5-amino-3-[[4-[[4-[[4-anilino-2-hydroxyphenyl]azo]phenyl]amino]-3-sulphophenyl]azo]-4-hydroxynaphthalene-2,7-disulphonic acid, sodium salt

Endpoint summary

Description of key information

NOAEL (subacute) (rat, male and female): 350 mg/kg bw/day, systemic toxicity

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

350 mg/kg bw/day

Study duration:

subacute

Species:

rat

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 following data was obtained for the Similar Substance 01. It is expected that the Target substance will present similar acute oral toxicity. Justification for the use of a read-across approach is provided in Section 13 of IUCLID.

The Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test was conducted to obtain information on the toxic potential of Similar Substance 01, following the testing method and testing procedures outlined into the OECD guideline 422. The substance was administered to rats orally (by gavage) once daily at 0 (vehicle only), 40, 120 and 350 mg/kg bw/day doses. The concentration of the test item in the dosing formulations was checked two times during the study and the concentrations varied within the range of 97 and 103 % in comparison to the nominal values. All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before the necropsy (altogether for 42 days). Females were additionally exposed through the gestation period and up to lactation days 14-16, i.e. up to the day before necropsy (altogether for 51-65 days). There was no test item related mortality at any dose level. One male animal at 350 mg/kg bw/day and one female animal at 120 mg/kg bw/day were found dead on Day 22 and on lactation day 10 (on Day 49), respectively. Based on clinical observation and necropsy findings, the cause of the death was independent from the test item. Clinical signs of systemic toxicity related to the test item were not detected at any dose level, neither at the daily nor at the detailed weekly clinical observations or at the functional observations. The body weight development was not adversely affected by the test item in male or in female animals, as well as the mean daily food consumption. A test item influence on the oestrous cycle was not found at any dose level and there were no toxicologically significant differences between the control and test item treated male or female animals in the examined parameters of reproductive performance or in the delivery parameters of dams. Haematological and clinical chemistry evaluations did not reveal adverse test item related changes in the examined parameters. There were no test item related changes in the serum thyroid hormone (T4 and TSH) levels at any dose (parental male or 13-day offspring). Macroscopic findings related to the effect of the test item were not found in male and female animals.

Black or grey coloured organs (spleen, submandibular or mesenteric lymph nodes) and presence of the test item or its metabolite(s) in the stomach and/or intestines were detected in male animals belonging to the groups dosed at 120 and 350 mg/kg bw/day at the terminal necropsy. In females, black or grey staining was observed mainly in mesenteric lymph nodes in several animals dosed at 120 mg/kg bw/day and in all animals dosed at 350 mg/kg bw/day; the kidneys staining was observed in 2/12 animals dosed at 350 mg/kg bw/day.

There were no test item related changes in the weights (absolute and relative to body or brain weights) of brain, testes and epididymides of male animals at any dose level. Non-statistically significant changes in spleen weights were observed in male animals at 40, 120 and 350 mg/kg bw/day and in female animals at 350 mg/kg bw/day; they were considered to be of little or no biological relevance. The examined organ weights of animals selected for toxicity examinations were comparable in the control and 40, 120 and 350 mg/kg bw/day groups at the end of the treatment period. Histopathological examinations revealed test item related minimal centrilobular vacuolation in the hepatocytes – sign of hepatic lipidosis – in male animals at 350 mg/kg bw/day. Hepatic lipidosis is considered as a slight reversible liver injury in connection with a disturbance of energy metabolism of affected hepatocytes. There were no histological patterns of hematopoietic (erythroid or myeloid) hyperplasia in the splenic tissues or in the livers of animals in accordance with organ weight changes.

Based on the new study outcomes, the dose level of 350 mg/kg bw/day can be considered as an appropriate No Observed Adverse Effect Level.

Justification for classification or non-classification

According to the CLP Regulation (EC) No 1272/2008, 3.9 Specific target organ toxicity - repeated exposure section, substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement, on the basis of the weight of all evidence available, including the use of recommended guidance values, which take into account the duration of exposure and the dose/concentration, which produced the effect(s), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed.

In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats. Nevertheless, they can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration (the assessment shall be done on a case-by-case basis). For example, for 28-day study the guidance values are increased by a factor of three, thus the limit for sub-acute studies should be 300 mg/kg bw/day.

Based on results obtained in the available subacute Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test performed on rats dosed by oral route, the substance does not produce significant effects up to the dosage of 350 mg/kg bw/day, which can be considered as the No Observed Adverse Effect Level.

In conclusion, the substance does not meet the criteria to be classified for specific target organ toxicity after repeated exposure, according to the CLP Regulation (EC) 1272/2008.