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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study. For justification of read across see endpoint summary.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD 416 (Two-generation reproduction toxicity study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
purity: 99.6 %

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses mentioned were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology, BASF Aktiengesellschaft, Germany. Analytical verifications of the stability of the test substance in doubly distilled water for a period of 8 days deep frozen at -20 0C were carried out before the study was initiated.
Duration of treatment / exposure:
F0: 20 weeks
F1: 19 weeks
Frequency of treatment:
once a day
Doses / concentrations
Remarks:
Doses / Concentrations:
0; 100; 300 and 1000 mg/kg body weight/day
Basis:
nominal in water
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
mortality; littering and lactation behavior; food consumption; body weight data

Results and discussion

Results of examinations

Details on results:
The clinical examinations of the F0 and F1 parental rats for general signs of toxicity revealed some substance-related effects at the high dose (1,000 mg/kg body weight/day). These were substantiated by unsteady gait and/or abdominal position, which occurred intermittently in several, but not all top dose rats shortly after gavage dosing and persisted only for some minutes. Moreover, all male and nearly all female F0 and F1 parental animals of the high dose group (1,000 mg/kg body weight/day) showed transient salivation during major parts of the treatment period. Salivation persisted in the respective animals only tor some minutes after daily gavage dosing. It is very likely, that the observed salivation was induced by bad taste of the test substance or local affection of the upper digestive tract. Salivation itself is not assessed as an adverse or toxic effect. There occurred no mortalities that could be causally related to the test substance. Food consumption and body weight data of the F0 and F1 parents, collected during premating, gestation, and/or lactation phases, were not influenced by the test substance administration.
Regarding pathology, kidneys, liver and/or thyroid glands proved to be the target organs in both genders of the two parental generations at the top dose (1,000 mg/kg body weight/day), and much less pronounced at the mid dose (300 mg/kg body weight/day). The absolute and relative kidney weights were statistically significantly increased in high dose F0 and F1 males and high dose F1 females. Histopathologically, high dose F0 and F1 males showed a slightly increased incidence of chronic progressive nephropathy with higher graded severity, when compared to controls. The increased kidney weights in high dose F0/F1 males are related to the increase of chronic nephropathy and thus are considered to demonstrate treatment-related, adverse effects. Furthermore, the increased kidney weights in high dose F1 females are also considered as substance-related. This weight increase had, however, no histopathological correlate and was therefore not considered as an adverse effect.
The mean liver weights were statistically significantly increased in high dose F0 males (relative) and in the top dose F1 males and F1 females (absolute and relative). The increased liver weights correlated with a minimal centrolobular hypertrophy of hepatocytes that was noted in seven high dose F1 males (controls: one F1 male). Although there was no histopathological correlate for the increased liver weights in F0 males and F1 females at 1,000 mg/kg, the increased liver weights of these rats are also considered as substance related.
For the increased mean relative liver weight in mid dose F1 males (300 mg/kg body weight/day), a substance-related effect cannot be ruled out with certainty.
However, the observed effects on the parental livers at 300 and 1,000 mg/kg body weight/day are considered to mirror an adaptive process and not an adverse effect.
The mean weights of the thyroid glands were statistically significantly increased in the top dose F0 and F1 males (relative), and in the mid and high dose F0 and F1 females (absolute and relative). For the increased thyroid weights a clear dose-response relationship was not present and there were no histopathological correlates. Therefore, it seems very unlikely, that the weight changes of the thyroid demonstrate an adverse effect.

Effect levels

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion