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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 significance.
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 mg/kg level.
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 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.
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 dosage level.
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 and hemorrhage.
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 studies.
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 toxicity.
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 (Laveglia, 1986).
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 adaptive responses.
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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