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Endpoint summary

Description of key information

Based on the oral and dermal LD50 values available for the read across substances, C12 -14 TMAC can be considered to be of moderate acute toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From August 03, 1982 to August 24, 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Principles of method if other than guideline:

Groups of 10 female Wistar rats were exposed to the test substance via oral gavage at 0, 250, 400, 630 and 1000 mg/kg bw. Clinical signs, mortality and bodyweight were recorded during 14 d post-dosing. At study end, a gross macroscopic examination was conducted. LD50 values were calculated by PROBIT analysis.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Präpagen 2916

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst breeding
- Females (if applicable) nulliparous and non-pregnant: [yes]
- Weight at study initiation: 233-253 g
- Fasting period before study: 16 h
- Diet (e.g. ad libitum): Altromin 1324 (Altromin GmbH, Germany)
- Water (e.g. ad libitum): tap water

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

The test substance was prepared as a 25% solution in water.

Doses:

0, 250, 400, 630 and 1000 mg/kg bw.

No. of animals per sex per dose:

10

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

LD50 calculated by PROBIT analysis (method of Linder and Weber). Confidentiality limits calculated according to Fieller.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

448 mg/kg bw

Based on:

test mat.

95% CL:

ca. 322 - ca. 593

Mortality:

250 mg/kg bw, 25% concentration: mortality = 2/10 animals
400 mg/kg bw, 25% concentration: mortality = 4/10 animals
630 mg/kg bw, 25% concentration: mortality = 6/10 animals
1000 mg/kg bw, 25% concentration: mortality = 10/10 animals

Clinical signs:

other: Clinical signs included hyperactivity, high leg posture, crouching, stomach and flanks tucked in, exophtalmia, noisy and sometimes irregular breathing, as well as rapid breathing. On Day 2, all surviving rats still showed noisy breathing. At 630 mg/kg bw,

Gross pathology:

Macroscopic examination revealed blood in the lungs, which were in part grey-red discolored, dark brown discoloration of the liver and diffuse digestive tract, in part strongly reddened. The gastrointestinal tract was gelatinous with isolated petechial bleedings. Its appearance was transparent and it was mostly filled with a yellow-reddish mass.

Interpretation of results:

other: Category 4 based on CLP criteria

Conclusions:

Under the study conditions, the acute oral LD50 for the test substance in rats was equivalent to 448 mg/kg bw (CL = 322 - 593 mg/kg bw).

Executive summary:

A study was conducted to determine the acute oral toxicity of the test substance, C12-14 TMAC (active ingredient 40%), in rats. Groups of 10 female Wistar rats were exposed to the test substance via oral gavage at 0, 250, 400, 630 and 1000 mg/kg bw. The test substance was prepared as a 25% solution in water. As it is not clear if the active ingredient corrections have been applied, the doses are mentioned as such. Clinical signs, mortality and bodyweight were recorded during 14 d post-dosing. At study end, a gross macroscopic examination was conducted. LD50 values were calculated by PROBIT analysis. Clinical signs included hyperactivity, high leg posture, crouching, stomach and flanks tucked in, exophtalmia, noisy and sometimes irregular breathing, as well as rapid breathing. On Day 2, all surviving rats still showed noisy breathing. At 630 mg/kg bw, high leg posture and flanks tucked in were recorded until end of Day 4. No clinical signs were apparent as of Day 5. Bodyweights of surviving animals were within normal ranges throughout the study. Macroscopic examination revealed blood in the lungs, which were in part grey-red discolored, dark brown discoloration of the liver and diffuse digestive tract, in part strongly reddened. The gastrointestinal tract was gelatinous with isolated petechial bleedings. Its appearance was transparent and it was mostly filled with a yellow-reddish mass. Under the study conditions, the acute oral LD50 for the test substance in rats was equivalent to 448 mg/kg bw (CL = 322 - 593 mg/kg bw) (Mayer and Weigand, 1982).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

From 12 June, 1986 to 13 September, 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

KL 2 due to RA

Justification for type of information:

Refer to the Quaternary ammonium salts (QAS) category or section 13 of IUCLID for details on the category justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

One animal in the lowest dose group was not observed for clinical findings at 4 h after dosing on Day 0. this deviation does not affect the scientific validity or integrity of the study.

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

One animal in the lowest dose group was not observed for clinical findings at 4 h after dosing on Day 0. this deviation does not affect the scientific validity or integrity of the study.

Qualifier:

according to guideline

Guideline:

other: Toxic Substances Control Act (TSCA) Health Effects Test Guidelines

Deviations:

yes

Remarks:

One animal in the lowest dose group was not observed for clinical findings at 4 h after dosing on Day 0. this deviation does not affect the scientific validity or integrity of the study.

