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Administrative data

Description of key information

Oral NOAEL: 542 mg/kg bw/day (chronic; rat)

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
542 mg/kg bw/day
Study duration:
chronic
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 substance under registration (CAS 13863-31-5) belongs to the category of Stilbene Fluorescent Whitening Agents. This substance and all other members of this category do not show acute toxic effects after oral, inhalation, and dermal administration. They are neither irritant to skin nor eyes, nor genotoxic in-vitro and in-vivo, nor sensitizing. In the 24 month chronic toxicity study in the rat, conducted on the acid form of the dihydroxyethylamino disulphonated derivative, no treatment-related clinical symptoms and no signs of systemic toxicity were observed throughout the study. Six over fourteen registered substances were tested for subchronic toxicity and four of them were tested for chronic toxicity up to two years with no relevant toxic effects.

Reliable data on repeated dose toxicity subacute and chronic after oral exposure of rats are available for CAS 16470-24-9 and CAS 4404-43, the tetrasulphonated sodium salt and disulphonic acid form, respectively and were taken as a reference.

In a subacute toxicity study (according to OECD 407, RCC - Research and Consulting Company AG. 1988), the test substance CAS 16470-24-9 was administered to Wistar rats by gavage at the dose levels of 0, 50, 200, and 1000 mg/kg bw/day for 28 days. No compound related effects were recorded in mortality, clinical signs, food consumption, and urinalysis. Statistically decreased body weights were observed in female animals dosed at 1000 mg/kg bw/day during the whole treatment period. In addition the body weight gain of the same animals was decreased between days 15 and 18 when the results were compared to those of the animals of the control group and the groups dosed at 50 and 200 mg/kg bw/day. The assessment of haematological data indicated some effects at the end of the treatment when compared to the controls. These findings primarily reflect a slight haemolytic anaemia for rats dosed at 1000 mg/kg bw/day, whereas the changes noted in the lower dose groups were only marginal in nature and therefore not considered significant in toxicological terms. For biochemical data treatment-related effects were noted for rats dosed at 200 and/or 1000 mg/kg bw at the end of the treatment when compared to the controls. These findings primarily reflect changes of an adaptive nature due to an increased functional load on the liver; however, slight injury to liver tissue is to be considered for the high dose group as indicated by the moderate increase in enzyme activity (ASAT and ALP) for males dosed at 1000 mg/kg bw/day. Significant differences in absolute and/or relative liver, kidney and testes weights were observed in animals dosed at 200 and 1000 mg/kg bw/day, respectively. The observed differences in absolute and relative liver weights of the female rats of group dosed at 50 mg/kg bw/day were not considered to be unequivocal to test article treatment. The differences animals dosed at 200 mg/kg bw/day are not considered to be toxicologically relevant because no abnormalities in urinary and biochemical parameters, macroscopic and histopathological findings were observed in this group. After 28 days of treatment, minimal to slight hepatic fatty changes and minimal to slight renal tubular epithelial degeneration and necrosis, considered to be treatment-related, were diagnosed in most rats of group dosed at 1000 mg/kg bw/day. The other histopathological lesions observed in this study are commonly diagnosed in rats of this strain and age and are not considered to be related to treatment with the test substance. The effects found in the subacute toxicity study reflect changes of an adaptive nature up to 200 mg/kg bw/day. Adverse effects are only found in group dosed at 1000 mg/kg bw/day, thus the NOAEL for the subacute toxicity study can be set to 200 mg/kg bw/day.

In a chronic toxicity study (equivalent to OECD 453, Bayer AG., 1978) the test substance CAS 16470-24-9 was administered to 50 Wistar rats/sex/dose in diet at dose levels of 0, 100, 1000, 10000 ppm (10000 ppm = 709 mg/kg bw/day for females and 521 mg/kg bw/day for males) for 24 months. There were no compound related effects in mortality, clinical signs, body weight, food consumption, haematology, clinical chemistry, urinalysis, organ weights, or gross and histological pathology. Therefore, the NOAEL was determined for females at 709 mg/kg bw/day and for males at 521 mg/kg bw/day. This chronic study in the rat is acceptable and satisfies the guideline requirements for a chronic oral study OECD 453 in rats.

The same chronic study (Bayer AG., 1978) was also performed on the acid form of the disulphonated derivative (CAS 4404-43-7). Appearance, behaviour, feed intake, body weights and mortality were not influenced in male and female animals of doses up to and including 10000 ppm. The animals in the dose groups of 10000 ppm did not show during the entire experimental period any treatment-related symptoms. The growth of the rats was not affected until the dose of 10000 ppm. The haematological investigations performed during and at the end of the test showed no dose of injuries. The clinical chemical analysis, sections and histopathological examinations revealed no evidence for treatment-related damage to the liver. Urinalysis, urea and creatinine concentrations in serum as well as macroscopic and histopathological organ findings did not indicate any influence. NOAEL: 779 mg/kg bw/day (actual dose received) (female) NOAEL: 542 mg/kg bw/day (actual dose received) (male).

Further studies were reported in literature, performed directly on the substance CAS 13863-31-5: the repeated dose toxicity was tested in a non-GLP study in the rat (Industrial Bio-Test Laboratories, 1973; Keplinger et al., 1974; Lyman et al., 1975). Rats were fed with 40, 200 and 1000 ppm in the diet (approximately 2, 8 and 40 mg/kg bw/day) for 2 years. The NOAEL was the highest dose tested. Additional repeated dose studies in the rat and dog were conducted by Industrial Bio-Test Laboratories and are not considered to be valid to assess the endpoint. Several studies for CAS 13863-31-5 and CAS 16090-02-1 were performed by Industrial Bio-Test Laboratories, which was closed down in 1978 after a routine inspection by the FDA in 1976 uncovered gross deficiencies in study conduct and recordkeeping. None of the studies have been subjected to an external audit. However, as a weight of evidence, they confirm the non toxic behaviour of the substance in long term studies at high concentrations and the similar outcome between the category members. Both the substance CAS 13863-31-5 and CAS 16090-02-1 were fed to rats and dog for 90 days at 10000 ppm (262 and 310 mg/Kg bw) with no adverse effects upon body weights, food consumption, survival and reactions, clinical parameters or gross and microscopic pathologic findings.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Several studies were reported and evaluated. A two year study on the acid form of the dihydroxyethylamino disulphonated derivative substance has been considered as key and the related NOAEL selected for the Chemical Safety Assessment.

Justification for classification or non-classification

According to CLP Regulation (EC 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.

Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges as:
- oral (rat): 10 < C ≤ 100 mg/kg bw/day

The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats. They can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration.

The No Observed Adverse Effect Level was established at 542 mg/kg bw/day, on the basis of the results from a chronic study of two years.

 

In conclusion, the available experimental data are adequate for classification and labelling purpose and the substance is not classified for repeated dose toxicity according to the CLP Regulation (EC 1272/2008).