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EC number: 907-672-2
CAS number: -
Repeated dose toxicity tests are available for the oral, inhalation and dermal route. Adverse effects were observed via the three routes of exposure. The main effects were observed on the skin, respiratory tract, plasma cholinesterase, kidney, bladder and the liver. These adverse effects did not justify a classification according to the CLP criteria.
To evaluate the subchronic toxicity of DBPP, Sprague-Dawley rats were
exposed daily to diets containing target dose levels of 5, 50 and 250 mg
of DBPP per kilogram of body weight for 91 days. Survival, clinical
signs, body weights, food consumption values, ophthalmoscopic
examination results, clinical pathology data, terminal body weights,
absolute and relative organ weights and gross and microscopic pathology
were evaluated for compound effects.
At 250 mg/kg, the high-dose level, dietary exposure to DBPP resulted in
derpessed weekly body weights and/or growth rates, as well as decreased
weekly food consumption in males and females and significantly lower
total food consumption in female rats. Inhibition of plasma, erythrocyte
and brain cholinesterase levels (females only for the brain
cholinesterase) was determined in this group of rats, with depression of
the plasma cholinesterase being most pronounced. Hematology effects
noted included depressed erythrocyte counts, hematocrits and hemoglobin
levels, as well as some slight changes in erythrocyte morphology. Total
cholesterol was increased in males only. Decreased terminal body weights
and increased absolute and relative liver weights were also noted as
treatment effects. Histopathologic changes were seen in the liver and
urinary bladder of males and females exposed to DBPP at this level.
Because the initial histopathology evaluation did not establish a
no-effect level with regard to changes in the urinary bladder, a second
pathologist reviewed the bladder slides without prior knowledge of
treatment or of the original pathologist's findings. There was a
consensus by both pathologists, and a conclustion by the coordinating
pathologist, that treatment related epithelial hyperplasia and
submucosal inflammation were present in the bladders of males and
females of the high-dose group. The liver findings were characterized by
decreased hepatocytic vacuolization in males and increased fatty change
in males and females. These liver findings are considered of
questionnable biological significance.
At 50 mg/kg, the mid-dose level, some depression of weekly body weights
and total food consumption was noted. Plasma cholinesterase levels were
inhibited in female rats only. The histomorphological changes in the
urinary bladder of epithelial hyperplasia and submucosal inflammation
were considered treatment effects in males at this level. The
coordinating pathologist drew the conclusion that in females the
incidence and severity of these bladder changes were not sufficient to
substantiate a treatment effect. Hepatocytic vacuolization in the liver
was observed in males, but again was of questionnable biological
No effects of exposure to DBPP were seen at the 5 mg/kg level. The
review of urinary bladders on a blind basis established no clear
difference in incidence or severity of urinary bladder findings between
this low-dose group and controls.
In conclusion, treatment-related effects on body weights, food
consumption, clinical pathology results, organ weights and
histopathology results were seen in males and females exposed at 250
mg/kg. Treatment-effects on body weights, food consumption, clinical
pathology results (females) and histopathology results (males) were
observed at 50 mg/kg. There were no treatment-related effects at the 5
4 groups of 25 male and 25 female Sprague/Dawley rats per group were
exposed to mean analytical concentrations of 0, 5.3, 100 or 300 mg
SKYDROL 500B-4 per m3 in air in 10 m3 inhalation
chambers. For period 1 animals a minimum of 28 6 h exposures were
conducted over an approximate 6 -week period. For Period 2 animals a
minimum of 62 6 h exposures were conducted over an approximate 14 -weel
period. Period 1 animals (10/sex/group) were sacrificed and used for
hematology and serum biochemical analyses only. All animals survived the
scheduled exposures. Red/pink nasal discharge, salivation, loss of hair,
and red ocular discharge were notable observations in the mid and high
exposure level animals. An insignificant incidence of observations were
noted in the control and low level animals. Additional observations
noted on weekly weigh days were red/brown perinasal encrustation,
salivation, and loss of hair. During the study and especially in the
final 3 weeks, high exposure level females weighed significantly less
than controls. Marginal decreases in erythrocytes (RBC, HGB, HCT) in
both males and females of the high exposure level occurred, However, the
only significant changes were in the high level females from period 2.
Moderate decreases in plasma cholinesterase levels in the high level
females were considered test exposure related. All other changes in
chemistry parameters were slight and/or sporadic and no correlation to
test material exposure could be made. No gross necropsy observations of
importance were noted. Both the absolute and relative hepatic weights in
the high exposure animals were increased. Microscopic findings related
to test material exposure were hepatocellular vacuolization of mild
severity in the livers of the high level males and centrilobular
hepatocellular hypertrophy of mild severity in the livers of the high
The "no-effect" level reported in the study is 100 mg/m3. However, based
on the observed effects at this dose that cannot be neglected, this dose
level should be considered as the LOAEC instead of the "no-effect" level.
