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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:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Alkenes, C6-11 (branched), hydroformylation products, distn. residues, heavy cracked fraction
Molecular formula:
CnH2n+2O2. n=24-33
IUPAC Name:
Alkenes, C6-11 (branched), hydroformylation products, distn. residues, heavy cracked fraction
Details on test material:
- Name of test material (as cited in study report): MRD-89-528
- Physical state: amber liquid
- Analytical purity: assumed 100%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: approximately 7 weeks
- Weight at study initiation: males (225 – 270), females (172 – 199)
- Housing: individually
- Diet (e.g. ad libitum): Purina certified rodent chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Amount of vehicle (if gavage): 2 ml/kg
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
once per day, seven days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.1, 0.5, 1 g/kg
Basis:
actual ingested
Control animals:
yes, concurrent vehicle

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily for signs of toxicity

BODY WEIGHT: Yes
- Time schedule for examinations: during the week prior to dosing, at dosing initiation, weekly thereafter, and at scheduled terminal sacrifice

FOOD CONSUMPTION:
- Monitored weekly

OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: survivors at terminal sacrifice
- Erythrocyte count, hematocrit, hemoglobin, leukocyte count, platelet count, prothrombin time, reticulocyte count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: survivors at terminal sacrifice
- Albumin, urea nitrogen, calcium, creatinine, electrolytes, gamma glutamyl transpeptidase, glucose, phosphorus, serum alanine aminotransferase, serum aspartate aminotransferase, total bilirubin, total protein.

OTHER:
Gross necropsy
Sacrifice and pathology:
GROSS PATHOLOGY: Adrenals, kidneys, ovaries, liver, heart, testis, spleen
Statistics:
Comparisons were limited to within sex analysis. Statistical evaluation of equality of means was done by an appropriate one way analysis of variance and a test for ordered response in the dose groups. First, Bartlett’s test was performed to determine if the dose groups have equal variance. If the variances are equal the testing was done using parametric methods, otherwise nonparametric techniques were employed.

For the parametric procedures, a standard one way ANOVE using the F distribution was used with Dunnett’s test to determine significance between groups. For the non-parametric data, the test of equality of means was performed using the Kruskal-Wallis test. If significant differences among the means were indicated, Dunn’s Summed Rank test was used to determine which treatment group differ significantly form controls.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
Mortality was limited to two animals and the result of dosing error. No adverse clinical signs were noted.

BODY WEIGHT AND WEIGHT GAIN
No significant differences.

FOOD CONSUMPTION AND COMPOUND INTAKE
No significant differences.

HAEMATOLOGY
A dose related increase in the mean prothrombin time was noted in female animals, but was not statistically significant.

CLINICAL CHEMISTRY
No significant effects

ORGAN WEIGHTS
A dose related increase in the female rat liver and mean relative liver weights, however there were no significant differences among the means.

GROSS PATHOLOGY
No significant effects

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

The objective of this study was to evaluate the effects of the registered substance when administered by the oral route. After a period of 28 days, toxicity was not apparent at even the highest dose level (1.0 g/kg) as indicated by the absence of treatment related mortality and clinical effects. Additionally, there were no statistically significant differences between the treated and control body weight or food consumption values. Analysis of the organ and relative organ weights did reveal a dose related increase in the mean liver and relative liver weights in the female rats, however these increases were not statistically significant. Hematology and serum chemistry analyses revealed minimal changes, none of which were considered biologically significant. Postmortem examination revealed no observable abnormalities in the majority of animals with no apparent trends within the treatment or control groups. Histopathological evaluation also revealed minimal findings, all of which were considered to be incidental and unrelated to treatment. Overall, all of the findings were slight and not considered indicative of a treatment related response.