hydrogenation products of (esterification products of 2-ethylhexan-1-ol with (Estolide formation products of oleic acid and Fatty acids, C8-18 and C18-unsatd. (branched or linear)).

Endpoint summary

Description of key information

No effects seen in the oral, inhalatory and dermal studies available.

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:

Study conducted between the 21st February and the 18th April 2013.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

Animals were received from Charles River, Raleigh NC, on 31 Jan 2013 and 05 Mar 2013. Following an acclimation period of at least five days, six healthy, non-pregnant and nulliparous female Sprague Dawley rats were assigned to treatment groups without conscious bias.

The animals were born the 05 Dec 2012 and 07 Jan 2013. The pretest body weight range was 196 - 240 grams. The weight variation of the animals used did not exceed ±20% of the mean weight of the previously dosed animals.

The animals were identified by cage notation and indelible body marks, and housed in suspended wire cages; five per sex per cage prior to dosing and three per sex per cage following dosing. Absorbent paper bedding was placed beneath the cages and changed at least three times per week.

Fresh PMI Rat Chow (Diet #5012) was freely available except for 16-20 hours prior to dosing. Water was available ad libitum. The animal room, reserved exclusively for rats on acute tests, was temperature controlled, had a 12-hour light/dark cycle, and was kept clean and vermin free.

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
No vehicle was used

Dosing:
The test article was used as received and the dose was based on the sample weight as calculated from the specific gravity. A single dose was administered orally by syringe and dosing needle at a dose level of 2000 mg/kg to six female rats.

Doses:

3 females were initially dosed at 2000 mg/kg, followed by a further three females.

No. of animals per sex per dose:

6 females dosed at 2000 mg/kg.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed at 15 minutes, 1, 2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects, and twice daily for mortality. Body weights were recorded immediately pretest, weekly, and at termination. All animals were examined for gross pathology.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no abnormal physical signs observed.

Clinical signs:

There were no abnormal physical signs observed.

Body weight:

All animals gained body weight by study termination.

Gross pathology:

The gross necropsy of all animals revealed no observable abnormalities.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

No effects were seen during the study on the test material (CAS# 1365345-64-7 (SE7B Batch 2137-0)). The test substance is not classified according to the Dangerous Substances Directive or to CLP.

Executive summary:

Objective:

To determine the potential for oral toxicity using the Acute Toxic Class Determination. This study was designed to comply with the standards set forth in current OECD Guidelines for the Testing of Chemicals, Guideline 423 adopted December 17, 2001. Guideline 423 is referred to in DPPTS 870.1000 as an acceptable method to assess lethality within a dose range. The test article is assigned to a toxic category based on the mortality results and significant clinical signs of toxicity up to the Category 4 value tested according to the current Globally Harmonized System of Classification and Labeling of Chemicals (GHS).

Method Synopsis:

Initially three healthy female Sprague Dawley rats were dosed orally with CAS# 1365345-64-7 (SE7B Batch 2137-0) at 2000 mg/kg. An additional three healthy females were dosed as a confirmatory group at 2000 mg/kg. The rats were observed at 15 minutes, 1, 2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects, and twice daily for mortality. Body weights were recorded immediately pretest, weekly, and at termination. All animals were examined for gross pathology. The test article was assigned to a toxic category based on the mortality response noted.

Summary:

All six females survived the single 2000 mg/kg oral dose. There were no abnormal physical signs observed. All animals gained body weight by study termination. The gross necropsy of all animals revealed no observable abnormalities.

Conclusion: CAS# 1365345-64-7 (SE7B Batch 2137-0) is considered to be in Acute Toxic Category 5, or unclassified. The oral LD50 is greater than 2000 mg/kg in female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January 22, 2015 - February 23, 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Rat (Rattus norvegicus) / CD / Crl: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species / Strain / Stock:
Rat (Rattus norvegicus) / CD / Crl: CD(SD)

Breeder:
Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany

Age(at start of administration):
Males: approx. 8 weeks
Females: approx. 9 weeks

Body weight(at start of administration):
Males: 247 - 258 g
Females: 228 - 250 g

Selection of species:
In accordance with OECD 436, the rat is the preferred species.

