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Administrative data

Description of key information

28-day study: oral NOAEL = 150 mg/kg bw/day (RCC, 2003)

Key value for chemical safety assessment

Additional information

In this subacute toxicity study, the test substance was administered daily by oral gavage to SPFbred Wistar rats of both sexes at dose levels of 50, 150 and 500 mg/kg body weight/day for a period of 28 days according to OECD 407 guideline and GLP (RCC, 2003). A control group was treated similarfy with the vehicle, PEG 300, only.

The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 500 mg/kg/day. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed.

Clinical signs, outside cage observation, food consumption and body weights were recorded penodically during pretest, the treatment and recovery periods. Functional observational battery, locomotor activity and grip strength were performed during week 4.

At the end of the dosing and the treatment-free recovery penod, blood samples were withdrawn for hematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals.

Because of possible test item-related findings noted in the animals treated with the test substance, the

kidney, stomach, and liver were evaluated in the animals of groups 2 and 3 to establish a no-observed-adverse-effect-level (NOAEL).

MORTALITY / VIABILITY

All animals survived until scheduled necropsy.

CLINICAL SIGNS

No test item related clinical signs were noted in males or females daily or weekly (weeks 1 -3).

FUNCTIONAL OBSERVATIONAL BATTERY

No test item related clinical signs were noted in males or females (week 4).

Grip Strength

No test item related differences were seen in mean fore- or hindlimb grip strength.

Locomotor Activity

No test item related differences were seen in mean locomotor activity:

FOOD CONSUMPTION

The mean daily and relative food consumption of test item treated animals were comparable with those of the control animals.

BODY WEIGHT

No test item related differences in mean body weights or mean body weight gain were observed when compared with controls.

CLINICAL LABORATORY INVESTIGATIONS

Hematology

No test item related differences in parameters of hematology were noted in animals after four or six weeks when compared with controls.

Clinical Biochemistry

No test item related differences in parameters of clinical biochemistry were noted in animals after four or six weeks when compared with controls.

Urinalysis

No test item related differences in parameters of urinalysis were noted in animals after four or six weeks when compared with controls.

ORGAN WEIGHTS

The mean liver weights, liver to body weight- and liver to brain weight-ratios were increased in females at 500 mg/kg/day when compared with controls after four weeks of treatment. The mean kidney to body weight ratio was increased in females at 500 mg/kg/day and the mean kidney to body weight- and kidney to brain weight ratios were increased in females at

150 mg/kg/day when compared with controls after four weeks of treatment. These findings were considered to be test item related because a dose response relationship could be observed and these findings compare well with the microscopic findings described

below. However, they were fully reversible after four weeks treatment followed by a two-week recovery period.

After four weeks of treatment followed by a two-week recovery penod the mean kidney weight and kidney to brain weight ratio were increased in males when compared witin controls. However no effects on absolute or relative kidney weights were observed in males treated at 500 mg/kg/day for four weeks.

No other test item-related changes in organ weights, organ to body- or organ to brain weight ratios were noted.

MACROSCOPIC / MICROSCOPIC FINDINGS

The following histopathological test item-related changes in rats administered the test substance were observed:

In the cortex of the kidneys an increased incidence and grade of basophilic tubuli in test itemtreated animals of group 4, especially in males of the recovery group was recorded. This finding may be a sign of an increased tubular regeneration after an preceeding tubular

damage. The change was still recorded after a 14-day treatment-free recovery penod, and was regarded as an adverse effect in group 4 animals (especially in males).

In the stomach a minimal to slight glandular ectasia was recorded. The slightly dilated crypts often were filled with mucus. Additionally a minimal to slight hyperkeratosis was recorded at the limiting ridge and/or the forestomach. The grades and incidences of both changes decreased to normal after the recovery period. These findings were regarded as adaptive effects.

The increased incidence of minimal to slight hepatocellular hypertrophy recorded in test itemtreated animals of group 4 of the main study decreased to normal incidences after the recovery period. This finding was not considered to be of adverse character, but was

deemed to be an adaptive effect.

Conclusion

Oral administration of the test substance to Wistar rats at doses of 50, 150 and 500 mg/kg/day, for 28 days resulted in no effects upon: Viability, food consumption, body weights, clinical signs (daily, weekly), functional observational battery (including grip strength and locomotor activity), hematology, clinical biochemistry or urinalysis.

In the cortex ofthe kidneys an increased incidence and grade of basophilic tubuli in test item treated animals of group 4, especially in males of the recovery group was recorded. This finding may be a sign of an increased tubular regeneration after an preceeding tubular damage. The change was still recorded after a 14-day treatment-free recovery period, and was regarded as an adverse effect in group 4 animals (especially in males). Based on the results of this study, 50 mg/kg body weight/day of the test substrance was established as the no-observed-effect-level (NOEL) for animals. As the no-observed-adverse-effect-level (NOAEL) 150 mg/kg body weight/day of the test substance could be established.

Justification for classification or non-classification

Based on the results of the 28 -day study, no classification and labeling according to DSD-DPD and CLP is required.