Registration Dossier

Administrative data

Description of key information

Based on the results from the Acute Exposure Oral Toxicity in rats, the acute oral LD50 for males, females and combined sexes was determined to be 1861.9 (1383.5 - 2505.7) mg/kg bw, 1591.4 (1283.5 - 1973.3) mg/kg be and 1716.2 (1446.5 - 2036.1) mg/kg bw, respectively.
No valid data available for acute inhalation toxicity that can be used for classification and labelling; the studies performed were intended to examine the toxicity of the vapour under realistic exposure conditions.
Based on the observations made in the Acute Exposure Dermal Toxicity Study in rabbits, the acute dermal LD50 in males and combined sexes was determined to be 1720.0 (1082.9-2732.0) mg/kg bw and 1465.4 (1074.6-1998.3) mg/kg bw, respectively. The data generated for the acute dermal LD50 in females did not lend itself to the statistical method employed.

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:
other: EPA FR Vol.50, No. 188, September 27, 1985
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
purity and storage conditions are not reported
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.,Wilmington, Massachusetts
- Age at study initiation: 6-10 weeks
- Weight at study initiation: 175-224 g
- Fasting period before study: yes
- Housing:individually in stainless steel 1/2'' wire mesh cages, sized in accordance with the "Guide for the Care and Use of Laboratory Animals'' of the Institute of Laboratory Animal Resources, National Research Council
- Diet (e.g. ad libitum): Harlan Teklad Lab Blox, ad libitum
- Water (e.g. ad libitum):no data
- Acclimation period: min. 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12h dark/12h light
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
800, 1250, 1600 and 2000 mg/kg bw
No. of animals per sex per dose:
10 (5♂ and 5♀)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: pharmacological and toxicological effects: at 1, 4 and 24 hours after dosing and once a day through 14 days; viability: once a day; body weight: d0, d7 and d14 or were found dead
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The method of Litchfield and Wilcoxon via Innovative programing Associates,LABCAT Module Version 4.22.
Preliminary study:
Dose-range -finding: 3 groups of 2 rats (1♂ and 1♀ per group) fasted and administrated test article at the dose levels: 500, 2500 and 5000mg/kg bw, orally by gavage. 0/2 animal died at the 500mg/kg bw dose level; 2/2 animals died at both the 2500 and 5000mg/kg bw dose levels.
Sex:
male
Dose descriptor:
LD50
Effect level:
1 861.9 mg/kg bw
Based on:
test mat.
95% CL:
1 383.5 - 2 505.7
Sex:
female
Dose descriptor:
LD50
Effect level:
1 591.4 mg/kg bw
Based on:
test mat.
95% CL:
1 283.5 - 1 973.3
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 716.2 mg/kg bw
Based on:
test mat.
95% CL:
1 446.5 - 2 036.1
Mortality:
0/10 animals died at both the 800 and the 1250mg/kg bw dose levels
5/10 animals died at the 1600 mg/kg bw dose level
7/10 animals died at the 2000 mg/kg bw dose level
Clinical signs:
decreased activity, abnormal gait, abnormal stance, prostration, diarrhea, lacrimation and dyspnea
Body weight:
normal weight gain has been observed
Gross pathology:
Necropsy of the animals dying on study revealed fluid-filled and distended intestines and stomachs and discolored lungs and intestines. No visible lesions were observed in any animal at terminal necropsy .
Interpretation of results:
other: CLP/EU GHS Category 4 (H302) according to Regulation (EC) No 1272/2008
Conclusions:
Based on the results from the Acute Exposure Oral Toxicity in rats, the acute oral LD50 for males, females and combined sexes was determined to be 1861.9 (1383.5 - 2505.7) mg/kg bw, 1591.4 (1283.5 - 1973.3) mg/kg bw and 1716.2 (1446.5 - 2036.1) mg/kg bw, respectively.
Executive summary:

An acute oral toxicity study with TETA was carried out in Sprague Dawley rats. Groups of 5 rats per sex were treated per gavage at 800, 1250, 1600 or 2000 mg/kg bw and were observed for 14 days thereafter. Mortality was 0, 0, 50 and 70%, respectively. The acute oral LD50 for males, females and combined sexes was determined to be 1861.9 (1383.5 - 2505.7) mg/kg bw, 1591.4 (1283.5 - 1973.3) mg/kg bw and 1716.2 (1446.5 - 2036.1) mg/kg bw, respectively.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 716 mg/kg bw
Quality of whole database:
Study was performed according to following guidelines: OECD 401, EPA Federal Register Vol.50, No. 188 , (September 27, 1985) and in compliance with the GLP Regulations. No significant deviations can be observed from the study guidelines, which could have an impact on the performed study. Well-documented; however, no data on purity were given.

