x August, 1987
t
PRONAMIDE
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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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 23950-58-5
Structural Formula
0 H CH3
C-N-C-CsCH
I
CH3
3,5-Dichloro(N-1,1-dimethyl-2-propynyl)benzamide
Synonyms
8 Kerb*; Kerb* SOW; Propyzamide; RH315 (Meister, 1983).
Uses
0 Pronamide is used as an herbicide for pre- or postemergence weed and
grass control in small, seeded legumes grown for forage or seed,
southern turf, direct seeded or transplanted lettuce, endive, escarole,
woody ornamentals, nursery stock and Christmas trees (Meister, 1983).
C12HnCl2ON
256.14
White crystals
154 to 156°C
8o5 x 10-5 mm Hg
0.48 gm/cc
0.015 mg/L
3.05 to 3.27
Properties (NIOSH, 1985; TDB, 1985)
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Vapor Pressure (25°C)
Specific Gravity
Water Solubility
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
Occurrence
0 Pronamide has been found in 18 of 258 ground water samples analyzed
(STORET, 1987). No surface water samples were collected, and samples
were collected from 252 ground water locations. Pronamide was found
only in California. The 85th percentile of all nonzero samples was
1 ug/L, and the maximum concentration found was 1 ug/L.
Environmental Fate
• 14c-Pronamide (100% radiopurity) at 1.5 ppm hydrolyzes very slowly
(10% of applied material) in sterile, deionized water buffered to
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Pronamide August, 1987
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pH 5, ~l, and 9 and incubated at 20°C for 28 days in the dark (Rohm
and Haas Bristol Research Laboratories, 1973). The following minor
hydrolysis products were identified: RH-24,644 (2-(3,5-dichlorophenyl)-
4,4-dimethyl-5methyleneoxazoline); RH-24,580 (3,5-dichloro-N-(l,l-
dimethylacetonyl) benzamide); and RH-25,891 (2-(3,5-dichlorophenyl)-
4,4-dimethyl-5-hydroxymethyl-oxazoline). Similar results were obtained
in other hydrolysis studies (Rohm and Haas Bristol Research Laboratories,
1970).
0 Pronamide has a half-life of 10 to 120 days in aerobic soils (Fisher,
1971; Walker, 1976; Walker and Thompson, 1977; Walker, 1978; Hance,
1979;). Complete experimental conditions and purity were not specified,
and/or a formulated product was applied. The degradation rate does
not appear to depend upon soil texture. However, increasing soil
temperature, and to a lesser extent, soil moisture and pH enhance
pronamide degradation. The major degradates are RH-24,580 and
RH-24,644. Soil sterilization greatly reduced the degradation rate
of pronamide. Pronamide (at a recommended application rate of 0.5 to
2 Ib/A) does not inhibit the growth or CC>2 evolution of bacteria and
fungi (Lashen, 1970).
0 Pronamide is moderately mobile in soils ranging in texture from loamy
sand to clay based on preliminary soil column and adsorption/desorption
tests (Walker and Thompson, 1977; Rohm and Haas Company, 1971; Fisher
and Satterthwaitte, 1971). The two major degradates of pronamide
(RH-24,580 and RH-24,644) are mobile in sand and clay soils (Fisher,
1973). The mobility of pronamide and its two major degradates tends
to decrease as the organic matter content, clay content and cation
exchange capacity of the soil increases.
0 The dissipation rate of pronamide from terrestrial field sites is
quite variable, with half-lives ranging from 10 to 90 days (Benson,
1973; Walker, 1976; Hance et al., 1978a; Hance et al., 1978b; Kostowska
et al., 1978; Walker, 1978; Zandvoort et al., 1979). Data are insuf-
ficient to determine the effect, if any, of meteorological conditions
or the role leaching may play in pronamide dissipation.
0 The environmental fate of pronamide is the subject of several unpub-
lished, undated reports (Cummings and Yin; Fisher and Cummings; Rohm
and Haas; Satterthwaite and Fisher; Yin).
III. PHARMACOKIN ETICS
Absorption
0 No information on the absorption of pronamide was found ir. the
available literature.
Distribution
0 No information on the distribution of pronamide was found in the
available literature.
