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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available data base is considered sufficient for hazard / risk characterization:
- in a guideline conform reproductive screening study accoring to OECD TG 421 following GLP with the registration substance, neither abnormalities with regard to reproductive indices nor adverse histopathological findings in the organs and tissues of the reproductive system were revealed.
- in a guideline conform one-generation study according to OECD TG 415 with the read-across compound Glucamide 24, no effects on reproductive parameters including sperm motility and all natural delivery and litter parameters were unaffected.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Quality of whole database:

The available data base is considered sufficient for hazard / risk characterization independent of the exposure route. There are no indications of adverse effects on reproductive organs or tissues from the available data.

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Quality of whole database:

The available data base is considered sufficient for hazard / risk characterization independent of the exposure route. There are no indications of adverse effects on reproductive organs or tissues from the available data. Based on the available data, no toxicologically relevant findings were noted for reproductive and developmental parameters. The overall NOAEL from these studies is considered 150 mg/kg body weight f

Additional information

Glucamide 810 (Test material GA AC93/13, 93.9%) was investigated for potential effects on male and female fertility and embryo-fetal development after repeated dose administration to rats per OECD TG 421 (reproduction and developmental toxicity screening test protocol). The test item was administered daily via gavage at doses of 0, 50, 125, or 312.5 mg/kg bw/day (doses selected on the basis of available acute and repeated dose toxicity data) to 10 male and 10 female animals per group. The treatment period was 54 days and comprised 14 days of pre-mating with a maximum of 14 days mating in both males and females, as well as the gestation period and up to post-natal day 3 in females.

Administration of the test substance revealed slight clinical symptoms in high dose animals and a slight but transient lower food consumption in high dose females. No test-item related effects on the duration of pre-coital interval and the duration of gestation were observed. Additionally, no abnormalities with regard to reproductive indices (i.e., copulation, fertility, delivery, and viability indices) were revealed. There were no test item related effects on the number of corpora lutea, number of implantation sites, total number of pubs, number of live pubs (post-natal days 0 and 4) still births or runts and percentage of pre- and post-implantation loss. Survival of pubs from post-natal days 0 through 4 was not affected. There were no macroscopic findings of toxicological relevance in pubs of any dose group and no gross external abnormalities were observed in pups of the dose groups compared to control. Additionally, there were no differences in absolute and relative organ weights and no test-item related adverse histopathological findings in the organs and tissues of the reproductive system (i.e., testes, epididymides, prostate, seminal vesicles, coagulating glands, ovaries, uterus and cervix, and vagina). Based on the study results, the NOAEL for general as well as for reproductive toxicity is considered to be 312.5 mg/kg bw/day. The NOEL for systemic effects was 125 mg/kg bw/day based on clinical symptoms and a slight effect on food consumption. These effects were not considered to be adverse because they did not reach the respective toxic range.

Higher tier fertility studies according to OECD 415 or TG 416 were not performed with Glucamide 810. However, based on close structural similarities and comparable physicochemical properties a read-across to data with Glucamide 24 is not only scientifically justified but advisable also for animal welfare reasons.

The potential effects of Glucamide 24 (Test material 10000506.01, 96.2%) on reproductive function were investigated following OECD TG 415 in a one-generation reproductive study in rats. The test substance was administered once daily via gavage from 70 days prior to mating, during cohabitation (up to 21 days) until the day before sacrifice to 3 groups of rats (25 Crl:CD®(SD)IGS BR VAF/Plus®/sex/dose) at dose levels of 14.8, 147.8, or 344.9 mg/kg bw/day. Males were sacrificed following cohabitation, females were sacrificed on postpartum day 21 and pups were culled on post-natal day (PND) 4 and those maintained were sacrificed on PND 21. Control animals received the vehicle (water) only.

No parental male or female rats died during the course of the study. Clinical observations considered test item related in males treated with 150 and 350 mg/kg bw/day included excess salivation, rales, chromorhinorrhea, red or died red perioral substance and chromodacryorrhea (350 mg/kg bw/day group only). Clinical observation in female rats considered test item related included excessive salivation and rales at 150 and 350 mg/kg bw/day. Though considered treatment and dose related at 150 mg/kg bw/day and above, findings of excess salivation, rales and red or dried red perioral substance were statistically significant in males treated with 350 mg/kg bw/day group as compared to control animals. 

