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Description of key information

NH-2 (trade name Clearlink 1000) caused vacuolative changes in various organs of rats at 10 mg/kg/day dose level in a 28-day repeated dose study by Keiji Shiraishi et al. (2002). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

Two studies have been conducted in order to evaluate repeated dose toxicity of Clearlink 1000. In the first study by Keiji Shiraishi et al. (2002) NH-2 (trade name Clearlink 1000) in olive oil was administered to male and female Crj:CD (SD) IGS rats by oral gavage with dose levels of 3, 10 and 30 mg/kg/day for 28-days.

No death occured during the study. No signs of test substance related toxicity were observed in autopsy or in urinanalysis. Body weight gain and food uptake were low in both sexes in the highest (30 mg/kg/day) dose level groups during the administration. Clinical signs (lowering of spontaneous motion, staining of nasal and peroral area, cyclopean eye and lacrimation in females, staining of lower abdomen and rough hair in males) were predominantly observed in the highest dose (30 mg/kg/day) group rats. Also increase in organ weights (relative weight of liver and kidneys, and absolute and relative weight of adrenals) were observed in the highest dose group (30 mg/kg/day) rats.Various hispopathological findings in several organs were reported, vacuolisation being the main effect.

Under the test conditions, the NOEL was indicated to be 3 mg/kg/day based on the presence of vacuolative changes in various organs of rats from the 10 mg/kg dose group. A review of the original study report was made at 2011 by George A. Parker. In the review summary report it is speculated that even the histopathological findings support the estimation of the NOEL, it should be noted that vacuolative changes of the type described in the report do not necessary indicate an adverse effect. Similar vacuolative changes have been observed in safety assessment studies of a number of marketed pharmaceutical products, and were determined to represent phospholipidosis. In addition, clinical pathology indications of hepatic injury were observed only in rats at the 30 mg/kg/day group. The absence of clinical pathology indications of hepatocellular injury in the 10 mg/kg/day group possibly indicates that the vacuolative changes were not adverse in that group. Based on this, the NOAEL is considered 10 mg/kg/day.

This study was selected as a key study since at the time of the submission of Clearlink 1000 dossier only draft report was available from the second study.

The study by F.M. van Ottedijk (2011) is combined 28-day repeated dose toxicity with the reproduction/developmental toxicity screening test. The data from this study will be included in the dossier once the final study report is available.

 


Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: lymph nodes; digestive: liver; respiratory: lung; urogenital: kidneys

Justification for classification or non-classification

Based on the study results of repeated exposure with rats (F.M. van Otterdijk et al., 2011) and according to Annex I of Regulation (EC) No 1272/2008 and Annex VI of Regulation 67/548/EEC no classification is required.

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