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Description of key information

The oral LD50 was > 5000 mg/kg bw in rats. A LD50 value of > 2850 mg/kg bw was observed for mouse after acute oral exposure. The determined dermal LD50 for Triisobutyl phosphate was > 5000 mg/kg bw in rabbits.
Furthermore, the 4-hour LC50 was > 5.14 mg Triisobutyl phosphate/ liter of air.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

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:
EPA OPP 81-1 (Acute Oral Toxicity)
Qualifier:
according to
Guideline:
other: TSCA
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material: Tri-isobutylphosphate
- Physical state: clear liquid
- Analytical purity: 99.7%
- Lot/batch No.: NBP 3983659
- Storage condition of test material: room temperature
Species:
rat
Strain:
other: CD (Sprague-Dawley derived)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Wilmington, Massachusetts, 01887
- Age at study initiation: 9-12 weeeks
- Weight at study initiation: males: 274-339 grams. Females: 224-242 grams
- Fasting period before study: approximately 18 hours
- Housing: Group-housed (six/cage) during equilibration. Individually housed during study. Cages: Suspended, stainless steel with wire mesh bottoms.
- Diet (ad libitum): Purina Laboratory Chow, #5001
- Water (ad libitum): Automatic watering system. Municipal water supply (Elizabethtown Water Co.)
- Acclimation period: 22 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.4-24.4°C
- Humidity (%): 30-70%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 hrs light, 12 hrs dark

IN-LIFE DATES: not specified
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
Not applicable

MAXIMUM DOSE VOLUME APPLIED:
5.2 mL/kg

DOSAGE PREPARATION:
No preparation was necessary

CLASS METHOD
not applicable
Doses:
5000 mg/kg
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Viability check: twice daily
Observations of Pharmacologic and Toxicologic Signs: App. 1, 2, and 4 hours after dosing and daily thereafter for 14 days.
Body weights: Pre-fast, Post-fast (just prior to dosing; weights used for calcuulation of doses). Day 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
Statistics:
Not specified
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
One female was found dead on day 1; all five males and four of the five females survived throughout the study.
Clinical signs:
Signs seen on the day of dosing in several animals included oral discharge, wet rales, urinary staining, fecal staining, unthrifty coat, abdominal griping and hypoactivity. Signs seen on the day after dosing included dry rales, hypoactivity and evidence of red nasal discharge. All surving animals had decreased food consumption on the day after dosing; this continued in some animals through Day 3. All surviving animals were free of significant abnormalities from Day 4 through termination of the study (Day 14).
Body weight:
The majority of surviving animals gained weight both 7 and 14 days after dosing. One of the five males exhibited a slight weight loss (4 grams) at Day 7 but gained weight between Days 7 and 14.
Gross pathology:
Examinations of the animal which was found dead revealed a variety of changes, primarily in the lungs and gastrointestinal tract. Changes seen in the intestine were suggestive of an irritant effect (the presence of red fluid), and apparent test material was found in the stomach. Except for two animals which exhibited dilated renal pelves and/or a renal pelvis containing white fluid, changes in animals killed after 14 days were similar to those seen in control animals in the laboratory killed by carbon dioxide inhalation.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
BASF-Test
Acute oral toxicity of Triisobutylphosphate (and Triisobutylphosphate with Isopropylalkohol) were tested on 12 rats and 12 mice with 50% and 20% dillutions in oil.
GLP compliance:
no
Test type:
standard acute method
Specific details on test material used for the study:
- Name of test material: Triisobutylphosphate (Etingal)
- Impurities (identity and concentrations): possibly 1% Mono- or diisobutylphosphate
- Substance type: waterclear fluid with slightly sharp odor.
- Decomposition temperature: ca. 237°C
- Solubility: poorly in water, completely in alcohol and vegetable oil.
Species:
other: rat and mice
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No data
Route of administration:
oral: unspecified
Vehicle:
other: oil
Details on oral exposure:
No data
Doses:
20 % and 50 % dilutions in oil
No. of animals per sex per dose:
12 rats and 12 mice
Control animals:
not specified
Details on study design:
Not specified
Statistics:
No data
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 4 180 mg/kg bw
Based on:
test mat.
Remarks on result:
other: rats
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 2 850 mg/kg bw
Based on:
test mat.
Remarks on result:
other: mice
Mortality:
Not specified
Clinical signs:
No characteristic symptoms
Body weight:
Not specified
Gross pathology:
Not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
5 000 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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material: Triisobutylphosphat
- Physical state: liquid
- Storage condition of test material: at 20°C in the dark
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: HOECHST AG, Kastengrund, SPF-Zucht
- Age at study initiation: 8-10 weeks
- Weight at study initiation: male; 201-211g. females; 182-193g
- Fasting period before study: no data
- Housing: Makrolon cages (type 4) on Softwood pellets
- Diet (ad libitum): Altromin 1324 (Altromin-GmbH, Lage/Lippe)
- Water (ad libitum): tap water in plastic bottles
- Acclimation period: minimal 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 50 ± 20 %
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 hours

