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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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP compliant, comparable to guideline study with acceptable restrictions.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): TAME
- Physical state: clear colourless non-viscous liquid
- Analytical purity: 94.5% by gas chromatography (CG-FID)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at start of study: 6-8 weeks
- Weight at study initiation: 200-250 gram (males); 150-200 gram (females)
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
dosage by gavage at a dose volume of 2 ml/kg
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
29 days
Frequency of treatment:
once per day, 7 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.125, 0.5, 1.0 g/kg bw/day
Basis:

No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
Rats were observed daily for clinical sings and body weight prior to the first dosing and weekly thereafter. Food consumption was measured weekly. Haematology and clinical chemistry parameters were determined from the blood sample collected at necropsy.
Sacrifice and pathology:
Organ weights were measured for the kidneys, adrenals, liver, testes and ovaries. These organs together wiht the heart and spleen from the control and high-dose group were microscopically examined and any tissues appearing abnormal (as well as these organs from animals that died during the study).
Statistics:
Data from the treated groups were compared to those of the control group using the following tests. Comparisons were limited to withinsex analysis. Bartlett's test of homogeneity of variance was used to determine if the groups had equivalent variance at the 1% level. If the variances were not statistically different, the groups were compated using a standard one-way analysis of variance. If significant differences among the means were indicated, Dunnett's test was used to determine which treatment groups differed from controls. Where groups did not have equivalent variance, the non-parametric Kruskall-Wallis test was used to assess differences in group means. If the means were different, Dunn's rank test was used to determine which treatment group differed from control.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
Four animals died in the high dose group. The deaths occurred between the days 6 and 9 and two of them were presumed test material related, although the precise cause of death was not identified.
The majority of animals did not exhibit unusual clinical signs during the experiment. Lung rales and anogenital staining was observed at low frequency in 1000 mg/kg animals.
Mean body weights were significantly lower in the 1000 mg/kg males on 7 (-14%), 21 (-18%) and 28 (-19%). Females had mean body weights comparable to controls. Food consumption was significantly lower in the 1000 mg/kg males and females during week 1 and also during week 2 in the 1000 mg/kg males.
A dose-related increase of relative (body) and absolute adrenal weight was noted and it was statistically significant in the 500 (mid) and the 1000 (high) mg/kg males. The following mean adrenal weights were measured (grams): ctrl: 0.057 ± 0.010, 125 mg/kg: 0.074 ± 0.015, 500 mg/kg: 0.082 ± 0.008*, 1000 mg/kg: 0.100 ± 0.010** (*p<0.05, **p < 0.01). The mid and high dose males also had increased relative kidney weights. The organ weight increases in the kidney and adrenals were not accompanied by any histopathological changes. The liver weights were not statistically significantly affected. Females displayed no statistically significant differences in any organ weights.
The high dose males had increased activated partial thromboblastin time and increased blood glucose but the biological significance of these findings was unknown.

Effect levels

Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: adrenal (absolute and relative) and kidney (relative) weight increase

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion