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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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.

Data source

Reference
Reference Type:
other: Body responsible for the test
Title:
Unnamed
Year:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 424 (Neurotoxicity Study in Rodents)
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
Aqueous solution of methylcellulose 0.5%.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
450 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 male and 5 females per doses
Control animals:
yes
Details on study design:
The doses were chosen on the basis of the results of a preliminary oral study carried out for 7 days in rats, in which the animals were treated with doses of 150, 450 and 1000 mg / kg / day.
Positive control:
None reported

Examinations

Observations and examinations performed and frequency:
Not reported
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight slowing of body weight gain is noted in males treated at a dose of 1000 mg / kg / day.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No toxicologically significant changes were noted for any of the parameters.
Blood biochemistry : Non-dose dependent increase in sodium and chlorine in males treated with 450 and 1000 mg/kg/day. Increased potassium in females at 1000 mg/kg/d
The toxicological significance of these minor abnormalities is questionable.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No significant difference was noted between control and treated animals.
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (nominal)
Based on:
other: nominal
Sex:
male/female
Remarks on result:
other: original NCD unit is mg/kg/day
Dose descriptor:
NOEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
other: nominal
Sex:
male/female
Remarks on result:
other: original NCD unit is mg/kg/day

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

The substance was clinically well-tolerated at all doses tested and no significant variation / observation was noted in organ weights and macroscopic examination.

Applicant's summary and conclusion

Conclusions:
No treatment related findings were observed at any of the nominal concentrations tested, except for a slight slowing of body weight gain noted in males treated at a dose of 1000 mg/kg/day. A non-treatment related finding of an increase in sodium and chlorine in males treated with 450 and 1000 mg/kg/day and increased potassium in females at 1000 mg/kg/d was also noted. Therefore, the substance was clinically well-tolerated at all doses tested and no significant variations or observations were noted in organ weights or macroscopic examinations. The NOAEL and NOEL were determined to be 450 and 150 mg/kg b.w./day, respectively.
Executive summary:

The test item was investigated for repeated dose oral toxicity to male and female Sprague Dawley rats at nominal concentrations of 150, 450 and 1000 mg/kg/b.w. day over 28 days with dosing 7 days / week. The study followed the standard guidelines OECD 424 and EU method B7. No treatment related findings were observed at any of the nominal concentrations tested, except for a slight slowing of body weight gain noted in males treated at a dose of 1000 mg/kg/day. A non-treatment related finding of an increase in sodium and chlorine in males treated with 450 and 1000 mg/kg/day and increased potassium in females at 1000 mg/kg/d was also noted. Therefore, the substance was clinically well-tolerated at all doses tested and no significant variations or observations were noted in organ weights or macroscopic examinations. The NOAEL and NOEL were determined to be 450 and 150 mg/kg b.w./day, respectively.

The study is a GLP compliant, guideline study and is suitable for assessment of this endpoint with restrictions.