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EC number: 941-809-7
CAS number: -
Dose Formulation Analyses
The analyzed dosing formulations contained 92.4% to 101% of the test substance which was within the protocol-specified range of target concentrations for solutions (90% to 110%). The test substance was not detected in the analyzed vehicle formulation that was administered to the control group (Group 1). Results of the analyses of dosing formulations are summarized below.Results of Concentration Analyses (mean concentration, mg/mL % of target))- Date of preparation: 2020-11-05. Group 2 (10 mg/mL) 9.49 mg/mL, Group 3 (30 mg/mL) 28.9 mg/mL, Group 4 (100 mg/mL) 95.1 mg/mL.- Date of preparation: 2020-11-19. Group 2 (10 mg/mL) 9.24 mg/mL, Group 3 (30 mg/mL) 30.4 mg/mL, Group 4 (100 mg/mL) 93.6 mg/mL.
Mortality and ObservationsThere were no test substance-related effects on survival. All animals survived to scheduled euthanasia and were gravid.Test substance-related increased incidences of abnormal breathing sounds were observed in 8 females at approximately 2 hours postdose in the 725 mg/kg/day group and persisted to the daily examinations in 3 females only during Gestation Days 7–21. These findings were considered non-adverse due to the animals being in otherwise general good health throughout the treatment period. Other clinical observations noted in the test substance-treated groups occurred infrequently, at similar frequencies in the control group, and/or in a manner that was not dose-related.
Body Weights and Gravid Uterine WeightsMean maternal body weights, body weight gains, adjusted body weights, adjusted body weight gains, and gravid uterine weights in the 72.5, 217.5, and 725 mg/kg/day groups were unaffected by test substance administration. Any statistically significant differences from the control group were transient, did not occur in a dose-responsive manner, and/or did not impact mean absolute body weights.
Food Consumption In the 725 mg/kg/day group, test substance-related statistically significantly lower mean food consumption was noted during Gestation Days 6–9 compared to the control group. Mean food consumption in this group was comparable to the control group for the remainder of the dosing period (Gestation Days 9–21) and when the entire dosing period (Gestation Days 6–21) was evaluated. There were no corresponding effects on mean body weights or body weight gains, and therefore, the effects on mean food consumption in the 750 mg/kg/day group were considered non-adverse.Mean food consumption in the 72.5 and 217.5 mg/kg/day were unaffected by test substance administration throughout the study. Differences from the control group were slight and not statistically significant.
Thyroid Hormone AnalysesThere were test substance-related effects on thyroid hormone values (TSH, T3, and T4) at any dose level. Differences from the control group were not statistically significant, observed in a manner that was not dose-related, and were within the ranges of the Historical Control Data.
Macroscopic PathologyNo test substance-related gross findings were noted. The gross findings observed were considered incidental, of the nature commonly observed in this strain and age of rat, and/or were of similar incidence in control and treated animals and, therefore, were considered unrelated to test substance administration.
Organ WeightsNo test substance-related organ weight changes were noted at any dose level.
Microscopic EvaluationsNo test substance-related microscopic findings in the thyroid gland or liver were noted. The microscopic findings observed were considered incidental, of the nature commonly observed in this strain and age of rats, and/or were of similar incidence and severity in control and treated animals and, therefore, were considered unrelated to test substance administration.
Ovarian and Uterine ExaminationsIntrauterine growth and survival were unaffected by test substance administration at dosage levels of 72.5, 217.5, and 725 mg/kg/day. Parameters evaluated included mean litter proportions of post implantation loss, mean number of live fetuses, mean fetal body weights, mean anogenital distance (absolute and relative to cube root of body weight), and fetal sex ratios. Differences from the control group were slight, not statistically significant, and/or noted in a manner that was not dose-related.Mean numbers of corpora lutea and implantation sites and the mean litter proportions of pre implantation loss were similar across all groups.
Fetal Morphological DataThe numbers of fetuses (litters) available for morphological evaluation were 317(25), 318(25), 301(25), and 333(25) in the control, 72.5, 217.5, and 725 mg/kg/day groups, respectively. Malformations were observed in 0(0), 1(1), 2(2), and 6(3) fetuses (litters) in these same respective dose groups.
External Malformations and VariationsNo test substance-related external malformations were noted in fetuses in this study. A single fetus in the 217.5 mg/kg/day group (No. 3518-09) was observed with proboscis and absent eye bulges, mouth, and lower jaw. These findings were noted in a single mid-dose fetus, and therefore were not considered test substance related. No other external malformations or external developmental variations were observed in fetuses on this study.
Visceral Malformations and VariationsNo visceral malformations were noted in fetuses in this study.No test substance-related visceral developmental variations were noted. Findings observed in the test substance treated groups were noted similarly in the control group.
