August, 1987
820K88106
DRAFT
CARBOXIN
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 th^se 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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Carboxin August, 1987
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 5234-68-4
Structural Formula
0 H
5,6-Dihydro-2-methyl-N-phenyl-1,4-Qxathin-3-carboxamide
Synonyms
• Carbathiin; Carboxine; D-735; DCMO; DMOC; F735; Vitavax (Meister,
1983).
Uses
0 Systemic fungicide; seed protectant; wood preservative (Meister,
1983).
Properties (Meister, 1983; Windholz et al., 1983; Wo and Shapiro, 1983;
Worthing, 1983; TDB, 1985)
Chemical Formula C| 2^302^
Molecular Weight 235.31
Physical State (25°C) Crystals
Boiling Point —•
Melting Point 93 to 95°C
Density —
Vapor Pressure (20°C) <1 mm Hg
Specific Gravity
Water Solubility (25°C) 170 mg/L
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor ~
Occurrence
8 No information was found in the available literature on the occurrence
of carboxin.
Environmental Fate
e Carboxin is rapidly metabolized (oxidized by flavin enzymes found in
fungi mitochondria) in aerobic soil. When applied to soil (aerobic
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Carboxin August, 1987
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conditions), more than 95% of the carboxin was degraded within 7
days. The major degradation product was carboxin sulfoxide, which
represented 31 to 54% of the applied radioactivity at 7 days after
treatment. Several minor degradation products were also formed
(carboxin sulfone, ^-hydroxy carboxin and ^^CO-^' Carboxin was
degraded in sterile soil but at a much slower rate than in nonsterile
soil (46 to 72% degraded in 7 days). This would indicate that soil
metabolism of carboxin under aerobic conditions is primarily by
microbial processes. Carboxin sulfoxide is stable in anaerobic soil
(Chin et al., 1972, 1969, 1970a,b; Dzialo and Lacadie, 1978; Dzialo
et al., 1978; Spare, 1979).
0 Carboxin sulfoxide, a major metabolite of carboxin, photodegrades to
unknown compounds. After 7 days of incubation, 49% of the applied
radioactivity was present as unknown compounds (Smilo et al., 1977).
0 Carboxin does not readily adsorb to soil [K value (adsorption coeffi-
cient) <1] and both carboxin and carboxin sulfoxide are very mobile
in soil with about half of the applied radioactivity leaching through
12-inch columns of clay loam soils (Lacadie et al., 1978; Dannals
et al., 1976).
8 In aqueous solution, carboxin was oxidized to carboxin sulfoxide and
carboxin sulfone within 7 days (Chin et al., 1970a).
III. PHARMACOKINETICS
Absorption
0 Waring (1973) administered carboxin (Vitavax) by gavage to groups
of four to six female New Zealand White rabbits (age not specified;
2.5 to 3 kg) and Wistar rats (age not specified; 200 to 250 g) at
1 mmol/kg (235 mg/kg). In the rats, an average of 40% of the dose
was excreted in the feces, mostly as unchanged carboxin. In the
rabbits, an average of 10% was recovered in the feces. These data
suggest that carboxin is not completely absorbed from the gut,
especially in rats.
Distribution
0 Waring (1973) administered single oral doses of carboxin (Vitavax,
6.3 uCi/rat) to female Wistar rats (age not specified; 200 to 250 g).
Carboxin was labeled either in the heterocyclic or aromatic ring and
distribution of label was assessed by autoradiography of whole-body
sections. After 2 hours, label was localized in the liver, intestinal
tract and salivary gland. After 6 hours, label was also present in
the kidney. Only trace levels remained in any tissue after 48 hours.
There were no differences in the distribution of the two labeled
compounds.
0 Nandan and Wagle (1980) fed carboxin to male albino rats (age not
specified) for 28 days at dietary levels of 0, 100, 1,000 or 10,000
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Carboxin August, 1987
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ppm. Based on the dietary assumptions of Lehman (1959), 1 ppm in the
diet of rats equals approximately 0.05 mg/kg/day. Therefore, these
levels correspond to 0, 5, 50 and 500 mg/)cg/day. In animals fed the
highest dose, maximum levels were detected in the liver (140 ug/g),
with lower levels in the kidney (123 ug/g), heart (58 ug/g) and
muscle (22 ug/g).
