D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-16 (even numbered) and C18 unsaturated acyl] derivs.

Endpoint summary

Description of key information

In a guideline conform 28-day subacute toxicity study with Glucamide CC according to GLP, no effects of toxicological significance were observed up to a dose of 700 mg/kg body weight per day. However, a 90-day subchronic study has not been conducted with Glucamide CC. Based on animal welfare consideration, available data for a 90-day repeated dose study with the structural and biological analogue Glucamide 24 has been used for further evaluation instead. This read-across approach, although considered to be conservative,  is regarded to be valid and toxicological justified. No target organ toxicity with human relevance was revealed following 90-day oral administration of Glucamide 24 to rats.  Dominating are nonspecific clinical effects and local effects, predominantly in the forestomach of rats. These points to a concentration dependent irritative mode of action, common for surfactants, leading to downstream effects on feed intake and body weight at the higher doses. The NOAEL in the 90-day repeate dose study was conservatively set at 200 mg/kg body weight per day. Considering that no toxicological significant effects were observed up to 700 mg/kg body weight per day in the 28-day repeated oral toxicity study with Glucamide CC, the NOAEL of 200 mg/kg body weight per day from the 90-day study with Glucamide 24 is considered to be conservative.

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:

subchronic

Species:

rat

Quality of whole database:

The used read-across is regarded to be conservative but reliable and the data used meet the criteria for classification & labelling requirements.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The available data allows for `route-to-route` extrapolation and/or expert judgement.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The available data allows for expert judgement concerning this endpoint.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The available data allows for `route-to-.route` extrapolation and/or expert judgment.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The available data allows for expert judgement concerning this endpoint.

Additional information

No effects of toxicological significance have been obeserved in a guideline conform 28-day repeated dose orla toxicity study with Glucamide CC in rats up to a dose of 700 mg/kg body weight per day. However, a subchronic 90-day toxicity study has not been conducted for Glucamide CC based on animal welfare considerations. Instead, available data from the structural and biological close analogue Glucamide 24 is used for evaluation purposes. The used read-across is considered to be conservative, but sufficiently valid and toxicological justified.

In this 90 day repeated dose toxicity study with Glucamide 24, 4 groups of 10 male and 10 female rats received Glucamide 24 (Test material E-4086.01, 4% active) at dose levels of 10, 50, 200 or 500 mg a.i./kg bw/day. Another group of 10 animals per sex per dose were allowed to recover for 28 days following the last administration. Daily administration of the test article at 500 mg/kg bw induced a significant reduction in food consumption in male and to a lesser extent in female animals; statistical significant findings were observed during weeks 1/2 and 5 through 10 for males and weeks 1/2, 7/8, and 12/13 for females with the values in males ranging from 83% to 96% of control values during the treatment period and the values in females ranging from 86% to 105% of control values during the treatment period. Sporadic differences in relative food consumption were also observed in the two highest doses. Reduced body weight gain was observed in male rats treated with 200 and 500 bw/day. The effect on high dosed males was significant from week 2-on with values just below 90% of the control group values in the latter half of the study (values for weeks 7-on ranged from 87-89% of the control groups). Clinical signs were observed in animals dosed with 50 mg/kg bw/day or more, but minimal in non-high dosed animals. In high dosed animals, breathing rales, dyspeea, labored respiration, ruffled fur, sedation, hunched posture and emaciation were considered treatment related. Premature death attributed to the treatment was observed in 3 male and 1 female rat of the high dose group. There were no treatment related findings with regard to ophthalmoscopy examinations. Hematology findings were limited to the two highest doses and were considered to be slight and suggestive of changes to basal fluidity (without hematological implications), incidental and of normal biological variation.Effects noted with regard to clinical chemisrry were not considered to be toxicologically significant, but signs of metabolic adaptation. The only finding with regard to urinalysis was a slight increase in overnight output (43 to 63%, both sexes) and was considered secondary to increased fluid intake. Findings with regard to organ to body weight ratios at termination of treatment were either considered reflective of metabolic adaptation, secondary to changes in terminal body weight, or reflective of increased urinary output. A reduction in terminal body weight was also observed in males of the high dose group. Histopathological findings included inflammatory changes were observed in the nasal cavity (exudate) and in the lungs of some animals especially in the high dose group. These changes were considered by the study pathologist to be related to the general poor condition of the animals and were consistent with reflux of irritating material. Other changes noted were either not treatment related (thymic atrophy and thymic hemorrhages in group 5 premature decedents) or congenital (“adrenocortical rest”); as such, it was concluded that there was no histopathological evidence of toxicity observed in the study. From the study results it was concluded, that the administration of Glucamide 24 at 500 mg/kg bw/day resulted in increased mortality as well as clinical, biochemical and histopathological changes which were considered to be mainly due to the poor general condition of the high dose animal. The findings at 200 mg/kg bw/day, which included a slight retardation of body weight gain in males, slightly ruffled fur in a few rats, as well as the dose related findings for respiration at 50 mg/kg bw/day and above were considered transient and slight and did not correlate with findings on other parameters. On this basis, the NOAEL was determined to be 200 mg/kg bw/day which will also be considered in the safety evaluation of Glucamide CC.

Considering that no toxicological significant effects were observed up to 700 mg/kg body weight per day in the 28-day repeated oral toxicity study with Glucamide CC, the NOAEL of 200 mg/kg body weight per day from the 90-day study with Glucamide 24 is considered to be conservative.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No effects of toxicological significance have been obeserved in a guideline conform 28-day repeated dose oral toxicity study with Glucamide CC up to a dose of 700 mg/kg body weight per day. However, no 90-day subchronic study has been conducted with Glucamide CC. Instead, based on animal welfare consideration, available data for a 90-day repeated dose study with the structural and biological analogue compound Glucamide 24 is used to further conclude on the systemic toxicity profile of the registration substance. The rational and toxicological justification of the validity of this read-across is provided as attachment. Overall this is considered a conservative approach.

Justification for classification or non-classification

Based on the results from the available repeated dose toxicity data and given that no human relevance is deducible from the effects on the forestomach seen in rats, it is concluded that Glucamide CC is not subject to classification and labelling according to the criteria of GHS and /or EU CLP.