The test substance was applied to the shaved backs of 4 female and 4
male rabbits at dosage levels of 10, 100 and 1000 mg/kg/d, 5 days a week
for 3 weeks. The 2 control groups, each composed of 4 male and 4 female
rabbits, received distilled water at a dosage level of 2 mL/kg/d on the
same regimen as the treated rabbits. The rabbits were observed daily.
Individual body weights were recorded weekly. Hematological and
biochemical studies and urinalysis were conducted once in the pretest
period and at 3 weeks of study. At necropsy the cholinesterase activitiy
of the brain was determined for all rabbits.
One male rabbit was found dead on day 3, and one male rabbit was
sacrificed in extremis on day 12 of the study period. Each of these
rabbits were in the 100 mg/kg/d dose group. No changes considered to be
related to the compound were seen in general appearance, body weights,
hematological studies or urinalysis.
At each dosage level, the test substance elicited erythema, edema,
atonia, desquamation, coriaceousness and fissuring on all the rabbits.
For 3 or more rabbits at each dosage level the erythema became marked
and the edema became moderate. Blanching accompanied the erythema for 3
and 8 rabbits in the 10 and 1000 mg/kg/d dosage levels, respectively.
The coriaceousness remained slight at the 10 mg/kg/d dosage levels but
became moderate for 3 and 6 rabbits at the 100 and 1000 mg/kg/d dosage
levels, respectively. At each dosage level the atonia, desquamation and
fissuring became moderate for 1or more rabbits. The number of rabbits on
which these signs of dermal irritation were noted increased with the
For both male and female treated rabbits the mean cholinesterase
activity of the plasma was, with the exception of the 100 mg/kg/d
females in control period, less than that of the control group at the
initiation as well as termination of the study. The differences between
the mean cholinesterase activitiy for the brain of the female rabbits
treated at the 1000 mg/kg/d dosage level and Control group II was
statistically significant. These differences may be biologically
significant, however, no physiological signs of decreased cholinesterase
activity were observed.
All rabbits which were sacrificed at termination or which died during
the study period were necropsied. All rabbits from the 3 experimental
groups had compound-related changes in the skin of the application
sites. Thinkening and fissuring were the most comonly observed lesions.
Other compound-related findings included scabbing, crusting, erythema
Microscopically, compound-related lesions were limited to the skin of
the application site where most rabbits from the 3 experimental groups
had acanthosis and hyperkeratosis. Most rabbits from the 100 and 1000
mg/kg/d groups had dermal edema. Accumulation of necrotic debris was
observed in several rabbits from each experimental group. Parakeratosis,
ulceration and vesicle formation occurred in occasional rabbits from one
or more experimental groups. Increased incidence of lymphoid hyperplasia
in the regional lymph nodes in the 3 experimental groups and
reticuloendothelial hyperplasia of the regional lymph nodes in 2 rabbits
from the 1000 mg/kg/d group were also considered compound-related.
Oral repeated dose toxicity was evaluated in 3 study reports
(Snyder, 1986 (key study); Jessup, 1980 (supporting study); Jessup, 1983
(supporting study)). All three study reports were 90-day repeated dose
In the key study (Snyder, 1986), the test compound was
administered in the diet of Sprague-Dawley rats at dose levels of5, 50
and 250 mg/kg bw/day. Treatment-related effects on body weights, food
consumption, clinical pathology, organ weights and histopathology
results were seen in males and females exposed at 250 mg/kg bw/day.
Treatment-effects on body weights, food consumption, clinical pathology
results (females) and histopathology results (males) were observed at 50
mg/kg bw/day. There were no treatment related effects at 5 mg/kgbw/day.
In the oldest supporting study (Jessup, 1980), the test compound
was administered in the diet of rats at dose levels of 50, 150 and 500
mg/kg bw/day. Kidneys, livers, ovaries and urinary bladders developed
lesions in response to compound administration. The kidneys were the
only organs affected at the 50 mg/kg bw/day level with the presence of a
yellowish-brown pigment in the epithelium of the renal tubules. This
compound-induced change at the lowest dose level precludes the
establishment of a NOAEL for DBPP in this study.
In the other supporting study (Jessup, 1983), rats were fed with a
control and with a dosage level of 5 mg/kg bw/day. The test substance
was fed in the diet and the concentration was adjusted weekly based upon
the most recent body weights and food consumption values. Observations
addressed clinical signs and mortality, body weights and weight gain,
food consumption and compound intake, haematology and clinical
chemistry, gross pathology and histopathology. There were no significant
findings in any of the criteria evaluated for treatment with the test
compound and as a consequence the dose level of 5 mg/kg bw/day is equal
to the NOAEL.
The results of the abovementioned studies are consistent with each
other. We conclude a NOAEL of 5 mg/kg bw/day for oral repeated dose
For repeated-dose toxicity via the inhalation route, read-across
to Skydrol 500B-4 (for details on composition see tabel in section 1.1
of the CSR) was applied.
