DIPHENAMID
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
August, 1987
DRAFT
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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Diphenamid
August, 1987
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 957-51-7
Structural Formula
HC-C-N(CH,)2
N,N-dimethyl-alpha-phenyl-benzeneacetamide
Synonyms
e Dymid; Enide (Meister, 1983).
Uses
0 Pre-emergent and selective herbicide for tomatoes, peanuts, alfalfa,
soybean, cotton and other crops (Meister, 1986).
C16H17ON
239.30
White crystalline solid
135°C
260 mg/L
Properties (Windholz et al., 1983)
Chemical Formula
Molecular Weight
Physical State (at 25°C)
Boiling Point
Melting Point
Density
Vapor Pressure (25°C)
Specific Gravity
Water Solubility (27°c)
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
Occurrence
0 Diphenamid has not been found in any of the water samples collected
and analyzed from 567 ground water locations (STORET, 1987).
Environmental Fate
Diphenamid is stable to hydrolysis at pH 5, 7 and 9 for 7, 12 and
10 days, respectively, at elevated temperature (49°C or 120°F)
(NOR-AM, 1986).
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Diphenamid August, 1987
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0 Diphenamid is intermediately mobile (class 3) on silt loam and silty
clay loam soil TLC plates; on sandy loam, it is in class 5, indicating
that it would leach readily in this soil (Helling and Turner, 1968).
III. PHARMACOKINETICS
Absorption
• No information was found in the available literature on the absorption
of diphenamid.
Distribution
0 No information was found in the available literature on the distri-
bution of diphenamid.
Metabolism
0 No information was found in the available literature on the metabolism
of diphenamid.
Excretion
0 No information was found in the available literature on the excretion
of diphenamid.
IV. HEALTH EFFECTS
Humans
0 No information was found in the available literature on the health
effects of diphenamid in humans.
Animals
Short-term Exposure
0 RTECS (1985) reported the acute oral LD5o values in the rat, mouse,
dog, monkey and rabbit to be 60C, 700, 1,000, 1,000 and 1,500 mg/kg,
respectively.
Dermal/Ocular Effects
0 Weddon and Brown (1976) applied a 90% wettable powder formulation of
diphenamid to intact or abraded skin of New Zealand rabbits (two/sex/
dose) for 24 hours at 0, 200, 1,000 or 2,000 mg/kg. No adverse
responses were observed in any of the exposed animals.
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Long-term Exposure
e Woodard et al. (1966b) administered technical diphenamid (purity
not specified) in the feed to beagle dogs (three/sex/dose) at dose
levels of 0, 3, 10 or 30 mg/kg/day for 103 weeks. No pathological
effects were reported at 3 mg/kg/day for clinical chemistry, hematology,
urinalysis, gross pathology and histopathology. Liver weights were
slightly increased in the 10- and 30-mg/kg/day dosage groups of both
sexes, and there were slight increases in numbers of portal macrophages
and/or fibroblasts when compared to untreated controls. Liver enzyme
levels were normal in all treated groups, except for elevation of
serum glutamic-oxaloacetic transaminase (SCOT) after 8 weeks in one
female dosed with 3 mg/kg/day. A No-Observed-Adverse-Effect-Level
(NOAEL) of 3 mg/kg/day and a Lowest-Observed-Adverse-Effect-Level
(LOAEL) of 10 mg/kg/day were identified by this study.
0 Hollingsworth et al. (1966) fed technical diphenamid (>98% pure) to
rats (30/sex/dose) at dose levels of 0, 3, 10 or 30 mg/kg/day for 101
weeks. A slight increase in the mean absolute liver weights of males
and the relative liver and thyroid weights of females in the high-
dose groups was observed. No other adverse effects were reported
at 10 mg/kg/day or less in general behavior, feed consumption, body
and organ weights, hematology, gross pathology and histopathology.
A NOAEL of 10 mg/kg/day was identified by this study.
Reproductive Effects
0 In a three-generation reproduction study, Woodard et al. (1966a)
supplied diphenamid to albino rats (10 males and 20 females/dose) at
dose levels of 0, 10 or 30 mg/kg/day. No reproductive or pathological
effects were observed for the parental generations (Fg, F-UJ, F?]-,)
at any dose tested. Weanlings of the F3b generation dosed with
30 mg/kg/day showed reversible liver changes, including slight
congestion, glycogen depletion and irregular size of the hepatocytes.