Identification of animals:
By coloured marks and cage label

Group / Number of animals:
One concentration of 3 males and 3 females (limit test)

Satellite animals forinterim necropsy(24-hour sacrifice):
3 males and 3 females

Concentrations:
5.07 mg/L air (limit test) for 4 hours and 5.06 mg/L air (satellite animals) for 4 hours

Duration of experiment:
At least 5 adaptation days
1 test day
2 recovery weeks (limit test)

The females were nulliparous and non-pregnant.
The animals were randomised before use. They were acclimatised to the test apparatus for approx. 1 hour on 2 days prior to testing. The restraining tubes did not impose undue physical, thermal or immobilization stress on the animals.

Diet
Commercial diet, ssniff® R/M-H V1534 served as food. Feeding was discontinued approx. 16 hours before exposure; only tap water was then available ad libitum.
Periodic analysis of the food for contaminants based on EPA/USA is conducted at least twice a year by LUFA-ITL.

Housing
Granulated textured wood was used as bedding material for the cages. The cages were changed and cleaned twice a week.
Periodic analysis of the bedding material for contaminants based on EPA/USA is conducted at least once a year by LUFA-ITL.
During the 14-day observation period, the animals are kept by sex in groups of 3 animals in MAKROLON cages (type III plus) at a room temperature of 22°C±3°C (maximum range) and a relative humidity of 55%±15% (maximum range). Deviations from the maximum range caused for example during cleaning procedures are dealt with in SOPs.
The rooms were lit (about 150 lux at approx. 1.50 m room height) and darkened for periods of 12 hours each.

Drinking water
Drinking water in bottles was offered ad libitum.
Drinking water was examined according to the 'Deutsche Trinkwasserverordnung 2011' [German Regulations on drinking water 2011] by the Hamburger Wasserwerke, 20539 Hamburg, Germany, at least four times a year.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose/head only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

2.488 µm

Geometric standard deviation (GSD):

2.97

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5.07 mg/L air (limit test) for 4 hours and 5.06 mg/L air (satellite animals) for 4 hours

No. of animals per sex per dose:

3 males and 3 females

Control animals:

yes

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.07 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No animal died prematurely.

Clinical signs:

other: Under the present test conditions, a 4-hour inhalation exposure to SE7B at a concentration of 5.07 mg/L air revealed slightly reduced motility and slight ataxia on test day 1 immediately after the end of exposure until 60 minutes post exposure, slight to

Body weight:

No influence on body weight gain was observed.

Gross pathology:

Macroscopic changes in the nasal cavity and lungs
Oedematous or oedematous and marbled lungs were observed in all animals of the main study (14-day sacrifice) and in all satellite animals (24-hour sacrifice).

Microscopic changes in the nasal cavity and lungs
Test item-related histopathological changes
The histomorphological examination of the organs (trachea, larynx, lungs and nose) from the acute inhalation toxicity study of SE7B in male and female rats of the satellite rats (24-hour sacrifice) and the main study animals (14 days recovery) did not reveal any morphological lesions which are considered to be test item-related.

Not test item-related histopathological changes
Satellite animals (24-hour sacrifice) and main study animals (14-day sacrifice):
• Nose (five levels):
The nasal cavity of level 1 to 5 revealed a normal squamous epithelium and a normal respiratory epithelium. The normal respiratory epithelium partially containing cilia consisted of three major cell types: the basal cells above the basement membrane, the ciliated epithelial and the secretory goblet cells.
Some rats showed in the respiratory epithelium minimal to mild subepithelial lympho-histiocytic infiltrations or lymphocytic follicles for nose levels 3 to 5.

In all animals a normal olfactory epithelium with 5 to 7 nuclear layers, normal basal cells, olfactory sensory cells and sustentacular cells were observed for nose levels 3 to 5.
There were no morphological differences between the satellite and main study animals.
• Lungs (five levels):
All 5 lung localizations revealed a normal lung structure. A minimal to mild congestion and in one rat a minimal foamy macrophages are coincidental findings and thus are not test item-related.
The trachea of some male and female animals revealed a focal minimal to mild subepithelial lymphoid hyperplasia with normal epithelial cells. The epithelium of the larynx was normal.
There were no morphological differences between satellite and main study animals.