Skeletal Malformations and VariationsSkeletal malformations were noted for 0(0), 1(1), 2(2), and 6(3) fetuses (litters) in the control, 72.5, 217.5, and 725 mg/kg/day groups, respectively; incidences in the test substance-treated groups were not statistically significantly higher than the concurrent control group. In the 725 mg/kg/day group, different types of vertebral malformations were noted in 3 individual litters: Fetus Nos. 4504 05, 4504-16, and 4504-17 were observed with absent lumbar vertebra, Fetus Nos. 4513-01 was observed with an absent rib and thoracic hemivertebra; this fetus was also noted with a lower body weight (3.87 g) compared to the group mean value (5.92 g), and Fetus Nos. 4521-04 and 4521-10 were observed with supernumerary lumbar vertebra. Because the skeletal malformations in the 725 mg/kg/day group were of specific types to fetuses in individual litters, they were considered familial and not related to the test substance administration. In the 217.5 mg/kg/day group, Fetus No. 3503 10 was observed with fused ribs, cervical centrum, cervical arches, and thoracic arches and absent cervical centrum and Fetus No. 3518 09 was noted with multiple malformations in the skull (absent mandible and jugal bones, misshapen nasal, premaxilla, maxilla, squamosal, frontal, parietal, and interparietal bones, small premaxilla, nasal, maxilla, squamosal, tympanic annulus, frontal, parietal, and interparietal bones, large supraoccipital bone, and unossified parietal bone), corresponding to the external malformations noted in this fetus. In the 72.5 mg/kg/day group, Fetus No. 2501-03 was observed with an absent lumbar vertebra. Skeletal malformations in the 50 and 150 mg/kg/day groups were limited to single fetuses, and therefore were not considered test substance related.Higher incidences (statistically significant) of skeletal developmental variations were noted in the 72.5 and 725 mg/kg/day groups. However, the individual findings were not observed in a dose related manner, the differences in the mean litter proportions were not statistically significant compared to the concurrent control group, and/or the values were within the ranges of the Charles River Ashland historical control data (version 2017.03). Therefore, the skeletal developmental variations were not considered test substance-related.
Summary of External, Visceral, and Skeletal ExaminationsThe numbers of fetuses (litters) available for morphological evaluation were 317(25), 318(25), 301(25), and 333(25) in the control, 72.5, 217.5, and 725 mg/kg/day groups, respectively. Malformations were observed in 0(0), 1(1), 2(2), and 6(3) fetuses (litters) in these same respective dose groups.When the total malformations and developmental variations were evaluated on a proportional basis, no statistically significant differences from the control group were noted, with the following exceptions. The mean litter proportion of fetuses with any skeletal developmental variations was statistically significantly higher in the 72.5 and 725 mg/kg/day groups compared to the control group; when individual developmental variations were evaluated, only the mean litter proportion of fetuses with incomplete ossification of the thoracic centrum was statistically significant in the 72.5 mg/kg/day group. Fetal malformations and developmental variations, when observed in the test article treated groups, occurred infrequently or at a frequency similar to that in the control group, did not occur in a dose-related manner, and/or were within the historical control data ranges. Based on these data, no fetal malformations or developmental variations were attributed to the test article.
In this developmental toxicity study according to OECD guideline 414 and OPPTS 870.3700, the test substance "Sophorolipids: fermentation products of glucose and fatty acids, C18-unsatd., esters with glycerol with yeast Candida bombicola, partially hydrolysed" was administered to 25 time-mated female Crl:CD(SD) rats/dose at dose levels of 0, 72.5, 217.5 and 725 mg/kg bw/day. Animals were dosed via oral gavage once daily during Gestation Days 6–20.
The following parameters and end points were evaluated in this study: clinical signs, body weights, body weight gains, gravid uterine weights, food consumption, thyroid hormone parameters (T3, T4, and TSH), organ weights, macroscopic and microscopic examinations, intrauterine growth and survival, and fetal morphology.
All females survived to the scheduled necropsy on Gestation Day 21. Test substance-related clinical observations noted at the daily examinations or approximately 2 hours postdosing were limited to abnormal breathing sounds in the 725 mg/kg/day group. The animals were otherwise in good health throughout the treatment period, so these effects were not considered adverse.
There were no test substance-related effects on mean maternal body weights, body weight gains, adjusted body weights, adjusted body weight gains, or gravid uterine weights at any dose level.
Test substance-related lower mean maternal food consumption was noted in the 725 mg/kg/day group during Gestation Days 6–9 but was comparable to the control group thereafter. Based on the transient nature of these effects and the lack of corresponding body weight effects, these effects on food consumption were considered non-adverse. No test substance-related effects were observed on food consumption in the 72.5 or 217.5 mg/kg/day groups.
There were no test substance-related effects on maternal thyroid hormone values at any dose level.
There were no test substance-related effects on maternal macroscopic pathology, organ weights, or microscopic evaluations at any dose level.
There were no test substance-related effects on intrauterine growth or survival at any dose level.
There were no test substance-related effects on external, visceral, or skeletal fetal morphology at any dose level.
Based on the absence of adverse maternal or fetal effects, a dosage level of 725 mg/kg/day (the highest dose level tested) was considered to be the no‑observed‑adverse‑effect level (NOAEL) for maternal toxicity and embryo/fetal development when the test substance "Sophorolipids: fermentation products of glucose and fatty acids, C18-unsatd., esters with glycerol with yeast Candida bombicola, partially hydrolysed" was administered orally by gavage to time-mated Crl:CD(SD) rats.
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