Reaction product with n-butanol of high-boiling stream resulting from the hydroxylation, oxidative cleavage and hydrolysis of vegetable oil saturated and unsaturated C16-C22 triglycerides.

Endpoint summary

Description of key information

There are two K1 studies available (Oberto, 2014) that both demonstrate the lack of toxicity after exposure through the oral and dermal exposure route up to 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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well-reported recent GLP study accroding to OECD guideline.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Italy s.r.l., San Pietro al Natisone (UD), Italy
- Age at study initiation: 7 weeks
- Weight at study initiation: 157-163 grams
- Housing: Polisulphone solid bottomed cages measuring 59.5x38x20 cm with nesting material provided into suitable bedding bags
- Diet (e.g. ad libitum): 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy). Diet supply Ad libitum throughout the study except for the dosing procedure.
- Water (e.g. ad libitum): Drinking water supplied to each cage via a water bottle, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-2°C
- Humidity (%): 55+/- 15%
- Air changes (per hr): Approximately 15 to 20 air changes per hour
- Photoperiod (hrs dark / hrs light): Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

2000 mg/kg

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: on dosing, 0.5h after dosing, 2h after dosing, 4h after dosing and after 2 X/day
- Necropsy of survivors performed: yes

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured

Clinical signs:

other: no clinical signs were observed in the 2 groups

Gross pathology:

no observed gross pathology

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test substance did not induce toxic effects in the rat following oral administration of a single dose at a level of 2000 mg/kg bw.

Executive summary:

The acute toxicity of FAV ES was investigated following a single oral administration to the Sprague Dawley rat followed by a 14-day observation period.

A first group of 3 female animals was initially dosed at 2000 mg/kg (Step 1). No mortality occurred and no clinical signs were observed. A second group of 3 female animals was then dosed at the same dose level (Step 2). No mortality occurred and no clinical signs were noted. Body weight changes recorded during the study were within the expected range for this strain and age of animals. No abnormalities were observed at necropsy examination performed at the end of the observation period on animals of both groups.

These results indicate that the test item FAV ES did not induce toxic effects in the rat following oral administration of a single dose at a level of 2000 mg/kg. The lack of mortality demonstrates the acute toxicity expected (ATE) to be greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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: Recent and well documented OECD guideline study following GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species and strain:
Rat, Hsd: Sprague Dawley SD

Sex:
Males and females (nulliparous and non-pregnant)

Age:
6 to 8 weeks old

Weight at order:
176 to 200 grams

Supplier:
Harlan Italy s.r.l., San Pietro al Natisone (UD), Italy

Weight range at arrival:
171 to 181 grams

Acclimatisation period:
At least 5 days

Animals per cage:
Up to 5 of one sex to a cage

Housing:
Clear polysulphone H-Temp solid bottomed cages (Techniplast Gazzada S.a.r.l., Buguggiate, VA, Italy) measuring 59.53820 cm during acclimatisation
period and 42.526.618.5 cm during the study with stainless steel mesh lid and floor.

Cage control:
Daily inspected and changed as necessary (at least 3 times/week)

Water:
Drinking water supplied to each cage via a water bottle

Water supply:
Ad libitum

Diet:
4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy)

Diet supply:
Ad libitum throughout the study

Room lighting:
Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours

Air changes:
Approximately 15 to 20 air changes per hour

Temperature range:
22 ± 2 °C

Relative humidity range:
55 ± 15%

Type of coverage:

semiocclusive

Details on dermal exposure:

Selection/Allocation:
Random at arrival. The body weight of each individual was within 20% of the mean and within the range of 200-300 grams. Animals were unequivocally numbered within the study. The animal number together with the study number ensured a unique animal numbering for any study employing computerised data collection.

Animal identification:
Animals were permanently identified, following arrival, by a combination of ear notch (units) and tattoo on the hind feet. Males and females were
identified by even and odd numbers, respectively.

Frequency of treatment:
Animals were dosed once only on Day 1.

Treatment area preparation:
On the day before dosing (Day –1), a single area was clipped free of hair (by an electric clipper equipped with a suitable blade) on the dorsal surfaces of the trunk of each animal (approximately 10% of body surface). Care was taken to avoid damage to the skin.

Dose calculation:
On the day of dosing (Day 1), the aliquots were weighed according to the body weight of each animal measured prior to dosing.

Dosing procedure:
An aliquot of the supplied test item was spread evenly over an area of approximately 10% of the body surface area. A patch of surgical gauze
covered by a strip of synthetic film was placed over the treated site and the whole assembly held in place by encircling the trunk of the animal with a
length of elastic adhesive bandage, this forming a semi-occlusive barrier.

Washing procedure
After exposure, the adhesive bandage and gauze patch were removed. The treatment area was cleaned by gentle swabbing of the skin with cotton wool soaked with lukewarm water.

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

A single group of 5 male and 5 female animals was dosed at a level of 2000 mg/kg.

Control animals:

not required

Details on study design:

In vivo observations

Mortality and morbidity:
Throughout the study all animals were checked twice daily.

Clinical signs:
Animals were observed for clinical signs as indicated below (and daily after a total of 14 days)

Day of dosing
– Session 1: on dosing
– Session 2: approximately 1 hour after dosing
– Session 3: 2 hours after dosing
– Session 4: 4 hours after dosing

Body weight
All animals were weighed at allocation to the study (Day -1), on the day of dosing (Day 1) and on Days 8 and 15. Body weight change calculated for Days 8 and 15 of the dosing phase was relevant to Day 1 of the phase.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the full duration of the test.

