Dacthal (CASRN 1861-32-1)
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0221
Dacthal;
CASRN 1861-32-1
Health assessment information on a chemical substance is included in IRIS
only after a comprehensive review of chronic toxicity data by U.S. EPA
health scientists from several Program Offices and the Office of Research
and Development. The summaries presented in Sections I and II represent
a consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Dacthal
File First On-Line 08/22/1988
Category (section) |
Status |
Last Revised |
---|---|---|
Oral RfD Assessment (I.A.) | on-line | 08/01/1994 |
Inhalation RfC Assessment (I.B.) | no data | |
Carcinogenicity Assessment (II.) | no data |
_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — Dacthal
CASRN — 1861-32-1
Primary Synonym — DCPA
Last Revised — 08/01/1994
The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Please refer
to the Background Document for an elaboration of these concepts. RfDs
can also be derived for the noncarcinogenic health effects of substances
that are also carcinogens. Therefore, it is essential to refer to other
sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.
__I.A.1. Oral RfD Summary
Critical Effect |
Experimental Doses* |
UF |
MF |
RfD |
---|---|---|---|---|
Effects on the lungs, 2-Year Rat Feeding Study ISK Biotech Corp., 1993 |
NOAEL: 1 mg/kg-day LOAEL: 10 mg/kg-day |
100
|
1
|
1E-2
mg/kg-day |
*Conversion Factors and Assumptions: None
__I.A.2. Principal and Supporting Studies (Oral RfD)
Note: The RfD for dacthal was originally verified on February 18, 1987. The
RfD was revised because of the availability of new information, including 2-
year feeding/oncogenicity studies in rats and mice, a 2-generation
reproduction study in rats, developmental toxicity studies in rats and rabbits
and subchronic feeding studies in rats and mice.
ISK Biotech Corporation. 1993. MRID No. 42731001, 42998401. HED Doc. No.
010513. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Groups of Sprague-Dawley CD rats (70/sex/dose) were administered technical
dacthal in the diet at dosage levels of 0, 1, 10, 50, 500 and 1000 mg/kg-day
for 2 years. Dacthal utilized in this study contained 0.13% of the
manufacturing impurity hexachlorobenzene (HCB). Test material intake was
calculated based on the nominal concentration in the diet provided each week
and the corresponding body weights and food consumption data for that week.
Additionally, concentrations of HCB at each dose level were calculated as
follows: 0.0013, 0.013, 0.065, 0.65 and 1.3 mg/kg-day for the 1, 10, 50, 500
and 1000 mg/kg-day dose levels, respectively.
Survival rates were comparable among the groups for both sexes for the
first year of the study. Survival in treated males was lower for all groups
compared with the control; males at the highest dose level displayed the
highest mortality (73% vs 52% in the controls). A significant trend (p<0.01)
in survival rates was observed when all male groups were included, but when
the highest dose level was excluded, no significant dose-related trend was
detected. Females displayed comparable survival among the groups. Males at
the two highest dose levels displayed signs of poor physical health, such as
anogenital staining, thin appearance, material around nose/mouth, and there
was an increase in the findings of few or no feces, soft feces, dark urine and
red urine/penile discharge. Females at the two highest dose levels appeared
thin. No other findings were considered treatment related. The cause of
death of some rats dying or sacrificed moribund during the first year included
suppurative pyelonephritis, chronic nephropathy and suppurative inflammation
in the kidney bladder, prostate and seminal vesicles.
In general, body weight was comparable among male groups during the first
year of the study. From week 54 on, statistically significant (p<0.01)
decreases were observed in males at 1000 mg/kg-day compared with control
values. The 500 mg/kg-day females displayed the lowest body weights at study
initiation, but were approximately 100% of control value. At weeks 6, 7, 13,
22 and from week 50 to termination, these females displayed statistically
significant decreases (p<0.01) from the control value. At the highest dose
level, females displayed decreased body weight compared with the controls at
week 14 and from week 46 to termination. Additionally, the 50 mg/kg-day
females displayed a statistically significant (p<0.01) decrease in body weight
(dose related) at terminal sacrifice. Body-weight gains were comparable among
males during the first year of the study, although at the highest dose, slight
decreases from control values reached statistical significance at week
intervals 0-5, 0-8 and 0-14. During the second year of the study, males at
1000 mg/kg-day displayed decreased gains compared with the control values.
