Reaction product of Fatty acids, C18 alkyl with amines, polyethylenepoly-tetraethylenepentamine fraction

Endpoint summary

Description of key information

The acute oral toxicity of Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and tetraethylenepentamine is low. The oral LD50 of the substance was determined to be > 2000 mg/kg bw in rats in an acute oral toxicity study (OECD Test Guideline 423) whereas the dermal LD50 of the substance was determined to be > 2000 mg/kg bw in rats in an acute dermal toxicity study (OECD Test Guideline 402). A waiver is proposed in accordance with Column 2 of Annex VIII of the REACH Regulation for acute inhalation toxicity on the basis that acute toxicity data are available for the oral and dermal routes. Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance.

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:

6th February 2012 to 21st June 2012.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study, conducted in accordance with the relevant guidelines.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

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

Principles of method if other than guideline:

Not applicable.

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: HsdHan:WIST

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Ltd, Bicester
- Age at study initiation: 8 to 10 weeks of age.
- Weight at study initiation: The weight variation did not exceed ±20% of the mean weight.
- Fasting period before study: Animals were fasted for a period of time from the evening of the day prior to dosing until approximately 3 hours after dosing.
- Housing: The animals were housed in groups of up to five during the acclimatisation period.
- Diet: SQC(E) Rat and Mouse Maintenance Diet No 1 was freely available at all times, except during the fasting period.
- Water: Mains water was provided, ad libitum, via cage-mounted water bottles.
- Acclimation period: 9 to 14 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24°C
- Humidity (%): 45 to 65%
- Air changes (per hr): 15 to 20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
Corn oil.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw.

DOSAGE PREPARATION (if unusual):
Due to the viscosity of the test article, it had to be diluted in order for it to be dosed. The test article was dispersed in corn oil because the test article did not suspend in purified water. The formulated concentrations were calculated from the selected dose level and the dose volume of 10 mL/kg bw. All formulations were used within two hours of preparation.
The formulations were maintained on a magnetic stirrer prior to administration to ensure homogeneity.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Since there were no data to indicate that deaths may occur at dose levels of less than 2000 mg/kg bw, the first dose level was 2000 mg/kg bw.

Treatment of animals was sequential. Sufficient time was allowed between each group to confirm the survival of the previously dosed animals.

Doses:

2000 mg/kg bw.

No. of animals per sex per dose:

3 females per group.

Control animals:

no

Details on study design:

Two groups of 3 female rats were administered 2000 mg/kg bw test material in a dose volume of 10 mL/kg bw. The treatment of the animals was sequential, with sufficient time allowed between the dosing of each group to allow time for confirmation of the survival of the previously dosed animals. Individual dose volumes (mL) were calculated using the fasted body weights of the rats on the morning of dosing (Day 1) and the dose volume of 10 mL/kg bw.

Rats were observed for clinical signs of reaction to treatment immediately post dose and at approximately 15 and 30 minutes post-dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. Individual records of clinical signs were maintained for each treated rat.

Body weights were recorded on the day prior to dosing and on days 1, 4, 8 and 15.

Rats were killed day 15. Examination of all external surfaces and orifices, all viscera and tissue within the abdominal, thoracic and cranial cavities, free-hand sectioning of the liver and kidneys and examination of representative sections of mucosal surfaces of the stomach, small and large intestines was conducted. No tissue preservation or histopathological assessment of tissues was performed.

Statistics:

Not required.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths following a single oral dose of TOFA_DimerFA_TEPA_PAA at 2000 mg/kg bw.

Clinical signs:

other: No clinical signs were observed.

Gross pathology:

No macroscopic changes were observed for animals killed on Day 15.

Other findings:

No other findings reported.

No additional information.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the acute median lethal oral dose level of the test article, TOFA_DimerFA_TEPA_PAA, was found to exceed 2000 mg/kg bw.

Executive summary:

The acute oral toxicity of TOFA_DimerFA_TEPA_PAA was evaluated in a GLP study conducted according to OECD Test Guideline 423 and Method B.1 tris of Council Regulation (EC) No 440/2008. Two groups of three female HsdHan:WIST rats were administered a single dose of TOFA_DimerFA_TEPA_PAA via oral gavage at a dose level of 2000 mg/kg bw. The test article was dispersed in corn oil and administered at a dose volume of 10 mL/kg bw.

