Registration Dossier

Administrative data

Description of key information

- Acute toxicity:
Oral: LD50: >2000 mg/kg in the rat
Inhalation (4 hours) LD50: > 2600 mg / m3 in the rat
Dermal: LD50: > 2000 mg/kg in the rabbit

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crj:CD (SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan
- Age at study initiation: 5 w
- Weight at study initiation: during treatment; males: 149-163 g; females: 126-140 g
- Fasting period before study:
- Housing: 5 same sex in stainless steel breeding cages
- Diet (e.g. ad libitum): yes, Oriental Yeast Co. Ltd, pelleted diet
- Water (e.g. ad libitum): yes drinking water
- Acclimation period: 7 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/- 2 degrees C
- Humidity (%): 55+/- 10
- Air changes (per hr): 20
- Photoperiod (hrs dark / hrs light): 12: 12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 40% w/v
- Amount of vehicle (if gavage): 5 ml/kg
- Justification for choice of vehicle: TOTM is soluble in oil
- Lot/batch no. (if required): No batch no. but supplied by Nakaraitesuku
- Purity: No data

MAXIMUM DOSE VOLUME APPLIED: 5.0 ml/kg

DOSAGE PREPARATION (if unusual): liquid mixed with oil

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: 3 preliminary studies performed previously
Doses:
2000 mg/kg; in preliminary study 200 and 2000 mg/kg did not cause mortality.
No. of animals per sex per dose:
5 males & 5 females
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days (or other?) 14d
- Frequency of observations and weighing: frequently for 6h on day of dosing then twice daily
- Necropsy of survivors performed: yes/no: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: clinical signs, body weight, macroscopic pathology
Statistics:
Not required as a limit test
Preliminary study:
In preliminary study 200 and 2000 mg/kg did not cause mortality.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No deaths occurred
Mortality:
None in controls or TOTM group
Clinical signs:
Loose stools were seen in both control and TOTM groups from 1-4h after dosing. The incidence was similar in both groups
Body weight:
based on the weights recorded on d 0, 7 & 14 there were no changes attributed to treatment with TOTM.
Gross pathology:
There were no differences between the incidence of findings in the control & TOTM groups.
Other findings:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 was established at > 2,000 mg/kg for both sexes.
Executive summary:

Acute oral toxicity (LD50) in the rat is in excess of 2000 mg/kg

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage Michigan USA
- Age at study initiation: No data
- Weight at study initiation: 210-275 g
- Fasting period before study: No data
- Housing: A 0.5 m3 stainless steel inhalation chamber (Young & Bertke Cincinnati Ohio) during exposure period
- Diet (e.g. ad libitum): yes, Zeigler NIH07 open block formula (Gardners Pennsylvania USA)
- Water (e.g. ad libitum): yes, via water bottles
- Acclimation period: 8d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72+/-3 degrees F
- Humidity (%): 40+/- 10%
- Air changes (per hr): 10-20 during exposure period
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: December 2 1981 To: December 24 1981
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
not specified
Vehicle:
not specified
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: A 0.5 m3 stainless steel inhalation chamber (Young & Bertke Cincinnati Ohio)
- Exposure chamber volume: 0.5m3
- Method of holding animals in test chamber: No data
- Source and rate of air: No data
- Method of conditioning air: No data
- System of generating particulates/aerosols: Jet Nebuliser (Rhema Co. West Germany)
- Method of particle size determination: No data
- Treatment of exhaust air: No data
- Temperature, humidity, pressure in air chamber: 2+/-3 degrees F; 40+/- 10%; 0.1-0.2 in. H20 (using a Magnehelix gauge)
TEST ATMOSPHERE
- Brief description of analytical method used: filter paper/gravimetric technique; samples taken approximately every 30 mins during 4h exposure period
- Samples taken from breathing zone: yes/no: No data

VEHICLE
- Composition of vehicle (if applicable): N/A
- Concentration of test material in vehicle (if applicable):
- Justification of choice of vehicle:
- Lot/batch no. (if required):
- Purity:

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: No data
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): No data

CLASS METHOD (if applicable): N/A
- Rationale for the selection of the starting concentration: No data
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
4 h
Concentrations:
Estimated concentration: 2,600 mg/m3
Actual concentration: 2, 588.6 mg/m3 by gravimetric measurement
No. of animals per sex per dose:
5 males & 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days (or other?): 14d
- Frequency of observations and weighing: mortality & clinical signs daily, body weights: pre-exposure & weekly thereafter
- Necropsy of survivors performed: yes/no: yes on d15
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: clinical signs, body weights & macroscopic observation at necropsy.
Statistics:
N/A limit test; means and SDs calculated
Preliminary study:
No data
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2 600 mg/m³ air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: single dose concentration
Mortality:
None
Clinical signs:
All animals had matted, drenched coats for days 1-2 of observation period. There were no signs of toxicity during the exposure, the subsequent observation period or at termination.
Body weight:
With respect to body weights pre exposure, body weight increased on days 7 & 14 of the observation period.
Gross pathology:
At necropsy on d15, 5/5 males & 3/5 females had reddened patches on the lung.
Other findings:
No data