From the third week on, females at the two highest dose levels displayed
decreased body-weight gains (dose related), although several intervals did not
attain statistical significance.
A dose-related increase was observed in the incidence and severity of
focal accumulations of foamy-appearing macrophages within the alveolar spaces
(mainly in the subpleural areas, although in the peribronchiolar areas in
several rats) in males at dose levels of 10 mg/kg-day and above in females at
the two-highest dose levels. With the exception of the 10 mg/kg-day male
group, these findings were statistically significant. These foci were
correlated with the white foci observed in the lungs at necropsy. Similar
findings were observed at the interim sacrifice in both sexes at dose levels
of 50 mg/kg-day and above and in rats receiving 500 and 1000 mg/kg-day that
died during the first year of the study.
Cholesterol clefts occurred in both sexes in the majority of the rats at
the two highest dose levels (statistically significant), as well as in
approximately 25% of the 50 mg/kg-day males. Additionally, cholesterol clefts
were observed in rats in the other dose groups that had pulmonary foci.
Reportedly these lesions may have occurred as a result of the breakdown of the
foamy-appearing macrophages, resulting in the release of the lipid material
that formed the cholesterol clefts. Also observed in the majority of the
lungs of rats displaying focal accumulations of foamy macrophages was a
thickening of the alveolar walls and fibrosis, as evidenced by the appearance
of collagen under polarized light (statistically significant in males
receiving 10 mg/kg-day and above and in females at 500 and 1000 mg/kg-day) and
focal interstitial pneumonitis, characterized by foci of mixed inflammatory
cells. When giant cells occurred in the areas of pneumonitis, a diagnosis of
focal granulomatous pneumonitis was made (statistically significant at 500 and
1000 mg/kg-day, both sexes). Similar findings in the lungs were observed at
the interim sacrifice and in rats dying during the final year of the study.
Additionally, focal accumulations of brown granular pigment, thought to be
hemosiderin, were increased (statistically significant) in the focal areas of
interstitial pneumonitis at the 500 and 1000 mg/kg-day dose levels in both
sexes at termination. Electron microscopy showed an increase of foci of foamy
macrophages that were laden with lipid spheres, vacuoles, lamellar bodies
and/or cholesterol clefts.
The liver, kidneys and thyroid are also known target organs for dacthal in
both males and females at doses of 10 mg/kg-day and greater. Additionally,
the eye appears to be a target organ in females. In females at study
termination, a dose-related increase in the incidence of bilateral retinal
atrophy was observed. Males at the 500 and 1000 mg/kg-day dose levels
displayed a 12 and 16% increase, respectively, in absolute liver weight at
interim sacrifice, and females at these dose levels displayed increases of 29
and 37%, respectively (statistically significant). At termination, the
increases were 35 and 40% greater for males (statistically significant) and 18
and 22% greater in females.
A dose-related (statistically significant) increase in the incidence and
severity of centrilobular hepatocytic swelling (hepatocytic hypertrophy) was
observed in both sexes at dose levels of 50 mg/kg-day and above at both the
interim and terminal sacrifices and in males at 10 mg/kg-day at terminal
sacrifice. This lesion was characterized by an increase in cellular size,
accompanied by a ground-glass appearance to the cytoplasm of the hepatocytes
located in close proximity to the central vein of each hepatic lobule. As the
severity of the lesion increased, larger portions of the lobule were affected,
which the study's author points out is consistent with metabolic activation
and an increase in smooth endoplasmic reticulum within the cell.
Additionally, an increased incidence of eosinophilic foci in both sexes was
observed at dose levels of 10 mg/kg-day and above and in rats dying during the
second year of the study, compared with control groups, with statistical
significance being attained at 500 and 1000 mg/kg-day in both sexes and at 50
mg/kg-day in males at the terminal sacrifice. Five high-dose males displayed
eosinophilic cytoplasmic inclusions at the interim sacrifice. The author
stated that eosinophilic foci are focal areas of cellular alteration in the
liver characterized by areas of hepatocytes with intensely eosinophilic
cytoplasm, enlarged hepatocytes, increases in hepatocyte numbers, and distinct
lesion borders occasionally resulting in compression of the adjacent
parenchyma. An increase in osmiophilic membranes and smooth endoplasmic
reticulum was observed in the hepatocytes of three high-dose males evaluated
by electron microscopy.
