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Description of key information

Repeated dose toxicity oral: NOAEL = 1000 mg/kg bw/day (2-year study), based on read-across

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data from handbook or collection of data. Peer-reviewed data. Only secondary source available.
Principles of method if other than guideline:
2-year chronic oral toxicity study in 200 rats.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Albino Sherman Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 100-250 g
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
24 months
Frequency of treatment:
7 days/week
Remarks:
Doses / Concentrations:
0.05, 0.2 and 1%
Basis:
other: nominal in the diet (Remark: the concentration of test material in the low dose group was increased to 2% after 6 months)
No. of animals per sex per dose:
25
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes (no further information)

BODY WEIGHT: Yes (no further information)

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 30, Day 90, 6 months and 24 months
- Parameters: red and white blood cell count, haemoglobin content and differential count

OTHER
FERTILITY ASSESSMENT: Yes (no further information)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Liver, spleen, heart, lungs, stomach, large intestine, small intestine, adrenal glands, gonads, pancreas and brain.
HISTOPATHOLOGY: Yes. Liver, spleen, heart, lungs, stomach, large intestine, small intestine, adrenal glands, gonads, pancreas and brain.
Rats were killed at 1, 3, 6 and 24 months for necropsy and tissues collected for microscopic examinations (no further information)
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
2% and 1 % in the diet: at 24 months minor hyperplasia of the stratified squamous epithelium with excess keratin formation of the cardiac mucosa of the stomach
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: At 1, 3 and 6 months, no significant differences were observed in mortality.

BODY WEIGHT AND WEIGHT GAIN: At 1, 3 and 6 months, no significant differences were observed in body weight gain.

HAEMATOLOGY: At 1, 3 and 6 months, no significant differences were observed in haematology.

GROSS PATHOLOGY: At 24 months, the only consistent difference that could be attributed to the test article was minor hyperplasia of the stratified squamous epithelium with excess keratin formation of the cardiac mucosa of the stomach in rats receiving the highest exposure to the test article (group 1: 2% in the diet after 6 months, group 3: 1% in the diet).

OTHER FINDINGS: No significant differences were observed in fertility in the 2 year study.
Dose descriptor:
NOAEL
Effect level:
>= 2 other: % in the diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Quality of whole database:
The available data comprises adequate and reliable (Klimisch score 2, due to read across) studies from reference substances with similar structure and intrinsic properties.
The selected study is thus sufficient to fulfil the standard information requirements set out in Anney VIII-IX, 8.6 in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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 sufficient data are available for repeated dose toxicity of Reaction products of oleoyl sarcosine with sodium hydroxide. In order to fulfil the standard information requirements set out in Annex IX, 8.6.2. and in accordance with Annex XI, 1.5., of Regulation (EC) No 1907/2006, read-across from the structurally related category members was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5., of Regulation (EC) No 1907/2006, whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, the substance listed below are selected as reference substances for hazard assessment.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13).

Discussion

Repeated dose toxicity oral

No studies are available investigating the repeated dose toxicity via the oral route of Reaction products of oleoyl sarcosine with sodium hydroxide. In order to fulfil the standard information requirements set out in Annex IX, 8.6.2. and in accordance with Annex XI, 1.5., of Regulation (EC) No 1907/2006, read-across from the structurally related category member Sodium N-lauroylsarcosinate (CAS 137-16-6) was conducted.

Sodium N-lauroylsarcosinate (CAS 137-16-6) was tested for chronic oral toxicity in a 2-year study in 200 rats (CIR, 2001; Technology Science Group Inc., 1994).

Groups of 25 Wistar rats per sex and dose were given 0.05, 0.2 and 1% of the test material in the diet, 7 days/week for 24 months. The concentration of the test material in the low dose group was increased to 2% (equiv. to 1000 mg/kg bw/day) after 6 months. A concurrent negative control group receiving the plain diet was included.