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Metabolism
0 About 54 and 0.6% of the radioactivity was recovered as unmetabolized
Kerb* in the feces and urine, respectively, of rats treated orally with
(14c-carbonyl)-pronamide (dose not specified) (Yin and Swithenbank,
undated). The major metabolite in the feces was 2-(3,5-dichlorophenyl)-
4,4-dimethyl-5-hydroxymethyloxazoline (15%), and the major metabolites
in the urine were <*-(3, 5-dichlorobenzamido) isobutyric acid (22.4%),
B-(3,5-dichlorobenzamido)-a-hydroxy-8 methyl-butyric acid (19.2%), and
two unknown metabolites (24.1 and 16.7%).
• Unmetabolized Kerb* did not appear in the urine of cows treated orally
with (14C-carbonyl) Kerb*; the major metabolite was 6-(3,5-dichloro-
benzamido)-o-hydroxy-B-methyl-butyric acid (71.4%)(Yin and Swithenbank,
undated).
Excretion
After oral ingestion of radiolabeled Kerb* by rats, unmetabolized
Kerb* accounted for 54 and 0.6% of the radioactivity recovered in
feces and urine, respectively. In the cow, oral ingestion of Kerb®
produced no unmetabolized Kerb* in the urine (Yih and Swithenbank,
undated).
IV. HEALTH EFFECTS
Humans
No information on the health effects of pronamide in humans was found
in the available literature.
Animals
Short-term Exposure
0 The acute oral LD50 in rats for pronamide (technical) is in the range
of 8,350 mg/kg bw (Meister, 1984) to 16,000 mg/kg bw (Powers, 1970a).
Dermal/Ocular Effects
0 Pronamide is not a primary dermal irritant to albino rabbits. In two
separate studies, an aqueous paste of 500 mg pronamide [50% active
ingredient (a.i.)] was applied to the skin of six rabbits for 24 hours
(Powers, 1970c; Regel, 1972). No signs of irritation were observed
by Powers (1970c). Twenty-four hours after exposure, Regel (1972)
observed erythema, which subsided at 72 hours.
0 Powers (1970b) administered 100 mg of Kerb* (50% a.i.) in the con-
junctival sac of 12 rabbits. Eye irritation and chemosis were noted
at 24 hours but disappeared by day 7, as confirmed by fluorescein
examination.
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Long-term Exposure
8 Rats (10/sex/dose) were fed a diet containing 0, 50, 150, 450, 1,350
or 4,050 ppm pronamide (100% a.i.) for 3 months (Larson and Borzelleca,
1967a). This corresponds to 0, 2.5, 7.5, 22.5, 67.5 or 202.5
nig/kg/day, assuming 1 ppm in feed is equivalent to 0.05 mg/Jcg/day
(Lehman, 1959). Significant body weight depression was observed at
the 4,050 ppm dose level. Initial significant body weight depression
also occurred in the rats fed 1,350 ppm, but disappeared on continued
feeding. At the 150 ppm dose, absolute and relative liver weights in
females were-significantly higher than in controls; no histological
lesions were seen, and no dose-related trend was observed for this
increase in relative liver weight. Individual data were not presented
for organ weights and several other parameters, clinical observations
were not presented and analytical determination of the test compound
was not reported. The No-Observed-Adverse-Effect-Level (NOAEL)
identified in this study was 2.5 mg/kg/day.
0 Beagle dogs (10 months old; one/sex/dose) were fed a diet containing
0, 450, 1350 or 4050 ppm pronamide (100% a.i.) for 3 months (Larson
and Borzelleca, 1967b). This corresponds to approximate doses of
0, 10, 30 or 90 mg/kg/day, assuming 1 ppm in feed is equivalent to
0.025 mg/kg/day (Lehman, 1959). A decrease in weight gain and food
consumption and an increase in serum alkaline phosphatase, liver
weight and liver-to-body weight ratios, as compared to controls,
were seen in the animals dosed at 4,050 ppm. No histological changes
were seen in the livers. The hematological and urinalysis findings
were within normal ranges. The NOAEL identified in this study was
30 mg/kg/day.
0 In a 2-year feeding study in beagle dogs (four/sex/dose) the addition
of pronamide (97% a.i.) to the diet at dose levels of 0, 30, 100 or
300 ppm (0, 0.75, 2.5 or 7.5 mg/kg/day, assuming 1 ppm in feed is
equivalent to 0.025 mg/kg/day; Lehman, 1959) caused no adverse effects
at any of the doses tested (Larson and Borzelleca, 1970b). A NOAEL
of 7.5 mg/kg/day (the highest dose tested) was identified in this
study.