Four groups of 25 male and 25 female Sprague-Dawley rats per group
were exposed to mean analytical concentrations of 0, 5.3, 100 or 300 mg/m3.
15 animals of each group were exposed for 3 months, the other 10 animals
for approximately 6 weeks. Red/pink nasal discharge and
salivation were notable observations in the mid and high exposure level
animals. Moderate decreases in plasma cholinesterase levels in the
high level females were considered test exposure related. All other
changes in chemistry parameters were slight and/or sporadic and no
correlation to test material exposure could be made. Both the absolute
and relative hepatic weights in the high exposure animals were
increased. Microscopically hepatocellular vacuolization of mild
severity was present either randomly or in centrilobular regions in the
livers of males (10/15, 5/15, 1/15 and 0/15 affected in high, mid, low
and control groups, respectively).Centrilobular hepatocellular
hypertrophy of mild severity was observed in the high level females.
The “no-effect” level reported in the study is 100 mg/m3.
However, based on the observed effects at this dose that cannot be
neglected, this dose level should be considered as the LOAEC instead of
the no-effect level. Consequently the NOAEC is 5.3 mg/m3.
Dermal repeated dose toxicity was evaluated in one study
DBPP was applied to the shaved backs of four male and four female
New Zealand White rabbits at dosage levels of 10, 100 and 1000 mg/kg
bw/day, 5 days a week for 3 weeks. The back (approximately 10% of the
body surface) of each rabbit was clipped as necessary during the study
and the skin of 2 rabbits of each sex group was abraded twice weekly by
producing a shallow incision (not sufficiently deep to cause bleeding)
by a scalpel blade.
At each dose level, the test compound elicited erythema, edema,
atonia, desquamation, coriaceousness and fissuring on all the rabbits.
For both the male and female rabbits treated at the 1000 mg/kg bw/day
level, the mean cholinesterase activity of the plasma was statistically
significant lower than that of either control group. These differences
may be biologically significant, however, no physiological signs of
decreased cholinesterase activity were observed. Increased incidence of
lymphoid hyperplasia in the regional lymph nodes in the 3 experimental
groups and reticuloendothelial hyperplasia of the regional lymph nodes
in 2 rabbits from the 1000 mg/kg bw/day group also were considered
compound-related. The observed effects in the lymph nodes are considered
A local NOAEL could not be derived due to the harmful effects of
the test substance on the skin at all test concentrations. The systemic
NOAEL was 100 mg/kg bw/day.
Repeated dose toxicity: oral
Of the concentrations tested in the evaluated study reports for
oral repeated dose toxicity, 50 mg/kg bw/day is the only dose with
treatment-related effects that fits in the guidance value range for a
STOT Category 2 classification (CLP Annex I, Table 3.9.3).
In the key study (Snyder, 1986), 50 mg/kg bw/day causes treatment
related effects on body weights and food consumption in males, clinical
pathology result in females (plasma cholinesterase) and histopathology
results in males (epithelial hyperplasia and submucosal inflammation in
the urinary bladder).
Small changes in body weight gain and food consumption do not
justify classification. It is possible that DBPP influences the
palatability of the feed. The other significant effects occurred only in
males or females.
In the oldest supporting study (Jessup, 1980), there was a
presence of a yellowish-brown pigment in the epithelium of the renal
tubules at the 50 mg/kg bw/day. But there was a decrease of incidence
with this pigment with increasing dosage and it did not occur in the
females at this dosage level.
We conclude that we cannot ascribe effects to a dose level of 50
mg/kg bw/day that support a classification for specific target organ
toxicity following repeated exposure for DBPP via the oral route.
Repeated dose toxicity: inhalation
Adverse effects in the 90-day inhalation repeated dose study were
observed at concentrations of 100 and 300 mg/m3/6 h/day (=
respectively 0.1 and 0.3 mg/L/6 h/day).
According to the CLP Regulation (Annex I, Table 3.9.3),
significant observed toxic effects between 0.02 and 0.2 mg/L/6 h/day
(mist) result in a STOT RE Cat. 2 classification.
The adverse effects observed at 100 mg/m3/6 h/day were
red/pink nasal discharge, salivation and microscopically hepatocellular
vacuolization of mild severity in males only. Since these effects do not
indicate significant toxicity, the test substance is not classified as
STOT RE via the inhalation route.
Repeated dose toxicity: dermal
In the dermal repeated dose study, 1000 mg/kg bw/day was the
lowest concentration at which a systemic adverse effect was observed.
The observed effect at this dose was a statistically significant
decrease in the mean cholinesterase activity. This effect can be
biologically significant but no physiological signs of decreased
cholinesterase activity were observed.
Regarding the high dose level that is required to result in the
decreased cholinesterase activity and the absence of physiological
signs, this substance will not be classified for specific target organ
toxicity STOT RE via the dermal route.
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