Solsperse 22000-Wirksubstanz

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

other: Body responsible for the test

Title:

Unnamed

Year:

2000

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

EEC Directive 87/302/EEC, Annex V of the EEC Directive 67/548/EEC, Part B: Methods for determination of Toxivology "Sub-chronic Oral Toxicity Test: 90-days repeated oral doseusing rodent species". Official Journal of the European Communities No. L 133, May 1988.
OECD "Guidelines for Testing of Chemicals", Section 4, Health Effects, No. 408, "Repeated Dose 90-Day Oral ToxicityStudy in Rodents", Paris Cedex, September 1998.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Polyethylene glycol 400

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Test duration: 90 days

Frequency of treatment:

Dosing regimen: 7 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

low dose

Doses / concentrations 3

Dose / conc.:

200 mg/kg bw/day (nominal)

Remarks:

mid dose

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

high dose

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

From week 2 onwards, the majority of group (1000 mg/kg) males and females showed and increased incidence of slight to moderate post-dosing salivation.
In addition, an increased incidence of brown staining of the back and tail was exhibited by animals of high dose group. A higher incidence of salivation was also recorded for females of mid dose group (200mg/kg) particularly during weeks 5 to 10.
The remaining clinical signs recorded consisted of varying degrees of alopecia and skin lesions (scabs, wounds). These signs are commonly seen among gang housed rats dosed by oral gavage and were considered to be unrelated to the test article.
Staining (e.g. red/brown) of various parts of the body were common to some animals in most groups including the control group.
Other findings were only noted incidentally and at minimal severity without a relationship with treatment with the test compound.

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 specified

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

no effects observed

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Higher absolute and relative adrenal weights were recorded for males and females of group 4 (1000 mg/kg) of which the difference from control values attained a level of statistical significance for the females.

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Treatment associated alterations were present in the adrenal glands and mesenteric lymph nodes.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

2

Key result

Dose descriptor:

NOEL

Effect level:

50 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Key result

Critical effects observed:

not specified

Lowest effective dose / conc.:

1 000 mg/kg bw/day (actual dose received)

System:

endocrine system

Organ:

adrenal glands

Applicant's summary and conclusion

Conclusions:

Classified as: Not classified

Executive summary:

The test substance was administered daily for at least 90 days by oral gavage to SPF-bred Wistar rats. One control group and three treated groups were used. each consististing of 10 males and 10 females. The following parameters were evaluated: Clinical signs, functional observations, body weight, food consumption and opthalmoscopy. Urine and faeces samples were collected in week 13 for possible future analysis. At termination: clinical pathology, macroscopy and organ weights. Histopathology was performed on a selection of tissues.

From the results presented in this report, a No Observed Effect Level (NOEL) of 50 mg/kg/day was established for males, whereas a NOEL could not be defined for females. However, since the findings in the adrenal cortex were also seen in one of the control females, the histiocytosis in the mesenteric lymph nodes was not accompanied by adverce tissue reaction and the post dosing salivation considered due to the bad taste of the substance a No Observed Adverse Effect Level (NOAEL) of 200 mg/kg/day may be considered for males and females.