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)
Deviations:
yes
Remarks:
purity not reported
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Denver PA
- Age at study initiation: young adults
- Weight at study initiation: 1.943-2.800 kg
- Fasting period before study: No
- Housing:individually in cages sized in accordance with the "Guide for the Care and Use of Laboratory Animals" of the Institute of Laboratory Animal Resources, National Research Council.
- Diet (e.g. ad libitum): Purina Lab Rabbit Chow H.F.
- Water (e.g. ad libitum): fresh tap water, ad libitum
- Acclimation period: min. 5d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C±3
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12h dark/12h light


Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area of trunk (clipped free of fur)
- Type of wrap if used: rubber dam and an elastic bandage


REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with water and gauze
- Time after start of exposure: 24h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1000, 2000 and 3000 mg/kg bw
- Constant volume or concentration used: yes


Duration of exposure:
24h
Doses:
1000, 2000 and 3000 mg/kg bw
No. of animals per sex per dose:
10 ( 5♂and 5♀)
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily through 14 days; body weight: d0,d7 and d14 or when dead
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, dermal observations
Statistics:
By the method of Litchfield and Wilcoxon via the Innovative Programming Associates, LABCAT Module Version 4.24.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 465.4 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 074.6 - <= 1 998.3
Sex:
male
Dose descriptor:
LD50
Effect level:
1 720 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 082.9 - <= 2 732
Mortality:
-2/10 animals died at the 1000 mg/kg bw dose level
-8/10 animals died at the 2000 mg/kg bw dose level
-9/10 animals died at the 3000 mg/kg bw dose level
Clinical signs:
- DECREASED ACTIVITY: 2/10 animals at 1000 mg/kg bw dose level; 7/10 animals at 2000 mg/kg bw dose level; 6/10 animals at 3000 mg/kg bw dose level;
-ABNORMAL GAIT: 1/10 animals at 1000 & 3000 mg/kg bw dose level; 6/10 animals at 2000 mg/kg bw dose level
- ABNORMAL STANCE: 1/10 animal at 1000 & 3000 mg/kg bw dose level; 6/10 animals at 2000 mg/kg bw dose level
-DECREASED MUSCLE TONE: 1/10 animal at 1000, 2000 & 3000 mg/kg bw dose level
-NECROSIS:10/10 animals at 1000, 2000 & 3000 mg/kg bw dose level
-PROSTRATION: 0/10 animal at 1000 mg/kg bw dose level; 5/10 animals at 2000 mg/kg bw dose level; 2/10 animals at 3000 mg/kg bw dose level
-RED URINE: 5/10 at 1000 mg/kg bw dose level; 9/10 animals at 2000 mg/kg bw dose level; 8/10 animals at 3000 mg/kg bw dose level
-POOR GROOMING: 4/10 at 1000 mg/kg bw dose level; 2/10 at 2000 mg/kg bw dose level; 1/10 at 3000 mg/kg bw dose level
-SLOUGHING: 4/10 at 1000 mg/kg bw dose level; 1/10 at 2000 mg/kg bw dose level; 0/10 at 3000 mg/kg bw dose level
-DEATH: 2/10 at 1000 mg/kg bw dose level; 8/10 bw at 2000 mg/kg dose level; 9/10 at 3000 mg/kg bw dose level
Body weight:
d0-d7: ♂ body weight increase and ♀ body weight decrease at the 1000 mg/kg bw dose level
d7-d14: both ♂ and ♀ : body weight increase at the 1000 mg/kg bw dose level
d0-d7-d14:♂ body weight decrease at the 2000 mg/kg bw dose level and ♀ (data not reported)
d0-d7-d14:♂ body weight decrease at the 3000 mg/kg bw dose level and ♀ (data not reported)
Gross pathology:
Necropsy of the animals that died on study revealed discolored and/or fluid-filled stomach, distended and/or fluid-filled intestines, discolored kidneys and liver, fluid-filled bladder and necrosis of the skin at the application site.
Terminal necropsy revealed discolored lungs in one animal and necrosis of the skin at the application site in all of the animals. No other visible lesions were observed in any animal at terminal necropsy .