0 Smith (1974) administered Kerb* (97% a.i.) to 6-week-old (C57 BL16 x
C3H Anf)Fi male and female mice (100/sex/dose), for 78 weeks at
dietary concentrations of 0, 1000 or 2000 ppm (0, 150 or 300 mg/kg/day,
assuming 1 ppm in feed is equivalent to 0.15 mg/kg/day; Lehman, 1959)
pronamide. Male and female mice that ingested 2000 ppm gained sig-
nificantly less weight (p <0.05); males also exhibited adenomatous
hyperplasia, degeneration, hyperplasia, intrahepatic cholestasis,
necrosis and/or fatty changes of the liver. Liver weights were
significantly increased over controls for males and females in both
treatment groups. Based on this information, a Lowest-Observed-Adverse-
Effect-Level (LOAEL) of 1,000 ppm (150 mg/kg/day) was identified.
0 Newberne et al. (1982) administered pronamide (94% a.i.) to male
B6C3F1 mice at dose levels of 0, 20, 100, 500 or 2,500 ppm (0, 3,
15, 75 or 375 mg/kg/day, assuming 1 ppm in feed is equivalent to
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0.15 mg/kg/day: Lehman, 1959) for up to 24 months. Another group was
fed 2,500 ppm (375 mg/kg/day) pronamide for 6 months. The mean body
weight of the mice fed 2,500 ppm was significantly depressed at 14 days
and thereafter throughout the study. At the 24-month sacrifice, the
mean body weight of this group was approximately 70% of the control
group. Survival of the mice was unaffected. The highest dose level
(2,500 ppm) resulted in liver lesions including bile duct hyperplasia,
parenchymal cell hypertrophy, parenchymal cell necrosis, hyperplasia
and cholestasis at all time periods examined. Based on this infor-
mation, a NOAEL of 500 ppm (75 mg/kg/day) was identified.
Reproductive Effects
0 In a teratogenicity study in New Zealand White rabbits (18/dose),
pronamide was administered at levels of 0, 5, 20 or 80 mg/kg/day
(technical, 97% pure) during gestation days 7 to 19 (Costlow and
Kane, 1985). Five abortions were observed in the 80 mg/kg/day group.
There were no compound-related effects on the incidence of implantations,
resorptions, fetal deaths or on fetal body weight at any dose tested.
Maternal toxicity (anorexia, vacuolation of hepatocytes) was observed
in the 20-mg/kg/day group. A NOAEL of 20 mg/kg/day was identified
based upon the absence of developmental/reproductive effects and a
NOAEL of 5 mg/kg/day was identified based upon the absence of maternal
toxicity.
0 In a three-generation reproduction study, 20 to 25 albino CD rats were
fed a diet containing pronamide (RH-315; purity not stated) at dose
levels of 0, 30, 100 or 300 ppm (Larson and Borzelleca, 1970c).
Assuming 1 ppm in the diet is equivalent to 0.05 mg/kg/day, this
corresponds to doses of 0, 1.5, 5 or 15 mg/kg/day (Lehman, 1959).
The authors reported no adverse reproductive effects in parents or
pups, but individual animal data were not available to validate the
above conclusions. Based on this information a NOAEL of 300 ppm (15
ing/kg/day, the highest dose tested) was identified.
Developmental Effects
0 In a teratogenicity study in New Zealand White rabbits (18/dose),
pronamide was administered at levels of 0, 5, 20 or 80 mg/kg/day
(technical, 97% pure) during gestation days 7 to 19 (Costlow and
Kane, 1985). An increased incidence of gross and microscopic liver
lesions, one materna^. death, five abortions and a significant
(p <0.05) decrease in the maternal body weight gain were observed at
the 80-mg/kg/day dose. At the 20-mg/kg/day dose, rabbits exhibited
anorexia, vacuolation of hepatocytes and a slight decrease in body
weight gain. There were no compound-related effects on the incidence
of implantations, resorptions, fetal deaths or on fetal body weight
at any dose tested. The NOAEL in this study was 5 mg/kg/day based
on maternal effects, and 80 mg/kg/day based on developmental effects.
0 In a study designed to evaluate fetal development, adult female rats
(FDRL) were administered 0, 7.5 or 15 mg/kg/day pronamide by gavage
in corn oil from days 6 through 16 of gestation (Vogin, 1972). No
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adverse effects were reported for the mean number of implantation
sites, the number of live or dead fetuses or the mean fetal weight.
