D-Glucitol, 1-deoxy-1-(methylamino)-, N-C8-10 acyl derivs.

Endpoint summary

Description of key information

Repeated dose toxicity studies with Glucamide 810 (28-day study period) and the read-across compound Glucamide 24 (90-day study period) revealed no distinct differences in the systemic toxicity profile.  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. This is supported by comparable NOAELs in repeated dose studies were 250 mg/kg and 200 mg/kg for Glucamide 810 and Glucamide 24 respectively, despite different exposure durations of 28 days and 90 days.

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:

Data reliable and meet 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

Potential systemic toxicity of Glucamide 810 (Test material GA AC93/13, 93.9%) was investigated in a subacute 28-day toxicity study in compliance with OECD test guideline 407. The test item was administered daily via gavage in graduated doses of 0, 100, 250, or 500 mg/kg bw/day to groups of 5 male and 5 female rats for a period of 28 days with a 14 day recovery period.

Mortality occurred at the highest dose level of 500 mg/kg bw/day in one male and 4 female rats. Causes of the deaths were most probably a consequence of inflammatory and irritative processes in the forestomach and/or due to accidental inhalation of the test material by regurgitation. No mortality occurred at doses of 100 or 250 mg/kg bw/day. Clinical symptoms were temporarely and unspecific in nature, most probably related to local effects, and consisted of moving the bedding after administration, salivation, respiratory sounds, piloerection and occasionally reduced spontaneous activity, hardened abdomen and diarrhea were observed at 100 mg/kg bw/day and above. These findings are considered secondary in nature.

A tendency towards a slightly attenuated body weight gain in male and female rats of the high dose group, which correlated with a trend towards a lower food intake in these animals, was most likely related to the local irritating properties of the test item and resulting histopathological effects in the forestomach. These effects were not fully recovered after the 14 day treatment free observation period. Comparable effects on body weight gain and food consumption were not observed in the mid and low dose animals. Slightly increased neutrophils and slightly decreased lymphocytes indicative of inflammatory processes in animals of the high dose group were the only remarkable hematological effects observed. Urinalysis revealed no abnormalities. With regard to organ weights, slightly (non-statistically significant) lower thymus weight in females of the high dose probably reflected a secondary stress response. In females, all treated animals had slightly higher weights of the uterus. Since this was dose related and not accompanied by a histopathological finding, the observation was not considered adverse. Other findings with regard to organ weights also lacked a dose response and a respective histopathology correlate.

Primary test item related findings were recorded in the forestomach of high dose animals that died prematurely. They consisted of forestomach erosion, ulceration, epithelial hyperplasia, hyperkeratosis and sub-mucosal inflammation and were partly also recorded in survivors of this high dose group. Further microscopic findings in the lungs of deceased animals, e.g., granulomatous inflammation and foreign material in bronchioles and alveoli, were considered to be most likely due to accidental inhalation of test item by regurgitation. Secondary stress-related microscopic lesions were observed in spleen, thymus and bone marrow from high-dose animals which died premature. These findings were considered to be of secondary nature, as a consequence of the inflammatory processes in the forestomach, trachea and lung. None of the microscopic findings were present in mid or low dose animals nor in high-dose animals surviving until the end of the recovery period. No adverse effects were observed at dose levels of 100 and 250 mg/kg body weight per day.

The only primary test item related changes considered to be adverse to the rat were local forestomach effects in the high dose animals having received 500 mg/kg bw/day. Application of rodent forestomach effect data for predicting risk or even hazard for humans is in general not justified, given that a human counterpart for the rodent forestomach does not exist. In assessing the relevance of such findings in rodents, aspects like the method of administration (e.g., gavage versus feeding) and the applicability of the forestomach to human organs (e.g., tissue concordance) have to be considered. Although findings in the forestomach of rats are not considered of biological relevance for humans (EFSA 2011; Proctor et al. 2007), the NOAEL of Glucamide 810 following repeated administration to rats for 28 days was conservatively established at 250 mg/kg bw/day.

No subchronic or chronic data are available with Glucamide 810. However, based on the very consistent toxicity profile of Glucamide 24, differing only in the chain-length of the alkyl moiety, a guideline complaint 90-day oral toxicity study on Glucamide 24 can be used for assessment purposes based on read-across principles. This approach is in line with general OECD principles and is justified by the close structural and physicochemical comparability of both Glucamides (see separate read-across justification).

In the 90 day study, 4 groups of 10 male and 10 female rats received Glucamide 24 (Test material E-4086.01, 45% 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 mg/kg 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, dyspnea, 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 chemistry 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 animals. 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 810.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
An OECD TG 407 guideline study according to GLP is available for the registration substance. No derivations and/or confounders. Klimisch rating 1 representing reliability without restrictions. Information is valid and meet data requirements. In addition, a subchronic 90-day study (OECD 408) is available for the read-across compound Glucamide 24 which is also considered valid (reliable without restriction).

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 810 is not subject to classification and labelling according to the criteria of GHS and /or EU CLP.