An increase in the severity of chronic nephropathy in males and an
increase in incidence and severity in females was observed at dose levels of
50 mg/kg-day and above compared with the respective control groups
(statistically significant at the two highest dose levels, both sexes).
Components of chronic nephropathy were listed as regenerative tubular
epithelium, dilated tubules, casts, interstitial fibrosis and mononuclear cell
infiltrates. The author noted that chronic nephropathy is a commonly observed
progressive lesion in Sprague-Dawley rats, especially males. Moreover, the
author stated that exacerbation of this common aging lesion was apparently the
main cause of spontaneous death or moribundity, which led to the early
sacrifice of high-dose males. Other findings in the kidneys of males at 500
and 1000 mg/kg-day that were considered most likely to be associated with the
increased severity of chronic nephropathy included infarcts and cysts, pelvic
hemorrhage, hyperplasia of transitional epithelium, papillary necrosis and
pelvic dilatation. At interim sacrifice, similar kidney lesions were observed
(increased incidence/severity of dilated tubules, mononuclear cell
infiltrates, foci of regenerative tubular epithelium) in the high-dose groups
and in males at 500 mg/kg-day. Tubular cell neoplasms of the kidney occurred
only in treated males.
Effects in the thyroid included increased organ weight as well as an
increase in the incidence and severity of follicular cell hypertrophy,
hyperplasia and basophilic clumped colloid. Additionally, a dose-related
decrease in thyroxine (T4) occurred throughout the study, and triiodothyronine
(T3) was decreased in a dose-related manner at 52 weeks. Thyroid stimulating
hormone (TSH) values were elevated at 52 weeks (dose related) and at 104 weeks
(no dose response). As discussed by the study author, thyroid hormones are
metabolized by the liver and excreted in the bile. Lower concentrations of
the thyroid hormones can result following metabolic activation, which can lead
to an increased release of TSH from the pituitary gland, via a feedback
mechanism, and stimulation of the follicular cells. This in turn can result
in follicular cell hypertrophy and hyperplasia following prolonged stimulation
and ultimately follicular cell neoplasms. The findings in this study with
respect to the liver and thyroid suggest a possible indirect effect of dacthal
on the thyroid.
Based on effects observed in the lungs, liver, kidney, thyroid and thyroid
hormones in both sexes and in the eyes of females, the LEL for systemic
toxicity is 10 mg/kg-day. The NOEL for systemic toxicity is 1 mg/kg-day.
__I.A.3. Uncertainty and Modifying Factors (Oral RfD)
UF — The uncertainty factor of 100 reflects 10 for interspecies extrapolation
and 10 for intraspecies variability.
MF — None
__I.A.4. Additional Studies/Comments (Oral RfD)
1) 2-Year Feeding Study: Principal study -- see previous description; Core
grade minimum (ISK Biotech Corp., 1993)
2) 2-Year Feeding - dog: Core grade minimum (Diamond Alkali Co., 1963a)
Groups of purebred beagle dogs (4/sex/dose) were administered dacthal in
the diet at dose levels of 0, 100, 1000 and 10,000 ppm (0, 2.5, 25 and 250
mg/kg-day). At the end of 1 year, one male and one female from the control
and each of the test groups were sacrificed. At the end of 2 years all of the
animals except one female from each group were sacrificed and the organs
weighed. These female dogs were sacrificed during the 114 week of the study.
The general appearance and behavior of the test animals were comparable
with those of the control animals. In general, the hematological picture for
all four dose groups of animals appear to be comparable and no toxicological
effects are evident. The organs of the male and female dogs from the three
different dosage levels presented histologic variations that were not
consistent nor indicative of a compound effect.
Since no effects were observed at any dose level tested, the NOEL for
systemic toxicity is equal to or greater than 10,000 ppm (250 mg/kg-day).