Based on reproductive end points, this study identifies a NOAEL of
30 mg/kg/day. Based on fetal toxicity, a NOAEL of 10 mg/kg/day and
a LOAEL of 30 mg/kg/day are identified.
Developmental Effects
0 Woodard et al. M966a) reported no developmental effects in rat pups
at any dose level. Reversible liver changes were observed in weanling
pups of the F3b generation dosed with 30 mg/kg/day. A NOAEL based on
fetotoxicity of 10 mg/kg/day can be identified.
Mutagenicity
0 Moriya et al. (1983) reported that diphenamid (up to 5,000 ug/plate)
did not increase reversion frequency in £. typhimurium or £. coli
test systems, either with or without metabolic activation.
0 Shirasu et al. (1976) reported that diphenamid (1%) was not mutagenic
in a recombination assay utilizing JJ. subtilis or in reversion assays
with E. coli or S. typhimurium.
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Carcinogenicity
0 In a 2-year feeding study in rats by Hollingsworth et al. (1966),
diphenamid was administered to albino rats (30/sex/dose) at dose
levels of 0, 3, 10 or 30 mg/kg/day for 101 weeks. Based on
histopathological examination of a variety of tissues and organs,
the authors reported that the type and incidence of neoplasms were
comparable in treated and control rats.
0 In a 2-year feeding study in dogs by Woodard et al. (1966b), diphenamid
was administered in the feed to beagle dogs (three/sex/dose) at dosage
levels of 0, 3, 10 or 30 mg/kg/day for 103 weeks. Histopathological
examinations were performed on a variety of tissues and organs, and
no evidence of increased tumor frequency was reported.
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 = (NOAEi. or LOAEL) x (BW) = /L ( u /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 diphenamid. It is therefore
recommended that the Drinking Water Equivalent Level (DWEL), adjusted for a
10-kg child (0.3 mg/L, calculated below), be used at this time as a conservative
estimate of the One-day HA value.
For a 10-kg child, the adjusted DWEL is calculated as follows:
DWEL = (0.03 mg/kg/day) (10 kg) = 0>3 mg/L
(1 L/day)
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where:
0.03 mg/kg/day = RfD (see Lifetime Health Advisory Section).
10 kg = assumed body weight of a child.
1 L/day » assumed daily water consumption of a child.
Ten-day Health Advisory
No information was found in the available literature that was suitable
for determination of the Ten-day HA value for diphenamid. It is therefore
recommended that the DWEL, adjusted for a 10-kg child (0.3 mg/L) be used at
this time as a conservative estimate of the Ten-day HA value.
Longer-term Health Advisory
No information was found in the available literature that was suitable
for determination of the Longer-term HA value for diphenamid. It is therefore
recommended that the DWEL value, adjusted for a 10-kg child (0.3 mg/L) be
used at this time as a conservative estimate of the Longer-term HA value.
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
carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The feeding study in dogs by Woodard et al. (1966b) has been selected to
serve as the basis for determination of the Lifetime HA value for diphenamid.
In this study, dogs were administered technical diphenamid (0, 3, 10 or 30
mg/kg/day) in the diet for 103 weeks. Based on clinical chemistry, hematology,
urinalysis, gross pathology and histopathology, this study identified a NOAEL
of 3 mg/kg/day and a LOAEL of 10 mg/kg/day. The study by Hollingsworth et al.
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Diphenamid August, 1987
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(1966), which identified a NOAEL of 10 mg/kg/day in a 101-week experiment in
rats, was not selected, since the rat appears to be somewhat less sensitive
than the dog (the NOAEL in the rat is the same as the LOAEL in the dog).
Using a NOAEL of 3 mg/kg/day, the Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (3 mg/kg/day) = 0>03 mg/kg/day
(100)
where:
3 mg/kg/day = NOAEL, based on absence of organ weight loss, clinical
chemistry, hematology, urinalysis, gross pathology and
histopathology in dogs exposed to diphenamid via the
diet for 103 weeks.