GLP compliance:

yes

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 Breeding Laboratories, Inc., Portage, Michigan
- Weight at study initiation: 205-262 g
- Fasting period before study: 18 h
- Housing: Individually housed in wire-mesh cages
- Diet: Purina certified rodent chow # 5002, ad libitum
- Water: Drinking water, ad libitum
- Acclimation period: Minimum 7 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): more than 40%
- Photoperiod (h dark/h light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 0.93 mL/kg

Doses:

0, 512, 620, 750 and 908 mg/kg bw .

No. of animals per sex per dose:

Five animals per sex per dose except for the highest dose which has only 5 males.

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 d
- Frequency of clinical observation: 1, 2.5 and 4 h after dosing on Day 0 and subsequently once daily for 14 d.
- Frequency of weighing: On Days 0, 7 and 14
- Necropsy of survivors performed: Yes
- Examinations performed: Clinical signs, body weight and gross pathological examination.

Statistics:

LD50 values and slopes (with 95% confidence limit) were calculated by method of Litchfield and Wilcoxon.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

684 mg/kg bw

Based on:

test mat.

95% CL:

ca. 629 - ca. 743

Remarks on result:

other: i.e., equivalent to 226 mg a.i./kg bw

Mortality:

There was no mortality in the 512 mg/kg bw group while 3 out of 10 and 7 out of 10 rats died in the 620 and 750 mg/kg bw groups, respectively. All the five animals died receiving the highest tested dose of 908 mg/kg bw.

Clinical signs:

other: Four males in the 512 mg/kg bw group had yellowish anogenital staining during early study period and one of these animals had diarrhoea. Several animals in the 620, 750 and 908 mg/kg bw showed anogenital staining, diarrhoea, brown staining around the mout

Gross pathology:

Changes were observed in the adrenal glands, brain, kidneys, stomach and intestines for more than one and half of all rats died during study. Abnormalities in the liver were found in of 7/15 of the dead rats. No significant changes for all tissues examined for rats that were terminally sacrificed, including control group.

In the range-finding study, all the rats dosed at 1000, 1500 and 2000 mg/kg bw died while rats dosed at 500 mg/kg bw survived.

Interpretation of results:

other: Category 3 based on CLP criteria

Conclusions:

Based on the results of the read across study, the oral LD50 value of the test substance can also be considered to be equivalent to 226 mg a.i./kg bw).

Executive summary:

A study was conducted to determine the acute oral toxicity of the read across substance, Coco TMAC (active ingredient 33%), in Sprague-Dawley rats according to OECD 401 and EPA OPP 81-2 Guidelines, in compliance with GLP. Groups of 10 fasted animals (five males and five females per dose except for five males only at the highest dose) were administered 0, 512, 620, 750 or 908 mg/kg bw of the test substance via the oral route. The animals were observed for 14 days after dosing and then sacrificed and subjected to gross pathological examination. There was no mortality in the 512 mg/kg bw group while 3 out of 10 and 7 out of 10 rats died in the 620 and 750 mg/kg bw groups, respectively. All five animals in the highest dose group (908 mg/kg bw) died. Under the study conditions, the acute oral LD50 of the test substance in Sprague-Dawley rats was determined to be 684 mg test substance/kg bw (i.e., equivalent to 226 mg a.i./kg bw) with 95% confidence limits of 629−743 mg/kg bw (Naas, 1987). Based on the results of the read across study, the oral LD50 value of the test substance can also be considered to be equivalent to 226 mg a.i./kg bw).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

226 mg/kg bw

Quality of whole database:

Good quality study

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

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:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

From 22 February, 1988 to 24 March, 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

KL2 due to RA

Justification for type of information:

Refer to the Quaternary ammonium salts (QAS) category or section 13 of IUCLID for details on the category justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Toxic Substances Control Act (TSCA) acute dermal toxicity guideline

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

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: Mochican Valley Rabbitry, Loidonville, Ohio
- Weight at study initiation: 2140 to 2990 g
- Housing: individual suspended wire-mesh cages
- Diet (e.g. ad libitum): Purina Certified rabbit chow # 5322, ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: Minimum 7 d

ENVIRONMENTAL CONDITIONS
- Humidity (%): 49-74%
- Photoperiod (h dark / h light): 12 h / 12 h

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: Shaved intact dorsal skin
- % coverage: 20%
- Type of wrap if used: Test substance was applied under gauze binders that were secured with non-irritating tape.

Duration of exposure:

24 h

Doses:

0, 520, 1020 and 2000 mg/kg bw.

No. of animals per sex per dose:

Five animals per sex per test group, three animals per sex in control group.

