[No public or meaningful name is available]

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2008-01-07 till 2008-02-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline-conform study under GLP without deviations.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

96/54/EG, B.7

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Details on test material:

Batch number: FEB 279-810

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

rat, Hsd:Wistar rats (HsdRccHan : WIST)
Age at start of study 7-8 weeks

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Method of administration:
Gavage of a suspension, using a stomach tube

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Mean Recovery Rate of the Test Item Concentration in the Test Samples:
50 mg/5 mL: 105 % of nominal (n = 4; SD = 1 %)
150 mg/5 mL: 103 % of nominal (n = 4; SD = 3 %)
1000 mg/5 mL: 110 % of nominal (n = 4; SD = 17 %)

Duration of treatment / exposure:

Test duration: 28 days
In total 28 applications per animal were administered.

Frequency of treatment:

Once daily,
Dosing regime: 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 150, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Male: 5 animals at 50 mg/kg bw/day Male: 5 animals at 150 mg/kg bw/day Male: 5 animals at 1000 mg/kg bw/day Female: 5 animals at 50 mg/kg bw/day Female: 5 animals at 150 mg/kg bw/day Female: 5 animals at 1000 mg/kg bw/day

Control animals:

yes, concurrent vehicle

Details on study design:

The highest dose level was chosen with the aim of inducing toxic effects but not death or severe suffering. Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dosage related response and no-observed-adverse effects at the lowest dose level (NOAEL).

Positive control:

not applicable

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:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:
No mortality occurred during the study period.

There were no test substance-related clinical signs in any
dose group. Daily food consumption and body weight
development of the test animals were unaffected during
treatment period.

No test substance-related effects were detected during
functional and behavioral assessments, responses to reflex
testing, and sensory reactivity assessments.

Laboratory findings:
No test substance-related differences of toxicological
significance were noted in haematology, clinical
biochemistry and urinalysis parameters when compared with
the control values.

Effects in organs:
The assessment of organ weight revealed increased absolute
and relative kidney weights (not statistically significant)
in males treated at 1000 mg/kg bw/d. Significant deviations
were observed in the liver, adrenals and brain. These
changes were either noted within the ranges of historical
control data, were only observed in one sex, or resulted
from a divergent control value. In absence of a dose
response relationship or corroborative findings in
microscopy, clinical biochemistry or other evidence of
severe organ dysfunction, these findings were considered to
be of no toxicological significance. The mean relative
testes weight was significantly increased in males at 1000
mg/kg bw/d in comparison to controls, which was found
without further corroborating findings.

No relevant changes occurred upon necropsy.

Histopathology revealed test substance-related findings in
the kidneys in males and females at 1000 mg/kg bw/d. There
was a cortical and modularly tubulopathy with casts, being
more prominent in males. The lesion was characterized by
mulitfocal areas of basophilic/regenerating tubules, dilated
tubules with minor tubuloepithelial single cell necrosis and
presence of intraluminal granular casts. In addition in
males, there was a tendency towards the occurrence of more
mononuclear cell infiltrates.

Effect levels

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Considering the reported data of this toxicity study it can be stated, that the Medium Dose of 150 mg/kg BW is the no observed adverse effect dose level (NOAEL) of the test substance after a total of 28 applications by gavage in Corn oil over a period of 28 days.