Registration Dossier

Administrative data

Description of key information

Oral:
-female rats, LD50: greater than 2000 mg/kg bw
-female rats, LD50 sorbitan stearate): greater than 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2008-12-09 to 2009-01-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study under GLP
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories Ltd.
- Age at study initiation: 11 weeks
- Weight at study initiation: 178.7 g - 207.9 g
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE

- Amount of vehicle (if gavage): 10 mL/kg body weight.

Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
6 animals (2 groups, 3 animal/group)
Control animals:
no
Details on study design:
Viability / Mortality: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (in common with the clinical signs) and twice daily during days 2-15.

Clinical Signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1, depending on the occurrence of clinical signs of toxicity. Once daily during days 2-15.

Body Weights: On test days 1 (prior to administration), 8 and 15.

All animals were killed at the end of the observation period by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
No deaths occurred during the study.
Clinical signs:
No clinical signs were observed during the course of the study.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose of Sorbitanmonocaprylat after single oral administration to female rats, observed over a period of 14 days, is:
LD50 (female rat): greater than 2000 mg/kg body weight.
Executive summary:

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with sorbitan caprylate by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was formulated in PEG 300 at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15.

All animals were necropsied and examined macroscopically.

All animals survived until the end of the study period.

No clinical signs were observed during the course of the study.

The body weight of the animals was within the range commonly recorded for this strain and age.

No macroscopic findings were recorded at necropsy.

The median lethal dose of sorbtian caprylate after single oral administration to female rats, observed over a period of 14 days, is: LD50 (female rat): greater than 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
reliable and robust; two studies available on target and source chemicals

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The acute toxicity of sorbitan caprylate was reasonably derived based on the experimental data and on the read-across approach using sorbitan stearate as source chemicals.

In both oral studies of the target and source chemicals, the LD50 is greater than 2000 mg/kg bw.

The analogue approach using sorbitan stearate as source chemical is justified:

Both chemicals are of comparable structures with minor deviations and can be characterized as an ester of sorbitan and a fatty acid. Compared to the source chemical, the target chemical has a shorter alkyl chains that affect its physicochemical properties. But based on the kinetic / metabolic investigations on both chemicals, the length of the alkyl chain is not considered to have significant impact on the metabolic pathway or toxicological mode of action. Oral gavage studies in rats administered C14 labeled sorbitan stearate in oil solutions have demonstrated that about 90% of the substance was absorbed and hydrolyzed to stearic acid and sorbitan. The metabolic fate of sorbitan caprylate was investigated using a lipase assay. The hydrolysis mediated by porcine pancreas lipase was quantitatively determined. The target chemical sorbitan caprylate is proved to be hydrolyzed and caprylic acid was formed . These findings suggest that metabolism of the sorbitan occur initially via enzymatic hydrolysis, leading to sorbitan and the corresponding natural acids.

Based on the above mentioned information, it is reasonable to consider that these two substances are comparable in their metabolic fate and thereby toxicological profiles. Hence, the source chemical is considered as “suitable with interpretation” analog.

According to the available toxicity studies, the findings are also comparable for target and source chemicals:

·        The findings in acute toxicity studies are comparable. Both chemicals are of no acute toxicity.

·        The findings in subacute dose toxicity studies are comparable. No treatment effects were observed in 28-day repeated toxicity studies in Wistar rats. The same NOEL of 1000 mg/kg bw/d was derived for both chemicals.

·        The findings in genetic toxicity are comparable. Both chemicals did not induce gene mutations in Ames tests, but induced structural chromosomal aberrations in cell lines of Chinese Hamster.

·        The findings in reproduction / developmental toxicity studies are comparable.

In an acute toxicity study, two groups, each of three female HanRcc:WIST (SPF) rats, were treated with sorbitan caprylate by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was formulated in PEG 300 at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. No clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

The median lethal dose of sorbtian caprylate after single oral administration to female rats, observed over a period of 14 days, is: LD50 (female rat): greater than 2000 mg/kg body weight.

In another study, two groups, each of three female SD rats, were treated with sorbitan stearate by oral gavage administration at a dosage of 2000 mg/kg body weight. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. Body weights were recorded on day 1, 2, 4, 8, 11, and 15. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. No clinical signs were observed during the course of the study. No reduction of body weight was observed No macroscopic findings were recorded at necropsy.

The median lethal dose of soribitan stearate after single oral administration to female rats, is: LD50 (female rat): greater than 2000 mg/kg body weight

Both oral studies were used for the assessment of acute toxicity of sorbitan caprylate. Based on the study results, no acute toxicity could be derived.


Justification for selection of acute toxicity – oral endpoint
Guideline study according to GLP

Justification for classification or non-classification

Based on the available data no classification is warranted according to the criteria laid down in the EU Dangerous Substances Directive (67/548/EEC) and in the EU Classification Labelling and Packaging Regulation (1272/2008/EC).