 states. The 85th percentile of
227.35
Colorless crystals
—
84 to 85°C
8.4 x 10~7 mm Hg
185 mg/L
-1.72 (calculated)
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Ametryn August* 1987
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all nonzero samples was 0.1 ug/L in surface water and 210 ug/L in
ground water sources. The maximum concentration found was 0.1 ug/L
in surface water and 450 ug/L in ground water.
Environmental Fate
0 In aqueous solutions, ametryn is stable to natural sunlight, with a
half-life of greater than 1 week. When exposed to artificial light
for 6 hours, 75% of applied ametryn remained. One photolysis product
was identified as 2-ethylamino-4-hydroxy-6-isopropylaminos-triazine
(Registrant CBI data).
0 Ametryn is stable to photolysis on soil (Registrant CBI data).
0 Soil metabolism of ametryn, under aerobic conditions, proceeds with
a half-life of greater than 2 to 3 weeks. Metabolic products include
2-amino-4-isopropylamino-6-methylthio-s-triazine, 2-amino-4-ethylamino-
6-methylthio-s-triazine and 2,4-diamino-6-methylthio-triazine. Under
anaerobic conditions the rate of metabolism decreases (t-|/2 = 122 days)
(Registrant CBI data).
0 Under sterile conditions ametryn does not degrade appreciably. There-
fore, microbial degradation is a major degradation pathway (Registrant
CBI data).
0 Neither ametryn nor its hydroxy metabolite leach past 0 to 6 in. depth
with normal rainfall. However, since both compounds are persistent
they may leach under exaggerated rainfall or flood and furrow irrigation.
This behavior is seen with other triazines (Registrant CBI data).
0 Ametryn's Freundlich soil-water partition coeficient values, Kd, range
from 0.6 in sands to 5.0 in silty clay soils. Specifically, the Kd
for a sandy loam is 4.8, and for 2 silty loams, 3.8 and 2.8,
respectively.
0 In the laboratory, Ametryn has a half-life of 36 days. In the field,
Ametryn degraded with a half-life of 125 to 250 days (Registrant CBI
data).
III. PHARMACOKINETICS
Absorption
8 Oliver et al. (1969) administered 14C-labeled ametryn orally to
Sprague-Dawley rats. Investigators stated that ametryn was admini-
stered by stomach tube to animals at dosage levels from 1 to 4 mg
per animal. When the label was in the ring, 32.1* was excreted in
the feces, indicating that over 70% had been absorbed. When the
label was in the ethyl or isopropyl side chains, only 2 to 5% was
excreted in the feces.
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Distribution
0 Oliver et al. (1969) administered ring-labeled ametryn orally to
male and female Sprague-Dawley rats and measured distribution of
label in tissues at 6, 48 and 72 hours after dosing. Tissue distri-
bution at 6 hours was greatest in kidney, followed by liver, spleen,
blood, lung, fat, carcass, brain, and muscle. Blood levels remained
relatively constant for 72 hours after dosing, while all other tissue
levels dropped rapidly to <0.1% of dose per gram of tissue.
Metabolism
0 Oliver et al. (1969) administered 14C-labeled ametryn orally to
groups of six male and six female Sprague-Dawley rats. When the
label was in the isopropyl side chain, 41.9% of the label appeared as
C02. When the label was in the ethyl side chain, 18.1% of the label
appeared as CO2. This indicated that the side chains were extensively
metabolized. When the ring was uniformly labeled with carbon-14 and
the compound fed orally to rats, 58% was excreted in the urine but it
was not determined whether excretion of the original compound or
metabolites had occurred.
Excretion
Oliver et al. (1969) studied the excretion of ametryn utilizing
uniformly labeled compound with 14C-ametryn in the ring or in the
ethyl or isopropyl side chains. Forty-eight hours after oral dosing
of six male and six female Sprague-Dawley rats, 57.6% of the ring
labeled activity had been excreted in the urine with 32.1% excreted
in the feces (total 89.7% of dose). When the fed compound was labeled
in the side chains, however, much of the 14C was excreted in expired
air as carbon dioxide. When fed compound labeled in the isopropyl
side chain, rats excreted 41.9% of the label in expired air 20% in
the urine, 2% in the feces and 7% remained in the carcass (total
70.9%) at 48 hours. When the ethyl side chain contained the label,
18.1% of the label was excreted as carbon dioxide, 45% in the urine,
5% in the feces and 9% remained in the carcass (total 77.1% of dose).
After 72 hours, total recovery was approximately 88% for both of the
side-chain labeled compounds.