The data generated for the acute dermal LD50 in females did not lend itself to the statistical method applied

Interpretation of results:
other: CLP/EU GHS Category 4 (H312) according to Regulation (EC) No 1272/2008
Conclusions:
Based on the observations made in the Acute Exposure Dermal Toxicity Study in rabbits, the acute dermal LD50 in males and combined sexes for 6933-6-20 was determined to be 1720.0 (1082.9-2732.0) mg/kg and 1465.4 (1074.6-1998.3) mg/kg, respectively. The data generated for the acute dermal LD50 in females did not lend itself to the statistical method employed.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 465 mg/kg bw
Quality of whole database:
Study was performed according to OECD 402 guideline and in compliance with the GLP Regulations. No significant deviations can be observed from the study guidelines, which could have an impact on the performed study. Data on purity are, however, not indicated.

Additional information

Oral toxicity:

An acute oral toxicity study with the registration substace was carried out in Sprague Dawley rats (Pharmakon, 1992, reliability 1). Groups of 5 rats per sex were treated via gavage of 800, 1250, 1600 or 2000 mg/kg bw of the registration substance and were observed for 14 days thereafter. The mortality rate was 0, 0, 50 and 70%, respectively. The acute oral LD50 for males, females and combined sexes was determined to be 1861.9 (1383.5 - 2505.7) mg/kg bw, 1591.4 (1283.5 - 1973.3) mg/kg bw and 1716.2 (1446.5 - 2036.1) mg/kg bw, respectively.

An acute oral toxicity study was performed with the registration substance pre-guideline and pre-GLP with rats of unknown sex (Oyen, 1953, reliability 4). The study report provided only limited information. 10% of the test substance in water was administered to the rats in doses of 3.0, 2.0, 1.0 and 0.3 g/kg bw. The LD50 is between 1000 -2000 mg/kg based on the results of this study.

The acute oral toxicity study with the registration substance was conducted according to an internal BASF method which in principle is comparable to the OECD Guideline 401 (BASF, 1977, reliability 2). A test group consisting of 5 animals/sex was treated by single gavage application with an aqueous solution of the test substance. The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period of 14 days, the surviving animals were sacrificed for the purpose of necropsy; animals that died during the observations period also were subjected to necropsy. At 2150 mg/kg bw 2 males and 4 females died within 24 h; 1 further male died within 48 h. At 1470 mg/kg bw 1 male and 4 females died within 24 h; 1 further male died within 48 and 7 days, respectively. At 1000 mg/kg bw 1 male and female each died within 7 days. The LD50 value was estimated to be ca. 1400 mg/kg bw.

A range-finding study was performed with the registration substance pre-guideline and pre-GLP with male rats (Meyers, 1976, reliability 4). Three groups of five male rats were administered 2.0, 4.0, 8.0 mL/kg bw via oral gavage. The animals were observed for two weeks. In the high dose group all animals died within 2.25 to three hours after dosing. They appeared sluggish after 20 minutes. In the mid-dose group all animals died one to four days after dosing. They appeared sluggish after 20 minutes. None of the animals died at 2.0 mL/kg, these animals did appear sluggish after 40 minutes. The LD50 is 2749 mg/kg bw (recalculated from 2.83 mL/kg bw based on density of the registration substance).

 

Dermal toxicity:

