Sodium 2-(1-carboxylatoethoxy)-1-methyl-2-oxoethyl laurate

Endpoint summary

Description of key information

In an oral toxicity study on a suitable read-across partners (sodium stearoyl lactylates), no adverse effects were observed up to doses far above the relevant limit dose of 1000 mg/kg bw/day. Therefore, sodium lauroyl lactylate is not considered to be hazardous substance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The source compound sodium stearoyl lactylate is considered a suitable read across partner for the target substance sodium lauroyl lactylate. This read-across is based on the hypothesis that source and target substances have similar toxicological properties because:
- structural similarity of the target and the source substances (long fatty acid chain with lactylate group)
- similarity in metabolic pathway (rapid hydrolysis of the ester bond resulting in the fatty acid chain and lactylate group, which get further processed to yield lactate and subsequently carbon dioxide).

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related clinical signs. The signs observed occurred in only one or a few animals of a group or the incidences were distributed about equally between groups. Many of the ocular lesions occurred following blood collection from the orbital plexus.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

- One male rat (number 240) of the high-dose group was humanely killed on day 28. On this day, the animal showed piloerection and an abdominal nodule. Between days 21 and 28, it showed weight loss and reduced food consumption whereas its water
consumption was relatively high. The animal showed several signs of renal pathology, including hydronephrosis and increased plasma levels of urea and creatinine.
- One female (number 91) of the low-dose group was humanely killed on day 315 when it was lethargic and pale and showed piloerection and haemorrhagic vaginal discharge. Between days 280 and 308, this animal showed weight loss and reduced food and water consumption.
- One female (number 147) of the mid-dose group was humanely killed on day 328 when it looked pale and showed haemorrhagic vaginal discharge. Before this day, the animal grew, ate and drank normally.
Gross and histopathological examinations showed that the untimely death of these 3 animals was not ascribed to treatment.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

From day 7, mean body weights of high-dose females were statistically significantly (ANOVA/Dunnett's test) lower than those of controls. The differences from controls were about 4-5% up to day 28 and generally about 6-7% thereafter. Trend analysis showed additional statistical significances in high-dose males and mid and low-dose females. However, the mean body weights in these groups were only slightly (about 3-4%) lower than in controls and not statistically significant upon analysis by ANOVA. Therefore, no toxicological significance was attached to these trend analysis results in high-dose males and low- and mid-dose females.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

High-dose males consumed somewhat less food than controls throughout the study. The difference from controls was generally statistically significant and most pronounced in the first week (12% on day 7, and about 4-6% thereafter). Food consumption of low and mid-dose males showed no appreciable difference from that of controls (a few statistically significant differences between the low- or mid-dose group and the control group were considered irrelevant).

In females, food consumption was statistically significantly decreased at all dose levels during the first eight weeks of the treatment period (dose-dependently; about 5% at the low-dose, 6-7% aI the mid-dose, and 10-12% at the high-dose). Thereafter, only the decreases in high-dose females generally remained statistically significant until the end of the study, whereas the decreases in mid-dose females were no longer statistically significant after day 196. Food consumption in low-dose females approached that of controls after week 8. Since the relative differences from controls were small, the lower body weight and feed consumption in high-dose females were not considered toxicologically significant.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, non-treatment-related

Description (incidence and severity):

High-dose females tended to drink less (about 7-10%) water than controls between days 42 and 168. Except for day 105-112, the differences from controls were not statistically significant. Water consumption of male rats showed no relevant differences between rats fed the test substance and controls. Water consumption data showed no consistent differences between the treated groups and the control group.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

Ophthalmoscopic examination revealed no treatment-related ocular changes.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Haematology results showed lower (about 20%) mean values for total white blood cells and the absolute numbers of lymphocytes, eosinophils and basophils in high-dose males at the end of the treatment period. Eosinophils (percentage and absolute number) in high-dose males were also lower than in controls in week 13 and week 26. The observation of these lower white blood cell values at the highest dose level is suggestive of a relation with treatment. However, there were no treatment-related changes in the primary lymphoid organs bone marrow (morphology) and thymus (morphology and weight). Moreover, white blood cell values in high-dose males were within the physiological rangel. Therefore, the lower white blood cell values noted in high-dose males were considered not to be related to the ingestion of the test substance.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Evaluation of clinical chemistry parameters revealed statistically significant increases in ALKP, ALT, SDH and albumin/globulin ratio, and decreases in total protein, 5'-ND, plasma lipids (cholesterol, phospholipids, and, less consistently, triglycerides) and PO4 primarily at the mid- and high-dose levels (2.5 and 5%) in both sexes. However, these changes were of low magnitude and not accompanied by corroborative pathological conditions (e.g., damage to the liver, kidneys, thyroid, or intestines), so they were considered of no toxicological significance.