Other findings:

The gravimetric aerosol concentrations of 5.07±0.02 mg (14-day sacrifice) and 5.06±0.02 mg (24-hour sacrifice) SE7B/L air were measured at the animal’s nose.
The particle size distribution was analysed using a cascade impactor. The Mass Median Aerodynamic Diameter (MMAD) was determined as 2.488 μm (14-day sacrifice) or 2.460 μm (24-hour sacrifice). The Geometric Standard Deviations (GSD) of the MMAD were calculated as 2.97 (main study, 14-day sacrifice) or 2.96 (satellite animals, 24-hour sacrifice).

The mean actual exposure concentrations in the breazing zone, the nominal concentration (total amount of the substance fed into the inhalation equipment divided by volume of air), MMADs and GSDs of SE7B were as follows:

Group	nominal concentration	gravimetric (actual) concentration	mass median aerodynamic diameter (MMAD)	geometric standard deviation (GSD)	Relation of actual to nominal concentration (assumed density = 1 g/mL)
	[μL/L air]	[mg/L air]	[μm]
main study, 14-day sacrifice	33.33	5.07	2.488	2.97	0.15
satellite animals, 24-hour sacrifice	33.33	5.06	2.46	2.96	0.15

Conclusion

Under the present test conditions, the LC50 value (males and females combined) for rats following inhalation of SE7B for 4 hours was determined as follows (gravimetric concentration):

LC50: > 5.07 mg SE7B/L air

According to the Globally Harmonized Classification System (GHS) the test item should be unclassified (as LD50 > 5 mg/L air). Based on the results of the macroscopic and histopathological investigations, SE7B appears to be slightly irritating for the respiratory epithelium, however, no histological changes could be observed. The changes were almost completely reversible during the 14-day recovery period.

Interpretation of results:

GHS criteria not met

Conclusions:

Conclusion
Under the present test conditions, the LC50 value (males and females combined) for rats following inhalation of SE7B for 4 hours was determined as follows (gravimetric concentration):
LC50: > 5.07 mg SE7B/L air
According to the Globally Harmonized Classification System (GHS) the test item should be unclassified (as LD50 > 5 mg/L air). Based on the results of the macroscopic and histopathological investigations, SE7B appears to be slightly irritating for the respiratory epithelium, however, no histological changes could be observed. The changes were almost completely reversible during the 14-day recovery period.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 070 mg/m³

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were received from Covance Research Products, Inc., Denver, PA on 27 Feb 2013. Following an acclimation period of at least one week, five healthy male and five healthy, non-pregnant and nulliparous female New Zealand White rabbits were randomly assigned to the treatment group using standard methods of randomization.


The animals were born on 22 Sep 2012 and 25 Sep 2012. The pretest body weight range was 2.3 - 2.8 kg for males and 2.4 - 2.9 kg for females. The weight variation of the animals used did not exceed ± 20% of the mean weight.


The animals were identified by cage notation and a uniquely numbered metal ear tag and housed one per cage in suspended wire cages. Absorbent paper bedding was placed beneath the cages and changed at least three times per week. Fresh PMI Rabbit Chow (Diet #5321) was provided daily. Water was available ad Iibitum. The animal room, reserved exclusively for rabbits on acute tests, was temperature controlled, had a 12-hour light\dark cycle, and was kept clean and vermin free.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
Approximately 24 hours prior to application of the test article, the dorsal area of the trunk of each animal was clipped free of hair. The prepared site was approximately 10% of the body surtace and remained intact.

DOSING:
A single dose of the test article was applied to the prepared site, over a porous gauze dressing measuring 10 x 15 cm at a dose level of 2000 mg/kg. The dose was based on the sample weight as calculated from the specific gravity. The torso was wrapped with a piece of porous dressing (semi-occlusive) and was secured with non-irritating tape. The test article remained in contact with the skin for 24 hours at which time the wrappings were removed. Residual test article was removed by gently washing with distilled water.

REMOVAL OF TEST SUBSTANCE
- Washing: Residual test article was removed by gently washing with distilled water.

VEHICLE
No vehicle

Duration of exposure:

The test article remained in contact with the skin for 24 hours at which time the wrappings were removed.

Doses:

2000 mg/kg.

No. of animals per sex per dose:

5 maes and 5 females were dosed at 2000 mg/kg.

