Octasodium 2-(8-(4-chloro-6-(3-((4-chloro-6-(3,6-disulfonato-2-(1,5-disulfonatonaphthalen-2-ylazo)-1-hydroxynaphthalen-8-ylamino)-1,3,5-triazin-2-yl)aminomethyl)phenylamino)-1,3,5-triazin-2-ylamino)-3,6-disulfonato-1-hydroxynaphthalen-2-ylazo)naphthalene-1,5-disulfonate

Endpoint summary

Description of key information

Summary of repeat-dose data

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Two studies of repeat dose exposure were conducted to assess the effects of the substance over prolonged exposure. The results were as follows:

 

Sub-acute 28-day study.

 

There were no treatment-related deaths or toxicologically significant effects on clinical condition, or food consumption.  There were no treatment-related effects on bodyweight during weeks 1 to 4 of treatment. However, during the recovery period, group mean bodyweight for animals from a l000mg/kg/day group was slightly, but not statistically significantly, lower than that of the concurrent controls.  Slight reductions in mean haemoglobin, haematocrit and red cell count were noted for females at 1000 mg/kg/day at terminal and recovery kill.  Mean plasma alanine transaminase and/or alkaline phosphatase activities were also reduced for males and/or females at 250 and/or 1000 mg/kg/day at terminal kill, only.

 

Higher group mean kidney weights were noted for males and/or females at 250 and/or 1000mg/kg/day at terminal kill and for females, only, from the 1000mg/kg/day group at recovery kill.  Kidney weights for two males from the l000 mg/kg/day group were also higher at recovery kill.  Higher group mean liver weights far males from the 1000 mg/kg/day group were also apparent at recovery kill, only increased hyaline droplet formation in the proximal tubules of the kidneys of all males at 1000mg/kg/day, and a dose-related degeneration of the proximal tubules of all females at 250 or 1000mg/kg/day, was noted at terminal kill.  At recovery kill, proximal tubule degeneration, similar to that seen for females at l000 mg/kg/day at terminal kill, was present in males and females from the 1000 mg/kg/day group.

 

Other histopathological changes considered to be related to treatment included minimal or slight mononuclear cell infiltration of the periportal areas of the liver from animals receiving 1000 mg/kg/day, at both terminal and recovery kills.

 

Widespread pink/purple staining of tissues and colouration of plasma, urine and/or faeces was seen for animals receiving 250 and/or 1000mg/kg/day throughout the dosing and/or recovery periods and was considered to be due to the highly coloured nature of the test material and not due to any histopathological change.

 

The no-observable effect level following daily oral administration to male and female rats for 28 days, is 50mg/kg/day.

 

 

Sub-chronic 90-day study

 

The oral administration of the test compound led to dose-dependent signs of toxicity. Main target organ was the kidney. Toxicity was further characterized by hypoplastic anemia with corroborating histopathological findings in spleen and bone marrow. Furthermore, as a consequence of severe systemic toxicity, also liver, ovaries, adrenal cortex, and serous coats were affected. By contrast, the discoloration of urine, feces, and/or skin was related to the tinctorial properties of the test substance (dye-stuff), but does not represent a toxicologically relevant finding

 

The slight changes in kidney pathology and/or urinalysis of individual low dose females can be interpreted as remnants of transient tubular degeneration. The slight decrease in hematocrit in females of this dose level is assessed as being a mild adverse effect, only due to the lack of a histopathological correlate or other concomitant changes in red blood cells.

 

The no observed adverse effect level (NOAEL) under the conditions of this study was 50 mg/kg bw/day in males, but below 50 mg/kg bw/day in females

 

It is considered that the substance is unlikely to be inhaled and the physicochemical and toxicological properties suggest low potential for significant rate of absorption through the skin. Hence evaluation of exposure via these routes is not applicable, given the use category of the substance.

The following information is taken into account for any hazard / risk assessment:

Assessment of repeated dose exposure by oral route is discussed below.

Value used for CSA (route: oral):

NOEL: ≤ 50 mg/kg bw/day (subacute; rat)

NOAEL: 50 mg/kg bw/day (subacute; rat)

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

Justification for classification or non-classification

The above studies have both been ranked reliability 1 according to the Klimish et al system. This ranking was deemed appropriate because the studies were conducted to GLP an 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. As the effects noted are at higher dose levels and a number are considered adaptive rather than toxicological, no classification is proposed.

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.