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Description of key information

Studies of acute oral, dermal and inhalation toxicity are available.  Mortality and toxicity seen in the acute oral and dermal toxicity studies are attributable to local corrosivity.  Mortality seen in one acute inhalation toxicity study is also associated with local effects.

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:
supporting study
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study appears to follow to OECD guideline 401. However it is not GLP (GLP was not mandatory when study was done). There is no information on the purity of test, the source and age of the animals, the period of acclimation, on housing and environmental conditions and on how often the clinical signs and mortality were checked. However, it is considered that the study still provides scientific and valid information.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
There is no information on the purity of test, the source and age of the animals, the period of acclimation, on housing and environmental conditions and on how often the clinical signs and mortality were checked.
GLP compliance:
no
Remarks:
GLP was not mandatory when the study was carried out
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Hllltop-Wi.tar albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 200 - 300 g
- Fasting period before study: Fasted overnight before dosing
- Diet (e.g. ad libitum): ad libitum
- Water: ad libitum

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
No information
Doses:
First test
0.125, 0.25, 0.5 and 1 mL/kg TMHD
Second test:
The acute oral test was repeated using a 5% (v/v) dilution in distilled water.
0.125, 0.25, 0.5, 0.71 and 1 mL/kg TMHD
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animal weights are recorded at days 0 (before dosing), 7 and 14 days (just prior to sacrifice).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs and body weights
Statistics:
LD50's are calculated by the moving average method (Thompson, 1947).
Sex:
male
Dose descriptor:
LD50
Effect level:
0.42 mL/kg bw
Based on:
test mat.
Remarks on result:
other: All the females died in the highest dose group. 4/5 female rats died in the 0.5 mL/kg dose group and 2 female died in the 0.25 mL/kg dose group. The 0.125 mL/kg dose group was not considered relevant because the small volume were difficult to administer.
Sex:
male
Dose descriptor:
LD50
Effect level:
336 mg/kg bw
Based on:
test mat.
Remarks on result:
other: relative density = 0.8
Sex:
female
Dose descriptor:
LD50
Effect level:
0.297 mL/kg bw
Based on:
test mat.
Remarks on result:
other: All the females died in the highest dose group. 4/5 female rats died in the 0.5 mL/kg dose group and 2 female died in the 0.25 mL/kg dose group. The 0.125 mL/kg dose group was not considered relevant because the small volume were difficult to administer.
Sex:
female
Dose descriptor:
LD50
Effect level:
238 mg/kg bw
Based on:
test mat.
Remarks on result:
other: relative density = 0.8
Mortality:
Undiluted test substance
At the highest dose level (1 mL/kg): 5/5 males died on day 1 and all females died on day 1..
At 0.5 mL/kg dose: 2 males died on day 1 and 1 male died on day 7. 3 females died on day 2 and one female died on day 3.
At 0.25 mL/kg: one male died on day 7. One female died on day 2 and the se second one on day 8.
At 0.125 mL/kg: one male died on day 2 and 2 males died on day 4. One female died on day 2 and 2 females died on day 3. However, due to the difficulties in administering this volume, this dose level was no considering when setting the LD50.
5% v/v dilution:
At the highest dose level (1 mL/kg): 3/5 males died on day 0 an 2/5 males died on day 1 and 3/5 females died on day 0 an 2/5 females died on day 1.
At 0.71 mL/kg dose: 3/5 males died on day 3 and 1 male died on day 4. No data reported or females.
At 0.5 mL/kg dose: No death was reported in males. 1 female died on day 2 and one female died on day 3.
At 0.25 mL/kg: No death was reported in males. 1 female died but the time is not reported.
At 0.125 mL/kg: All the animals survived.
Clinical signs:
Undiluted test material
The following clinical signs were reported for males:
1.0 mL/kg dose group: sluggishness at 15 minutes.
0.5 mL/kg dose group: sluggishness at 20 minutes, red crusty discharge on nose and eye area at day 1 (one animal recovered on day), emaciation, gasping on day 5. Survivors recovered at 7 days.
0.25 mL/kg dose group: none
0.125 mL/kg: ruffled fur, discharge on mouth, nose and eyes at day 1, emaciation at 6 days. Survivors recovered at 9 days.
The following clinical signs were reported for females:
1.0 mL/kg dose group: sluggishness at 15 minutes, lacrimation, piloerection in 2 animals at 4 hours.
0.5 mL/kg dose group: sluggishness at 20 minutes, piloerection, mild lacrimation at 1 day, emaciation, black crusty discharge on eyes in one animal a 5 days. Survivors recovered at 9 days
0.25 mL/kg dose group: slight red crusty area on nose and mouth at day 1. Survivors recovered at 2 days.
0.125 mL/kg: ruffled fur, red discharge on mouth, nose and eyes at day 1, gasping and sluggishness at 2 days. Survivors recovered at 4 days.
5% v/v dilution:
The following clinical signs were reported for males:
1.0 mL/kg dose group: sluggishness, low carriage and eyes partially closed were noted in males prior to death.
0.71 mL/kg dose group: sluggishness, eyes partially closed, piloerection were noted within 4 hours post treatment and severe sluggishness was noted on day 1
0.5 mL/kg dose group: sluggishness at 20 minutes, slight red crusty discharge on eyes I, nose and mouth on day 1. All animals recovered by day 2.
0.25 mL/kg dose group: none
0.125 mL/kg: none
The following clinical signs were reported for females:
1.0 mL/kg dose group: sluggishness, low carriage and eyes partially closed were noted in females prior to death.
0.5 mL/kg dose group: sluggishness, slight red crusty discharge on eyes , nose and mouth on day 1. Emaciation was noted at day 7. All animals recovered by day 8.
0.25 mL/kg dose group: none
0.125 mL/kg: none
Body weight:
Undiluted test material
In the 0.5 mL/kg treated group, two males survived. One male showed a weight loss at 7 days but at the end of the study, both animals had gained weight. in the 0.25 mL/kg dose group, all surviving animals gained weight. In the 0.125 mL/kg, one animal lost weight throughout the course of the study while one animal gained weight.