The authors concluded that pronamide administered orally to rats at
doses up to 15 mg/kg/day was not teratogenic, but individual animal
data were not available to validate these conclusions. Based on this
information a NOAEL of 15 mg/kg/day (the highest dose tested) was
identified.
Mutagenicity
0 In a cytogenetic study, pronamide (Kerb®, analytical) administered
by intragastric intubation at dose levels of 5, 50 or 500 mg/kg to
rats did not produce any aberrations of the bone marrow chromosomes
(Fabrizio, 1973).
Carcinogenicity
0 In a study evaluating the carcinogenic potential of Kerb®, 6-week-old
(C57 BL16 x C3H Anf)F1 male and female mice (100/sex/dose) were fed
pronamide (97% a.i.) in the diet at doses of 0, 1,000 or 2,000 ppm
(0, 150 or 300 mg/kg/day, assuming 1 ppm in feed is equivalent to
0.15 mg/kg/day; Lehman, 1959) for 78 weeks (Smith, 1974). Male and
female mice that ingested 2,000 ppm gained significantly less weight
(p <0.05); the animals also gained slightly less weight at the 1,000-ppm
level, but the change was not significant. No increase in tumors was
observed for female mice treated with pronamide over controls. For
male mice, a total of 35 of the 99 animals in the high-dose group,
21 of the 100 animals in the low-dose group and 7 of the 100 animals
in the control group developed hepatic neoplasms, of which 24, 18
and 7 were carcinomas in the high-dose, low-dose and control groups,
respectively. A total of 28 of 99 male mice that ingested 2,000 ppm
exhibited intrahepatic cholestasis, but did not have carcinomas of
the liver.
0 In a 2-year study in male B6C3F-J mice (Newberne et al., 1982),
pronamide was fed to the animals (63 animals/dose) at dose levels of 0,
20, 100, 500 or 2,500 ppm (0, 3, 15, 75 or 375 mg/kg/day, assuming 1
ppm in feed is equivalent to 0.15 mg/kg/day; Lehman, 1959). Another
group was fed 2,500 ppm ('375 mg/kg/day) pronaaide for 6 months. The
mean body weight of mice fed 2,500 ppm was significantly depressed at
14 days and thereafter throughout the study. At the 24-month sacrifice,
the mean body weight of this group was approximately 70% of the con-
trol group. Survival of the mice was unaffected. The highest dose
(2,500 ppm) resulted in liver lesions, including bile duct hyperplasia,
parenchymal cell hypertrophy, parenchymal cell necrosis, hyperplasia
and cholestasis at all time periods examined. At 18 months, the
2,500-ppm dose group had increased parenchymal cell neoplasms, but
this was not statistically different from the controls. At 24 months,
there was a statistically significant increased incidence of hepatic
adenomas and carcinomas in the 500- and 2,500-ppm dose groups. The
incidence of hepatic carcinomas was 5/63, 9/63, 12/63, 18/63 and
14/61 in the control, 20-ppm, 100-ppm, 500-ppm and 2,500-ppm groups,
respectively. Thus, the liver appears to be the target organ for
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neoplasia. According to the authors, hypertrophy and hyperplasia
are not uncommon in untreated older mice of this strain. However,
pronamide tended to shift the onset of these lesions to an earlier age.
0 Pronamide in the diet at dose levels of 0, 30, 100 or 300 ppm (0,
1.5, 5 or 15 mg/kg/day, assuming 1 ppm in feed is equivalent to
0.05 mg/kg/day; Lehman, 1959) fed to rats (30/sex/group) for 2 years
did not produce any carcinogenic effects (Larson and Borzelleca,
1970a). However, doses used in this study were too low to assess the
carcinogenic potential of pronamide.
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)
(UF) 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).
One-day Health Advisory
No information was found in the available literature that was suitable
for determination of the One—day HA value for pronamide. It is therefore
recommended that the Lifetime HA value of 0.052 mg/L (52 ug/L) be used at
this time as a conservative estimate of the One-day HA value for pronamide.
Ten-day Health Advisory
Little information is available on the acute toxicity of pronamide.
