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Description of key information

MTDID 25575 (trade name Clearlink 1000) caused urothelial hyperplasia of the urinary bladder at 1 mg/kg/day (males) and 3 mg/kg/day (females) in a 28-day repeated dose study by F.M. van Otterdijk et al. (2011). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 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.

The study by F.M. van Ottedijk (2012) is combined 28-day repeated dose toxicity with the reproduction/developmental toxicity screening test of MTDID 25575 (trade name Clearlink 1000) in rats by oral gavage followed by a 14- and 28 -day recovery period. The test substance was well tolerated by the animals during the treatment/post-coitum/lactation period, there were no in-life finding indicative of toxicity. Changes in haematology and biochemistry ocurred in males at 10 mg/kg. However, these changes had resolved during the 28 -day recovery period. There were morphological alterations in adrenal glands, kidneys (males only), liver, lungs, mesentric lymph node, prostate gland, skeletal muscle and urinary bladder. Most of the findings were recorded at minor degrees of severity and at incidences slightly above spontaneous background levels, and were essentially reversible within a 14- or 28 -day recovery period.

The skeletal muscle fibre degeneration in males and females at 10 mg/kg occurred in the absence of any supportive clinical signs or changes during functional observation tests or in motor activity, which indicates that the motor-function integrity of rats is not adversely affected. Also, this finding was fully reversible in males within 14 days following the last treatment, and was also seen in three male control animals. Therefore, this lesion was considered not to be adverse in nature within the context of this study.

The urothelial hyperplasia of the urinary bladder in group 3 (males) and 4 (males and femlaes) at the end of treatment and females) at the end of treatment and persisting until the end of the 28 -day treatment free recovery period was considered to be adverse in nature. However, according to expert judgement (Samuel M. Cohen, 2012) MTDID 25575 (trade name Clearlink1000) is a highly irritating chemical that produces urothelial toxicity when administered by oral gavage for twenty-eight days. Clearlink 1000 is non-DNA reactive and non-genotoxic in vivo and it is likely that the non-genotoxic mode of action involves cytotoxicity and regeneration secondary to excretion and concentration of the highly irritative chemical and/or metanoite in the urine. The urothelial hyperplasia is an adaptive response to this irritation. 

No reproduction or developmental toxicity was observed up tot he highest dose level tested (10 mg/kg).

Based on urothelialal hyperplasia of the urinary bladder,the NOAEL-value of 1 mg/kg/day (males) and 3 mg/kg/day (females) were derived. This study was selected as a key study, because of the lower NOAEL and higher reliability.

 


Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: urinary bladder

Justification for classification or non-classification

MTDID 25575 (trade name Clearlink 1000) caused urothelial hyperplasia of the urinary bladder at 1 mg/kg/day (males) and 3 mg/kg/day (females) in a 28-day repeated dose study by F. M. van Otterdijk et al. (2011). According to expet judgement (Samuel M.Cohen, 2012) the urothelial hyperplasia is an adaptive response to the irritative effects of Clearlink 1000. The mode of action involves cytotoxicity and regeneration secondary to excretion and concentration of the highly irritative chemical and/or metabolite in the urine.

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.