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Description of key information

Summary of repeated dose toxicity data

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Additional information

In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (Kubaszky, 2011), REACTIVE RED F08-0146 administered daily by oral gavage to Wistar rats did not result in test item related mortality or clinical adverse effects or changes in the body weight, food consumption, haematology, coagulation or urinalysis parameters at dose levels of 62.5, 250, or 1000 mg/kg bw/day during either the treatment or after a 14-day recovery period.

 

Administration of Reactive Red F08-0146 at 250 and 1000 mg/kg bw/day was associated with red-brown pigment depositions in the kidneys, luminal/adhered red foreign material and/or red pigment depositions in the stomach, small intestine, caecum colon and/or rectum observed microscopically, with a clear dose response in terms of severity and/or incidence. Cessation of treatment followed by observation/recovery period of 14 days resulted in regression for most of the changes in the stomach and intestine. However resolution of the microscopic alterations in the kidneys was not completed although a decrease of their severity from minimal to mild to predominantly minimal was detected. A few clinical chemistry parameters, considered possibly correlated with the REACTIVE RED F08-0146- related histopathological findings noted in the kidneys at 250 and 1000 mg/kg bw/day, showed statistically significant higher values compared to control, mainly in the Main High and/or Mid dose males. These variations included statistically higher up to 4% Na+ and Cl-, up to 22%, total protein, and up to 23% albumin, at 250 and 1000 mg/kg bw/day. In the females, the differences in these clinical chemistry parameters were minor, showing only a trend to similar variations and did not reach statistical significance.

 

During the treatment period, reddish discoloration of the faeces was noted in the High dose Main animals administered 1000 mg/kg bw/day REACTIVE RED F08-0146 from Day 1 onwards, one day after the onset of treatment on Day 0. Orange urine was noted at 1000 mg/kg bw/day. These changes were ascribed to elimination of REACTIVE RED F08-0146 or its metabolites through faeces (cage side observations) or urine (urine collection in metabolic cages) and an expected staining effect.

 

Under the conditions of this study, the no observed adverse effect level (NOAEL) for REACTIVE RED F08-0146 for parental/adult systemic toxicity is considered to be 62.5 mg/kg bw/day, based on the histopathological changes in the kidneys, stomach and/or intestines, possibly correlated with minor variations in the clinical chemistry and organ weights at 250 and 1000 mg/kg bw/day only. The histopathological changes in the kidneys, stomach and/or intestines are considered to be caused by adaptive changes in order to absorb, catabolise and eliminate the dye substance.

Justification for classification or non-classification

The above study has been ranked reliability 1 according to the Klimisch et al system. This ranking was deemed appropriate because the study was conducted to GLP and in compliance with agreed protocols. Sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds.

The above results triggered no classification under the Dangerous Substance Directive (67/548/EEC) and the CLP Regulation (EC No 1272/2008). No classification for prolonged effects is therefore required.

The histopathological changes in the kidneys, stomach and/or intestines are considered to be caused by adaptive changes in order to absorb, catabolise and eliminate the dye substance. No classification for prolonged effects is therefore required.