3) 2-Generation Reproduction - rat: Core grade minimum (ISK Biotech Corp.,
1990a)
Groups of Sprague-Dawley CD VAF/Plus (35/sex/dose) were administered
dacthal in the diet at dosage levels of 0, 1000, 5000 and 20,000 ppm (Male: 0,
45, 233 and 952 mg/kg-day; Female: 0, 63, 319 and 1273 mg/kg-day) over two
generations. On day 0 of lactation of the F2b litters, the low- and mid-dose
level diets were replaced by diets containing 200 ppm (18 mg/kg-day) and 500
ppm (47 mg/kg-day), respectively, in order to ensure a NOEL for pup body
weight. For the remainder of the study, including the F2 growth phase, the
dietary concentrations were 200, 500 and 20,000 ppm. No change in the dietary
concentration was made for F1 males or for F1 females that did not produce an
F2b litter.
No differences were observed in reproductive performance at any dose level
tested during the growth phase, mating, gestation and lactation for two
generations and two litters per generation. Body weight and body-weight gain
of parental animals of both generations were decreased mainly in the mid- and
high-dose groups (with females affected more than males) and, although
decreases were statistically significant, in general the difference compared
with control values was slight. Food consumption was similarly affected,
mainly for females, and only slightly. During gestation and lactation, the
mid- and high-dose dams displayed decreases in body weight, which were also
small in magnitude but again statistically significant. During lactation, the
magnitude of the decrease from control value grew smaller with time.
Offspring showed good viability, but body weight was affected at the mid- and
high-dose levels. No effects on reproductive performance were observed.
Based on decrease body weight and body-weight gain, the LEL for maternal
toxicity is 5000 ppm (319 mg/kg-day). The NOEL for maternal toxicity is 1000
ppm (63 mg/kg-day). Based on decreased body-weight gain, the LEL for paternal
toxicity is 20,000 ppm (952 mg/kg-day). The NOEL for paternal toxicity is
5000 ppm (233 mg/kg-day).
The NOEL for reproductive toxicity can be set at 1000 ppm (63 mg/kg-day)
and the LEL at 5000 ppm (319 mg/kg-day) based on decreased pup body weight.
There was an apparent increase in stillborn pups at the high-dose level, which
was more pronounced in the second generation than in the first. Because
decreases in pup body weights were observed at the mid- and high-dose levels
in the F1a, F1b and F2a litters, the dose levels for the mid- and low-dose
groups were lowered at the beginning of lactation of the F2b litters to ensure
an NOEL for this parameter. The NOEL for offspring toxicity can be set at 200
ppm (18 mg/kg-day) and the LEL at 500 ppm (47 mg/kg-day) based on body-weight
effects.
4) Developmental Toxicity - rat: Core grade minimum (SDS Biotech Corp., 1986)
Groups of pregnant Sprague-Dawley Crl:COBS CD rats (25/dose) were
administered dacthal orally by gavage at dose levels of 0, 500, 100 and 2000
mg/kg-day from day 6 through 15 of presumed gestation.
No adverse effects were noted for maternal rats or their offspring.
Although no effects were observed, the dose levels were deemed adequate. The
NOEL for maternal and developmental toxicity can be set at 2000 mg/kg-day.
5) Developmental Toxicity - rat: Core grade minimum (SDS Biotech Corp., 1985)
Groups of pregnant Charles River Crl:COBS CD(SD)BR rats (25/dose) were
administered dacthal diacid orally by gavage at dose levels of 0, 625, 1250
and 2500 mg/kg-day from day 6 through 15 of gestation.
The high-dose dams showed signs of toxicity manifested in slightly
decreased body-weight gains on days 6-9 and significantly decreased food
consumption on these days. Some overt signs of toxicity were also observed in
the high-dose animals, including reddened anal exudate, labored breathing in
one animal and red colored mucus in the feces. A few mid-dose as well as
high-dose animals displayed excess salivation and soft or liquid stools.
Based on food consumption changes and slight body-weight changes, the LEL for
maternal toxicity is 2500 mg/kg-day. The NOEL for maternal toxicity is 1250
mg/kg-day.