Control animals:

yes, concurrent vehicle

Details on study design:

- Duration of observation period following administration: Animals were observed at 1, 3 and 4 h post-dosing on Day 0 and twice daily for mortality and once daily for clinical observations for 14 d. Application sites were examined for erythema, oedema and other dermal findings at 30−60 min after bandage removal and daily thereafter for 13 d. Erythema and oedema were graded according to Draize method.
- Frequency of observations and weighing: Day 0, 7 and 14
- Necropsy of survivors performed: yes

Statistics:

LD50 and slopes (with 95% confidence limits) were calculated by method of Litchfield and Wilcoxon.

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 1 300 mg/kg bw

Based on:

test mat.

95% CL:

ca. 800 - ca. 1 900

Remarks on result:

other: i.e., equivalent to 429 mg a.i./kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 1 900 mg/kg bw

Based on:

test mat.

95% CL:

ca. 1 500 - ca. 2 400

Remarks on result:

other: i.e., equivalent to 627 mg a.i./kg bw

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 1 600 mg/kg bw

Based on:

test mat.

95% CL:

ca. 1 200 - ca. 2 100

Remarks on result:

other: i.e., equivalent to 588 mg a.i./kg bw

Mortality:

Control: 0/6 animals
520 mg/kg bw: 0/10 animals
1020 mg/kg bw: 2/5 males and 0/5 females
2000 mg/kg bw: 4/5 males and 3/5 females

Clinical signs:

other: Lethargy and ataxia were major clinical findings. Other findings included hypothermia, decreased respiratory rate, laboured respiration, nasal discharge, decreased defecation, emaciation, red staining around the mouth, diarrhoea.

Gross pathology:

Treatment-related abnormality on the application sites of all rabbits. No substance-related internal abnormalities in rabbits that died during study or terminally sacrificed.

Other findings:

Test substance induced moderate to severe erythema and oedema with other significant dermal findings such as necrosis, desquamation, scabbing, eschar, exfoliation, fissuring and blenching. Subcutaneous haemorrhage was present on the application sites of one rabbit in the 2000 mg/kg bw group that survived and all animals that died.

Only (systemic) pathology observed in animals sacrificed at termination were kidney abnormalities (pale, reddened, pitted) in 5/21 of the terminally sacrificed dosed rabbits. Pale kidneys were also observed for one female in the control group. The skin of the animals that died showed eschar, subcutaneous haemorrhage, blanching and thickening. Internal abnormalities included hemorrhagic thymus glands (6/9) (typical agonal change), red foci or dark red area in the stomach (3/9), brain haemorrhages (3/9) and liver soft or pale and soft (2/9). No internal abnormalities were observed among rabbits that died which could be attributed to the test substance. There were no test substance related internal changes for rabbits that were terminally sacrificed.

Considering the generally low dermal absorption of Coco TMAC (<10% in Bartnik and Wingen, 1979 study), it is likely that severe corrosive effects upon the 24 h exposure of the concentrated product were more cause to the death of the animals, than real systemic toxicity. This is supported by the relatively limited observations on internal organs upon necropsis of the animals that died. The most commonly observed internal abnormalities were hemorrhagic thymus glands (6/9), which is a typical agonal change, and likely not a specific sign of toxicity.

Interpretation of results:

other: Category 3 based on CLP criteria

Conclusions:

Based on the results of the read across study, the acute dermal LD50 value of the test substance, C12-14 TMAC, can also be considered to be 528 mg a.i./kg bw (429-627 mg a.i./kg bw for males and females).

Executive summary:

A study was conducted to determine the acute dermal toxicity of the read across substance, Coco TMAC (active ingredient 33%), in albino rabbits according to OECD 402 Guideline, in compliance with GLP. The test substance at 0, 520, 1,020 or 2,000 mg/kg bw was applied under semi-occlusive conditions for 24 h in a single application to the shaved, intact skin of groups of 10 rabbits (five per sex). Animals were observed at 1, 3 and 4 h post-dosing. Following the 24 h exposure period, animals were observed for mortality, clinical signs and skin response for 14 d. There was no mortality in the control or 520 mg/kg bw group. Two males died in the 1,020 mg/kg bw group while 4 males and 3 females died in the 2,000 mg/kg bw group. Under the conditions of the test, the acute dermal LD50 for male and female albino rabbits were determined to be 1,300 mg/kg bw (i.e., equivalent to 429 mg a.i./kg bw) and 1,900 mg/kg bw (i.e., equivalent to 627 mg a.i./kg bw) respectively, and the combined dermal LD50 value for males and females was determined to be 1,600 mg/kg bw (i.e., equivalent to 528 mg a.i./kg bw). Considering the generally low dermal absorption potential of Coco TMAC (<10% in Bartnik and Wingen, 1979 study), the observed systemic effects and mortality were attributed to the severe corrosive properties of the test substance following 24 h exposure rather than real systemic toxicity. This is supported by the relatively limited observations on internal organs upon necropsis of the animals that died (Naas, 1988). Based on the results of the read across study, the acute dermal LD50 value of the test substance, C12 -14 TMAC, can also be considered to be 528 mg a.i./kg bw (429-627 mg a.i./kg bw for males and females).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