IN-LIFE DATES: not specified
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: not specified
- Exposure chamber volume: 60 Liter
- Method of holding animals in test chamber: not specified
- Source and rate of air: 800 L/hr
- System of generating particulates/aerosols: the test substance was injected by static speed by a continuous infusion apparatus into the nozzle. Through riser the aerosol was injected into the inhalation chamber.
- Method of particle size determination: The cascade impactor was operated with a vacuum throughput of 9.5L/Min, resulting in a flow rate of ca. 1.25 m/sec The calculation of the mean aerodynamic diameter and geometric standard deviation of the particle size distribution was determined by probit analysis
(Probit against logarithms of the cumulative frequency of the aerodynamic diameter)
- Treatment of exhaust air: Bottom of the inhalation chamber was a suction device, with Buehler filters, a wash bottle with Tetrachloroethylene, a wash bottle with deionized water and a Calciumchlorid bottle where air was extracted with 1100 Liters of air per hour.
- Temperature, humidity, pressure in air chamber: a with water 1000 mL bottle flows through with 100 liters of air per hour. The with moisture-enriched air was passed directly into the chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: during inhalation, the test amosphere was continuous tested by Hartmann Brown; CO, CO2, 02, humidity and temperature in the exposure chamber is measured.
- Samples taken from breathing zone: yes

VEHICLE
- Concentration of test material in vehicle: 5.14mg/L
- Justification of choice of vehicle: not specified

TEST ATMOSPHERE
- Particle size distribution:
< 0,6 µm: 3,9 %
0,6 - 0,8 µm: 17,6 %
0,8 - 1,5 µm: 36,3 %
1,5 - 3,0 µm: 39,2 %
3,0 - 4,8 µm: 2,9 %
4,8 - 7,0 µm: 0 %
7,0 - 10,3 µm: 0 %
>10,3 µm: 0 %
cumulative: 99,9%
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Anderson-Kaskadenimpaktor Mark III, Firma Anderson Samples INC, Atlanta
The analysis of particle size distribution showed a mean mass-based aerodynamic diameter (MMAD) of 1.3 microns with a geometric standard deviation of 1.6.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5.14 mg/liter
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 21 days
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
Statistics:
Not specified
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.14 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: no mortality occurred
Mortality:
No mortality occurred
Clinical signs:
The animals showed irregular breathing, jerky breathing, gasping, cooing and crackling sound of breathing, tremors, long-legged, uncoordinated and staggering gait, decreased spontaneous activity, ruffled fur, squatting, retracted flanks, reduced parking and legreflex, blood-colored crusted Noses, sneezing, narrowed palpebral fissures, red-stained saliva and nasal discharge and swollen belly.
On day 21 all clinical signs had disappeared in all animals, except on one female.
Body weight:
In the first week some effect in body weight were observed. At the end of the observation period all animals showed normal body weight gain, except for one female.
Gross pathology:
Two male and found females showed effects on lungs. The other animals were free of macroscopic effects.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
5 140 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:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Qualifier:
according to
Guideline:
other: TSCA
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material: Tri-siobutylphosphate
- Physical state: clear liquid
- Analytical purity: 99.7%
- Lot/batch No.: NBP 3983659
- Storage condition of test material: room temperature
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Animals, Inc. Denver, Pennsylvania
- Age at study initiation: at least 8 weeks old
- Weight at study initiation: Males: 2.4 - 2.9 kg. Females: 2.6 - 3.0 kg
- Fasting period before study: not specified
- Housing: individually housed. Suspended, stainless steel
- Diet (ad libitum): Lab Rabbit Chow HF (Purina #5326), (125 g/day while on test) .
- Water (ad libitum): Automatic watering system, Municipal water supply (Elizabethtown Water Co.).
- Acclimation period: 57 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15.6- 21.1°C
- Humidity (%):30-70%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