No signs of developmental toxicity were observed. All parameters measured
were within control values. There was a statistically significant decrease at
all doses tested of percent live male fetuses/litter. Apparently, no dose-
response relationship was evident in treated groups and the control value was
somewhat high compared with historical controls. Treated values were within
the historical control range. Based on the lack of developmental effects at
any dose level tested, the NOEL for developmental toxicity is equal to or
greater than 2500 mg/kg-day.
6) Developmental Toxicity - rabbit: Core grade minimum when considered with
the other rabbit developmental toxicity study (Fermenta Plant Protection Co.,
1989)
Groups of pregnant New Zealand White rabbits (20/dose) were administered
dacthal orally by gavage at dose levels of 0, 125, 250 and 500 mg/kg-day from
day 7 though day 19 of gestation.
Maternal reproductive parameters were not affected by treatment and no
embryotoxicity, fetotoxicity or teratogenicity was observed at any dose level
tested. When the results of the second rabbit developmental toxicity study
(dose levels tested were 0, 500, 1000 and 1500 mg/kg-day) are considered along
with the results of this study, a NOEL for maternal toxicity can be set at 250
mg/kg-day and a LEL of 50 mg/kg-day based on maternal deaths. The NOEL for
developmental toxicity can be set at 500 mg/kg-day, the highest dose tested.
7) Developmental Toxicity - rabbit: Core grade minimum when considered with
the other rabbit developmental toxicity study (Fermenta Plant Protection Co.,
1989)
Groups of pregnant New Zealand White rabbits (20/dose) were administered
dacthal orally by gavage at dose levels of 0, 500, 1000 and 1500 mg/kg-day
from day 6 though day 19 of gestation. The doses for this study were based on
a range-finding study in which doses of 500 to 4000 mg/kg-day were tested.
Deaths occurred at 2000 and 4000 mg/kg-day but not at 1000 mg/kg-day and
below.
Dacthal was toxic to the maternal animals, with deaths occurring in 4 low-
dose, 13 mid-dose and 12 high-dose animals. A dose-related increase in
adverse clinical signs was observed compared with control animals, which
included decreased motor activity, ataxia, impairment or loss of the righting
reflex, morbundity and dried or absent feces. These clinical signs were
mainly observed in those rabbits that died during the study. Also, a dose-
related increase in the incidence of gastric ulcerations ws observed, with the
mid- and high-dose animals displaying a statistically significant difference
compared with controls. Maternal reproductive parameters were not affected by
treatment and no embryotoxicity, fetotoxicity or teratogenicity was observed
at the dose levels tested.
When the results from the other rabbit developmental toxicity study (dose
levels tested were 0, 125, 250 and 500 mg/kg-day) are considered along with
the results from this study, a NOEL for maternal toxicity can be set at 250
mg/kg-day and a LEL of 500 mg/kg-day based on maternal deaths. The NOEL for
developmental toxicity can be set at 500 mg/kg-day, the highest dose tested.
Other Data Reviewed:
8) 2-Year Feeding/Oncogenicity - mouse: Core grade minimum (Fermenta Plant
Protection Co., 1988)
Groups of CD-1 mice (90/sex/dose) were administered dacthal in the diet at
dosage levels of 0, 100, 1000, 3500 and 7500 ppm (Male: 0, 12, 123, 435 and
930 mg/kg-day; Female: 0, 15, 150, 510 and 1141 mg/kg-day) for 2 years.
Additionally, 20 animals/sex were used for health status purposes prior to
study.
The only effects observed following exposure to the test material were on
the liver, namely: 1) increased relative liver weight (7500 ppm at termination
in both sexes); 2) increased glutamic-pyruvic transaminase (GPT, ALT) and
sorbitol dehydrogenase (SDH) activities in both sexes at week 76 sacrifice in
1000, 3500 and 7500 ppm; not dose-related; SDH and GPT increased at
termination only in 7500-ppm females; slight increases in ketones in the urine
with increasing dose; increased cholesterol levels at week 76 in 3500- and
7500-ppm females (dose-related) and at termination in the 7500-ppm females;
and 3) increased incidence of hepatocyte enlargement/vacuolation in both sexes
at 7500 ppm.
