Registration Dossier

Diss Factsheets

Administrative data

Description of key information

In a chronic dietary study in rats, the highest dose of 2000 ppm (ca 58 - 147 mg/kg bw)  caused no indication of toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
58 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A valid 90-day study in dogs is available. It was performed prior to the introduction of GLP but is reported in adequate detail. The design is sufficiently similar to the current OECD testing method. The test item was administered by incorporation into the diet to one group of 10 (5 per sex) and two groups of 8 (4 per sex) dogs for not less than 3 months. The nominal concentrations of the test item were 10000 (group 4), 3000 (group 3) and 1000 (group 2) ppm but analyses of diet samples showed that the mean concentrations throughout the study were 8092 (group 4), 2208 (group 3) and 719 (group 2) - equivalent to an average daily intake of 318, 80 and 28 mg/kg. A control group (5 per sex) received a similar diet without the addition of test material. There were no deaths during the study. Loose feces and diarrhea occurred occasionally in all groups (including controls) and appeared to be due to the diet, not the compound. Growth rates and food consumption were within normal limits in all groups. No effect in eye and hearing tests were noted. There were no relevant changes in laboratory parameters (hematology, clinical chemistry and urine analysis). Neither at autopsy nor on histopathological examination were any changes seen related to the administration of the test article. The "no effect" level was 8092 ppm equivalent to an average daily intake of 318 mg/kg body weight.

A 90-day gavage study was performed in rats. The study design is similar to guideline 408. The study has the following limitations: For clinical biochemistry urea, glucose, total serum protein, albumin, AG ratio, breakdown products of albumin, alpha1-, alpha2-, beta- and gamma-globulins, SAP, SGPT, sodium and potassium were determined. The organ weight of epididymides and thymus was not determined. Accuracy, stability, and homogeneity of the formulations was not checked, but the formulations were freshly prepared each day. No functional observations performed. The test item was administered orally by gavage to groups of 20 male and 20 female Sprague Dawley rats. Administration continued for 13 weeks, followed by a withdrawal period of 4 weeks (5 additional animals per sex in control and high dose groups). Dose levels were 0, 125, 250, 500 and 1000 mg/kg body weight. In the high dose group, higher kidney weights in females at the end of the 13 week treatment period and the 4 week withdrawal period were recorded. Histological examination revealed no treatment related change. The kidney weights of males were similar to those of the control. At 500 mg/kg body weight, higher kidney weights in females were recorded. It should be noted that in this group there is one outlier (determination based on outlier test by F.E. Grubbs, Annals of Mathematical Statistics 21, pp. 27-58). If this outlier is excluded, no statistically significant difference is found by the t-test (P >0.05). It is therefore concluded that this dose level may be regarded as the no effect level. The performance of rats treated at 125 and 250 mg/kg was similar to that of the controls. The increased kidney weights at the 1000 mg/kg level were unlikely to be of toxicological significance as they were not supported by histopathological changes. Overall, no significant toxicity was observed up to the highest dose group. Results are consistent with those of a 28-day study in rats.

The key study for hazard assessment is the chronic feeding study in rats. It was performed just prior to the introduction of GLP and OECD testing guidelines and is reported in adequate detail for hazard assessment. The study was performed with groups of 70 male and 70 female rats of the CD strain. The animals received diet containing the test item at concentrations of 0 (control), 250, 750 or 2000 ppm for two years. At termination of the treatment period, all surviving animals were killed and submitted to necropsy and histological evaluation. Mortality among females receiving 750 ppm was significantly higher (P < 0.05) than it was among control females. This difference arose during the terminal stages of the study and was considered fortuitous and unrelated to treatment. In comparison with control males, significantly fewer (P < 0.05) male rats receiving 2000 ppm bore subcutaneous masses. This was generally in agreement with the results of the microscopic examination conducted terminally. Food consumption of males receiving 2000 ppm was consistently slightly higher than that of the controls. Significantly increased bodyweight gain (P < 0.01) was recorded during the first year of treatment for females receiving 2000 ppm. During the first six months of treatment, slightly increased food utilisation efficiency was recorded for males receiving 2000 ppm and for all three treated female subgroups. Ophthalmoscopy, hematology, blood chemistry and urinalysis did not reveal any persistent differences between control and treated rats. Analysis of organ weights recorded for rats killed at termination of testing did not reveal any significant inter-group differences. The macroscopic and microscopic examination of the tissues revealed, in all groups, a range of morphologic change and neoplasms which were of a type and frequency commonly found in the CD rat. It was concluded that test material administered at dietary concentrations as high as 2000 ppm for a two year period, i.e. throughout most of the life-span of the CD rat was tolerated without adverse effect.

Justification for classification or non-classification

There are conclusive but not sufficient data for classification of the test substance with regard to repeated dose toxicity in accordance to the CLP Regulation (EC) No 1272/2008. The substance does not require classification and labelling for repeated dose toxicity.