IN-LIFE DATES:
Not specified
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: the dorsal area of the trunk
- % coverage: not specified
- Type of wrap if used: impervious plastic sleeve. The sleeve was secured with tape.

REMOVAL OF TEST SUBSTANCE
- Washing: with gauze and water
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount(s) applied: 5.2 mL/kg

VEHICLE
Not applicable
Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Viability Check: twice Dail y
Observations of Phamacologic and Toxicologic Signs: Approximately 1, 2 and 4 hours after dosing and daily thereafter for fourteen days.
Body Weights: Pre-test (at the time of clipping). Pre-dose (weights used for calculation of doses). Day 7 and 14
- Necropsy of survivors performed: yes (day 14)
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
Statistics:
No data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality occurred
Mortality:
All animals survived throughout the study.
Clinical signs:
Most animals exhibited severe dermal effects (necrosis, followed by eschar formation, and exfoliation of the eschar tissue) at a small portion or
less than half the dose site which persisted throughout the study. Single occurrences of nasal discharge, and evidence of urinary and fecal staining were also seen. All animals were free of signs of abnormalities from Day 8 through termination of the study (Day 14).
Body weight:
Most animals exhibited slight body weight losses at Day 7, but gained weight between Days 7 and 14.
Gross pathology:
Except for one animal which exhibited clear fluid in the abdominal cavity, other gross postmortem observations were similar to those seen in control animals in this laboratory or were considered to represent normal physiological variation.
Other findings:
Most animals had decreased food consumption on Days 2 and 3; this continued in a few animals through Day 7 .
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
5 000 mg/kg bw

Additional information

Oral toxicity

Triisobutyl phosphate was administered in a single dose, 5000 mg/kg bw, orally by gavage to 10 rats (males and females) in a GLP study according to guidelines EPA OPP 81-1 (Acute Oral Toxicity) and TSCA (Bio/dynamics, 1989). The LD50 values (14 days) were determined. Data regarding mortality, clinical signs, body weights and gross pathology were reported. One female was found dead on day 1; all five males and four of the five females survived throughout the study. Examinations of the animal which was found dead revealed a variety of changes, primarily in the lungs and gastrointestinal tract. Changes seen in the intestine were suggestive of an irritant effect (the presence of red fluid), and apparent test material was found in the stomach. Except for two animals which exhibited dilated renal pelves and/or a renal pelvis containing white fluid, changes in animals killed after 14 days were similar to those seen in control animals in the laboratory killed by carbon dioxide inhalation. The oral LD50 for Triisobutyl phosphate was >5000 mg/kg bw in rats.

Furthermore, Triisobutyl phosphate was administered orally to 12 rats and 12 mice in a BASF-guideline study (BASF, 1953). The LD50 values were determined. The calculated oral LD50 for Triisobutyl phosphate was > 4180 mg/kg bw in rats. And the calculated oral LD50 for mice is > 2850 mg/kg bw.

Supportingly, Triisobutyl phosphate was tested in several acute oral studies in rats, mice and hen. The calculated LD50 in rats was 3200 – 6400 mg/kg bw (Eastman Kodak, 1968), and 3072 - 6144 mg/kg bw (Fassett, 1963). The calculated LD50 in mice was 6400 – 12800 mg/kg bw (Eastman Kodak, 1968). For hens de calculated LD50 was 1500 mg/kg bw (Carrington, 1989).