The only other effect noted was an apparent increase in the incidence of
corneal opacity with increasing dose (observed in males); however, the
registrant provided additional information stating that the eye effect may
have resulted from irritative effects of feed particles rather than from the
test material. Additionally, the registrant conducted a 2 year rat
ophthalmology study (Fermenta ASC Corp., 1990) that showed no eye effects at
the highest dose tested, 20,000 ppm (1000 mg/kg-day).
Therefore, based on liver effects, the LEL for systemic toxicity is 7500
ppm (Male: 930 mg/kg-day; Female: 1141 mg/kg-day). The NOEL for systemic
toxicity is 3500 ppm (Male: 435 mg/kg-day; Female: 1141 mg/kg-day).
9) 2-Year Ophthalmology Study - rat: No core grade (Fermenta ASC Corp., 1990)
Groups of VAF Plus Crl:CD BR Sprague-Dawley rats (20/sex/dose) were
administered dacthal in the diet at dosage levels of 0, 2000 (from weeks 1-
22), 1000 (from weeks 23-104) and 20,000 ppm (0, 100/50 and 1000 mg/kg-day)
for 2 years. This study was performed specifically to investigate the effects
of dacthal on the eye only because of an apparent increase in corneal opacity
observed in the chronic feeding/oncogenicity study in mice (Fermenta Plant
Protection Co., 1988).
In general, the animals of all dose groups were found to be without ocular
lesions in either eye. A low incidence of viral infection (signs of
sialodacroadenitis) was observed in all dose groups, which is common in
laboratory animals. The findings at terminal sacrifice included changes
expected in older rats (e.g., cataracts and corneal lesions); no increase in
the incidence of these effects with test material exposure was noted.
Due to the lack of any evidence of ocular toxicity at any of the dose
levels tested, the NOEL for eye effects is equal to 20,000 ppm (1000 mg/kg-
day).
10) 2-Year Feeding/Oncogenicity - rat: Core grade supplementary (Diamond
Alkali Co., 1963b)
Groups of rats (35/sex/dose) were administered dacthal in the diet at
dosage levels of 0, 100, 1000 and 10,000 ppm (0, 5, 50 and 500 mg/kg-day).
Interim sacrifices were made at 13 and 52 weeks.
The appearance and behavior of the test animals were generally comparable
with the control animals throughout the study. Growth for the males and
females in all three dose groups was comparable with controls. Food
consumption from week 28 to week 52 for mid-dose males and high-dose males and
females was significantly higher as compared with the corresponding controls.
Food consumption for the control and test groups during the second year was
not elevated statistically; however, inspection of the data revealed higher
weekly mean values from week 80 through week 104 for high-dose males and mid-
and high-dose females as compared with controls. At 104 weeks, the kidney
weight for high-dose males and the adrenal weights for the high-dose females
were found to be significantly higher than those for the corresponding
controls.
Based on increased kidney weights in males and adrenal weights in females,
the LEL for systemic toxicity is 10,000 ppm (500 mg/kg-day). The NOEL for
systemic toxicity is 1000 ppm (50 mg/kg-day).
11) 13-Week Feeding - rat: Core grade minimum (ISK Biotech Corp., 1991)
Groups of CD VAF/Plus Sprague-Dawley rats (15/sex/dose) were administered
dacthal in the diet at dosage levels of 0, 10, 50, 100, 150 and 1000 mg/kg-day
for 13 weeks. Two additional satellite groups (10/sex/dose) were administered
dacthal in the diet at dosage levels of 0 and 1000 mg/kg-day for 60 days. The
satellite groups were used to examine lungs only.
No treatment-related effects were observed on survival or clinical signs
in either sex at any dose level tested. Body weight was comparable among the
groups throughout the study for both sexes, although a significant trend
toward lower body weight with increasing dose in females was observed. At
study termination, body-weight gain for high-dose males and females was 8 and
14%, respectively, lower than the control values. Food consumption on a mean
absolute basis was consistently lower in the high-dose females throughout the
study compared with control values. Food consumption relative to body weight
did not indicate any consistent difference for either sex. Dose-related
effects were observed on the liver (increased weight and centrilobular
hypertrophy), lung (increased accumulation of foamy macrophages), kidney
(increased weight, epithelial hyperplasia, tubular hypertrophy, regenerative
epithelium in males) and thyroid (follicular hypertrophy) in both sexes at
dose levels of 50, 100, 150, and 1000 mg/kg-day.
