Registration Dossier

Administrative data

Description of key information

Acute oral toxicity
A LD50 (rat) > 2000 mg/kg has been determined for ATEHC in a GLP test according to OECD 423.
Acute dermal toxicity
A LD50 (rat) > 2000 mg/kg has been determined for ATEHC in a GLP test according to OECD 402.

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:
1999-12-08 - 2000-05-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
(1996-03-22)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
(1996-09-30)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: HanIbm: WIST (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: Females: 10 weeks, males: 8 weeks
- Fasting period before study: approximately 16.5 to 17.5 hours, but with free access to water
- Diet (e.g. ad libitum): Pelleted standard Kliba 3433, batch no. 42/99, rat maintenance diet available ad libitum (except for the overnight fasting period prior to application).
- Water (e.g. ad libitum): Community tap water from Itingen, available ad libitum.
- Acclimation: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): relative humidity 40-70% (values above 70% during cleaning process possible)
- Air changes (per hr): Air-conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
- Other: Recorded music was played for approximately 8 hours during the light period
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.2 g/mL
- Amount of vehicle (if gavage): 10 mL/kg

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg

DOSAGE PREPARATION: The test article was placed into a glass beaker on a tared Mettler balance and the vehicle (polyethylene glycol PEG 400) was added. A weight by volume dilution was prepared using a magnetic stirrer as homogenizer. Homogenicity of the test article in the vehicle was maintained during treatment. The preparation was made shortly before each dosing.
Doses:
2000 mg/kg
No. of animals per sex per dose:
3 rats per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality / Viability - Four times during test day 1 and once daily during days 2-15; body weights - On test day 1 (pre-administration), 8 and 15; clinical signs - Each animal was examined for changes in appearance and behaviour four times during day 1, and once daily during days 2-15.
- Necropsy of survivors performed: yes
Statistics:
No statistical analysis was used as no deaths occurred.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No death occurred during the study.
Clinical signs:
No clinical signs were noted during the observation period.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were observed at necropsy.

The median lethal dose of the substance after single oral administration to rats of both sexes, observed over a period of 14 days, could not be estimated as no death occurred.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The LD50 was identified to be >2000 mg/kg body weight. The test material did not induce treatment-related mortality. Further no clinical signs or macroscopic findings were observed.
Executive summary:

tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate (ATEHC) was tested in an acute oral toxicity study according to the acute toxic class method (OECD 423 and EU method B.1 tris; 2000). Two groups, each using three female or three male HanIbm: WIST (SPF) rats, were treated with the test substance at 2000 mg/kg by oral gavage. The test article was suspended in vehicle (polyethylene glycol PEG 400) at a concentration of 0.2 g/mL and administered at a volume of 10 mL/kg. The animals were examined for clinical signs and mortality / viability. Body weights were recorded and all animals were necropsied and examined macroscopically. No death occurred during the study, also no clinical signs were noted during the observation period; the body weight of the animals was within the range commonly recorded for this strain and age and no macroscopic findings were observed at necropsy.

The median lethal dose after single oral administration to rats of both sexes, observed over a period of 14 days, could not be estimated as no death occurred. The LD50 (rat) was identified to be >2000 mg/kg body weight, therefore the test material was considered to be relatively non-toxic under the conditions of the test.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
good quality

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
exposure considerations
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:
2000-05-09 - 2000-06-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented GLP study
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: EEC Directive (67/548/EEC), 7th Amended Directive (92/32/EEC) & EEC Directive 93/21/EEC
Deviations:
not specified
Qualifier:
according to
Guideline:
other: GefahrstoffVerordnung (GefStofiV) of 29 September 1994 (BGB1.1, p. 2557)
Deviations:
not specified
Principles of method if other than guideline:
None
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: male: 225 - 246 g; female: 168 - 182 g
- Housing: Before the animals arrived, the study room and cages were cleaned and disinfected. During the study, the room and cages were cleaned at regular intervals. The rats were housed individually in cages.
- Diet (e.g. ad libitum): Pelleted diet, offered ad libitum
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking bottles.
- Acclimation period: 6 days (range finding); 8 days (main test)
- Other: Identification with coloured markings; cage labelled with sex, study no., date of study initiation

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3° C (monitored twice daily)
- Humidity (%): between 30 and 70 % (monitored twice daily)
- Air changes (per hr): Air was changed about 16 times per hour and filtered adequately.
- Photoperiod (hrs dark / hrs light): Artificial light was set to give a cycle of 12 hours light and 12 hours dark with light on at 7.00 a.m.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 male and 5 female animals
Control animals:
not required
Details on study design:
A single dermal administration of the undiluted test article was performed. Since the density of the liquid test article was 0.97 g/mL, the animals were administered a volume of 2.06 mL/kg body weight which corresponded to the dose of 2000 mg/kg. The test article was held in contact with the skin by an occlusive dressing using a 4 x 5 cm patch (filter paper). The exposure period was 24 h. All animals were weighed before dosing and the individual doses expressed as mL/kg were adjusted according to the body weight.
Preliminary study:
There were no deaths in the preliminary study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: after 24h and 14 d
Mortality:
No animal died during the course of the main test after the single dermal administration of 2000 mg/kg.
Clinical signs:
No abnormal clinical signs were observed.
Body weight:
There was no influence of the treatment on the body weight development in the male animals during the 14-day observation period.
In the female animals, a reduced body weight or a very slight weight gain was observed after the first week of treatment followed by a slight weight gain after the second week of treatment.
Gross pathology:
Gross pathological examinations at day 14 p.a. (terminal necropsy) revealed no test article-related findings. In one female animal, red discolouration of the thymus was observed.
Other findings:
Skin Reactions: Neither erythema nor oedema or other skin reactions were observed.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
LD50 (rat, after 24 h and 14 d) >2000 mg/kg
Executive summary:

The acute dermal toxicity of tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate (ATEHC) was assessed in a fixed dose procedure in one group of rats comprising 5 males and 5 females according to OECD 402 and EU method B.3 and in compliance with GLP (2000). On the basis of the range finding test, the animals were given a single dermal administration of the test substance at the dose of 2000 mg/kg. The skin was exposed to the test article for 24 h. Clinical observations were carried out at regular intervals during the 14-day observation period. Signs of erythema and oedema were evaluated once daily for 14 days. Body weights were determined immediately before treatment and on days 7 and 14 p.a. Gross pathological examinations were carried out at study termination on all animals and the following results were obtained: No animal died during the 14-day observation period, no abnormal clinical signs, neither signs of erythema nor oedema were observed. There was no influence of the treatment on the body weight development in the male animals during the 14-day observation period. In the female animals, reduced body weight and very slight to slight weight gain were recorded during the 14-day observation period. Gross pathological examinations on day 14 p.a. did not reveal test article-related findings in the rats. Since no deaths were caused in Wistar rats after the dermal treatment with the test substance at a dose of 2000 mg/kg, the LD50 values after 24 h and 14 days were as follows: Male and female > 2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
good quality

Additional information

Acute oral toxicity:

Tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate (ATEHC) was tested in an acute oral toxicity study according to the acute toxic class method (OECD 423 and EU method B.1 tris; Rosner, 2000). Two groups, each using three female or three male HanIbm: WIST (SPF) rats, were treated with the test substance at 2000 mg/kg by oral gavage. The test article was suspended in vehicle (polyethylene glycol PEG 400) at a concentration of 0.2 g/mL and administered at a volume of 10 mL/kg. The animals were examined for clinical signs and mortality / viability. Body weights were recorded and all animals were necropsied and examined macroscopically. No death occurred during the study, also no clinical signs were noted during the observation period; the body weight of the animals was within the range commonly recorded for this strain and age and no macroscopic findings were observed at necropsy.

The median lethal dose after single oral administration to rats of both sexes, observed over a period of 14 days, could not be estimated as no death occurred. The LD50 (rat) was identified to be >2000 mg/kg body weight, therefore the test material was considered to be relatively non-toxic under the conditions of the test.

Acute dermal toxicity:

The acute dermal toxicity of tris(2-ethylhexyl) 2-(acetyloxy)propane-1,2,3-tricarboxylate (ATEHC) was assessed in a fixed dose procedure in one group of rats comprising 5 males and 5 females according to OECD 402 and EU method B.3 and in compliance with GLP (Bien, 2000). On the basis of the range finding test, the animals were given a single dermal administration of the test substance at the dose of 2000 mg/kg. The skin was exposed to the test article for 24 h. Clinical observations were carried out at regular intervals during the 14-day observation period. Signs of erythema and oedema were evaluated once daily for 14 days. Body weights were determined immediately before treatment and on days 7 and 14 p.a. Gross pathological examinations were carried out at study termination on all animals and the following results were obtained: No animal died during the 14-day observation period, no abnormal clinical signs, neither signs of erythema nor oedema were observed. There was no influence of the treatment on the body weight development in the male animals during the 14-day observation period. In the female animals, reduced body weight and very slight to slight weight gain were recorded during the 14-day observation period. Gross pathological examinations on day 14 p.a. did not reveal test article-related findings in the rats. Since no deaths were caused in Wistar rats after the dermal treatment with the test substance at a dose of 2000 mg/kg, the LD50 values after 24 h and 14 days were as follows: Male and female > 2000 mg/kg.


Justification for selection of acute toxicity – oral endpoint
GLP and guideline study

Justification for selection of acute toxicity – inhalation endpoint
Inhalation is not a relevant route of exposure, oral and dermal route are the main routes of possible exposure.

Justification for selection of acute toxicity – dermal endpoint
GLP and guideline study

Justification for classification or non-classification

Acute oral toxicity:

The test material does not meet the criteria for classification and will not require labelling for oral toxicity in accordance with European Regulation (EC) No. 1272/2008.

Acute dermal toxicity:

The test material does not meet the criteria for classification and will not require labelling for dermal toxicity in accordance with European Regulation (EC) No. 1272/2008.