Toxicity from acute exposure to pronamide has been assessed in three
reproduction/teratology studies, but it is not possible to evaluate the
most sensitive end point for acute toxicity from these studies. No effects
were observed in rats exposed to pronamide via gavage (Vogin, 1972) or in
feed (Larson and Borzelleca, 1967b) at doses as high as 15 mg/kg/day. No
higher doses were tested in the rat, but higher doses have been tested in the
rabbit (Costlow and Kane, 1985). In this study, New Zealand White rabbits
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were administered pronamide during gestation days 7 through 19 at dose levels
of 0, 5, 20 or 80 mg/kg/day. Toxic effects observed at the highest dose
include a statistically significant decrease in maternal body weight gain
and an increased incidence of gross and microscopic liver lesions. Less
significant effects on body weight and liver toxicity were observed at the
20-mg/kg/day dose, and a NOAEL of 5 mg/kg/day was identified. This value
is similar to the NOAEL identified from a 2-year feeding study in dogs
(7.5 mg/kg/day; Larson and Borzelleca, 1970b), which is used as the basis
for the Lifetime HA. Considering the limitations of the database on pronamide,
it is therefore recommended that the Lifetime HA value of 0.052~mg/L (52 ug/L),
calculated below, be used at this time as a conservative estimate of the
Ten-day HA value for pronamide.
Longer-term Health Advisory
Liver toxicity has been observed after acute, subchronic and chronic
administration of pronamide to experimental animals. Adverse effects on the
liver have been observed after acute exposure of rabbits to 80 mg/kg/day via
gavage (Costlow and Kane, 1985), subchronic exposure of rats and dogs to
7.5 mg/kg/day and 90 mg/kg/day, respectively (Larson and Borzelleca, 1967a,b),
and chronic feeding of 300 and 375 mg/kg/day to mice (Smith, 1974; Newberne
et al, 1982). In contrast to the subchronic rat feeding study, a NOAEL of
15 mg/kg/day was identified in a 2-year rat feeding study (Larson and-
Borzelleca, 1970a); however, this study was invalidated (U.S. EPA, 1985).
Both rat studies suffer similar deficiencies, which make them unsuitable to
serve as the basis for HA values (U.S. EPA, 1985a). Considering the limita-
tions of the database on pronamide and the potential for this compound to
cause liver damage, it is therefore recommended that the Lifetime HA value
of 0.052 mg/L (52 ug/L) be used at this time as a conservative estimate of
the Longer-term HA value for pronamide.
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 classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
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Pronamide August, 1987
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carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Two-year chronic pronamide feeding studies have been performed in three
species: the rat (Larson and Borzelleca, 1970a), dog (Larson and Borzelleca,
1970b), and mouse (Newberne et al., 1982). For the rat and dog studies, only
low doses were used and no toxic effects were observed. The highest doses
tested, 15 mg/kg/day (rat) and 7.5 mg/kg/day (dog), were identified as NOAELs
for these studies. Because of various deficiencies in the rat study, this
study was not validated (U.S. EPA, 1985), and is therefore not acceptable as
the basis for the Lifetime HA value. The 2-year study performed on mice
(Newberne et al., 1982) was rejected as the basis for the Lifetime HA because
of the relative insensitivity of mice to pronamide compared to other species.
The NOAEL of 75 mg/kg/day identified in this study was higher than doses
causing liver toxicity in subchronic feeding studies in both the rat and dog
(Larson and Borzelleca, 1967a,b). Taking all of these studies into consid-
eration, the 2-year feeding study in dogs (Larson and Borzelleca, 1970b) was
selected as the basis for determination of the Lifetime HA for pronamide.
In this study, beagle dogs fed a diet containing pronamide at dose levels of
0, 30, 100 or 300 ppm (0, 0.75, 2.5 or 7.5 mg/kg/day) for 2 years showed no
adverse effects at any of the doses tested. A NOAEL of 7.5 mg/kg/day (the
highest dose tested) was identified in this study.
Using a NOAEL of 7.5 mg/kg/day, the Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (7'5 mg/kg/day) = 0.075 mg/kg/day
(100)
where:
7.5 mg/kg/day » NOAEL, based on the absence of adverse effects in
dogs administered pronamide in the diet for 2 years.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.075 mg/kg/day) (70 kg) , 2.6 mg/L (2,600 ug/L)
2 L/day
where:
0.075 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
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Pronamide August, 1987
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Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (2'6 mg/D (20%) = 0.052 mg/L (52 ug/L)
(10)
where:
2.6 mg/L = DWEL.
20% = assumed relative source contribution from water.
10 = additional uncertainty factor per ODW policy to account
for possible carcinogenicity.
Evaluation of Carcinogenic Potential
0 Applying the criteria described in EPA's final guidelines for assess-
ment of carcinogenic risk (U.S. EPA, 1986a), pronamide has tentatively
been 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 A Provisional Acceptable Daily Intake (PADI) of 0.0750 mg/kg/day and
a calculated Theoretical Maximum Residue Concentration (TMRC) of
0.0409 mg/day that utilizes 0.91% of the PADI has been established
(U.S. EPA, 1985a).