An acute dermal toxicity study with the registration substance which is in compliance with GLP and according to OECD guideline 402, with male and female New Zealand White rabbits, is available and has been used as a key study (Pharmakon, 1993, reliability 1). Groups of 5 rabbits per sex were treated for 24 hours under occlusive conditions with 1000, 2000, or 3000 mg registration substance/kg bw and were observed for 14 days thereafter. Mortality was 20, 80, and 90%, respectively. The following clinical signs were observed: decreased activity (2/10 animals at 1000 mg/kg bw, 7/10 animals at 2000 mg/kg bw, 6/10 animals at 3000 mg/kg bw), abnormal gait (1/10 animals at 1000 & 3000 mg/kg bw and 6/10 animals at 2000 mg/kg bw), abnormal stance (1/10 animal at 1000 & 3000 mg/kg bw and 6/10 animals at 2000 mg/kg bw), decreased muscle tone (1/10 animal at 1000, 2000 & 3000 mg/kg bw), prostration (0/10 animal at 1000 mg/kg bw, 5/10 animals at 2000 mg/kg bw and 2/10 animals at 3000 mg/kg bw), red urine (5/10 at 1000 mg/kg bw, 9/10 animals at 2000 mg/kg bw and 8/10 animals at 3000 mg/kg bw), poor grooming (4/10 at 1000 mg/kg bw, 2/10 at 2000 mg/kg bw and 1/10 at 3000 mg/kg bw), sloughing (4/10 at 1000 mg/kg bw, 1/10 at 2000 mg/kg bw and 0/10 at 3000 mg/kg bw). Necropsy of the animals that died during the study revealed discoloured and/or fluid-filled stomach, distended and/or fluid-filled intestines, discoloured kidneys and liver, fluid-filled bladder and necrosis of the skin at the application site. Terminal necropsy revealed discoloured lungs in one animal and necrosis of the skin at the application site in all of the animals. No other visible lesions were observed in any animal at terminal necropsy. Based on the observations made in this study, the acute dermal LD50 in males and combined sexes for the registration substance was determined to be 1720.0 (1082.9-2732.0) mg/kg bw and 1465.4 (1074.6-1998.3) mg/kg, respectively. The data generated for the acute dermal LD50 in females did not lend itself to the statistical method employed.

 

An additional acute dermal toxicity study with the registration substance which is pre-GLP and pre-Guideline, but similar to OECD guideline 402, with male New Zealand White rabbits, is available and has been used as a supporting study (Meyers, 1976, reliability 4). Three groups of five male rats were administered 0.25, 0.5, 1.0 mL/kg bw undilted on the skin for 24 hours under occlusion. The animals were observed for two weeks. In the high dose group three out of four animals died within one to four days after dosing. In the mid-dose group two out of four animals died four and nine days after dosing. None of the animals died at 0.25 mL/kg bw. In the animals that died the lungs were congested and kidneys were pale. The livers were congested or mottled. In the animals that survived no effects were noted. Necrosis of the skin was observed. The LD50 is 545 mg/kg bw (recalculated from 0.561 mL/kg bw based on density of the registration substance).

In a further supporting study performed with the registration substance according to a BASF test with Sprague-Dawley and LD50 between 1000 and 2000 mg/kg bw was observed (BASF, 1977). 5 rats per sex were dosed with 400, 1000 or 2000 mg registration substance in olive oil/kg bw under occlusive conditions and observed for 14 days. No mortality was observed in the 400 and 1000 mg/kg bw dose group. At 2000 mg/kg bw all rats died within 48 hours. Necrosis was observed in all animals. At necropsy survivors showed no abnormalities. Animals that died during the study revealed acute dilatation in the heart, bleeding ulceration in the stomach, pattern on hepatic lobes, haemorrhagic contents in the intestines and in the lung despite congestion noticeable hyperemia.

Inhalation toxicity

Three old inhalation studies were available in which rats had been exposed to the vapour of the registration substance generated at room temperature (21 or 25°C) or at 100°C for a single period of 7 to 8 hours (BASF, 1966; Meyers, 1976; Oeyen, 1953). No mortality occurred. In none of the studies the concentration had been measured. It was, however, noted that in one of the studies (BASF, 1966) no substance loss but an increase in substance weight was recorded. This is an indication that the test substance is hygroscopic and only a marginal fraction of the test substance might have been volatile. From a toxicologists point of view it is therefore doubtful if the animals were exposed to the test substance by inhalation and which concentration the generated vapour was of because the vapour pressure of the test substance is very low (0.346 Pa at 20°C) which would result in a vapour saturation of 0.02 mg/L. This is the maximum concentration which the animals were probably exposed to. This is far below the the concentration level which is needed for classification. Since the substance is classified as corrosive to skin no further acute inhalation toxicity test is required according to Reach Regulation Annex VIII point 8.5.


Justification for classification or non-classification

Reliable data with the registration substance on acute oral and dermal toxicity concludes that the registered substance meets the criteria for classification with Category 4 (H302 and H312) according to Regulation (EC) No. 1272/2008.