Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: hydrolysis product
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
>99,5%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
90d
Frequency of treatment:
7/wk
No. of animals per sex per dose:
10 animals per sex and dose
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Chemical analyses

Stability of TS solutions over a period of 8 days was confirmed.Concentration control analyses yielded 92-105% of the nominal values.

1. Clinical observations

Mortality: one control male died on day 40; one low dose male was sacrificed moribund on d 86.

Clinical examinations: no finding observed that could be related to treatment.

Food and water intake: unaffected except from a transient statistical significantly reduced (-8%) food intake in low dose females on day 14. Not regarded as being substance-related.

Body weights: few statistical significant, but spontaneous body weight increases were noted in both sexes at various times during treatment. Regarded as spontaneous and not substance-related. The same applies to food efficiency. Ophthalmological examinations: no substance-related effects noted.

Functional observation battery, FOB: Deviations from "zero" was noted in all animal groups including control regarding home cage and open field observations, sensimotor tests and reflexes, and quantitative parameters pertaining to grip strength, landing foot-splay etc.. No dose-relation was noted and observations were equally distributed between control and treated groups. Therefore, no substance-related effect was observed.

Motor activity: no substance-related effect noted.

Estrous cycle determination: no substance-related effect noted.

2. Clinical pathology

Hematology revealed no substance-related effects.

Clinical chemistry: no treatment-related changes except decreased chloride and serum globulins in animals of both sexes at 180 mg/kg/d, and decreased protein and albumin values in high dose females.

Urinalysis: at the end of the study urine sediments of high dose animals revealed increased numbers of transitional epithelial cells in both sexes. Most of these cells were degenerated. No other treatment-related changes were noted. Sperm analysis: no treatment related changes noted at any dose level.

3. Pathology

Significant effects on absolute or relative organ weight changes were only noted in high dose animals at 180 mg/kg/d. Target organs were liver (relative weights +7.5% in males, +2.6% in females) and kidney (relative weight + 9.1% in males).

Only few scattered gross lesions were noted. No relation to treatment was seen.

Histopathology

Treatment related microscopic findings were noted in kidneys and liver. They consisted of a slight or moderate diffuse accumulation of a2µ-microglobulin (1/1/1/10) in the epithelia and lumina of the proximal tubules of the renal cortex, as shown by the widely used Mallory-Heidenhain staining. Specificity for a2µ-microglobulin could be demostrated by immunohistochemical staining. The microglobulin accumulation was not associated with any further alterations of the tubular epithelium. It was regarded as a substance-related effect in high dose males.

Minimal or slight centrolobular hypertrophy of liver cells was noted in males (0/0/0/9) and in females (0/0/0/2) which correlated with increased absolute (females) and relative (males and females) liver weights. No other histological or morphological effects in the liver were noted.

Applicant's summary and conclusion

Conclusions:
Imidazole was tested in a thorough 90-d study according to
OECD 408 including several functional tests (FOB, motor activity, ophthalmological examinations, sperm parameters).
Liver and kidney were identified as target organs. At the high dose (180 mg/kg/d) significant and substance-related
changes noted consisted of centrolobular liver cell hypertrophy in both sexes (9/10 males and 2/10 females); diffuse a2u-microglobulin accumulation in proximal tubules of the renal cortex in male rats; increased absolute (females) and relative (males and females) mean liver weight; increased absolute and relative mean kidney weight in male rats; and blood chemistry changes (decreases in serum protein and albumin in females, and in chloride and globulins in both sexes).
No other substance-related finding was noted. This includes the histopathological examination of reproductive organs of both sexes, and sperm parameters examined as an indicator of the integrity the male reproductive organs.
Since the substance-related findings described above were limited to the high dose group animals and absent in low dose and intermediate dose group animals, the no observed adverse effect level (NOAEL) for both sexes was 60 mg/kg/d in this study.