8 Residue tolerances have been established for pronamide and its metabo-
lites in or on raw agricultural commodities that range from 0.02 ppm
to 10.0 ppm (U.S. EPA, 1985b).
VII. ANALYTICAL METHODS
0 Analysis of pronamide 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
pronamide, 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
Reverse osmosis (RO) is a promising treatment method for pesticide-
contaminated water. As a general rule, organic compounds with
molecular weights greater than 100 are candidates for removal by RO.
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Larson et al. (1982) report 99% removal efficiency of chlorinated
pesticides by a thin-film composite polyamide membrane operating at a
maximum pressure of 1,000 psi and at a maximum temperature of 113°F.
More operational data are required, however, to specifically determine
the effectiveness and feasibility of applying RO for the removal of
pronamide from water. Also, membrane adsorption must be considered
when evaluating RO performance in the treatment of pronamide-contami-
nated drinking water supplies.
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IX. REFERENCES
Benson, N.R. 1973. Efficacy, leaching and persistence of herbicides in
apple orchards. Bulletin 863. Washington State University, College of
Agriculture Research Center.
Costlow, R.D., and W.W. Kane.* 1985. Teratology study with Kerb technical (no
clay) in rabbits. Unpublished study no. 83R-026 prepared and submitted
by Rohm and Haas Company, Spring House, PA. Accession no. 256590.
Cummings, T.L., and R.Y. Yih. Undated. Metabolism of Kerb (3,5-dichloro-N-
(l,l-dimethyl-2-propynyl)benzamide) in different types of soil.
Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA.
Memorandum Report No. 52.
Fabrizio, P.O.A.* 1973. Final report: Cytogenetic study: Kerb analytical.
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Kensington, MD for Rohm and Haas Company, Philadelphia, PA. April 16.
MRID 00038031.
Fisher, J.D. 1971. Dissipation and metabolism study of Kerb in soil and its
effects on microbial activity. Unpublished report prepared by Rohm and
Haas Co., Philadelphia, PA. Lab. 11 Research Report No. 11-229.
Fisher J.D. 1973. Soil leaching study with Kerb degradation products RH-24,
580 and RH-24,644. Unpublished report prepared by Rohm and Haas Co.,
Philadelphia, PA. Tech. Report No. 3923-73-4.
Fisher, J.D., and T.L. Cummings. Undated. Biodegradation study of carbonyl-
!4C-Kerb and ring-!4C-3,5-dichlorobenzoate in a semicontinuous activated
sludge test. Unpublished study prepared by Rohm and Haas Co, Philadelphia,
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Fisher, J.D., and S.T. Satterthwaite. 1971. Leaching and metabolism studies
of !4C-Kerb in soils. Unpublished report prepared by Rohm and Haas Co.,
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Hance, R.J. 1979. Effect of pH on the degradation of atrazine, dichlorprop,
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Hance, R.J., P.O. Smith, T.H. Byast and E.G. Cotterill. 1978a. Effects of
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Hance, R.J., P.O. Smith, E.G. Cotterill and D.C. Reid. 1978b. Herbicide
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Larson, P.S., and J.F. Borzelleca.* 1967a. Toxicologic study on the effect
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Larson, R.E., P.S. Cartwright, P.K. Eriksson and R.J. Petersen. 1982.
Applications of the FT-30 reverse osmosis membrane in metal finishing
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Lashen, E.S. 1970. Inhibitory effects of Kerb and Kerb transformation
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by Rohm and Haas Co., Philadelphia, PA. Memorandum Report No. 22.
Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs and
cosmetics. Assoc. Food Drug Off. U.S., Q. Bull.
Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister
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of Toxic Effects Chemical Substances.
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Powers, M.B.* 1970a. Final Report (Study 1) - Acute Oral - Rats. Unpublished
study. Project No. 417-337, prepared by TRW, Inc., Vienna, VA for Rohm
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lished study, Project No. 417-337, prepared by TRW, Inc., Vienna, VA for
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Powers, M.B.* 1970c. Final Report (Study 4) - Primary Skin - Rabbits.
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U.S. EPA. 1985b. U.S. Environmental Protection Agency. Code of Federal
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Confidential Business Information submitted to the Office of Pesticide
Programs.
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