Registration Dossier

Administrative data

Description of key information

Oral (similar to OECD 401), male rat: LD50 = 1182 mg anhydrous TMT/kg bw; female rat: LD50 > 1680 mg anhydrous TMT/kg bw
Dermal (OECD 402), rat: LD50 > 1100 mg anhydrous TMT/kg bw

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:
other: Comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no body weight determination
Principles of method if other than guideline:
No reference to OECD guideline is made in the report.
GLP compliance:
no
Remarks:
study performed prior to implementation of GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: males 44 - 49 days, females 57 - 63 days
- Weight at study initiation: males 127 - 147 g, females 128 - 148 g
- Fasting period before study: 16 h
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C +/-2°C
- Humidity (%): 50-60%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The following dose volumes of the test substance were applied: 4.64, 6.81 and 10 mL/kg bw
MAXIMUM DOSE VOLUME APPLIED: 10.0 mL/kg bw
Doses:
5197, 7627, 11200 mg/kg bw (related to product TMT 15)
equivalent to
780, 1144 and 1680 mg anhydrous TMT/kg bw
1418, 2080, 3055 mg TMT55/kg bw

No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: at 0.5, 1, 2, 4, 8, 24 h, 2 days after dosing and once daily thereafter
- Frequency of weighing: day 0 (prior to dosing)
- Necropsy of survivors performed: yes
- Other examinations performed: gross examination of organs at necropsy
Statistics:
The LD50 value was calculated using the Probit Analysis.
Sex:
male
Dose descriptor:
LD50
Effect level:
7 878 mg/kg bw
Based on:
test mat.
Remarks:
TMT 15
95% CL:
6 364 - 9 752
Remarks on result:
other: Probit analysis
Sex:
male
Dose descriptor:
LD50
Effect level:
1 182 mg/kg bw
Based on:
other: anhydrous form
Remarks on result:
other: recalculated value based on 15% TMT
Sex:
male
Dose descriptor:
LD50
Effect level:
2 149 mg/kg bw
Based on:
other: hydrated form (TMT 55)
Remarks on result:
other: calculated value for TMT 55
Sex:
female
Dose descriptor:
LD50
Effect level:
> 11 200 mg/kg bw
Based on:
test mat.
Remarks:
TMT 15
Sex:
female
Dose descriptor:
LD50
Effect level:
> 1 680 mg/kg bw
Based on:
other: anhydrous form
Remarks on result:
other: recalculated value based on 15% TMT
Sex:
female
Dose descriptor:
LD50
Effect level:
> 3 055 mg/kg bw
Based on:
other: hydrated form (TMT 55)
Remarks on result:
other: calculated value for TMT 55
Mortality:
All mortalities occurred between 4 h and 2 days after administration.
males: 0/5 at 5197 mg TMT 15/kg bw, 2/5 at 7627 mg TMT 15/kg bw, 5/5 at 11200 mg TMT 15/kg bw
females: 0/5 at 5197 mg TMT 15/kg bw, 1/5 at 7627 mg TMT 15/kg bw, 2/5 at 11200 mg TMT 15/kg bw
Clinical signs:
No clinical signs were noted in animals receiving the lowest dose. Piloerection, laboured respiration, increased pain perception, stilted gait and clonic convulsions were observed in rats administered the mid and high dose.
Gross pathology:
Accumulation of reddish-brown fluid in the stomach was observed in animals that died as well as in animals that were sacrificed at the end of the study. No further effects were noted in any of the organs at necropsy.
Interpretation of results:
other: not classified for the test substance TMT 15, Toxicity Category V (OECD GHS) for TMT 55, Toxicity Category IV for anhydrous TMT
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
In this acute oral toxicity study with TMT 15 the obtained LD50 values were 7878 mg/kg bw (corresponding to 1182 mg anhydrous TMT/kg bw) for male rats and >11200 mg/kg bw (corresponding to > 1680 mg anhydrous TMT/kg bw) for female rats.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 182 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: CD(SD)BR VAF/PlusT
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: males 7 weeks, females 8 weeks
- Weight at study initiation: males 200-253 g, females 197-222 g
- Housing: individually in stainless-steel mesh cages
- Diet: Agway Prolab Animal diet (RMH 3000) certified pellets, ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (° C): 21-22
- Humidity (%): 59-66
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 04 May 1993 To: 09 June 1993
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: an area of the dorsal skin
- Type of wrap if used: a fiber pad and an occlusive wrap

REMOVAL OF TEST SUBSTANCE
- Washing (if done): running water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Constant volume or concentration used: yes
- For solids, paste formed: the test material was administered as a solid moistened thoroughly with water
Duration of exposure:
24 hours
Doses:
2000 mg TMT 55/kg bw (equivalent to 1100 mg anhydrous TMT/kg bw)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations (mortality, clinical signs, irritation using Draize scale): at day 0 and once daily thereafter (a total of 14 calendar days)
- Frequency of weighing: day 0 (prior to dosing), day 7 and day 14
- Necropsy of survivors performed: all animals were necropsied at the completion of the 14-day observation period

Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: hydrated form TMT 55
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 100 mg/kg bw
Based on:
other: anhydrous form
Remarks on result:
other: recalculated value for anhydrous TMT based on 55% TMT
Mortality:
All animals survived to the end of the study.
Clinical signs:
Skin irritation was observed ranging from barely perceptible signs of irritation (slight erythema), to signs of strong irritation (servere erythema, slight edema) with irreversible skin damage. At the end of the observation period, scars were present at the application site for one of five males and all five females. In one female, a reduced amount of feces was noted on day 3. No other abnormal clinical signs were evident at any time during the 14-day observation period.
Body weight:
No effect on body weight observed. All animals gained weight normally.
Gross pathology:
A large spleen, noted for a single male, was processed for microscopic examination. Histologically, the increased size of the spleen was associated with hyperplastic lymphoid follicles. The cause for this change was not identified, but may have been related to the inflammatory response associated with the skin damage seen in this rat. No other treatment-related changes or signs of organ toxicity were evident at necropsy.
Interpretation of results:
other: not classified for hydrated form TMT 55; inconclusive for anhydrous TMT
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
In this acute dermal toxicity study in the rat the LD50 for the test item TMT 55 was greater than 2000 mg/kg bw (corresponding to > 1100 mg anhydrous TMT/kg bw) for both sexes.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

In a non-GLP acute toxicity test similar to OECD Guideline 401 rats were given TMT 15 via gavage at dose levels of 5197, 7627 and 11200 mg/kg bw (92-0043-DKT). The dose levels are equivalent to 780, 1144, 1680 mg anhydrous TMT/kg bw. All males and 2/5 females of the high dose group died. After administration of 1144 mg anhydrous TMT/kg bw 2/5 males and 1/5 females did not survive. All mortalities occurred between 4 hours and 2 days after application of the test substance. Clinical signs, like piloerection, laboured respiration, increased pain perception, stillet gait and clonic convulsions were observed starting at 15 min after test substance administration. Accumulation of red-brownish fluid was noted in the stomach of animals, which died. Thus, based on the observed mortality, a LD50 of 1182 mg anhydrous TMT/kg bw for males was calculated by Probit analysis. For female rats a LD50 of > 1680 mg anhydrous TMT/kg bw was obtained.

 

Inhalation

Due to the negligible vapour pressure, exposure considerations und animal welfare considerations, further testing by the inhalation route does not need to be conducted in accordance with Annex VIII, Column 2, Section 8.5.2, of Regulation (EC) No 1907/2006.

 

Dermal

Rats were exposed dermally to TMT 55 in a GLP Guideline study according to OECD 402 (93-0163-FGT). The test substance was applied under occlusive conditions on the dorsal skin for 24 hours. The tested dose level of TMT 55 was 2000 mg/kg bw corresponding to 1100 mg anhydrous TMT/kg bw. At the end of the exposure period, residual test material was washed off. All animals (5 per sex) survived until the end of the 14-day observation period and gained weight normally. Abnormal clinical signs were limited to skin irritation and ranged from barely perceptible signs of irritation (slight erythema) to signs of strong irritation (severe erythema with slight edema) with irreversible skin damage. At the end of the observation period, scars were present at the application site for all females and one male rat. At necropsy a large spleen was observed in one single male rat. Histologically, the increased spleen size was associated with hyperplastic lymphoid follicles, which may have been related to the inflammatory response due to the observed skin damage in this rat. No further findings were observed at necropsy.

Thus, based on the results of this acute dermal toxicity study, the LD50 value for anhydrous TMT was > 1100 mg/kg bw.

 


Justification for selection of acute toxicity – oral endpoint
There is only one study available. Based on the observed mortality, a LD50 of 1182 mg anhydrous TMT/kg bw for male rats was determined. For female rats a LD50 of > 1680 mg anhydrous TMT/kg bw was obtained.
 

Justification for selection of acute toxicity – inhalation endpoint
No study required since exposure of humans via inhalation is unlikely taking into account the physico-chemical properties of the substance and exposure considerations.

Justification for selection of acute toxicity – dermal endpoint
There is only one study available. No mortality occurred up to the highest dose tested (2000 mg TMT 55/kg bw equivalent to 1100 mg anhydrous TMT/kg bw).

Justification for classification or non-classification

Oral

Based on available data on acute oral toxicity, anhydrous TMT meets the criteria for classification as Acute Oral Cat. 4, H302 according to Regulation (EC) 1272/2008 and as Xn, R22 according to Directive 67/548/EEC.

Inhalation

There is no data available on acute inhalation toxicity.

Dermal

No mortality occurred up to the dose level of 2000 mg TMT 55/kg bw and therefore, the data for TMT 55 is conclusive but not sufficient for classification according to Regulation (EC) 1272/2008 and according to Directive 67/548/EEC. However, the available data on acute dermal toxicity is insufficient for the classification or non-classification of anhydrous TMT (LD50 > 1100 mg anhydrous TMT/kg bw).