Metabolism
0 In the study by Waring (1973), as described previously, female New
Zealand White rabbits (age not specified; 2.5 to 3 kg) and Wistar
rats (age not specified; 200 to 250 g) were given single oral doses of
carboxin by gavage at 1 mmol/kg (235 mg/kg). The principal metabolic
pathway was found to be ortho- or parahydroxylation, followed by
glucuronidation. In the rats, 32% of the dose was excreted in urine
as glucuronides and 7% as unconjugated phenols. In the rabbits, 85%
of the dose was excreted in urine as glucuronides and 3% as free
phenols. The pattern of phenolic metabolites was the same for carboxin
labeled in either the heterocyclic or the aromatic rings, indicating
that cleavage of the compound did not occur.
Excretion
In the study by Waring (1973), as described previously, female New
Zealand White rabbits (age not specified; 2.5 to 3 kg) and Wistar
rats (age not specified; 200 to 250 g) were given single oral doses
of carboxin by gavage at 1 mmol/kg (235 mg/kg). In the rats, 41% was
excreted in the feces (largely unchanged carboxin) and 54% was excreted
in the urine (15% parent compound, 32% glucuronides, 7% free phenols).
In the rabbits, 10% was excreted in the feces and 90% was excreted in
the urine (2% parent compound, 85% glucuronides, 3% free phenols).
IV. HEALTH EFFECTS
Humans
A seven-year-old boy developed headaches and vomiting within 1 hour
after ingesting several handfuls of wheat seed treated with carboxin.
He was administered ipecac (an emetic) and was asymptomatic 2 hours
later. No estimate of the ingested dose was provided (PIMS, 1980).
Animals
Short-term Exposure
0 Reagan and Becci (1983) reported that the acute oral LDso for tech-
nical carboxin (purity not specified) in young CD-1 mice (age not
specified) was 4,150 mg/kg for males and 2,800 mg/kg for females.
The average LDso was reported to be 3,550 mg/kg.
RTECS (1985) reported that the acute oral LD5Q for carboxin (purity
not specified) in the rat (age not specified) was 430 mg/kg.
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0 Nandan and Wagle (1980) fed carboxin to male albino rats (age not
specified) for 28 days at dietary levels of 0, 100, 1,000 or 10,000
ppm. Based on the authors' measurements of food consumption and
assuming average body weights of 0.1 kg, these levels corresponded to
doses of about 0, 5.5, 59.0 or 311 mg/kg/day. A Lowest-Observed-
Adverse-Effect-Level (LOAEL) of 100 ppm (5.5 mg/kg/day) was tentatively
identified in this study based on fluid accumulation in the liver.
However, due to a number of deficiencies in this study, it is not
possible to accurately evaluate its validity. These deficiencies
include a lack of information on the test animals (e.g., condition at
study initiation, numbers used) and the absence of statistical analyses„
Dermal/Ocular Effects
0 Holsing (1968a) applied carboxin (D-735; purity and vehicle not
specified) to the intact or abraded abdominal skin of rabbits
(10/sex/dose; age not specified) at concentrations of 1,500 or
3,000 mg/kg. Five animals of each sex served as controls. Test
animals were exposed occlusively for 6 to 8 hours, 5 days per week,
for 3 weeks (15 applications). No signs of dermal irritation were
observed. The test material stained the skin and precluded readings
for erythema.
Long-term Exposure
0 Ozer (1966) administered carboxin (D-735; purity not specified) to
weanling FDRL (Wistar-derived) rats (10/sex/dose; controls: 15/sex)
for 90 days at dietary concentrations of 0, 200, 600, 2,000, 6,000
or 20,000 ppm, intended by the author to correspond to approximate
dosage levels of 0, 10, 30, 100, 300 or 1,000 mg/kg/day. All animals
survived the 90-day treatment period. Growth, food efficiency,
hematology, blood chemistry and urinalysis were reported to be similar
in all groups with the exception of increased blood urea nitrogen and
decreased hemoglobin at the 12-week interval in females that received
20,000 ppm (1,000 mg/kg/day). No significant dose-related gross
pathological changes were observed. Microscopically, a significant
number of inflammatory degenerative renal changes were found in
animals that received doses of 600 ppm (30 mg/kg/day) or higher.
