reaction mass of: pentasodium bis[6-anilino-3,5'-disulfonatonaphthalene-2-azobenzene-1,2'-diolato]cobaltate(III);tetrasodium [6-anilino-3,5'-disulfonatonaphthalene-2-azobenzene-1,2'-diolato][6-anilino-5'-sulfamoyl-3-sulfonatonaphthalene-2-azobenzene-1,2'-diolato]cobaltate(III);trisodium bis[6-anilino-5'-sulfamoyl-3-sulfonatonaphthalene-2-azobenzene-1,2'-diolato]cobaltate(III)

Endpoint summary

Description of key information

NOAEL (oral, 28 d) = 200 mg/kg/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

System:

haematopoietic

Organ:

spleen

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

The repeated dose toxicity of the substance was evaluated in a subacute 28-day toxicity study, according to the OECD Guideline 407 (1995) and the method B.7 of the Directive 96/54/EC. The substance was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 50, 200 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, bidistilled water, only. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest, treatment and recovery periods. Functional observational battery, locomotor activity and grip strength were performed during week 4. At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for haematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals. From the animals of the low and middle dose groups, the spleen and bone marrow were examined to establish a no-effect level.

No mortality, no clinical signs of toxicological relevance during daily and weekly observations, no effects on functional observational battery (including locomotor activity and grip strength), and no effects on food consumption or body weight. Test item-related findings were generally restricted to changes in haematology parameters (indicative of compensated reticulocytosis) at 1000 mg/kg/day, changes in clinical biochemistry (indicative of changes in liver metabolism) at 1000 mg/kg/day, changes in urinalysis parameters (indicative of the renal pathway for elimination) at 1000 mg/kg/day, elevated spleen weights (females only) at 1000 mg/kg/day, macroscopic changes (mostly discoloration) in the digestive tract, kidney and mesenteric lymph nodes at 1000 mg/kg/day, microscopical findings in the bone marrow (fatty atrophy) at 1000 mg/kg/day, spleen (increased extramedullary hematopoietic activity) at 200 mg/kg/day (males only) and 1000 mg/kg/day (both sexes), and kidneys (tubular hyaline change in males and cytoplasmic inclusions in both sexes) at 1000 mg/kg/day.

NOAEL was considered to be 200 mg/kg b.w./day, as the changes seen at 200 mg/kg/day were noted in males only and reversible. Thus, the lowest dose inducing significant/severe target organ toxicity can be established to be 1000 mg/kg b.w./day.

Justification for classification or non-classification

According to the CLP Regulation (EC n. 1272/2008), classification in Category 1 for repeated dose toxicity applies to substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure. Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Classification in Category 2 applies to substances that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to be harmful to human health following repeated exposure. Substances are classified in Category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. If classification is based on results obtained from studies conducted in experimental animals, the dose/ concentration guidance values that classify refer to effects seen in a standard 90-day toxicity study conducted in rats. These guidance values are presented in the CLP Regulation (EC n. 1272/2008) in Annex I, Part 3, Table 3.9.2 for classification in Category 1 and in Annex I, Part 3, Table 3.9.3 for classification in Category 2.

For a 28-day study the guidance values is increased by a factor of three: classification in category 1 applies when toxicity by oral route is seen at concentrations below 30 mg/kg/d, while category 2 applies for toxicity at doses between 30 and 300 mg/kg/d.

Based on the results of Repeated Dose 28-Day Oral Toxicity Study OECD 407, the lowest dose of the substance inducing significant/severe target organ toxicity can be established to be 1000 mg/kg b.w./day. Thus, no classification for repeated dose toxicity is warranted under the CLP Regulation (EC n. 1272/2008).