All test animals were observed for 14 days and clinical signs, body weight and mortality were recorded. All test animals were killed on Day 15 and subsequently underwent a full necropsy. There were no deaths following a single oral dose of TOFA_DimerFA_TEPA_PAA at 2000 mg/kg bw. There were no clinical signs. All rats gained weight during the first and second weeks of the observation period, with the exception of one animal which did not gain weight during the second week of the observation period. Macroscopic examination of these animals revealed no abnormalities. The acute median lethal oral dose level of the test article, TOFA_DimerFA_TEPA_PAA, was found to exceed 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch score = 1. Study compliant with current test guidelines and GLP.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

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

Study period:

13 November 2012 to 19 December 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to relevant testing guidelines, with no significant deviations.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HsdHan:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were 8-10 week old male and female HsdHan:WIST rats, obtained from Harlan UK Ltd., Bicester. Females were nulliparous and non-pregnant. The males weighed 246 to 344 g on Day 1 and females weighed 169 to 219 g. The acclimatisation period was 8 to 16 days.
Rats were housed in same sex groups of up to 5 during the acclimatisation period, and individually from the day prior to dosing. After the Day 3 observation the animals were returned to group housing. The rats were fed SQC(E) Rat and Mouse Maintenance Diet No. 1 (Special Diet Services Ltd., Witham, UK) ad libitum, and mains water was available ad libitum. The animal rooms were maintained at a temperature of 20 to 24°C, relative humidity of 45% to 65% and there were 15 to 20 air changes per hour. Fluorescent lighting was provided on a 12 hour light/dark cycle.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

All hair was removed from the dorsum of each rat on the day before dosing. The test site was an area of at least 10% of the total body surface area, calculated according to the largest animal in each group using the following formula: Surface area (cm²) = K x body weight (g)²/³ (where K = 9).
The test material was spread as uniformly as possible over the test site. The dose volume was 2.12 mL/kg bw, and was calculated from the body weights of the rats on the morning of dosing and the density of the test material. A dense gauze patch was placed over the treated skin and retained in place by an elasticated, open-weave, adhesive compression bandage. This was wrapped securely around the torso of the animal. At the end of the exposure period the dressings were removed and the test site was lightly brushed clean of any solid residues and swabbed with water-moistened cotton wool.
The test material was administered as supplied, and corrections for purity or active content were not made.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5/sex (including preliminary study)

Control animals:

not required

Details on study design:

A preliminary study was conducted with one male and one female rat. Each rat received a single dermal dose of the test substance at 2000 mg/kg bw. Since no mortalities were observed in the preliminary test, the test material was applied dermally to four male and four female rats at a dose of 2000 mg/kg bw. The rats were observed for 14 days after dosing. Treated rats were observed for clinical signs of toxicity immediately post-dose, at approximately 15 and 30 minutes post-dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to the last day of the observation period. Checks for mortality and general health were made at the beginning and end of each working day throughout the acclimatisation period and study period. Body weights were recorded the day prior to dosing, and on Days 1, 4, 8 and 15. The test site was evaluated for dermal reactions following removal of the dressings on Day 2 and daily therefore for the remainder of the observation period.
Rats were sacrificed on Day 15, and full necropsy was performed and all lesions were recorded. The necropsy procedure included inspection of external surfaces and orifices, the dermal test site, all viscera and tissue within the abdominal, thoracic and cranial cavities, free hand sectioning of the liver and kidneys and examination of representative sections of mucosal surfaces of the stomach and intestinal tract.

Statistics:

Not required.

Preliminary study:

No mortalities occurred in the preliminary study.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities occurred.

Clinical signs:

other: No clinical signs of toxicity were observed.

Gross pathology:

One male and one female were found to have large, mottled livers at necropsy. Sore appearance of the test site was noted in two males and all females.

Other findings:

Very slight to well-defined erythema was noted at the test sites of all males and two females on Day 2, with very slight erythema noted on Day 3. Very slight erythema persisted in two males up to Day 5 and in one female up to Day 14. Discolouration was noted at the test site of one male on Days 2 and 3 and in two males from Day 4 to Day 14. Discoloration was noted at the test site of one male on Day 15. Scabbing was noted at the test sites of three males from Day 4 to Day 15. Scabbing was also noted at the test site of one female on Days 2 and 3 and in all females from Day 4 to Day 15.
It could not be confirmed if the discolouration of the skin was a treatment-related effect. The test article wa sdescribed as a brown/yellow liquid but the treatment sites were washed following removal of the bandages and in the majority of cases, the discoloration did not develop until Days 3 or 4.

No additional information.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute dermal LD50 was found to exceed 2000 mg/kg bw in rats.

