Triisooctylamine

Endpoint summary

Description of key information

LD50(oral) >300 and < 2000 mg/kg bw (Bioassay, 2015)
LD50(dermal) > 2000 mg/kg bw (Bioassay, 2014)

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:

guideline study

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Lot/batch No.: 0008924462

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Germany
- Age at study initiation: female animals approx. 10 weeks
- Weight at study initiation: animals of comparable size and weight
- Fasting period before study: Feed was withdrawn from the animals at least 16 hours before administration, but water was available ad libitum.
- Housing: Single housing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +- 3
- Humidity (%): 30 – 70
- Air changes (per hr): ca. 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: unchanged (no vehicle) or corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: only for 300 mg/kg: 15 g/100 mL
- Amount of vehicle (if gavage): 2 mL/kg bw
- Justification for choice of vehicle: corn oil was a suitable vehicle

MAXIMUM DOSE VOLUME APPLIED: 2.47 mL/kg bw (undiluted) or 2 mL/kg (300 mg/kg)

Doses:

300 and 2000 mg/kg

No. of animals per sex per dose:

3 females at 2000 mg/kg and 6 females at 300 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: A check for any dead or moribund animals was made at least once each workday. Clinical signs for each animal were recorded several times on the day of administration and at least once during each workday thereafter. Individual body weights shortly before administration (day 0), weekly thereafter and on the day of death or sacrifice moribund starting with study day 6.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy with gross-pathology examination was performed on the last day of the observation period after sacrifice by CO2-inhalation in a chamber with gradually increasing concentrations. Necropsy of all animals that died as early as possible after death.

Statistics:

N/A

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One animal of the 2000 mg/kg bw test group was found dead on study day 6 (delayed mortality), while the two remaining animals were sacrificed in a moribund state on the same day. No mortality occurred in both 300 mg/kg bw test groups.

Clinical signs:

other: In the animal of the 2000 mg/kg bw test group that was found dead on study day 6 impaired general state and piloerection were observed from study day 1 until study day 3, while exsiccosis and body weight reduction were noted from study day 2 until study d

Gross pathology:

Due toe the advanced putrefaction no macroscopic pathological findings could be determined in the animal that was found dead on study day 6. In the animals which were sacrificed in a moribund state on study day 6 no macroscopic pathological findings were observed. There were no macroscopic pathological findings in the animals sacrificed at the end of the observation period (300 mg/kg bw: 6 females).

Under the conditions of this study the median lethal dose of Triisooctylamine after oral administration was found to be greater than 300 mg/kg bw and less than 2000 mg/kg bw in rats.

Interpretation of results:

Category 4 based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

GLP and guideline study.

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:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Lot/batch No.: 0008924462

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Germany
- Age at study initiation: male animals approx. 8 weeks, female animals approx. 12 weeks
- Weight at study initiation: animals of comparable size and weight
- Fasting period before study: N/A
- Housing: Single housing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C +- 3 °C
- Humidity: 30 – 70 %
- Air changes (per hr): ca. 10
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal and dorsolateral parts of the trunk)
- % coverage: About 40 cm² (corresponds to at least 10% of the body surface)
- Type of wrap if used: The test item was covered with an air-permeable dressing (4 layers of absorbent gauze (Ph. Eur. supplied by Lohmann GmbH & Co., KG) and stretch bandage (Fixomull® Stretch (adhesive fleece) supplied by Beiersdorf AG).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): rinsing of the application site with warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.47 mL/kg
- Constant volume or concentration used: yes

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs for each animal were recorded several times on the day of application and at least once during each workday thereafter. Individual body weights shortly before application (day 0), weekly thereafter and on the last day of observation. Individual readings 30 – 60 minutes after removal of the semi-occlusive dressing (day 1), several times (see results) until the last day of observation. A check for any dead or moribund animals was made at least once each workday.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy with gross-pathology examination was performed on the last day of the observation period after sacrifice by CO2-inhalation in a chamber with gradually increasing concentrations.

Statistics:

N/A

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality occurred

Mortality:

No mortality occurred

Clinical signs:

other: No systemic clinical signs were observed during clinical examination. Local effects see below.

Gross pathology:

No macroscopic pathologic abnormalities were noted in the animals (5 males and 5 females) examined on the last day of observation.

Local effects males:

In all animals of the male group well-defined erythema (grade 2) was observed on study day 1 and persisted in four of these animals until study day 2, while in one animal severe erythema (grade 4) was noticed on the same day. On study day 3, one male showed moderate erythema (grade 3), while in the other animals severe erythema (grade 4) was noted. Severe erythema (grade 4) was noted persisted in three animals until study day 8, and in one male each until day 10 or day 13. Thereafter, moderate erythema (grade 3) was observed in two males from study day 9 until study day 10 or day 14. In another animal this grade was observed from study day 13 until study day 14, while in a further male animal grade 3 was observed only on study day 14. The fifth animal revealed well-defined erythema (grade 2) from study day 9 until study day 14.

Slight edema (grade 2) was noted in all male animals on study day 1 and persisted in four animals until study day 2. In one animal moderate edema (grade 3) was observed from study day 2 until day 3 and in the other four animals on study day 3. On study day 6, all animals showed severe edema (grade 4) which persisted in one animal up to study day 7. In this animal the finding decreased to moderate edema (grade 3) on day 8. In the other animals moderate edema (grade 3) was observed on study day 7 and persisted in one animal until day 8 and in two other animals until study day 10. Slight edema (grade 2) was seen in two male animals from study day 8 or 9 until study day 10 and in a third animal from day 9 until day 14. The two other animals revealed slight edema from study day 13 up to study day 14. In two animals edema decreased to very slight edema (grade 1) and was seen from study day 13 until study day 14. Dermal blisters were noted in 4 male animals on study day 1. From study day 2 until study day 14, incrustations were noted in all animals. In addition, scaling was seen in all males from study day 6 until study day 10 and persisted in one male until day 14.. Erythema and edema beyond the application area were noted in three animals from study day 6 until study day 10 or 13. Descriptions of any dermal finding were recorded in the table of results as raw data.