5% v/v dilution:
In the 0.5, 0.25 and 0.125 mL/kg treated group, all males gained weight throughout the study. In the 0.5 mL/kg treated group, one female lost weight on day 7 but had received by the end of the study. The remaining of the females in that group gained weight. In the 0.25 and 0.125 mL/kg all the females gained weight throughout the course of the study.
Gross pathology:
At gross pathology, the following findings were noted in the groups treated with the undiluted test material mottled and red lung (in male and females), red fluid In the stomach (in males and females), ulceration of the stomach, mucosa and gas or liquid-filled intestines (in females).
At gross pathology, the following findings were noted in the groups treated with the diluted test material pale red lungs stomach and lntestines filled with dark red liquid and with fluid in the thoracic cavity. Nothing remarkable was noted in the survivors.
Interpretation of results:
Toxicity Category III
Remarks:
Migrated information Acute Tox. 3 Criteria used for interpretation of results: EU
Conclusions:
Based an the results of thls study, the acute oral LD50 for TMHD in the rat should be considered to be 0.420 mL/kg (equivalent to 336 mg/kg) for males and 0.297 mL/kg (equivalent to 238 mg/kg) for females.
Executive summary:

Groups of five Hilltop-Wistar 344 rats/sex/dose were administered a single dose of the undiluted test material by gavage at the following doses 0.125mL/kg, 0.25, 0.5 and 1 mL/kg NIAX Catalyst C-210. The animals were observed for mortality, clinical signs during a 14-day observation period. Body weights were recorded on days 0, 7 and 14 post dosing. Gross pathology was carried out on all animals. All female and male rats died in the 1 mL/kg. 3/5 males and 4/5 males died in the 0.5 mL/kg group. At 0.25 mL/kg, 1/5 male and 2/5 females were reported dead. 3/5 males and 3/5 females died in the 0.1 mL/kg treated group. However this last dose group was not considered in the derivation of the LD50 due to difficulties in administering such a low dosage. Based on the results of this study, the acute oral LD50 for TMHD in the rat should be considered to be 0.420 mL/kg (equivalent to 336 mg/kg bw) for males and 0.297 mL/kg (equivalent to 238 mg/kg bw) for females. It is therefore concluded that the substance classified as Acute Tox Cat. 3 under Regulation (EC) No 1272/2008 and is assigned the hazard statement H301 "Toxic if swallowed".