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 = (0.03 mg/kg/day) (70 kg) = uo mg/L (1f000 ug/L)
(2 L/day)
where:
0.03 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 = (1.0 mg/L) (20%) = 0.2 mg/L (200 ug/L)
where:
1.0 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 No evidence of carcinogenic potential was detected in rats (30/sex/dose)
fed diphenamid in the diet for 2 years at a dose level of 30 mg/kg/day
(Hollingsworth et al., 1966), or in dogs (three/sex/dose) fed diphenamid
in the diet for 2 years, also at a dose of 30 mg/kg/day (Woodward
et al., 1966b). These studies are limited by the low doses and the
small number of animals employed.
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Diphenamid August, 1987
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0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of diphenamid.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986a), diphenamid is classified in
Group D: not classified. This category is for substances with
inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 Tolerances in or on raw agricultural commodities of 0.01 ppm for milk
to 2 ppm for peanut hay and forage have been set for diphenamid (U.S.
EPA, 1985).
VII. ANALYTICAL METHODS
0 Analysis of diphenamid 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
diphenamid 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
0 Available data indicate that granular activated carbon (GAC) adsorp-
tion will remove diphenamid from water.
8 whittaker (1980) experimentally determined adsorption isotherms for
diphenamid on GAC.
0 Whittaker (1980) reported the results of GAC columns operating under
bench-scale conditions. At a flow rate of 0.8 gpm/sq ft and an empty
bed contact time of 6 minutes, diphenamid breakthrough (when effluent
concentration equals 10% of influent concentration) occurred after
500 bed volumes (BV). When two bi-solute diphenamid solutions were
passed over the same column, diphenamid breakthrough occurred after
235 BV for diphenamid-propham solution and after 290 BV for diphenamid-
fluometuron solution.
0 GAC adsorption appears to be the most effective treatment technique
for the removal of diphenamid from contaminated water. However,
selection of individual or combinations of technologies to attempt
diphenamid removal from water must be based on a case-by-case technical
evaluation, and an assessment of the economics involved.
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Diphenamid August, 1987
IX. REFERENCES
Helling, C.S., and B.C. Turner. 1968. Pesticide mobility: Determination
by soil TLC. Science. 16:562-563.
Hollingsworth R.L., M.W. Woodard and G. Woodard.* 1966. Diphenamid safety
evaluation by dietary feeding to rats for 101 weeks. Final Report.
Unpublished study. MRID 00076381.
Meister, R.T., ed. 1986. Farm Chemicals Handbook. Willoughby, OH: Meister
Publishing Co.
Moriya, M., T. Ohta, K. Watanabe, T. Miyazawa, K. Kato and Y. Shirasu. 1983.
Further mutagenicity studies on pesticides in bacterial reversion assay
systems. Mutat. Res. 116:185-216.
NOR-AM. 1986. NOR-AM Chemical Company. Diphenamid: Hydrolysis study (ground
water data call-in). Wilmington, DE. Unpublished study submitted to the
Office of Pesticide Programs.
RTECS. 1985. Registry of Toxic Effects of Chemical Substances. National
Institute for Occupational Safety and Health. Washington, DC. National
Library of Medicine On-Line File.
Shirasu, Y., M. Moriya, K. Kato, A. Furuhashi and T. Kada. 1976. Mutagenicity
screening of pesticides in the microbial system. Mutat. Res. 40:19-30.
STORET. 1987.
TDB. 1985. Toxicology Data Bank. MEDLARS II. National Library of Medicine's
National Interactive Retrieval Service.
U.S. EPA. 1985. U.S. Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 180.230.
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.
Weddon T.E., and P.K. Brown.* 1976. Enide 90 W—Dermal LD50 and skin
irritation evaluation in New Zealand rabbits. Technical Report No.
124-9610-MWG-76-6. Unpublished study. MRID 00054611.
Whittaker, K.F. 1980. Adsorption of selected pesticides by activated carbon
using isotherm and continuous flow column systems. Ph.D. Thesis, Purdue
University.
Windholz, M., S. Budavari, R.F. Blumetti and E.S. Otterbein, eds. 1983. The
Merck Index, 10th ed. Rahway, NJ: Merck and Co., Inc.
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Woodard M.W., G. Woodard and M.T. Cronin.* 1966a. Diphenamid: three-genera-
tion reproduction study in rats. Unpublished study. MRID 00076383.
Woodard M.W., G. Woodard and M.T. Cronin.* 1966b. Diphenamid safety evaluation
by dietary feeding to dogs for 103 weeks. Final Report. Unpublished
Study. MRID 00076382.
Confidential Business Information submitted to the Office of Pesticide
Programs.
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