Based on increased liver weight and microscopic findings, the LEL for
systemic toxicity is 50 mg/kg-day. The NOEL for systemic toxicity is 10
mg/kg-day.
12) 13-Week Feeding - mouse: Core grade minimum (Fermenta Plant Protection
Co., 1986)
Groups of CD-1 mice (15/sex/dose) were administered dacthal in the diet at
dosage levels of 0, 625, 1250, 2500 and 7500 ppm (Males) and 0, 1000, 2500,
5000 and 10,000 ppm (Females) for 13-weeks. The group mean weekly achieved
intakes of dacthal over the study for males was 0, 100, 199, 406 and 1235
mg/kg-day and for females was 0, 223, 517, 1049 and 2198 mg/kg-day.
No treatment-related effects were observed on survival, body weight/body-
weight gain, food consumption or clinical signs in either sex. The only
treatment-related effects observed were in the liver. An increased incidence
of minimal centrilobular hepatocyte enlargement in the liver was noted,
however, in the high-dose males and in the two highest doses in females,
compared with their respective control groups. Fine vacuolation of
centrilobular hepatocytes was observed in both sexes, but this was not
considered to be related to liver enlargement and no dose-related difference
in the incidence of the lesion was observed.
Based on histopathological effects observed in the liver, the LEL for
systemic toxicity is 7500 ppm (1235 mg/kg-day) for males and 5000 ppm (1049
mg/kg-day) for females. The NOEL for systemic toxicity is 2500 ppm (Male: 406
mg/kg-day; Female: 517 mg/kg-day) for both sexes.
13) 36-Day Gavage Study - rat: Core grade supplementary (SDS Biotech, 1985)
Groups of CD Sprague-Dawley rats (10/sex/dose) were administered dacthal
diacid by gavage at dose levels of 0, 100, 500 and 2000 mg/kg-day.
Suspensions of dacthal diacid were prepared weekly in vehicle (0.5% w/v methyl
cellulose solution). Doses were based on most recent body weight. Dose was a
constant volume of 10 ml/kg, with controls receiving 10 mg/kg vehicle alone.
No treatment-related changes were observed in mortality, organ weights, or
histopathology. Treatment-related effects were noted, however, in clinical
chemistry and hematology in high-dose males. Hematocrit (p<0.01) and
hemoglobin (p<0.05) were increased in high-dose males along with albumin
(p<0.05) and potassium (p<0.01), whereas blood glucose in the animals
decreased. Soft stools were evident in both high-dose males and females. No
other treatment-related changes were evident.
Based on the effects observed at the highest dose tested, the LEL for
systemic toxicity is 2000 mg/kg-day. The NOEL for systemic toxicity is 500
mg/kg-day.
14) 28-Day Feeding - rat: No core grade (ISK Biotech Corp., 1990b)
Groups of CD Sprague-Dawley rats (5/sex/dose) were administered dacthal in
the diet at dosage levels of 0, 250, 1000 and 2000 mg/kg-day for 28 days.
Food and water were available ad libitum.
No treatment-related effects were observed on survival, clinical signs,
body weight, body-weight gain or food consumption in either sex at any of the
dose levels tested. A dose-related effect was observed on the liver, that
displayed an increase in weight and the incidence of hypertrophy of the
centrilobular hepatocytes at dose levels. Other differences noted between
control and treated animals could not be definitely attributed to the test
material. Based on the effects observed in the liver at all dose levels
tested, the LEL for systemic toxicity is 250 mg/kg-day. A NOEL for systemic
toxicity was not established.
Data Gap(s): None
__I.A.5. Confidence in the Oral RfD
Study — High
Database — High
RfD — High
The principal study was well conducted and is given a high confidence rating. Additional studies are of good quality and generally supportive of the principal study. Therefore, the database is given a high confidence rating. High confidence in the RfD follows.
__I.A.6. EPA Documentation and Review of the Oral RfD
Source Document — This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation — None
Agency Work Group Review — 11/21/1985, 06/24/1986, 12/16/1986, 02/18/1987, 10/14/1987,
06/22/1988, 02/17/1994
Verification Date — 02/17/1994
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Dacthal conducted in November 2001 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__I.A.7. EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).