These changes included focal chronic inflammation, protein casts and
cortical tubular degeneration. In two animals that received 2,000 ppm
(100 mg/kg/day), some fibrosis in the medulla was observed. Based on
renal changes, a LOAEL of 600 ppm (30 mg/kg/day) and a No-Observed-
Adverse-Effect-Level (NOAEL) of 200 ppm (10 mg/kg/day) can be identified.
0 Jessup et al. (1982) administered carboxin (technical Vitavax; purity
not specified) to six-week old Charles River CD-1 mice (50/sex/dose;
controls: 75/sex) for approximately 84 weeks at dietary concentra-
tions of 0, 50, 2,500 or 5,000 ppm. The authors indicated that these
dietary levels corresponded to doses of about 0, 8, 385 or 751 mg/kg/day
for males and 0, 9, 451 or 912 mg/kg/day for females. No compound-
related effects on general behavior or appearance were reported.
Survival rates of females receiving 5,000 ppm (912 mg/kg/day) were
significantly (p <0.01) lower than controls. No compound-related
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effects on body weight gain, food consumption, or various hematological
parameters were reported. No gross pathologic lesions that were
considered to be related to compound administration were observed
at necropsy in any mice in any treatment group. Microscopically,
compound-related effects on the liver, consisting of hypertrophy of
the centrilobular parenchymal cells, were observed in mice in the
2,500- or 5,000-ppm dose groups (385 and 751 mg/kg/day for males; 451
and 912 mg/kg/day for females). No other nonneoplastic lesions that
could be attributed to compound administration were observed. The
NOAEL in this study is 50 ppm (8 mg/kg/day for males; 9 mg/kg/day for
females) based on hepatic effects.
Holsing (1969a) administered carboxin (technical D-735; considered
to be 100% active ingredient) to Charles River rats (30/sex/dose;
controls: 60/sex) for 2 years at dietary concentrations of 0, 100,
200 or 600 ppm. Based on the dietary assumptions of Lehman (1959),
1 ppm in the diet of rats equals approximately 0.05 mg/kg/day.
Therefore, these dietary levels correspond to dose levels of approxi-
mately 0, 5, 10 or 30 mg/kg/day. While the age of the animals was
not specified, the weights of the male rats at initiation ranged from
65 to 88 g and the weight of the female rats ranged from 59 to 85 g.
No compound-related effects in terms of physical appearance, behavior,
hematology, blood chemistry or urinalysis were reported at any dose
level. Observations at terminal necropsy did not reveal any compound-
related gross or microscopic changes in the organs of animals at any
dose level. At the 600-ppm level (30 mg/kg/day), body weight gain
was significantly depressed in both sexes, and food consumption by
males was lower than that of controls throughout most of the study
(significantly lower during the first 26 weeks). Food consumption by
females at all dose levels was generally comparable to controls.
Compound-related effects included an increase in mortality at 18
months in males that received 600 ppm (30 mg/kg/day), and changes in
absolute and relative organ weights at all dose levels, including
increases in thyroid weight and decreases in kidney, heart and spleen
weight and histopathological changes in the kidneys at the 12-month
interval in both sexes at 200 and 600 ppm. Most of these effects
were inconsistent and were not observed at the end of the study
period. At the end of the 2-year study, decreased kidney weights
were observed in males at 600 ppm (30 mg/kg/day). Therefore, based
on the information presented in this study, a NOAEL of 200 ppm
(10 mg/kg/day) was identified.
Holsing (1969b) administered carboxin (technical D-735; considered
to be 100% active ingredient) to young adult beagle dogs (4/sex/dose;
controls: 6/sex) for 2 years at dietary concentrations of 0, 100,
200 or 600 ppm. Based on the dietary assumptions of Lehman (1959),
1 ppm in the diet of rats equals approximately 0.05 mg/kg/day.