Executive summary:

The acute dermal toxicity of TOFA_DimerFA_TEPA_PAA was investigated in male and female HsdHan:WIST rats, in a GLP study according to OECD Test Guideline 402. A preliminary study was conducted with one male and one female rat. Following the preliminary study an additional 4 rats per sex were treated. The test material was applied undiluted to the clipped dorsum of the rats at a dose of 2000 mg/kg bw. The test site was covered with a semi-occlusive dressing for 24 hours. Following dressing removal the animals were observed for dermal reactions at the test site, clinical signs of toxicity and mortality for 14 days. All animals were sacrificed at the end of the observation period and subject to full necropsy.

There were no mortalities and no clinical signs of toxicity. Very slight to well-defined erythema, scabbing and discolouration were noted at the test site of treated animals on Day 2, lasting up to Day 15. All males and two females lost weight during the first week of the study, all animals gained weight during the second week of the study. Abnormalities noted at necropsy were large, mottled liver in one male and one female and sore appearance of the test site in two males and all females. Under the conditions of the study, the acute dermal LD50 of TOFA_DimerFA_TEPA_PAA was found to exceed 2000 mg/kg bw in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch score = 1. Study compliant with current test guidelines and GLP.

Additional information

Acute oral toxicity

The acute oral toxicity of Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and tetraethylenepentamine is low. The oral LD₅₀of the substance was determined to be > 2000 mg/kg bw in an acute oral toxicity study conducted in rats according to OECD Test Guideline 423 and EU Method B.1 tris (Williams, 2012). 

In the study, two groups of three female fasted rats were given the test article as a single dose on Day 1 by oral gavage at a dose level of 2000 mg/kg bw. The test article was dispersed in corn oil and administered at a dose volume of 10 mL/kg bw. Animals were observed for 14 days following treatment and during this observation period, mortality, abnormal clinical signs and bodyweight were recorded. All animals were killed on Day 15 and subsequently underwent a full necropsy. There were no deaths and no clinical signs were observed. All rats gained weight during the first and second weeks of the observation period, with the exception of one animal which did not gain weight during the second week of the observation period. Macroscopic examination of these animals revealed no abnormalities. Under the conditions of this study, the acute median lethal oral dose level (LD₅₀) of the test article, Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and tetraethylenepentamine, was found to exceed 2000 mg/kg bw.

Acute dermal toxicity

The acute dermal toxicity of Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and tetraethylenepentamine is low. The dermal LD₅₀of the substance was determined to be > 2000 mg/kg bw in an acute dermal toxicity study conducted in rats according to OECD Guideline 402 and EU Method B.3 (Dreher, 2013a).

A preliminary study was conducted using one male and one female rat. Following the preliminary study an additional 4 rats per sex were treated. The test material was applied undiluted to the clipped dorsum of the rats at a dose of 2000 mg/kg bw. The test site was covered with a semi-occlusive dressing for 24 hours. Following dressing removal the animals were observed for dermal reactions at the test site, clinical signs of toxicity and mortality for 14 days. All animals were sacrificed at the end of the observation period and subject to full necropsy. There were no mortalities and no clinical signs of toxicity. Very slight to well-defined erythema, scabbing and discolouration were noted at the test site of treated animals on Day 2, lasting up to Day 15. All males and two females lost weight during the first week of the study, all animals gained weight during the second week of the study. Abnormalities noted at necropsy were large, mottled liver in one male and one female and sore appearance of the test site in two males and all females. Under the conditions of the study, the acute dermal LD₅₀of the test material, Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and tetraethylenepentamine was found to exceed 2000 mg/kg bw in rats.

Acute inhalation toxicity

A waiver is proposed for acute inhalation toxicity studies in accordance with Column 2 of Annex VIII of the REACH Regulation on the basis that acute toxicity data are available for the oral and the dermal routes. Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance. The substance is a non-volatile liquid and the use pattern indicates that significant inhalation exposure is unlikely. No additional testing is therefore warranted.

 

Justification for selection of acute toxicity – oral endpoint
Sole study; guideline and GLP compliant.

Justification for selection of acute toxicity – dermal endpoint
Sole study; guideline and GLP compliant.

Justification for classification or non-classification

Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and tetraethylenepentamine has low acute toxicity: the oral LD₅₀and dermal LD₅₀values in rats have both been determined to be > 2000 mg/kg bw/day. The substance does not therefore meet the criteria for classification for acute toxicity according to Regulation 1272/2008/EC or Directive 67/548/EEC.