_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Substance Name — Dacthal
CASRN — 1861-32-1
Primary Synonym — DCPA
Not available at this time.
_II. Carcinogenicity Assessment for Lifetime Exposure
Substance Name — Dacthal
CASRN — 1861-32-1
Primary Synonym — DCPA
This substance/agent has not undergone a complete evaluation and determination under US EPA's IRIS program for evidence of human carcinogenic potential.
_III.
[reserved]
_IV. [reserved]
_V. [reserved]
_VI. Bibliography
Substance Name — Dacthal
CASRN — 1861-32-1
Primary Synonym — DCPA
Last Revised — 08/01/1994
_VI.A. Oral RfD References
Diamond Alkali Company. 1963a. MRID No. 00083584. HED Doc. No. 003299,
005866. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Diamond Alkali Company. 1963b. MRID No. 00083577. HED Doc. No. 003299,
005866. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Fermenta Plant Protection Company. 1986. MRID No. 41064801. HED Doc. No.
008373. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Fermenta Plant Protection Company. 1988. MRID No. 40958701. HED Doc. No.
007250, 008095. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Fermenta Plant Protection Company. 1989. MRID No. 41054820. HED Doc. No.
008229, 008409. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Fermenta ASC Corporation. 1990. MRID No. 41349101, 41750102. HED Doc. No.
008373. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
ISK Biotech Corporation. 1990a. MRID No. 41750103, 41905201. HED Doc. No.
008134, 008444. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
ISK Biotech Corporation. 1990b. MRID No. 41790901. HED Doc. No. 008408.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
ISK Biotech Corporation. 1991. MRID No. 41767901. HED Doc. No. 008366.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
ISK Biotech Corporation. 1993. MRID No. 42731001, 42998401. HED Doc. No.
010513. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
SDS Biotech Corporation. 1985. MRID No. 00158010. HED Doc. No. 005706.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
SDS Biotech Corporation. 1986. MRID No. 00160685. HED Doc. No. 005866,
009515. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
SDS Biotech. 1985. MRID No. 00158011. HED Doc. No. 005706. Available from
EPA. Write to FOI, EPA, Washington, DC 20460.
_VI.B. Inhalation RfD References
None
_VI.C. Carcinogenicity Assessment References
None
_VII. Revision History
Substance Name — Dacthal
CASRN — 1861-32-1
Primary Synonym — DCPA
Date |
Section |
Description |
---|---|---|
08/22/1988 | I.A. | Oral RfD summary on-line |
01/01/1990 | I.A. | Prinicpal study citation year and MRID No. corrected |
01/01/1990 | VI. | Bibliography on-line |
01/01/1992 | IV. | Regulatory Action section on-line |
03/01/1994 | I.A. | Oral RfD noted as pending change |
03/01/1994 | I.A.6. | Work group review date added |
08/01/1994 | I.A. | Oral RfD summary replaced; RfD changed |
08/01/1994 | VI.A. | Oral RfD references replaced |
04/01/1997 | III., IV., V. | Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. |
12/03/2002 | I.A.6. | Screening-Level Literature Review Findings message has been added. |
_VIII. Synonyms
Substance Name — Dacthal
CASRN — 1861-32-1
Primary Synonym — DCPA
Last Revised — 08/22/1988
- 1861-32-1
- 1,4-BENZENEDICARBOXYLIC ACID, 2,3,5,6-TETRACHLORO-, DIMETHYL ESTER
- BENZOIC ACID, 3,6-DICHLORO-2-METHOXY-
- CHLOROTHAL
- CHLORTHAL-DIMETHYL
- CHLORTHAL-METHYL
- DAC 893
- Dacthal
- DACTHALOR
- DCPA
- DIMETHYL TETRACHLOROTEREPHTHALATE
- DIMETHYL 2,3,5,6-TETRACHLOROTEREPHTHALATE
- FATAL
- TETRACHLOROTEREPHTHALIC ACID DIMETHYL ESTER
- 2,3,5,6-TETRACHLOROTEREPHTHALIC ACID, DIMETHYL ETHER
- 2,3,5,6-TETRACHLORPHTHALSAURE-DIMETHYLESTER