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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
March 1984 and February 1985
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Description of the method is not provided.

Data source

Reference
Reference Type:
publication
Title:
Peroxisome induction studies on seven phthalate esters
Author:
Barber E D
Year:
1987
Bibliographic source:
Toxicology and Industrial Health, vol. 3, nº 2:7-24

Materials and methods

Principles of method if other than guideline:
- Principle of test: DUP was tested for its ability to produce peroxisome proliferation in the Fischer 344 rat.
- Short description of test conditions: Samples were taken from the liver of sacrificed animals and prepared for both light and electron microscopy. No details of the test method were provided.
- Parameters analysed / observed: Serum samples were assayed for both triglyceride and cholesterol. The remaining portion of the liver was homogenized and assayed for cyanide-insensitive palmitoyl-CoA oxidation, lauric acid 11-hydroxylase and lauric acid 12-hydroxylase.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Diundecyl phthalate
EC Number:
222-884-9
EC Name:
Diundecyl phthalate
Cas Number:
3648-20-2
Molecular formula:
C30H50O4
IUPAC Name:
1,2-diundecyl benzene-1,2-dicarboxylate

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Once for the 21d treatment period
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
21 days
Frequency of treatment:
Continuously
Doses / concentrationsopen allclose all
Dose / conc.:
0 other: %
Remarks:
nominal in diet
Dose / conc.:
0.3 other: %
Remarks:
nominal in diet
Dose / conc.:
1.2 other: %
Remarks:
nominal in diet
Dose / conc.:
2.5 other: %
Remarks:
nominal in diet
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on previous studies with DEHP performed at BIBRA.
Positive control:
di(2-ethylhexyl)phthalate (DEHP) at dietary concentration of 1.2% was used as internal study control.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: Yes
- How many animals: all
- Parameters examined. serum triglycerides & total cholesterol
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Other examinations:
Biochemical analysis of the liver:
Transmission electron microscopy
Cyanide-insensitive palmitoyl-CoA oxidation was measured by the method of Gray et al. (1983). Lauric acid 11- and 12-hydroxylases were measured in washed microsomal preparations (Lake et al., 1984).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs attributed to treatment.
Mortality:
no mortality observed
Description (incidence):
No deaths occurred during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduction in body weight gains was observed compared to the controls.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Serum triglyceride & cholesterol levels in DUP treated male rats were lower than the controls.
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Liver weight (absolute & relative) in rats given DUP were significantly higher than those of controls.

Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Hepatic enzyme levels: There was a significant increase in cyanide insensitive palmitoyl-CoA oxidation and significant increases of lauric acid 11 and 12 hydroxylase activities.
Electron microscopy: there was a moderate increase in peroxisomes.

Effect levels

Key result
Dose descriptor:
NOAEL
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable

Target system / organ toxicity

Key result
Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The substance caused a moderate proliferation of peroxisomes in the liver of rats following repeated exposure over 21 days. This is in agreement with effects described with other phthalate esters.

Executive summary:

DUP was tested for its ability to produce peroxisome proliferation in Fischer 344 rats. DUP was administered in the diet of 5 females and 5 males per group for a period of 21 days at levels of 2.5%, 1.2% and 0.3%. DEHP at dose of 1.2% was used as a study control group as well as a negative (undosed) control group. The rats given DEHP responded as expected to a known peroxisome proliferator therefore the results obtained with DUP were regarded as valid. The electron microscopic examination of samples of liver from rats showed it to cause a moderate proliferation of peroxisomes. This was accompanied to various extents at all dose levels by, changes in other measurements that have been associated with peroxisome stimulation. These measurements were liver weight increases (absolute and relative to bodyweight), greater activities of palmitoyl CoA oxidation and lauric acid hydroxylation and, in males, lower concentrations of serum triglycerides and cholesterol.