Therefore, these dietary levels have been calculated to correspond
approximately to 0, 2.5, 5.0 or 15.0 mg/kg/day. No treatment-related
effects were reported on survival, body weight gain, food consumption,
organ weights, organ-to-body weight ratios, hematological, blood
chemistry or urinary parameters, liver and kidney function tests or
gross and histopathological observations. Based on this information,
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Carboxin August, 1987
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a NOAEL of 600 ppm (15 mg/kg/day; the highest dose tested) was
identified.
Reproductive Effects
0 In a three-generation reproduction study, Holsing (1968b) administered
carboxin (technical D-735; 97% active ingredient) to Charles River
rats (10 males/dose, 20 females/dose; controls: 15 males, 30 females)
(age not specified) at dietary concentrations of 0, 100, 200 or 600 ppm*
Based on the dietary assumptions of Lehman (1959), these dietary levels
have been calculated to correspond to dose levels of approximately
0, 5, 10 or 30 mg/kg/day. Criteria evaluated included fertility,
gestation, live birth and lactation indices, litter size and the
physical appearance and growth of the pups. No compound-related
effects on reproductive performance were reported at any dose level.
A compound-related effect on the progeny (moderate growth suppression
in the nursing male and female pups of all three generations) was
observed at the 600-ppm (30 mg/kg/day) dose level. Based on the
information presented in this study, a NOAEL of 200 ppm (10 mg/kg/day)
was identified.
Developmental Effects
0 Schardein and Laughlin (1981) administered technical Vitavax
(carboxin; 99% active ingredient) by gavage at doses of 0, 75, 375
or 750 mg/kg/day to seven- to eight-month-old Dutch Belted rabbits
(10/dose) on days 6 through 27 of gestation. The compound was
administered in a 0.5% carboxymethyl cellulose vehicle. No treatment-
related effects on maternal mortality, appearance, behavior or body
weight were reported. Four females aborted on days 27 and 28 of
gestation (one at 375 mg/kg/day, three at 750 mg/kg/day). Examination
for fetal malformations revealed no compound-related differences
between the control and treatment groups. Based on the frequency of
abortion, a NOAEL of 75 mg/kg/day and a LOAEL of 375 mg/kg/day were
identified.
0 Knickerbocker (1977) administered carboxin (technical Vitavax; purity
not specified) in corn oil by gavage at doses of 0, 4, 20 or 40 mg/kg/day
to sexually mature (age not specified) Sprague-Dawley rats (20/dose)
on days 6 through 15 of gestation. No compound-related effects were
observed on reproduction, gestation or in skeletal or soft tissue
development. Based on the information presented, a NOAEL of 40
mg/kg/day (the highest dose tested) was identified.
Mutagenicity
0 Brusick and Weir (1977) conducted a mutagenicity assay using Salmonella
typhimurium strains TA 1535, 1537, 1538, 98 and 100, and Saccharomyces
cerevisiae strain D4. Carboxin (purity not specified) was tested
without activation at concentrations up to 500 ug/plate and with
activation at concentrations up to 100 ug/plate. No mutagenic activity
was detected in this assay.
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0 Byeon et al. (1978) reported that carboxin (Vitavax; purity not
specified) tested at concentrations up to 1 mg/plate was not found to
be mutagenic in an Ames assay using £>. typhimurium strains TA 1535,
1538, 98 and 100.
• Brusick and Rabenold (1982) conducted an Ames assay using technical
carboxin (Vitavax, 98% active ingredient) at concentrations' up to
5,000 ug/plate. No mutagenic activity was detected, with or without
activation, in £. typhimurium strains TA 1535, 1537, 1538, 98 and 100.
0 Myhr and McKeon (1982) reported the results of a primary rat hepatocyte
unscheduled DNA synthesis assay using carboxin (technical Vitavax;
98% active ingredient). The test compound produced significant
increases in the nuclear labeling of primary rat hepatocytes over a
concentration range of 5.13 to 103 ug/mL.