At one, three and six months no significant differences were observed in mortality, body weight gain and haematology. At the end of the study period, the only consistent difference observed in the gross pathology was minor hyperplasia of the stratified squamous epithelium with excess keratin formation of the cardiac mucosa of the stomach in rats receiving the highest exposure to the test article (group 1: 2%; group 3: 1% in the diet) due to the local irritating effects of the test substance. Furthermore, fertility assessment did not show any significant differences (no further information).

Based on the lack of adverse effects, a NOAEL of 1000 mg/kg bw/day (m, f) was identified in this study.

Sodium N-lauroylsarcosinate (CAS 137-16-6) was tested for subchronic repeated dose oral toxicity in a 90-day study, conducted according to OECD test guideline 408, and in compliance with GLP (Mandella, 1997).

Groups of 15 Sprague-Dawley derived outbred albino rats per sex and dose received the test item at doses of 30, 100 and 250 mg/kg bw/day on 7 days per week for 91 or 92 days, respectively (depending on scheduled sacrifice). Concurrent negative control animals received the vehicle only (sterile, distilled water). No treatment-related mortality or clinical signs of toxicity were observed throughout the study period. Statistically significant decreased body weight gain with 7 and 9% decreased body weights at study termination compared to controls was observed for the mid-and high-dose males (100 and 250 mg/kg bw/day, respectively). In contrast, females of the same dose groups showed recognisable, but statistically not significant lower body weight gain with 4% decreased body weights at necropsy compared to controls. Since animals still gained weight, and the decrease of body weight in comparison to the controls was <10%, this effect is considered to be not adverse. At necropsy, increased absolute stomach weights, stomach/body and stomach/brain weight ratios were noted in both males and females of the 100 and 250 mg/kg bw/day dose groups. All values were statistically significant, except absolute stomach weight in mid-dose females. The effect was associated with increased stomach wall thickness and yellow discolouration of non-glandular gastric mucosa. Histopathological examination revealed increased incidence and severity of squamous cell hyperplasia, hyperkeratosis/parakeratosis, inflammation and oedema of the non-glandular gastric mucosa of both males and females in these dose groups. No effects were observed in low-dose animals (30 mg/kg bw/day). Since this effect was noted in a dose-related manner, it is considered to be treatment-related. However, the effects reported were localised to the stomach only, reflecting the irritant characteristics of the test substance, and no further signs of systemic toxicity were observed in any of the animals in any dose-group throughout the study period. Thus, the NOEL of this study is 30 mg/kg bw/day, the LOAEL for local effects in the stomach is 100 mg/kg bw/day, and the systemic NOAEL was set to ≥ 250 mg/kg bw/day.

In summary, both available oral repeated dose toxicity studies revealed local effects to the stomach only. Since the chronic study is the one with the longest study duration, and considering the lack of any systemic effects in both chronic and subchronic studies, the overall NOAEL for systemic toxicity for Sodium N-lauroylsarcosinate (CAS 137-16-6) was set to 1000 mg/kg bw/day.

Conclusion for repeated dose toxicity, oral

In summary, a subchronic oral and a 2-year oral study of Sodium N-lauroylsarcosinate (CAS 137-16-6) showed no adverse systemic effects resulting in NOAELs of ≥ 250 mg/kg bw/day derived from the subchronic study and 1000 mg/kg bw/day derived from the chronic study. Since the NOAEL of 1000 mg/kg bw/day was derived from the study with the longest study duration and no adverse effect was observed in the subchronic study up to and including the highest dose of 250 mg/kg bw/day tested, the higher value is considered to be the most reliable dose descriptor. Thus, as a weight of evidence approach, a NOAEL of 1000 mg/kg bw/day after chronic oral application is concluded.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across based on a category approach. The selected study is the study with the longest duration and is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties among the category members and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

The available data on repeated dose toxicity of a structurally related category member to Reaction products of oleoyl sarcosine with sodium hydroxide do not meet the criteria for classification according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.