Mean (SD) Body weights (g) of 5 male & 5 female rats exposed to 2600 mg/m3TOTM

Intervals

Males

Females

 

 

 

Pre-exposure

265.1 ± 8.40

213.9 ± 2.66

Day 7

297.8 ± 14.02

223.2 ± 3.96

Day 14

329.7 ± 15.27

238.1 ± 4.82

 

 

 

Interpretation of results:
GHS criteria not met
Conclusions:
The authors concluded that under the conditions of this experiment 2,600 mg/m3 Nuoplaz 6959/Tris (2-ethylhexyl)trimellitate had little or no effect on the rat after a 4h exposure.
Executive summary:

The acute 4 hour inhalation toxicity (LC50) in the rat is in excess of 2600 mg/m3

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
2 600 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
Study period:
October 23 - November 04 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
according to
Guideline:
other: Federal Insecticide, fungicide & rodenticide Act part 163, Title 40; Code of the federal Regulations 40 CRF 163.81 & Principles & procedures for evaluating the toxicity of household substances Publication 1138, National Academy of Sciences-National Resear
GLP compliance:
yes
Test type:
other: Limit Test
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Becker Centalia Kansas USA
- Weight at study initiation: 2.3-3.2 Kg
IN-LIFE DATES: From: October 22 To: November 04
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back with longitudinal abrasions over the exposure area. Abrasions penetrated the stratum corneum but not deeply enough to cause bleeding
- % coverage: 10
- Type of wrap if used: gauze covered by rubber dam

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes area wiped
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.0 ml/kg
- Concentration (if solution): 100% (as supplied)
- Constant volume or concentration used: yes/no constant concentration
- For solids, paste formed: yes/no: N/A

VEHICLE: N/A
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:
Duration of exposure:
24h
Doses:
2.0 ml/kg
No. of animals per sex per dose:
3 male & 3 females in TOTM group
2 males & 2 females in control group
Control animals:
yes, concurrent no treatment
Details on study design:
- Duration of observation period following administration: 14 days (or other?): 14d
- Frequency of observations and weighing: weighing on d 1, 7, 14
- Necropsy of survivors performed: yes/no: yes d15
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other:
Statistics:
No. N/A single dosage used.
Preliminary study:
No data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 mL/kg bw
Based on:
test mat.
Remarks on result:
other: No confidence limits calculable as no mortality
Mortality:
None
Clinical signs:
No signs of toxicity seen during exposure & subsequent observation periods
Body weight:
No effects of exposure on body weight. All animals gained weight on days 7 & 14.
Gross pathology:
No observed abnormalities at necropsy.

Mean (±SD) Body weights (g) of 3 male & 3 female rabbits exposed to 2.0 ml/kg TOTM and 2 male & 2 female control rabbits

Intervals

Males

Females

 

Control1

TOTM 2.0 ml/kg

Control1

TOTM 2.0 ml/kg

 

 

 

 

 

Pre-exposure

3.2

2.33 ± 0.06

2.8 ± 0.14

2.37 ± 0.06

Day 7

3.4

2. 30 ± 0.10

3.1± 0.07

2.53 ± 0.06

Day 14

3.6

2.46 ± 0.06

3.2 ± 0.14

2.67 ± 0.06

 

 

 

 

 

1Controls were untreated

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this test TOTM has an acute dermal LD50 in rabbits of >2.0 ml/kg.
Executive summary:

Acute dermal toxicity (LD50) in the rabbit is in excess of 2 mL/kg

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Assessment is based on published information on the substance.

 

Data are available from a number of studies: for the oral route, 4 studies in the rat and 2 in the mouse; for the dermal route, single studies in the rabbit and the guinea pig; and, for the inhalation route, 2 studies in the rat. A number of these are older studies and the details available are not adequate to permit robust evaluation of the reported findings.

 

It is noted that, when assessing acute toxicity by the inhalation route, the limit concentrations for gases, vapours, and aerosols are 20000 ppm, 20 mg/L, and 5 mg/L, respectively (or the maximum attainable concentration). It is recognized that it is technically challenging to generate limit concentrations as aerosols and, with most substances, a concentration of 2 mg/L (2000 mg/m3) is the approximate limit at which a respirable particle size can be achieved.

Justification for classification or non-classification

Classification with regard to acute oral and dermal toxicity is not justified based on the observed lack of mortality at a dose level of 2000 mg/kg.

Classification with regard to acute (4 hour) inhalation toxicity is not justified based on the observed lack of mortality at an exposure level of 2600 mg / m3, assumed to be the highest achievable exposure concentration