IV. HEALTH EFFECTS
Humans
No information was found in the available literature on the health
effects of ametryn in humans.
Animals
Short-term Exposure
0 The following acute oral 1.050 values .for ametryn in rats were
reported: Charles River CD rats, 1,207 mg/kg (males), 1,453 mg/kg
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Ametryn August, 1987
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(females) (Grunfeld, 1981); mixed male and female rats (strain not
specified), 1,750 mg/kg (Stenger and Planta, 1961a); male and female
Wistar rats, 1,750 mg/kg (Consultox Laboratories Limited, 1974).
0 Piccirillo (1977) reported the results of a 28-day feeding study in
male and female mice. Animals were 5 weeks of age and weighed
21 to 28 g at the beginning of the study. Animals (five/sex/dose)
were fed diets containing 0, 100, 300, 600, 1,000, 3,000, 10,000 or
30,000 ppm of ametryn (technical). 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, 15, 45, 90, 150, 450, 1,500 or 4,500
mg/kg/day. At 30,000 ppm in the diet, all animals died within 2
weeks. At 10,000 ppm, 3 of the 10 died within 2 weeks. No other
deaths occurred at any other dose level. Clinical signs in the two
highest dose groups included hunched appearance, stained fur and
labored respiration. At the 3,000-ppm dose level, only 1 of the
10 animals showed clinical signs of toxicity. Body weight gain was
comparable in all survivors by the end of week 4. Gross pathology in
animals that died showed a dark-red mucosal lining of the gastro-
intestinal tract and ulcerated areas of the gastric mucosa. There
was no histopathological examination of tissues in this study.
0 Stenger and Planta (1961b) reported a 28-day study of the toxicity
of ametryn in rats. Dose levels of 100, 250 or 500 mg/kg/day were
administered 6 days/week by gavage to groups of five male and five
female rats. The study indicated that there was a control group but
no data were given. At the 500-mg/kg/day dose level, animals became
emaciated, weight gain was limited and 7 of 10 rats died. Histo-
pathological examination of the animals that died indicated severe
vascular congestion, centrilobular liver necrosis and fatty degeneration
of individual liver cells. At 250 mg/kg/day, 1 of 10 rats died
during the study and there was depressed growth rate in the survivors.
Histological examination of liver, kidney, spleen, pancreas, heart,
lung, intestine and gonads showed no major degenerative changes. No
effects were reported in animals administered 100 mg/kg/day, which
was identified as the No-Observed-Adverse-Effect-Level (NOAEL) in
this study.
0 Ceglowski et al. (1979) administered single oral doses of 88 or 880
mg/kg of ametryn to mice 5 days before, on the day of or 2 days after
immunization with sheep erythrocytes ('purity not specified). All
mice receiving the highest dose (880 mg/kg) of ametryn had significant
depression of splenic plaque-forming cell numbers when assayed 4 days
later. Animals receiving the low dose showed no effect. Similarly,
animals receiving 88 mg/kg for 8 or 28 consecutive days prior to
immunization exhibited no significant reduction in antibody plaque
formation.
Dermal/Ocular Effects
0 Two of six rabbits showed mild skin irritation when ametryn was left
in contact with intact or abraded skin (500 mg/2.5 cm2) for 24 hours
(Sachsse and Ullmann, 1977).
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0 In a sensitization study with Perbright White guinea pigs (Sachsse
and Ullmann, 1977), 10 male and 10 female guinea pigs weighing 400
to 450 g received 10 daily intracutaneous 0.1-mL injections of 0.1%
ametryn in polyethylene glycol:saline (70:30). Fourteen days after
the last dose, animals were challenged by an occlusive dermal applica-
tion of ametryn or by an intradermal challenge. Animals showed no
sensitization reaction following the dermal application of the challenge
dose but there was a positive response after the intradermal challenge«
0 Kopp (1975) found that ametryn (technical grade) placed in the eyes
of rabbits produced slight conjunctiva! redness at 24 hours. This
cleared completely within 72 hours.
0 Sachsse and Bathe (1976) applied 2,150 mg/kg or 3,170 mg/kg ametryn
in suspension to the shaved backs of five male and five female rats
weighing 180 to 200 g. Hie occlusive covering was removed at
24 hours, the skin was washed and animals were observed for 14 days.
There was no local irritation or adverse reaction, and at necropsy
there were no gross changes in the skin. The acute dermal LDgQ in
male and female rats was reported to be >3,170 mg/kg.
e Ametryn (2,000 mg/kg) was applied daily to the skin of five male and
five female rats weighing approximately 200 g (Consultox Laboratories
Limited, 1974). After 14 days of treatment, no deaths had occurred
and no other effects were reported. The 14-day dermal LDsg was re-
ported to be >2,000 mg/kg/day.