Other statistically significant differences in clinical chemistry parameters were sporadic across treatment group, sex, and/or time and were not ascribed to treatment.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Significant changes in urinalysis data were limited to a slight increase in pH in the high-dose (5%) group males (week 52) and mid- and high-dose (2.5 and 5%) group females (weeks 26 and 52). An isolated increase in urinary pH was considered not to be
of toxicological significance.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Evaluation of information available from daily clinical observations, FOB and motor activity testing did not reveal any neurobehavioural effects from the test substance.

Immunological findings:

no effects observed

Description (incidence and severity):

Immunotoxicity screening by evaluation of relevant data from haematology, clinical chemistry, weights of thymus and spleen, and pathology did not reveal any primary indicator of immunotoxicity.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Organ weights showed no significant changes with the exception of slightly lower mean values for absolute and relative liver weight in males at all dose levels. The decreases in liver weights were only slight (5–10%), and not reflective of hepatotoxicity as corroborated by a lack of treatment-related pathological changes in the liver.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Gross examination of the surviving animals did not reveal treatment-related changes.

Neuropathological findings:

no effects observed

Description (incidence and severity):

Evaluation of information available from daily clinical observations, FOB and motor activity testing, gross examination at necropsy, weight of the brain and routine microscopic examinations did not reveal any changes indicative of neurotoxic effects of the test substance.

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic examination of the organs and tissues revealed tumorous and nontumorous histopathological changes in all groups, including controls. The non-tumourous changes were of a type commonly observed in rats of this strain and age, and occurred only incidentally or at comparable or random incidences between the groups, including controls. Various tumours were observed in a few rats of all groups, including controls (i.e., cortical adenoma of the adrenal
gland [benign], lymphoma [malignant], hepatocellular adenoma [benign], adenocarcinoma in mammary gland [malignant], adenoma [benign] in the pituitary gland, adenocarcinoma [malignant] in the pituitary gland, C-cell adenoma [benign] and cystic follicular cell adenoma [benign] in the thyroid). These tumuors were considered not to be related to treatment because they were observed in a single or a few animals only and are known to occur spontaneously in older (1 year or older) rats of this strain and age.

The only noteworthy microscopic observation in this study was an increase in the incidence of endometrial stromal polyps, a benign uterine tumor, in mid- and high-dose (2.5 and 5%) females. The endometrial stromal polyps were observed in the uterus of one control, two low-dose (1.25%), six mid-dose (2.5%), and six high-dose (5%) females. The lesion varied from a macroscopically not detected small sessile nodule restricted to the endometrial wall to an oedematous (congested) polypoid mass protruding into the uterine lumen or through the cervix into the vagina as observed in two of the rats that were sacrificed prior to week 53. All polyps had a fibrovascular stroma with various amounts of collagen and were covered with cuboidal to columnar epithelium which was continuous with and similar with respect to oestrous cycle morphology to the surrounding lining endometrial epithelium. Some had a cystic appearance due to dilated endometrial glands. There were no observed hyperplasia of endometrial glands, increased mitotic activity, cellular atypia, or a relationship between dose level and the size of the mass. Altogether, the reported effects were considered not to be related to treatment.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic examination of the organs and tissues revealed tumorous and nontumorous histopathological changes in all groups, including controls. The non-tumourous changes were of a type commonly observed in rats of this strain and age, and occurred only incidentally or at comparable or random incidences between the groups, including controls. Various tumours were observed in a few rats of all groups, including controls (i.e., cortical adenoma of the adrenal
gland [benign], lymphoma [malignant], hepatocellular adenoma [benign], adenocarcinoma in mammary gland [malignant], adenoma [benign] in the pituitary gland, adenocarcinoma [malignant] in the pituitary gland, C-cell adenoma [benign] and cystic follicular cell adenoma [benign] in the thyroid). These tumuors were considered not to be related to treatment because they were observed in a single or a few animals only and are known to occur spontaneously in older (1 year or older) rats of this strain and age. Therefore, the reported effects were considered not to be related to treatment.

