1,4-Benzenedisulfonic acid, 2,2'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)imino[6-[bis(2-hydroxypropyl)amino]-1,3,5-triazine-4,2-diyl]imino]]bis-, sodium salt (1:6)

Endpoint summary

Description of key information

Category assessment used to read across:
oral: subacute (28 day, gavage): NOAEL = 200 mg/kg bw/day, OECD 407 and GLP compliant study
         chronic (2 years, feed): NOAEL = 10000 ppm (similar to OECD 453)

Additional information

Reliable data on repeated dose toxicity of Stilbene fluorescent whitening agents after oral exposure of rats are available for CAS 4404 -43 -7, 16090 -02 -1, and 16470 -24 -9.

CAS 4404 -43 -7: In a chronic toxicity study (Bayer AG 1977a and 1978a) 4,4'-Bis[4-[bis(2-hydroxyethyl)amino]-6-anilino-1,3,5-triazin-2-yl]amino]stilbene-2,2'-disulphonic acid , (89.1% a.i.)  was administered to 50 male and female rats (Wistar II) in diet at dose levels of 0, 100, 1000, 10000 ppm (0, 5.42, 54.2, 542 mg/kg bw/day for males and 0, 7.79, 77.9, 779 mg/kg bw/day for females) for 2 years. At 10000 ppm only in male rats a transiently reduced body weight was observed. The body weight in female rats was normal at all dose groups. There were no compound related effects in mortality, clinical signs, food consumption, hematology, clinical chemistry, urinanalysis, organ weights, or gross and histologic pathology.  The NOAEL for male and female rats is 10000 ppm since no adverse effects were observed.

This chronic study in the rats is acceptable and satisfies the guideline requirement for a chronic oral study, OECD 453 in rats.

CAS 16090 -02 -1:

Subacute: In a GLP compliant subacute 28-day toxicity study following OECD testing guideline 407, the test substance was administered daily by gavage to SPF-bred Wistar rats. The test substance was administered to 4 groups each of 5 male and 5 female SPF-bred Wistar rats by oral gavage at daily doses of 0, 50, 200, 1000 mg/kg bw/day (corresponding to 0, 41, 165 and 825 mg/kg bw/day of active ingredient) for 28 consecutive days (CIBA-Geigy AG, Switzerland 1991b). Two groups of 5 male and 5 female rats were treated accordingly at 0 and 825 mg/kg bw/day for 28 days followed by a 14-day treatment free recovery period. The dose levels used in this study are based on data from acute and subacute studies, especially a subacute 5-day range-finding study (CIBA-Geigy AG, Switzerland 1991a) in which dose levels of 0, 200 and 1000 mg test substance per kg body weight and day were administered to rats. There were no compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, urinanalysis, organ weights, or gross and histologic pathology observed after 4 weeks of treatment nor at termination of the treatment-free recovery period when the results from the animals of the test article treated groups were compared to those of the control animals. Based upon the results obtained in this study, the "no-adverse-effect-level" of the test substance is 1000 mg/kg body weight (825 mg/kg bw/day active ingredient) for male and female rats when administered orally by gavage for a period of 28 days followed by a treatment-free 14-day recovery period. The various statistically significant differences observed (increase/decrease) in food consumption (absolute/relative) and organ weights (relative) were considered to be of no toxicological relevance and did therefore not provide any evidence of toxicity of the test substance at any of the dose levels tested.

Chronic: In a chronic toxicity study (Bayer 1978) the test substance was administered to 50 Wistar rats/sex/dose in diet at dose levels of 100, 1000, 10000 ppm (10000 ppm = 791 mg/kg bw/day for females and 524 mg/kg bw/day for males) for 24 months. There were no compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, urinanalysis, organ weights, or gross and histologic pathology. The NOAEL is for females 791 mg/kg bw/day and for males 524 mg/kg bw/day. The various statistically significant differences observed (increase/decrease) in organ weights (absolute in males), number of reticulocytes/trombocytes, and ALAT (GPT) activities and serum protein were considered to be of no toxicological relevance and did therefore not provide any evidence of toxicity of the test substance at any of the dose levels tested.

CAS 16470 -24 -9:

In a chronic toxicity study (equivalent to OECD 453, Bayer AG 1978c) the test substance 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, hematology, clinical chemistry, urinanalysis, organ weights, or gross and histologic pathology. The NOAEL is for females 709 mg/kg bw/day and for males 521 mg/kg bw/day. The NOAEL for males and females is set to 615 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.

In a subacute toxicity study (according to OECD 407, CIBA-Geigy AG 1988) the test substance was administered to 5 to 10 Wistar rats/sex/dose by gavage at dose levels of 0, 50, 200, and 1000 mg/kg bw/day for 28 days.There were no compound related effects in mortality, clinical signs, food consumption, and urinanalysis. Statistically decreased body weights were observed in female animals of group 4 (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 groups 1 (control), 2 (50 mg/kg bw/day) and 3 (200 mg/kg bw/day). The assessment of hematological data indicated some effects at the end of the treatment when compared to the controls. These findings primarily reflect a slight hemolytic anemia for rats of group 4, 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 of groups 3 and/or 4 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 of group 4. Significant differences in absolute and/or relative liver, kidney and testes weights were observed in animals of groups 3 and 4 respectively. The observed differences in absolute and relative liver weights of the female rats of group 2 were not considered to be unequivocal to test article treatment. The differences in group 3 are not considered to be toxicologic 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 4. 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 (group 3). Adverse effects are only found in group 4 (1000 mg/kg bw/day), so that the NOAEL for the subacute toxicity study can be set to 200 mg/kg bw/day.

Therefore, it is concluded that Stilbene fluorescent whitening agents and then, reading across, also the substance CAS 371756 -75 -1, are not toxic when administered orally to rat over 2 years and have not to be classified for repeated oral toxicity.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the category members are not considered to be classified for repeated toxicity under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the category members are not considered to be classified for repeated toxicity under Regulation (EC) No. 1272/2008.