Long-term Exposure
0 Domenjoz (1961) administered ametryn in water via stomach tube
6 days/week for 90 days to Meyer-Arendt rats (1 2/sex/dose). Ttie
initial material was 50% ametryn in a powder vehicle. Two dose
levels of the material (20 or 200 mg/kg/day) provided dose levels of
ametryn of 10 or 100 mg/kg/day. Two control groups were included;
one group received water only and the other received the powder
vehicle only suspended in water. Over the 90-day period, all animals
gained weight at comparable rates and there was no visible effect on
appearance or behavior. One control rat and one rat in the 100-mg/kg
dosage group died. This death was not considered compound-related.
At the 90-day necropsy, organ-to-body weight ratios were comparable
to controls. Liver, Sidney, spleen, heart, gonads, small intestine,
colon, stomach, thyroid and lung were microscopically examined. The
Lowest-Observed-Adverse-Effect-Level (LOAEL) was associated with fatty
degeneration of the liver. Based on this study, a LOAEL of 100 mg/kg/day
(the highest dose tested) was identified. All tissues were comparable
to controls at the lowest dose (10 mg/kg/day), which was identified
as the NOAEL.
Reproductive Effects
e No information was found in the available literature on the reproduc-
tive effects of ametryn.
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Developmental Effects
• No information was found in the available literature on the developmental
effects of ametryn.
Mutagenicity
0 Anderson et al. (1972) reported that ametryn was not mutagenic in
eight strains of Salmonella typhimurium. No metabolic activating
system was utilized.
0 Simmons and Poole (1977) also reported that ametryn was not mutagenic
in five strains of Salmonella typhimurium (TA 98, 100, 1535, 1537 and
1538), with or without metabolic activation provided by an S9 fraction
from rats pretreated with Aroclor 1254.
0 Shirasu et al. (1976) reported ametryn was not mutagenic in the
rec-assay system utilizing two strains of Bacillus subtilis, in
reversion assays utilizing auxotrophic strains of Escherichia coli
(WP2) and in _S. typhimurium strains TA 1535, 1536, 1537 and
1538 (without metabolic activation).
Carcinogenicity
0 No information was found in the available literature on the carcinogenic
effects of ametryn.
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) . /L ( /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.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
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One-day Health Advisory
No data were found in the available literature that were suitable for
determination a One-day HA value for ametryn. It is, therefore, recommended
that the Ten-day HA value for the 10-kg child (8.6 mg/L, calculated below) be
used at this time as a conservative estimate of the One-day HA value.
Ten-day Health Advisory
The study by Stenger and Planta (1961b) has been selected to serve as
the basis for determination of the Ten-day HA value for the 10-kg child.
This study identified a NOAEL of 100 mg/kg/day, based on normal weight gain
and absence of histological evidence of injury in rats following 28 days of
exposure by gavage. The study also identified a LOAEL of 250 mg/kg/day,
based on reduced body weight gain, although no major histological changes
were noted. One death occurred in the 250-mg/kg/day group, but it could not
be determined if this was compound-related. The NOAEL identified in this
study (100 mg/kg/day) is supported by the 28-day feeding study in rats by
Piccirillo (1977), which identifed a NOAEL of 150 mg/kg/day and a LOAEL of
450 mg/kg/day, and by the study of Ceglowski et al. (1979), which identified
a NOAEL of 88 mg/kg/day and a LOAEL of 880 mg/kg/day.
Using the NOAEL of 100 mg/kg/day, the Ten-day HA for a 10-kg child is
calculated as follows:
Ten-day HA = (100 mg/kg/day) (10 kg) (6/7) z 8.6 mg/L (8,600 ug/L)
(100) (1 L/day)
where:
100 mg/kg/day • NOAEL, based on absence of effects on weight gain
or histology in rats dosed by gavage for 28 days.
10 kg = assumed body weight of a child.
100 * uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from a study in animals.
6/7 * conversion from 6 to 7 days.
1 L/day = assumed daily water consumption of a child.
Longer-term Health Advisory
The 90-day oral dosing study in rats by Domenjoz (1961) has been selected
to serve as the basis for determination of the Longer-term HA. At two dose
levels (10 or 100 mg/kg/day), no deaths were reported and no other effects
were noted during the 90-day period. Terminal necropsy findings and histo-
logical examination of tissues from treated animals were comparable to
controls. At the highest dose tested, there was fatty degeneration in the
livers examined. Based on these data, a NOAEL of 10 mg/kg/day (the lowest
dose tested) was identified.