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

Analysis of faeces: Compared with controls, the total amounts (in 3 days) of food consumed and faeces excreted were lower in high-dose females, whereas food consumption per kg body weight was not significantly affected.

Both the total amount of fat consumed and the faecal crude fat content were higher in high-dose females than in controls. In contrast, the amount of crude fat excreted in the faeces expressed as percentage of the amount of fat consumed ('proportion excreted') was significantly lower in the high-dose females. The faecal content of dry matter, protein, ash and carbohydrate showed no significant intergroup differences, whereas the total amounts of these constituents excreted and, to a lesser extent, their 'proportion excreted' were significantly lower in high-dose females than in controls.

The (calculated) total amount of energy consumed during the 3-day test period was about 10% lower in high-dose females than in controls. This difference was not statistically significant. The energy consumption per kg body weight per day was comparable between the groups fed SSL and controls. The faecal energy excretion (total in 3 days and kcal/kg body weight/day) was signhcantly lower in high-dose females than in controls.

These results do not indicate that the ingestion of diet containing tp to 5% SSL causes loss of energy in the faeces.

Key result

Dose descriptor:

NOAEL

Effect level:

2 641 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: neoplastic

histopathology: non-neoplastic

immunology

mortality

neuropathology

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

Key result

Dose descriptor:

NOAEL

Effect level:

2 214 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: neoplastic

histopathology: non-neoplastic

immunology

mortality

neuropathology

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

Key result

Critical effects observed:

no

Conclusions:

The results of this study in Wistar rats did not reveal adverse effects of sodium stearoyl lactylate (SSL) upon administration in the diet at levels up to 5 % (w/w) for one year. Therefore, the No-Observed-Adverse-Effect Level (NOAEL) of SSL under the conditions of this study was set at 5% in the diet, the highest concentration tested. This dietary level was equivalent to 2214 and 2641 mg SSL/kg body weight/day in males and females, respectively.

Executive summary:

The toxicity of the test substance sodium stearoyl lactylate (SSL; read-across substance for sodium lauroyl lactylate) was examined in Wistar rats fed diets containing 0, 1.25, 2.5, and 5% SSL for one year, equivalent to mean daily intakes of 558, 1115, and 2214 mg/kg/day in males and 670, 1339, and 2641 mg/kg/day in females, respectively. SSL was well tolerated at these dietary levels as evidenced by the absence of toxicologically significant changes in the general condition and appearance of the rats, survival, neurobehavioural endpoints, growth, feed and water intake, ophthalmoscopic examinations, haematology and clinical chemistry parameters, urinalysis, or necropsy findings. The occurrence of uterine endometrial stromal polyps was the only finding of potential significance. Given the frequent occurrence of these benign tumours in rats, wide variability in the reported incidence of this type of polyps in rats, the lack of statistical significance and lack of biological evidence to suggest a mechanism for the slightly greater incidence in the groups fed 2.5 and 5% SSL, it was concluded that the endometrial stromal polyps observed in females fed SSL were not related to treatment. The no observed adverse effect level (NOAEL) of SSL was placed at 5%, the highest dietary level tested (equivalent to 2214 mg/kg/day for males and 2641 mg/kg/day for females).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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

Additional information

No data is available for the target substance sodium lauroyl lactylate. Thus available data from a suitable read-across partner was used to assess the repeated-dose toxicity of the target substance. For justification of read-across please refer to IUCLID section 13.

The results of a repeated dose toxicity study in Wistar rats did not reveal adverse effects of sodium stearoyl lactylate (SSL) upon administration in the diet at levels up to 5 % (w/w) for one year. Therefore, the No-Observed-Adverse-Effect Level (NOAEL) of SSL under the conditions of this study was set at 5% in the diet, the highest concentration tested. This dietary level was equivalent to 2214 and 2641 mg SSL/kg body weight/day in males and females, respectively.

Justification for classification or non-classification

Due absence of any toxicologically relevant effects up to and above the relevant limit concentration of 1000 mg/kg bw/day obtained in repeated-dose toxicity study conducted with a suitabel read-across partner, classification of sodium lauroyl lactylate for repeated dose toxicity is not warranted in accordance with CLP Regulation 1272/2008.