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
238 mg/kg bw
Quality of whole database:
Lowest reported value

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not specified
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study appears to follow to OECD guideline 403. However it is not GLP (GLP was not mandatory when study was done). There is no information on the purity of test, the source and age of the animals, the period of acclimation, on housing and environmental conditions and how often the clinical signs and mortality were checked. No analytical method was used to monitor the concentration of test material in the chamber and it is not known if equilibration was reached. There is no information on exposure data and the dose level that the animals were exposed to.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
No information on the purity of test, the source and age of the animals, on housing and environmental conditions, how often the clinical signs and mortality were checked, no analytical method used, no information on exposure data and the dose level used.
GLP compliance:
no
Remarks:
[not mandatory at the time of the study]
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Hilltop-Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 200 - 300 g
- Diet (e.g. ad libitum): ad libitum
- Water: ad libitum
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The vapour is produced by passing air (at 2.5 liters/min) through the sample and then through a 9-liter animal chamber (dynam ic conditions). Oxygen is added, as neededm for static exposures to maitain a chamber oxygen constant of approximately 20%.
- Exposure chamber volume: 9 liter
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
ca. 6 h
Concentrations:
Not specified but only one concentration
No. of animals per sex per dose:
5 animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days (or other?) 14 days
- Frequency of observations and weighing: Weighing was carried out 7 and 14 days after exposure
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight and gross pathology
Statistics:
Not applicable
Preliminary study:
No deaths occurred during the course of the study.
Sex:
male
Dose descriptor:
LC50
Based on:
test mat.
Exp. duration:
6 h
Remarks on result:
other: Exposure level unknown
Sex:
female
Dose descriptor:
LC50
Based on:
test mat.
Exp. duration:
6 h
Remarks on result:
other: Exposure level unknown
Mortality:
No mortality occurred during the course of the study in any of the animals
Clinical signs:
No clinical signs were noted
Body weight:
All animals gained weight during the course of the study.
Gross pathology:
Gross pathology did not find anything remarkable.
Other findings:
Not applicable
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the absence of death, no classification is proposed for acute inhalation toxicity
Executive summary:

Group of 5 male and 5 female Hilltop Wistar rats were exposed to saturated vapours of the test substance for 6 hours. No mortality (0/5 males and 0/5 females died) was observed. All animals gained weight during the course of the study. There were no clinical signs and nothing was reported at necropsy. It was not possible to derive the LC50 since the exposure level is not reported in the study. However, in the absence of mortality and clinical signs it is considered that the substance is to be considered as non-toxic for acute inhalation toxicity.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
410 mg/m³
Quality of whole database:
Three studies of acute inhaltion toxicity are available, of which two are considered to be reliable.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No information provided
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study appears to follow to OECD guideline 402. However it is not GLP (GLP was not mandatory when study was done). There is no information on the purity of test, the source of the animals, the period of acclimation, on housing and environmental conditions, how often the clinical signs and mortality were checked and the size of the test site. However, it is considered that the study still provides scientific and valid information.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
There is no information on the purity of test, the source of the animals, the period of acclimation, on housing and environmental conditions, how often the clinical signs and mortality were checked and the size of the test site.
GLP compliance:
no
Remarks:
not mandatory when the study was carried out
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: between 2.0 and 3.0 kg
- Housing: immobilised during the 24 hour exposure period
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Skin of the trunk
- Type of wrap if used:impervious sheeting

REMOVAL OF TEST SUBSTANCE
After the contact period, excess fluid is removed.

Duration of exposure:
24 hours
Doses:
0.2, 0.4 and 0.8 mL/kg
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days (or other?) 14days
- Frequency of observations and weighing: 1 hour, 7 days and 14 days after exposure
- Necropsy of survivors: yes
- Other examinations performed: clinical signs, body weight, gross pathology
Statistics:
Not indicated
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
0.492 mL/kg bw
Based on:
test mat.
95% CL:
>= 0.358 - <= 0.678
Sex:
male/female
Dose descriptor:
LD50
Effect level:
394 mg/kg bw
Based on:
test mat.
Remarks on result:
other: relative density 0.8
Mortality:
At the highest dose level (0.8 mL/kg): 4/5 males died and 3/5 females died on day 1. The surviving male died on day 2 and the surviving females died on day 2.
At 0.4 mL/kg dose: 1 males died on day 3 and 1 female died on day 5.
At 0.2 mL/kg: all males and females survived.
Clinical signs:
All males and females at the highest dose levels displayed immediate discomfort and sluggishness. Unsteady gait and prostration were also reported. All survivors had recovered at 6 days at 0.4 mL/kg and by 5 days at 0.2 mL/kg.
Body weight:
Most surviving males and all surviving females at 0.4 mL/kg lost weight throughtout the study. All males and most females in the 0.2 mL/kg treated group lost weight at 7 days however all males and most females had gained weight by the end of the study.
Gross pathology:
At gross pathology findings were as follows: intestines with paste-like to hard fecal material anbd livers with tan, to red mottling. Nothing remarkabkle was reported in survivors.
Other findings:
Skin reactions included erythema, ecchymosis, necrosis, oedema, desquamation and scabs which are attributable to corrosivity.
Interpretation of results:
toxic
Remarks:
Migrated information Acute Tox 3 Criteria used for interpretation of results: EU
Conclusions:
Based an the results of thls study, the acute dermal LD50 for TMHD in the rat should be considered to be 0.492 mL/kg (equivalent to 394 mg/kg) for males and females.
Executive summary:

Groups of five New Zealand White rabbits/sex/dose were exposed to a single dose of the undiluted test material t the following doses 0.2mL/kg, 0.4, 0.5 and 0.8 mL/kg NIAX Catalyst C-210. The active substance was applied to the clipped intact skin of the trunk of animals for 24 hours. The animals were observed for mortality, clinical signs during a 14-day observation period. Body weights were recorded on days 0, 7 and 14 post dosing. Gross pathology was carried out on all animals. All female and male rats died in the 0.8 mL/kg. 3/5 males and 4/5 males died in the 0.5 mL/kg group. 1/5 male and 1/5 females died in the 0.4 mL/kg treated group. No death was reported at 0.2 mL/kg. Skin reactions included erythema, echymosis, necrosis, oedema, desquamation and scabs which are attributable to corrosivity. Signs of toxicity such as immediate discomfort, sluggishness, unsteady gait and prostration were reported. At necropsy, gross pathology findings included intestines with paste-like to hard faecal material and livers with tan to red mottling. Based an the results of this study, the acute dermal LD50 for TMHD in the rat should be considered to be 0.492 mL/kg (equivalent to 394 mg/kg) for males and females. It is therefore concluded that the substance classified as Acute Tox 3 under Regulation (EC) No 1272/2008 and is assigned the hazard statement H311 "Toxic in contact with skin".

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
394 mg/kg bw
Quality of whole database:
No data are available.

Additional information

Three studies of acute oral toxicity in the rat are available for the substance and report comparable results. One study (BASF AG, 1983) reports an acute oral LD50 of 316 -464 mg/kg bw. Derelanko (1985) reports an acute oral LD50 value of 0.25 -0.5 mL/kg bw (equivalent to 200 -400 mg/kg bw based on the reported density of 0.8 g/mL). Myers (1983) reports acute oral LD50 values of 0.420 mL/kg bw (336 mg/kg bw) for males and 0.297 mL/kg bw (238 mg/kg bw) in females. Effects in the acute oral toxicity studies are associated with local corrosivity in the gastrointestinal tract. A second study reports an LD50 of 0.25 -0.5 mL/kg bw (200 -400 mg/kg bw); a third study reports LD50 values of 0.420 mL/kg bw (336 mg/kg bw) in males and 0.297 mL/kg bw (238 mg/kg bw) in females.

Two studies of acute dermal toxicity studies are available for the substance. One study in the rabbit (BASF AG, 1982) reports an acute dermal LD50 value in excess of 400 mg/kg bw; only one dose level was used in this study and was associated with 20% mortality. A second study of acute dermal toxicity in the rabbit (Myers, 1983) reports an acute dermal LD50 value of 0.492 mL/kg bw (394 mg/kg bw). Effects in these studies are associated with local corrosivity.

Three studies of acute inhalation toxicity are available for the substance. One study (BASF, 1982) reports an LC50 in excess of a vapour concentration of 1.54 mg/L. No mortality observed was observed at this exposure concentration. A second study (Anonymous) similarly reports an absence of mortality at the (unquantified) saturated vpour concentration. A third study performed using liquid aerosols of the substance reports 40% mortality at the single exposure concentration of 0.41 mg/L.


Justification for selection of acute toxicity – oral endpoint
This study reports the lowest endpoint

Justification for selection of acute toxicity – inhalation endpoint
This study reports the lowest endpoint

Justification for selection of acute toxicity – dermal endpoint
This study reports the lowest endpoint

Justification for classification or non-classification

Based on the rangeof acute oral LD50 values reported, classification in CLP Category III for acute oral toxicity is appropriate. Based on the acute dermal LD50 value of 394 mg/kg bw; classification in CLP Category 3 for acute dermal toxicity is appropriate. 40% mortality was seen in this study at the single exposure concentration of 0.41 mg/L. Based on the results of this study, the LC50 can be estimated to fall in the range 0.5-1.0 mg/L. Classification of the substance in CLP Category 3 for acute inhalation toxicity is therefore considered appropriate.