Local effects females:

In all animals of the female group well-defined erythema (grade 2) was noted from study day 1 until study day 2 and persisted in two of these animals up to study day 3, while in the other three females moderate erythema (grade 3) was noted on the same day. Thereafter, severe erythema (grade 4) was observed in all animals until study day 10 and persisted in four females up to study day 14, while in the fifth female moderate erythema (grade 3) was seen from study day 13 until study day 14. In all females slight edema (grade 2) was observed from study day 1 until study day 2 and persisted in four females up to study day 3, while in one animal moderate edema (grade 3) was observed on study day 3. On study day 6, severe edema (grade 4) was seen in all female animals and persisted in four of these females up to study day 7. In one female moderate edema (grade 3) was seen on study day 7, which decreased to slight edema (grade 2) from study day 8 until day 14. Moderate edema (grade 3) was noticed in four females on study day 8 and persisted in two of these females up to study day 10. Slight edema (grade 2) was noticed in two of these females on study day 9 and persisted in these animals up to study day 10 or 14.

In three females very slight edema (grade 1) was noted from study day 13 until study day 14. Dermal blisters with partly destroyed uppermost layer of the skin were noted in one female animal on study day 1. Eczema like skin lesion was seen in two females from study day 9 until day 14. From study day 2 or 3 until study day 14 incrustations were noted in all animals. In addition, scaling was seen from study day 6 until study day 14 in these animals. Erythema and edema beyond the application area were noted from study day 6 until study day 13 or 14 in three animals. In the two remaining animals findings beyond the application area were noted on study day 13 only. Descriptions of any dermal finding were recorded in the table of results as raw data.

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Acute oral toxicity

In an acute oral toxicity study (Bioassay, 2015) performed according to the Acute Toxic Class method (OECD 423 guideline and GLP), doses of 2000 and 300 mg/kg bw of the test item Triisooctylamine (undiluted or preparations in corn oil Ph.Eur.) were administered by gavage to three test groups of three fasted Wistar rats each (2000 mg/kg bw in 3 females, 300 mg/kg bw in 6 females). The following test substance-related clinical observations were recorded, clinical signs occurred within 6 days after administration:

2000 mg/kg (single test group):

Delayed mortality in one animal on day 6

Two animals were sacrificed in a moribund state on day 6

Impaired general state in all animals

Poor general state in two animals

Dyspnoea in two animals

Piloerection in all animals

Staggering in two animals

Chromodacryorrhea in all animals

Apathy in two animals

Exsiccosis in all animals

Reduced defecation in two animals

Body weight reduction in all animals

Urine smeared fur in one animal

Macroscopic pathological findings in the animal that was found dead: Due to the advanced putrefaction no macroscopic pathological findings could be determined. No macroscopic pathological findings were noted in the two animals that were sacrificed in a moribund state.

300 mg/kg (first test group):

No mortality occurred

No clinical signs were observed

300 mg/kg (second test group):

No mortality occurred

Impaired general state in all animals

Piloerection in all animals.

The mean body weight of the surviving animals increased within the normal range throughout the study period with one exception in the first 300 mg/kg bw test group. In one female animal the body weight increased within the normal range during the first week, but the female revealed a stagnation of body weight during the second week. This effect is observed at times in the rat strain used, because in the required age range the female animals have already reached the phase of slow growth. As the affected animal did not show any concurrent clinical symptoms or change in behavior, the observed stagnation of body weight is considered to be unspecific. There were no macroscopic pathological findings in the surviving animals sacrificed at the end of the observation period. The acute oral LD50 was calculated to be LD50, oral, rat > 300 < 2000 mg/kg bw.

Acute dermal toxicity

In an acute dermal toxicity study (Limit Test) according to OECD 402 guideline and GLP (Bioassay 2014), young adult Wistar rats (5 males and 5 females) were dermally exposed to a single dose of 2000 mg/kg bw of the undiluted test item Triisooctylamine to the clipped skin (dorsal and dorso-lateral parts of the trunk) and covered by semi-occlusive dressing for 24 hours. The application area comprised at least 10% of the total body surface area. The animals were observed for 14 days.

No mortality occurred.

No signs of systemic toxicity were observed.

The following test item-related local effects were recorded during the course of the study, local effects occurred within 14 days after application:

Well-defined to severe erythema (grade 2 to 4)

Very slight to severe edema (grade 1 to 4)

Scaling

Incrustations

Eczema like skin lesion

Dermal blisters, partly with destroyed uppermost layer of the skin

Additionally, erythema and edema were noted beyond the application site.

In the male group three animals showed loss of body weight during the first week, while one animal showed stagnation of body weight during the first week, but body weights were in all animals in a normal range during the second week. In the female group all animals showed loss of body weight during the first week, but they gained weight in a normal range during the second week. This effect was probably caused by the severe local findings during the study period. No macroscopic pathologic abnormalities were noted in the animals examined at the end of the study (5 males and 5 females). Accordingly, the acute dermal median lethal dose (LD50) was determined to be LD50, dermal, rat > 2000 mg/kg bw.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The oral LD50 was smaller than 2000 but greater than 300 mg/kg bw. As a result the substance is considered to be classified for acute oral toxicity cat 4 (H302 "harmful if swallowed") under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.

Classification concerning acute dermal toxicity is not warranted.