Clinical signs:

other: No signs of toxicity were observed in male or female animals after treatment during the observation period. Brown staining on the dorsal region, due to the colour of the test item, was observed from day 2 up to day 4 of the observation period in females.

Gross pathology:

No abnormalities were found at necropsy examination performed on all
animals at termination of the study.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The results indicate that the test item, FAV-ES, has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg.The dermal LD50 of FAV-ES was determined to be > 2000 mg/kg.

Executive summary:

The acute toxicity of FAV ES was investigated following dermal administration of a single dose to the rat. A single dose of 2000 mg/kg was administered to a group of 5 male and 5 female animals for 24 hours. The test was carried out according to OECD and GLP guidelines.

After 14 days, all animals were killed and subjected to necropsy examination. No mortality occurred and no signs of toxicity were observed in male or female animals during the observation period. The body weight changes observed during the study were within the expected range for this species and age of animals. No abnormalities were found at necropsy in the animals at termination of the study, nor at the treated site. These results indicate that the test item, FAV ES, has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg. The lack of mortality demonstrates the LD50 to be greater than 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Acute toxicity data are available for the target substance and for a number of read-across substances.

 

The acute toxicity of FAV ES was investigated following a single oral administration to the Sprague Dawley rat followed by a 14-day observation period (Oberto, 2014). A first group of 3 female animals was initially dosed at 2000 mg/kg (Step 1). No mortality occurred and no clinical signs were observed. A second group of 3 female animals was then dosed at the same dose level (Step 2). No mortality occurred and no clinical signs were noted. Body weight changes recorded during the study were within the expected range for this strain and age of animals. No abnormalities were observed at necropsy examination performed at the end of the observation period on animals of both groups.

The acute toxicity of FAV ES was also investigated following dermal administration of a single dose to the rat. A single dose of 2000 mg/kg was administered to a group of 5 male and 5 female animals for 24 hours. After 14 days, all animals were killed and subjected to necropsy examination. No mortality occurred and no signs of toxicity were observed in male or female animals during the observation period. The body weight changes observed during the study were within the expected range for this species and age of animals. No abnormalities were found at necropsy in the animals at termination of the study, nor at the treated site. These results indicate that the test item, FAV ES, has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg. The lack of mortality demonstrates the LD50 to be greater than 2000 mg/kg.

Furthermore, literature publications are available in which the acute toxicity of the following source substances has been described:

 

Butyl stearate (Smith, 1953): The acute toxicity of butyl stearate was examined by oral administration of the undiluted test substance to 5-6 week old male rats, in doses ranging from 4000 to 32000 mg/kg bw. Surviving animals were weighed daily for 7 days. The single oral administration of doses of butyl stearate as high as 32000 mg/kg bw were tolerated without lethal effects. Increased perspiration was a uniform occurrence in all rats of the highest dose group. The reaction was evident five minutes after the compound was administered and persisted for one to two days. No gross pathological changes were noted in any of the animals. From these data it can be concluded that butyl stearate has an LD0 of 32000 mg/kg bw.

Dibutyl sebacate (Smith, 1953): The acute toxicity of dibutyl sebacate was examined by oral administration of the undiluted test substance to 5-6 week old male rats, in doses ranging from 4000 to 32000 mg/kg bw. Surviving animals were weighed daily for 7 days. The single oral administration of doses of dibutyl sebacate up to 16000 mg/kg bw were tolerated without lethal effects. A single dose of 32000 mg/kg bw caused the death of all animals in that dose group. No gross pathological changes were noted in any of the animals in the different dose groups. From these data it can be concluded that dibutyl sebacate has an LD0 of 16000 mg/kg bw and an LD100 of 32000 mg/kg bw.

Medium- and Long-Chain Triacylglycerol oil (Matulka, 2006): The actue toxicity of medium- and long-chain triacylglycerol oils was examined by oral administration (via gavage) of 5000 mg/kg bw of the test substance to two groups of 5 -week old Wistar rats. The animals were observed for 6h after administration, and once daily for the following 14 days. Body weight measurements were performed on the day of test substance administration and on days 1, 2, 3, 4, 7 and 14 thereafter. At the end of the observation period, the animals were euthanized and a gross autopsy was carried out.

The experimental results show that all rats survived the 14d observation period, and showed typical body weight gain throughout the observation period, with no significant differences compared to the control group. Therefore, it can be concluded that the LD50 exceeds 5000 mg/kg bw.

The results obtained for the read-across substances are in line with those found for FAV-ES, thus substantiating the read-across approach.

Justification for selection of acute toxicity – oral endpoint
This study is a well documented, recent GLP study according to international guidelines.

Justification for selection of acute toxicity – inhalation endpoint
The substance considers a viscous oil and exposure to humans via the inhalation route is not likely. Both oral and dermal exposure routes are covered in the study reports by Oberto, 2014 and showed no adverse effects.

Justification for selection of acute toxicity – dermal endpoint
This study is a well documented, recent GLP study according to international guidelines.

Justification for classification or non-classification

Based on the acute toxicity results, showing LD50 values > 2000 mg/kg bw for oral and dermal administration and a lack of clinical signs suggesting toxicity, the substance should not be classified for acute toxicity nor for Specific Target Organ Toxicity following Single Exposure (STOT-SE) according to the criteria described in EU Regulation No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures (CLP). Likewise, classification for acute toxicity is not required under the conditions described in Directive 67/548/EEC (Dangerous Substances Directive).