Dermal

Triisobutyl phosphate was administered a single dose, 5000 mg/kg bw, dermally to 10 New Zealand White rabbits (males and females) in a GLP study according to guidelines EPA OPP 81-2 (Acute Dermal Toxicity) and TSCA (Bio/dynamics, 1989). The LD50 values (14 days) were determined. Data regarding mortality, clinical signs, body weights and gross pathology were reported. All animals survived throughout the study. Single occurrences of nasal discharge and evidence of urinary and fecal staining were also seen. All animals were free of signs of abnormalities from Day 8 through termination of the study (Day 14). Most animals exhibited slight body weight losses at Day 7, but gained weight between Days 7 and 14. Most animals exhibited severe dermal effects (necrosis, followed by eschar formation, and exfoliation of the eschar tissue) at a small portion or less than half the dose site which persisted throughout the study. Except for one animal which exhibited clear fluid in the abdominal cavity, other gross postmortem observations were similar to those seen in control animals in this laboratory or were considered to represent normal physiological variation. Most animals had decreased food consumption on Days 2 and 3; this continued in a few animals through Day 7.

The dermal LD50 for Triisobutyl phosphate was > 5000 mg/kg bw in rabbits.

Supportingly, Triisobutyl phosphate was tested in an acute dermal toxicity study in guinea pig. The calculated LD50 was > 9600 mg/kg bw (Eastman Kodak, 1968).

Inhalation

Triisobutyl phosphate was tested in an acute inhalation toxicity study, according to OECD 403 (Hoechst, 1989). 5 Male and 5 female Wistar rats were exposed during 4 hours to the test substance at 5.14 mg / liter air.

The analysis of particle size distribution showed a mean mass-based aerodynamic diameter (MMAD) of 1.3 microns with a geometric standard deviation of 1.6.

The animals showed irregular breathing, jerky breathing, gasping, cooing and crackling sound of breathing, tremors, long-legged, uncoordinated and staggering gait, decreased spontaneous activity, ruffled fur, squatting, retracted flanks, reduced parking and legreflex, blood-colored crusted noses, sneezing, narrowed palpebral fissures, red-stained saliva and nasal discharge and swollen belly.

On day 21, all clinical signs had disappeared in all animals, except in one female.

In the first week, some effect in body weight was observed. At the end of the observation period all animals, except one female, grew normally. Two males and three females showed gross changes of the lungs. The other animals were free of macroscopic effects.

No deaths occurred, so the 4-hour LC50 was > 5.14 mg Triisobutyl phosphate / liter of air.

Supportingly, several acute inhalation tests in rats provided the following results; IRT: 1.7 mg/L air (BASF, 1953) and 1.35 mg/L air (Fassett, 1963). Furthermore, a cat exposed for 30 minutes to an aerosol of Triisobutyl phosphate at ca. 52 mg/L air showed reversible clinical signs (BASF, 1953).

In acute studies by other routes with Triisobutyl phosphate, the following results were obtained; LD50 mouse, subcutaneous: 2850 mg/kg bw (BASF, 1953). LD50 rat, intraperitoneal: 768 – 1536 mg/kg bw (Fassett, 1963). LD50 rat, intraperitoneal: 200-400 mg/kg bw (Eastman Kodak, 1968). LD50 mouse, intraperitoneal: 800-1600 mg/kg bw (Eastman Kodak, 1968).

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 1272/2008. One out of five animals died at the limit dose of 5000 mg/kg bw in an acute oral toxicity study and no mortality occurred in an acute inhalation study at 5.14 mg/L air and in an acute dermal toxicity study at 5000 mg/kg bw. As a result, the substance is not considered to be classified for acute oral, inhalation or dermal toxicity under Regulation (EC) No. 1272/2008, as amended for the tenth time in Regulation (EC) No. 2017/776.