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Administrative data

Description of key information

Repeated dose toxicity, 90-days, oral (feed), dog (Beagle): 
Dosage: 8.5, 24.7, 84.1 mg/kg bw/day for males and 9.2, 28.3, 90.2 mg/kg bw/day for females. NOAEL of 84.1 (males) and 90.2 mg/kg bw/day (females) was deduced. No treatment-related effects have been observed.
Repeated dose toxicity, 90-days, oral (feed), rat (Sprague-Dawley):
Dosage: 40, 122, 376 mg/kg bw/day for males and 48, 136, 420 mg/kg bw/day for females. NOEL of 122 (males) and 136 mg/kg bw/day (females) was deduced. Slight impairment of growth during the first 6 weeks of treatment, lower efficiency of food utilisation and elevated SAP levels among males were reported.
Repeated dose toxicity, 28-days, oral (gavage), rat (Sprague-Dawley):
Dosage: 100, 300, and 1000 mg/kg bw. NOEL of 100 mg/kg bw/day was deduced. The liver was identified as target organ, because the organ weight increased at 1000 and 300 mg/kg.

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
84.1 mg/kg bw/day
Study duration:
subchronic
Species:
dog

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

Three studies are available where the repeated administration of the test substance was investigated.

In the key study (LSR, 1990) six Beagle dogs per sex were dosed daily with 200, 600, and 2000 ppm test substance (nominal concentration in food) for 13 weeks. Actual doses were 8.5, 24.7, 84.1 mg/kg bw/day for males and 9.2, 28.3, 90.2 mg/kg bw/day for females. No mortalities occurred and treated and control dogs remained similar in all aspects of behaviour and appearance. No treatment-related findings were reported for body-weights, food consumption or blood and urine parameters. After pathology unilateral cryptorchidism was present in two animals in the high dose group. This finding confirmed similar observations recorded during physical observation before the commencement of treatment. Due to the observed cryptorchidism, both dogs had a unilateral juvenile epididymis and testis. In one of these dogs, the epididymis was also found to be small. In addition, a small number of other changes was present and all are considered incidental and those commonly found in dogs. Comparison of organ weights, expressed either in absolute or bodyweight-relative terms, gave no indication of any differences attributable to test substance administration. After histopathology no changes were detected that could be related to treatment with the test substance. There was a range of banal degenerative and inflammatory lesions present, similar in type and incidence to those considered usual in beagle dogs of this age. In conclusion, no treatment-related adverse effects have been observed, thus a NOAEL of 84.1 (males) and 90.2 mg/kg bw/day (females), respectively, was derived, which was the highest concentration tested.

In the second key study a total of 180 Sprague-Dawley rats of the CD strain (20 males and 20 females per dose group with a 4-weeks recovery group of 5 males and 5 females in the control and high dose group) were fed with a diet for 13 weeks containing 0, 700, 2'000 and 6'000 ppm of the test substance in the feed (Huntingdon, 1979). No mortality occurred throughout the whole study period. Evidence of reduced grooming activity among the majority of males and females in the high dose group during the second half of the treatment period, and to some extent during the withdrawal period was observed. The growth of males and females of the high dose group was impaired during the first six weeks, but was similar to that of the controls thereafter. Associated in part with the lower growth rate was a lower efficiency of food utilization, recorded among males and females of the high dose group during the first six weeks. An increased number of neutrophils was recorded in males and females of the high dose group at week 4, but not at weeks 12 or 17 (4th week of withdrawal). Elevated serum alkaline phosphatase levels were recorded among males of the high dose group at weeks 4 and 12, but not during recovery period. No organ weight changes considered to be related to treatment were seen at the 13 or 17 week examinations. No macroscopic lesions attributable to treatment with the test substance were recorded at the end of the treatment or withdrawal period, and no treatment-related changes were seen in the sections examined histopathologically. Based on the data recorded an NOEL was derived at the dietary level of 2000 ppm in feed, equivalent to a calculated average intake of 122 mg/kg/day for males and 136 mg/kg/day for females.

Additionally, a subacute oral 28-day study with Sprague-Dawley rats was performed. The animals were dosed daily by gavage with 100, 300, and 1000 mg/kg bw (Huntingdon, 1977). No mortality was observed at any dose level. Higher liver weights were recorded for males and females of the high dose group. Histological examination revealed a minimal increase in cytoplasmic basophilia of periportal hepatocytes in 3 males. Minimal enlargement of centrilobular and mid-zonal hepatocytes was seen in 2 males. Macroscopic examination after 4 weeks of treatment revealed thickening of the nonglandular region of the stomach in 5 males and 1 female of the high dose group. Histological examination revealed minimal hyperplasia of the squamous epithelium of the non-glandular region in 6 males and 1 female. Caecal enlargement not associated with any morphological change was seen in 4 males and 3 females. All of these findings were reversible. The effects observed in stomach and caecum were also reported in the mid dose group (300 mg/kg), however in less animals. Based on the results of this study, a NOEL of 100 mg/kg body weight was derived for the test substance when administered to rats for 28 consecutive days.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
similar to guideline

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

-No classification required for repeated dose toxicity.

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008:

- No classification required for specific target organ toxicity after repeated exposure through oral route.