Carcinogenici ty
0 Holsing (1969a) administered carboxin (technical D-735; considered to
be 100% active ingredient) to Charles River rats (30/sex/dose,- controls:
60/sex) for 2 years at dietary concentrations of 0, 100, 200 or 600 ppnu
Based on the dietary assumptions of Lehman (1959), 1 ppm in the diet
of rats equals approximately 0.05 mg/kg/day. While the age of the
animals was not specified, the weights of the male rats at initiation
ranged from 65 to 88 g and the weights of the female rats ranged from
59 to 85 g. Therefore, dietary levels correspond to approximately 0,
5, 10 or 30 mg/kg/day. No evidence of increased tumor frequency was
detected by either gross or histological examination of tissues.
0 Jessup et al. (1982) administered carboxin (technical Vitavax; purity
not specified) to six-week-old Charles River CD-1 mice (50/sex/dose;
controls: 75/sex) for approximately 84 weeks at dietary concentra-
tions of 0, 50, 2,500 or 5,000 ppm. The authors indicated that these
dietary levels corresponded to dosage levels of approximately 0, 8,
385 or 751 mg/kg/day for males and 0, 9, 451 or 912 mg/kg/day for
females. Survival rates of females receiving 5,000 ppm (912 mg/kg/day)
were significantly (p <0.01) lower than those of controls. No compound-
related gross pathologic lesions were observed at necropsy in any
treatment group. Microscopically, compound-related effects on the liver,
v consisting of hypertrophy of the centrilobular parenchymal cells, were
observed in mice in the 2,500 or 5,000 ppm dose groups (385 and 751
ing/kg/day for males; 451 and 912 mg/kg/day for females). In males, the
incidence of pulmonary adenoma/alveolar-bronchiolar adenoma was 13/75,
7/49, 7/50, and 17/50 at 0, 50, 2,500, and 5,000 ppm, respectively.
The incidence at the high dose (34%) may have been compound-related
based on comparison with the incidence in controls (17%). The difference
was statistically significant (p <0.01) using Cox's test for adjusted
trend and the Kruskall Wallis tests for life-table data and adjusted
incidence. However, based on the opinions of pathologists who reviewed
the data and on historical data on tumor incidence in control Charles
River CD-1 mice, the authors concluded that the increased incidence
was not compound-related. Historical data indicate that in six
18-month studies, the incidence of lung adenomas ranged from 6.3 to
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16.7%; in seven 20- to 22-month studies, the incidence of lung adenomas
ranged from 4.0 to 31.1%.
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
Appropriate data for calculating a One-day HA value are not available.
It is recommended that the Longer-term HA value for the 10-kg child (1.0 mg/L,
calculated below) be used as the One-day HA value.
Ten-day Health Advisory
Appropriate data for calculating a Ten-day HA value are not available.
The 22-day rabbit teratogenicity study by Schardein and Laughlin (1981)
was considered for the development of the Ten-day HA. However, the NOAEL
(75 mg/kg/day) identified in this study is far in excess of the NOAEL
(10 mg/kg/day) identified in the 90-day rat feeding study reported by Ozer
(1966) suggesting that the rat is the more sensitive species. It is, therefore,
recommended that the Longer-Term HA value for the 10-kg child (1.0 mg/L,
calculated below) be used as the Ten-day value.
Longer-term Health Advisory
The study by Ozer (1966) has been selected to serve as the basis for
calculating the Longer-term HA for carboxin. In this study, weanling rats
were exposed to carboxin in the diet for 90 days. At 30 mg/kg/day there was
histological evidence of renal injury. At 10 mg/kg/day, no effects were
detected on any parameter measured, including growth, hematology, blood
chemistry, urinalysis, gross pathology and histopathology. Based on these
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data, a NOAEL of 10 mg/kg/day was identified. This value is supported by the
subchronic (84 week) feeding study in mice by Jessup et al. (1982) which
identified a NOAEL of 8 to 9 mg/kg/day, based on the absence of effects on
appearance, behavior, mortality, weight gain, hematology, gross pathology and
his topa tho1ogy.