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The Longer-term HA for a 10-kg child is calculated as follows:
Longer-term HA » (10 mg/kg/day) (10 kg) (6/7) . 0>86 mg/L (860 /L)
(100) (1 L/day)
where:
10 mg/kg/day = NOAEL, based on the absence of histological evidence
of toxicity in rats exposed to ametryn via gavage for
90 days.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from a study in animals.
6/7 = conversion from 6 to 7 days of exposure.
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 = (10 mg/kg/day) (70 kg) (6/7) . 3 /L (3,000 ug/L)
(100) (2 L/day)
where:
10 mg/kg/day = NOAEL, based on the absence of histological evidence
of toxicity in rats exposed to ametryn via gavage 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 a study in animals.
6/7 = conversion from 6 to 7 days of exposure.
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
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concentration equals 10% of influent concentration) occurred after
896 bed volumes (BV). When a bi-solute ametryn-propham solution was
passed over the same column, ametryn breakthrough occurred after 240 BV.
In a laboratory study (Nye, 1984) GAC was employed as a possible
means of removing ametryn from contaminated wastewater. Ihe results
show that the column exhaustion capacity was 111.2 mg ametryn adsorbed
on 1 g of activated carbon.
Treatment technologies for the removal of ametryn from water are
available and have been reported to be effective. However, selection
of individual or combinations of technologies to attempt ametryn
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
Anderson, K.J., E.G. Leighty and M.T. Takahasi. 1972. Evaluation of herbicides
for possible mutagenic activity. J. Agr. Food Chem. 20:649-656.
Ceglowski, W.S., D.D. Ercegrovich and N.S. Pearson. 1979. Effects of pesticides
on the reticuloendothelial system. Adv. Exp. Med. Biol. 121:569-576.
CFR. 1985. Code of Federal Regulations. July 1, 1985. 40 CFR 180.258.
pp. 300-301.
Consultox Laboratories Limited.* 1974. Ametryn: Acute oral and dermal toxieity
evaluation. Unpublished study. MRID 00060310.
Domenjoz, R. 1961.* Ametryn: Toxieity in long-term administration. Unpub-
lished study. MRID 00034838.
Grunfeld, Y. 1981.* Ametryn 80 w.p.: Acute oral toxieity in the rat.
Unpublished study. MRID 00100573.
Kopp, R.W.* 1975. Acute eye irritation potential study in rabbits. Final
Report. Project No. 915-104. Unpublished study. MRID 00060311.
Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs and
cosmetics. Association of Food and Drug Officials of the United States.
Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister
Publishing Co.
Nye, J.C. 1984. Treating pesticide-contaminated wastewater. Development
and evaluation of a system. American Chemical Society.
Oliver, W.H., G.S. Born and P.L. Zeimer. 1969. Retention, distribution, and
excretion of ametryn. J. Agr. Food Chem. 17:1207-1209.
Piccirillo, V.J.* 1977. 28-day pilot feeding study in mice. Final Report.
Project No. 483-126. Unpublished study. MRID 00068169.
Sachsse, K. and R. Bathe.* 1976. Acute dermal LD50 in the rat of technical
G34162. Project No. Siss. 5665. Unpublished study. MRID 00068172.
Sachsse, K. and L. Ullmann.* 1977. Skin irritation in the rabbit after
single application of technical grade G34162. Unpublished study.
MRID 00068174.
Shirasu, Y., M. Moriya, K. Kato, A. Furuhashi and T. Kada. 1976. Mutagenic
screening of pesticides in the microbial system. Mutat. Res. 40:19-30.
Simmons, V.F. and D. Poole.* 1977. In-vitro and in-vivo microbiological
assays of six Ciba-Geigy chemicals. SRI project LSC-5686. Final. Report.
Unpublished study. MRID 00060642.
Stenger, P. and V. Planta.* 1961 a. Oral toxieity in rats. Unpublished
Study. MRID 00048226.
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Ametryn August, 1987
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Stenger, P. and V. Planta.* 1961b. Subchronic toxicity test no. 257.
Unpublished study. MRID 00048228.
STORET. 1987.
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. 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.
WSSA. 1983. Weed Science Society of America. Herbicide handbook. 5th
ed. Champaign, IL: Weed Society of America, pp. 16-19.
Whittaker, K.F. 1980. Adsorption of selected pesticides by activated carbon
using isotherm and continuous flow column systems. Ph.D. Thesis, Purdue
University.
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Programs.
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