Control animals:

no

Details on study design:

The test sites were scored for dermal irritation at 24 hours postdose and on Day 14 using the numerical Draize scoring code below:
Erythema & Eschar
No erythema - 0
Very slight erythema (barely perceptible) - 1
Well defined erythema - 2
Moderate to severe erythema - 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) - 4

Edema:
No edema - 0
Very slight edema (barely perceptible) - 1
Slight edema (edges of area well-defined by definite raising) - 2
Moderate edema (raised approximately 1.0 mm) - 3
Severe edema (raised more than 1.0 mm, extending beyond the area of exposure) - 4

The animals were observed 1 and 4 hours postdose and once daily for 14 days for mortality, toxicity and
pharmacological effects.

Body weights were recorded pretest, weekly and at termination.

All animals were humanely sacrificed using CO2 following study termination and examined for gross pathology.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Mortality:

All ten rabbits survived the single 2000 mg/kg 24-hour dermal exposure.

Clinical signs:

There were no abnormal physical signs observed.

Body weight:

All of the animals gained body weight by study termination.

Gross pathology:

The gross necropsy of all animals revealed no observable abnormalities.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The dermal LD50 of CAS# 1365345-64-7 (SE7B Batch 2137-0) is greater than 2000 mg/kg of body weight in rabbits.

Executive summary:

Objective: To determine the potential for toxicity of the test article when applied dermally. This study is designed to comply with the standards set forth in OECD GUIDELINES FOR TESTING CHEMICALS, NUMBER 402, adopted February 24, 1987.

Method Synopsis:

Five healthy male and five healthy female New Zealand White rabbits were dosed dermally with CAS# 1365345-64-7 (SE7B Batch 2137-0) at 2000 mg/kg of body weight. The test article was kept in contact with the skin for 24 hours. Dermal responses were recorded at 24 hours postdose and on Day 14. Animals were observed for mortality, toxicity and pharmacological effects at 1 and 4 hours postdose and once daily for 14 days. Body weights were recorded pretest, weekly and at termination. All animals were examined for gross pathology.

Summary:

All ten rabbits survived the single 2000 mg/kg 24-hour dermal exposure. There were no abnormal physical signs observed. At 24 hours, erythema was very slight to well-defined and edema was absent to slight. By Day 14, erythema and edema were absent. All of the animals gained body weight by study termination. The gross necropsy of all animals revealed no observable abnormalities.

Conclusion: The dermal LD50 of CAS# 1365345-64-7 (SE7B Batch 2137-0) is greater than 2000 mg/kg of body weight in rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Justification for selection of acute toxicity – oral endpoint
No effects were seen during the study on the test material (CAS# 1365345-64-7 (SE7B Batch 2137-0)). The test substance is not classified according to the Dangerous Substances Directive or to CLP.

Justification for selection of acute toxicity – inhalatory endpoint

Conclusion Under the present test conditions, the LC50 value (males and females combined) for rats following inhalation of SE7B for 4 hours was determined as follows (gravimetric concentration): LC50: > 5.07 mg SE7B/L air According to the Globally Harmonized Classification System (GHS) the test item should be unclassified (as LD50 > 5 mg/L air). Based on the results of the macroscopic and histopathological investigations, SE7B appears to be slightly irritating for the respiratory epithelium, however, no histological changes could be observed. The changes were almost completely reversible during the 14-day recovery period.

Justification for selection of acute toxicity – dermal endpoint
The dermal LD50 of CAS# 1365345-64-7 (SE7B Batch 2137-0) is greater than 2000 mg/kg of body weight in rabbits.

Justification for classification or non-classification

Under CLP, the data available indicates the substance should not be considered for classification.

Oral:

All six females survived the single 2000 mg/kg oral dose. There were no abnormal physical signs observed. All animals gained body weight by study termination. The gross necropsy of all animals revealed no observable abnormalities.

Conclusion: The oral LD50 is greater than 2000 mg/kg in female rats.

Dermal:

All ten rabbits survived the single 2000 mg/kg 24-hour dermal exposure. There were no abnormal physical signs observed. At 24 hours, erythema was very slight to well-defined and edema was absent to slight. By Day 14, erythema and edema were absent. All of the animals gained body weight by study termination. The gross necropsy of all animals revealed no observable abnormalities.

Conclusion: The dermal LD50 is greater than 2000 mg/kg of body weight in rabbits.