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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: older study; not conducted in accordance with GLP guidelines
Qualifier:
no guideline followed
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Rats were given a total of 11 treatments over a 15-day span
Frequency of treatment:
once daily
Remarks:
Doses / Concentrations:
100 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
Groups of five male rats were gavaged with 1000 or 100 mg compound/kg/day for a total of eleven treatments over a 15 day span. A control group of five animals were gavaged with distilled water at a dose of 1000 mg/kg/day. Weight gain and feed intake were comparable between groups.
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
Weight gain and feed intake were measured at the beginning and end of the study period
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
a single high-dose animal exhibited porphyrin nasal discharge, weight loss and possible aspiration pneumonia
Mortality:
mortality observed, treatment-related
Description (incidence):
a single high-dose animal exhibited porphyrin nasal discharge, weight loss and possible aspiration pneumonia
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
statistically-significant differences were noted in the high-dose group, including increased platelets and monocytes. All other indices were comparable to controls
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
A moderate decrease in serum glucose and a slight increase in creatinine in the high-dose animals; all other serum chemistry indices were comparable to controls
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
A statistically-significant increase in relative liver weights were observed in the high-dose group
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Enlarged hearts were observed in 3 of 5 rats in the high-dose group, which was considered to have occurred as a result of general respiratory stress associated with extensive consolidation of the lung
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Weight gain and feed intake were comparable between groups. No abnormal clinical signs were observed with the exception of a single high-dose animal which exhibited porphyrin nasal discharge, weight loss, and possible aspiration pneumonia. Several slight but statistically significant differences were noted in hematology in the high dosed group at autopsy. These included a slight increase in platelets and an increased percentage of monocytes. Both increases were dosage related. All other hematological parameters (red blood cell count, hemoglobin concentration, hematocrit, red cell indices, white blood cell counts and the remaining portions of the differential white blood cell count) were comparable to controls. There was a moderate decrease in serum glucose and a slight increase in creatinine in the high dosed animals, but all other serum clinical chemistries (alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, and urea nitrogen) were unaffected by treatment. No alterations in hematology or serum clinical chemistry were noted in blood from the low dose group.

No significant changes in absolute or relative kidney or spleen weights were noted. There was, however, a trend which implied a dose dependent increase in both absolute and relative liver weights. The relative liver weights were statistically significantly increased in the high dose group. Gross pathology examination revealed enlarged hearts in 3/5 high dosed animals but no compound related effects were seen at histopathology examination. The enlarged hearts were observed in animals exhibiting extensive consolidation of the lung. The hearts in these animals may have hypertrophied in response to general respiratory stress resulting from compromise of the lung. The liver may be a site of toxic action, and the no effect level may be in the range of 100 mg/kg.
Key result
Dose descriptor:
NOEL
Effect level:
ca. 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
Remarks on result:
not determinable due to absence of adverse toxic effects
Conclusions:
Based upon the results of this study, daily doses of 1000 mg/kg of p-diisopropylbenzene administered via gavage to male rats daily over a 2-week period produced increased relative liver weights and incidental findings in serum chemistry (decreased glucose; increased creatinine) and hematology (increased platelets and % moncytes) but no abnormal histopathological findings. A daily dose of 100 mg/kg was considered to be a no effect level (NOEL).
Executive summary:

The test article, p-diisopropylbenzene, was evaluated in a 2-week (subacute) oral toxicity study. Groups of five male rats were gavaged with 1000 or 100 mg compound/ kg/day for a total of eleven treatments over a 15 day span. A control group of five animals were gavaged with distilled water at a dose of 1000 mg/kg/day. Weight gain and feed intake were comparable between groups. No abnormal clinical signs were observed with the exception of a single high-dose animal which exhibited porphyrin nasal discharge, weight loss, and possible aspiration pneumonia. Several slight but statistically significant differences were noted in hematology in the high dosed group at autopsy. These included a slight increase in platelets and an increased percentage of monocytes. Both increases were dosage related. All other hematological parameters (red blood cell count, hemoglobin concentration, hematocrit, red cell indices, white blood cell counts and the remaining portions of the differential white blood cell count) were comparable to controls. There was a moderate decrease in serum glucose and a slight increase in creatinine in the high dosed animals, but all other serum clinical chemistries (alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, and urea nitrogen) were unaffected by treatment. No alterations in hematology or serum clinical chemistry were noted in blood from the low dose group.

No significant changes in absolute or relative kidney or spleen weights were noted. There was, however, a trend which implied a dose dependent increase in both absolute and relative liver weights. The relative liver weights were statistically significantly increased in the high dose group. Gross pathology examination revealed enlarged hearts in 3/5 high dosed animals but no compound related effects were seen at histopathology examination. The enlarged hearts were observed in animals exhibiting extensive consolidation of the lung. The hearts in these animals may have hypertrophied in response to general respiratory stress resulting from compromise of the lung. The liver may be a site of toxic action, and the no effect level (NOEL) may be in the range of 100 mg/kg.

Additional information

Justification for classification or non-classification