The Longer-term HA for the 10-kg child is calculated as follows:
Longer-term HA = (10 mg/kg/day) (10 kg) . K0 ng/L (1 000 ug/L)
(100) (1 L/day)
where:
10 mg/kg/day = NOAEL, based on absence of effects on growth, hematology,
blood chemistry, urinalysis, gross pathology and
histopathology in rats exposed to carboxin in the diet
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 an animal study.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for the 70-kg adult is calculated as follows:
Longer-term HA - (10 mg/kg/day) (70 kg) = 3<5 mg/L (3 500 ug/L)
(100) (2 L/day)
where:
10 mg/kg/day = NOAEL, based on absence of effects on growth, hematology,
blood chemistry, urinalysis, gross pathology and
histopathology in rats exposed to carboxin in the diet
for 90 days.
70 kg = assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
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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.
Hie 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 study by Holsing (1969a) has been selected to serve as the basis for
calculation of the Lifetime HA for carboxin. In this study, rats were exposed
to carboxin in the diet for 2 years. At 10 mg/kg/day, no significant effects
were detected on appearance, behavior, body weight, mortality, hematology,
blood chemistry, urinalysis, gross pathology or histopathology. Based on
these data, a NOAEL of 10 mg/kg/day was identified. This value is supported
by a 90-day rat study (Ozer, 1966) which also identified a NOAEL of 10 mg/kg/day,
a 2-year feeding study in dogs by Holsing (1969b) which identified a NOAEL of
15 mg/kg/day, and an 84-week mouse study (Jessup et al., 1982) which identified
a NOAEL of 8 mg/kg/day for males and 9 mg/kg/day for females.
Using the NOAEL of 10 mg/kg/day, the Lifetime HA for carboxin is calculated
as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (10 mg/kg/day) = 0<1 mg/kg/day
where:
10 mg/kg/day = NOAEL, based on absence of effects on appearance,
behavior, body weight, mortality, hematology, blood
chemistry, urinalysis, gross pathology or histopathology
in rats exposed to carboxin 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 = (0.1 mg/kg/day) (70 kg.) = 3.5 mg/L (3f50Q /L)
(2 L/day)
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where:
0.1 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 = (3.5 mg/L) (20%) * 0.7 mg/L (700 ug/L)
where:
3.5 mg/L - DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 Jessup et al. (1982) reported a possible compound-related increase
in pulmonary adenoma/alveolar-bronchiolar adenoma frequency in male
CD-1 mice that received carboxin in the diet at 751 mg/kg/day.
0 Holsing (1969a) fed Charles River rats carboxin at dietary levels up
to 30 mg/kg/day for 2 years, and detected no compound-related histo-
pathologic changes. This study is limited, however, by the following
factors: inadequate numbers of animals were used; survival was
generally poor and, therefore, late-developing lesions may not have
been detected; all tissues from all animals were not examined micro-
scopically; and there was no adjustment in dietary levels of carboxin
to account for growth of the test animals.
0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of carboxin.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986a), carboxin is classified in
Group D: not classified. This category is for substances with
inadequate human and animal evidence of carcinogenicity or for which
no data are available.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 No existing criteria or standards for oral exposure to carboxin were
located.
0 The U.S. EPA (OPP) has proposed an Acceptable Daily Intake (ADI) of
0.4 mg/kg/day, based on a NOAEL of 200 ppm established in a 2-year
rat feeding study and an uncertainty factor of 100 (U.S. EPA, 1981).
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0 The U.S. EPA has established residue tolerances for carboxin in or
on raw agricultural commodities that range from 0.01 to 0.5 ppm
(CFR, 1979).
VII. ANALYTICAL METHODS
0 Analysis of carboxin is by a gas chromatographic (GC) method applicable
to the determination of certain nitrogen-phosphorus containing pesti-
cides 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 carboxin 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 No information regarding treatment techniques to remove carboxin from
contaminated waters is currently available.
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Carboxin August, 1987
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•Confidential Business Information submitted to the Office of Pesticide
Programs.
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