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Diss Factsheets

Administrative data

Description of key information

No-observed-adverse-effect-level (NOAEL) was considered to be 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes of toxicological relevance were noted during daily observations in rats at any dose level.
Orange feces were recorded in males and females treated with 1000 mg/kg bw/day from day 2 of treatment onwards, and persisted for two days of the recovery period. This was considered to be a typical passive effect resulting from large oral doses of a dyestuff.
Diverse alopecia was noted in one control male (days 12-16), one control female (days 27-29), and one female treated with 1000 mg/kg bw/day (days 20-28), accompanied in the latter case with a dermal scab (days 20-25). The low incidence of dermal findings in test item treated rats was considered to be incidental.

DETAILED CLINICAL OBSERVATIONS (WEEKLY)
No test item-related changes of toxicological relevance were noted during weekly observations (weeks 1-3) in rats at any dose level. Diverse alopecia was recorded in one control male at week 2 and in one high dose female (accompanied by a dermal scab) at week 3.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One control male (no. 8) was found dead shortly after administration on day 22. Dosing error was considered to be a possible cause of death. All other animals survived until scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weights and the body weight gain of the control and test item-treated rats were similar.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean daily food consumption of the test item-treated rats compared favorably with those of the controls during the treatment and recovery periods.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No test item-related differences in the hematology parameters were noted in any dose level after the treatment and recovery periods.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related differences in the clinical biochemistry parameters were noted in any dose level after the treatment or recovery periods.
Significant reductions of the mean calcium levels in males treated with 50 mg/kg bw/day (p<0.01) and 1000 mg/kg/day (p<0.05), and significant elevations of the mean sodium level in males treated with 1000 mg/kg bw/day (p<0.05) and chloride level in males treated with 50 mg/kg bw/day (p<0.05) were considered to be incidental in the absence of other changes in electrolytes.

After the recovery period in males previously treated with 1000 mg/kg bw/day significantly reduced mean plasma concentrations were noted in creatinine (p<0.05), alanine aminotransferase (p<0.01) and globulin (p<0.01). In females previously treated with 1000 mg/kg bw/day significantly elevated mean plasma concentrations were noted in total bilirubin (p<0.05), triglycerides (p<0.01), calcium (p<0.05), protein (p<0.05) and albumin (p<0.05). These changes were not considered to be late effects of toxicological relevance.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related differences in the urinalysis parameters were noted in any dose level after the treatment or recovery periods.
In males treated with 1000 mg/kg/day leukocyte concentration was significantly elevated (p<0.05) and urine appearance was cloudy to turbid. In females treated with 1000 mg/kg bw/day nitrite was found in the urine. Both findings were considered to be unrelated to the test item and may result from spontaneous bacterial activity in urinary tract.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes of toxicological relevance were noted during functional observational battery (week 4) in rats at any dose level. Diverse alopecia was recorded in one high dose female at week 4.

Grip Strength
The mean fore- and hind limb grip strength of the test item-treated rats were similar to those of the controls.

Locomotor Activity
In females treated with 1000 mg/kg bw/day, elevated mean locomotor activity was noted from 0-10 minutes (p<0.01), 10-20 minutes (p<0.01) and 20-30 minutes (p<0.05). These differences resulted in an overall increase (p<0.01, 0-60 minutes) when compared with controls. As similar differences were not seen in males, a relationship with the test item treatment was considered unlikely. All differences noted in females treated with 50 mg/kg bw/day or 200 mg/kg bw/day were considered to be of no toxicological relevance.
In test item-treated males, the mean locomotor activity was not affected by the test item administration. The slightly elevated locomotor activities recorded from 30-40 minutes (p<0.05) in males treated with 50 mg/kg bw/day resulted in significant changes in the overall locomotor activity (p<0.05, 0-60 minutes), as well as from 0-10 minutes (p<0.05) and 30-40 minutes (p<0.05) of males treated with 200 mg/kg/day. In the absence of any dose-response relationship, these changes were considered to be incidental.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
After 4 Weeks
The mean absolute and relative organ weights of the test item-treated rats and the control rats were similar.