Findings in females treated with 350 mg/kg bw/day were also statistically significant; though the observation of rales was also statistically significant at 150 mg/kg bw/day during the lactation period. Males at the high dose had reduced body weight gain and significantly reduced terminal body weights. Maternal body weight gains and absolute feed consumption were significantly reduced in the 350 mg/kg bw/day group for the entire gestation period. However, there were no effects on the fertility index, mating index, pre-coital index and no significant or biologically relevant differences in the number of the percentage of motile or non-motile sperm.

Differences in the weight of epididymides, testes, seminal vesicles, ovary, uterus, pituitary and brain or the ratios of these organs to the terminal body or brain weights were not observed in the male or females. All natural delivery and litter parameters were unaffected by dosages of the test substance as high as 350 mg/kg bw/day. Clinical and necropsy observations in the F1 generation pups revealed no differences between the dosed groups versus the control. Additionally, substance-related microscopic changes in the brain, pituitary or reproductive organs were not revealed. Based on the data, the NOAEL with regard to reproductive and developmental effects was considered to be greater 350 mg/kg bw/day (corrected value 344.9 mg/kg bw/day). The NOAEL for parental toxicity is considered to be 147.8 mg/kg bw/day, based effects on body weight and food consumption.  Clinical effects observed at this and the highest dose were considered indicative of gavage (bolus) administration of a substance with irritating properties. 

Short description of key information:
Relevant information regarding the endpoint reproductive toxicity is available from a guideline conform OECD 421 study on the registration substance as well as from a guideline conform OECD TG 415 study with the read-across compound Glucamide 24. Based on the results from these studies, the overall NOAEL with regard to reproductive effects is considered to be >= 350 mg/kg body weight per day.

Justification for selection of Effect on fertility via oral route:
Guideline study according to GLP. No derivations and/or confounders. Klimisch rating 1 representing reliability without restrictions. Information is valid and meet data requirements.

Effects on developmental toxicity

Description of key information

Developmental toxicity evaluation following OECD TG 414 are not available for Glucamide 810. However, a guideline conform OECD 414 Segment II study with the read-across compound Glucamide 24 has not revealed developmental or reproductive toxic effects at any dose level tested. 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

363 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available data base is considered sufficient for hazard / risk characterization for this endpoint. There are no indications of adverse effects on reproductive organs or tissues from repeated dose toxicity studies as well as reproductive and/or developmental toxicity studies.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Quality of whole database:

The available data base is considered sufficient for hazard / risk characterization independent of the exposure route. There are no indications of adverse developmental effects and/or effects on reproductive organs or tissues from the available data.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Quality of whole database:

The available data base is considered sufficient for hazard / risk characterization independent of the exposure route. There are no indications of adverse developmental effects and/or effects on reproductive organs or tissues from the available data.

Additional information

Developmental toxicity following OECD TG 414 was not performed with Glucamide 810. However, based on close structural similarities and comparable physicochemical properties a read-across to data with Glucamide 24 is not only scientifically justified but advisable also for animal welfare reasons.

In this respect, an OECD 414 Segment II study was performed on 3 groups of 25 rats to determine the developmental toxicity of including teratogenic potential of Glucamide 24 (Test material SS0001.01, 45% active). Analytically determined dosage levels of 15, 150, or 363 mg a.i./kg bw/day were orally administered via gavage as a single daily dose on gestation days (GD) 6 through 15. The control group received the vehicle (water) only. Animals were sacrificed on GD20. Maternal toxicity included clinical signs (material around nose and/or mouth, post-dose increased salivation and decreased activity) and significant reduction in body weight gain observed at the highest dose level of 363 mg/kg bw/day. However, no developmental or reproductive toxic effects were observed at any dose level. The NOAEL for maternal toxicity was considered to be 150 mg a.i./kg bw/day, whereas a NOAEL of greater 363 mg a.i./kg bw/day for developmental toxicity was established. 

Justification for selection of Effect on developmental toxicity: via oral route:
Well documented guideline study according to GLP with minor deviations. Information is valid and meet data requirements.

Justification for classification or non-classification

Administration of Glucamide 810 and/or the read-across compound Glucamide 24 up to maternal toxic doses did not result in any significant changes of reproductive and/or developmental effects. Based hereupon classification and labelling of the registered substance concerning reproductive toxicity is not warranted.