After 6 Weeks
No test item-related changes were noted in the mean absolute and relative organ weights of rats previously treated with 1000 mg/kg bw/day. In males previously treated with 1000 mg/kg bw/day, the mean absolute liver weights were reduced (p<0.01) when compared with controls, and the mean brain-to-body weight ratio was increased (p<0.01) when compared with controls. The elevated mean absolute brain weight resulted in reduced organ-to-brain weight ratios for heart (p<0.05), liver (p<0.01), kidneys (p<0.01) and adrenals (p<0.05). These differences were considered to be artifacts and of no toxicological relevance.
Gross pathological findings:
no effects observed
Description (incidence and severity):
After the treatment and recovery periods no test item-related gross lesions were observed. The macroscopic findings recorded were considered to be within the range of normal background lesions, which may seen in rats of this strain and age in this study type and were considered incidental, reflecting the usual individual variability.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
A variety of changes were found in this study. These findings commonly occur in laboratory rats of this strain and age, neither their incidences nor their distribution or morphologic characteristics gave any indication of a treatment-related association.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
no

None

Conclusions:
The no-observed-adverse-effect-level (NOAEL) was considered to be 1000 mg/kg bw/day.
Executive summary:

No study is available for assessment of toxicity on repeated exposure to FAT 41048. However, structural analogue, FAT 41039/A was evaluated for potential to cause toxicity on repeated exposure in a study conducted according to OECD Guideline 407 and EU Method B.7. Oral administration of FAT 41039/A to Wistar rats at doses of 50, 200 and 1000 mg/kg bw/day, for 28 days resulted in no test item-related deaths (one control male died from a suspected dosing error), no clinical signs during daily or weekly (weeks 1-3) observations, no clinical signs during the functional observation battery (week 4), no effects upon fore- or hindlimb grip strength or mean locomotor activity, mean daily food consumption and mean body weight, no changes or effects upon hematology, clinical biochemistry or urinalysis and no changes in mean absolute or relative organ weights. No macroscopical or microscopical changes of toxicological relevance were seen at any dose level. Therefore, the no-observed-adverse-effect-level (NOAEL) was considered to be higher than the highest dose level tested, 1000 mg/kg bw/day. Using the principles of read across, NOAEL for FAT 41048 when orally administered over 28 days was considered to be 1000 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Good quality GLP study

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

Mode of Action Analysis / Human Relevance Framework

None

Additional information

No study is available for assessment of toxicity on repeated exposure to FAT 41048. However, structural analogue, FAT 41039/A was evaluated for potential to cause toxicity on repeated exposure in a study conducted according to OECD Guideline 407 and EU Method B.7. Oral administration of FAT 41039/A to Wistar rats at doses of 50, 200 and 1000 mg/kg bw/day, for 28 days resulted in no test item-related deaths (one control male died from a suspected dosing error), no clinical signs during daily or weekly (weeks 1-3) observations, no clinical signs during the functional observation battery (week 4), no effects upon fore- or hindlimb grip strength or mean locomotor activity, mean daily food consumption and mean body weight, no changes or effects upon hematology, clinical biochemistry or urinalysis and no changes in mean absolute or relative organ weights. No macroscopical or microscopical changes of toxicological relevance were seen at any dose level. Therefore, the no-observed-adverse-effect-level (NOAEL) was considered to be higher than the highest dose level tested, 1000 mg/kg bw/day. Using the principles of read across, NOAEL for FAT 41048 when orally administered over 28 days was considered to be 1000 mg/kg bw/day.

Justification for classification or non-classification

FAT 41048 is considered to have no adverse effects on repeated exposure upto 1000 mg/kg bw/day. Hence, the substance does not warrant classification as per the Regulation (EC) No. 1272/2008 (CLP) criteria.