528 mg/kg bw

Quality of whole database:

Guideline and GLP compliant study

Additional information

Oral

Study 1: A study was conducted to determine the acute oral toxicity of the test substance, C12-14 TMAC, in rats. Groups of 10 female Wistar rats were exposed to the test substance via oral gavage at 250, 400, 630 and 1000 mg/kg bw. Clinical signs, mortality and bodyweight were recorded during 14 d post-dosing. At study end, a gross macroscopic examination was conducted. LD50 values were calculated by PROBIT analysis. Clinical signs included hyperactivity, high leg posture, crouching, stomach and flanks tucked in, exophtalmia, noisy and sometimes irregular breathing, as well as rapid breathing. On Day 2, all surviving rats still showed noisy breathing. At 630 mg/kg bw, high leg posture and flanks tucked in were recorded until end of Day 4. No clinical signs were apparent as of Day 5. Bodyweights of surviving animals were within normal ranges throughout the study. Macroscopic examination revealed blood in the lungs, which were in part grey-red discolored, dark brown discoloration of the liver and diffuse digestive tract, in part strongly reddened. The gastrointestinal tract was gelatinous with isolated petechial bleedings. Its appearance was transparent and it was mostly filled with a yellow-reddish mass. Under the study conditions, the acute oral LD50 for the test substance in rats was equivalent to 448 mg/kg bw (CL = 322 - 593 mg/kg bw) (Mayer and Weigand, 1982).

Study 2: A study was conducted to determine the acute oral toxicity of the read across substance, Coco TMAC (active ingredient 33%), in Sprague-Dawley rats according to OECD 401 and EPA OPP 81-2 Guidelines, in compliance with GLP. Groups of 10 fasted animals (five males and five females per dose except for five males only at the highest dose) were administered 0, 512, 620, 750 or 908 mg/kg bw of the test substance via the oral route. The animals were observed for 14 days after dosing and then sacrificed and subjected to gross pathological examination. There was no mortality in the 512 mg/kg bw group while 3 out of 10 and 7 out of 10 rats died in the 620 and 750 mg/kg bw groups, respectively. All five animals in the highest dose group (908 mg/kg bw) died. Under the study conditions, the acute oral LD50 of the test substance in Sprague-Dawley rats was determined to be 684 mg test substance/kg bw (i.e., equivalent to 226 mg a.i./kg bw) with 95% confidence limits of 629−743 mg/kg bw (Naas, 1987). Based on the results of the read across study, the oral LD50 value of the test substance can also be considered to be equivalent to 226 mg a.i./kg bw).

In absence of purity correction details for the study with the test substance, the oral LD50 value from the read across substance has been considered further for hazard assessment.

Dermal

A study was conducted to determine the acute dermal toxicity of the read across substance, Coco TMAC (active ingredient 33%), in albino rabbits according to OECD 402 Guideline, in compliance with GLP. The test substance at 0, 520, 1,020 or 2,000 mg/kg bw was applied under semi-occlusive conditions for 24 h in a single application to the shaved, intact skin of groups of 10 rabbits (five per sex). Animals were observed at 1, 3 and 4 h post-dosing. Following the 24 h exposure period, animals were observed for mortality, clinical signs and skin response for 14 d. There was no mortality in the control or 520 mg/kg bw group. Two males died in the 1,020 mg/kg bw group while 4 males and 3 females died in the 2,000 mg/kg bw group.Under the conditions of the test, the acute dermal LD50 for male and female albino rabbits were determined to be 1,300 mg/kg bw (i.e., equivalent to 429 mg a.i./kg bw) and 1,900 mg/kg bw (i.e., equivalent to 627 mg a.i./kg bw) respectively, and the combined dermal LD50 value for males and females was determined to be 1,600 mg/kg bw (i.e., equivalent to 528 mg a.i./kg bw). Considering the generally low dermal absorption potential of Coco TMAC (<10% in Bartnik and Wingen, 1979 study), the observed systemic effects and mortality were attributed to the severe corrosive properties of the test substance following 24 h exposure rather than real systemic toxicity. This is supported by the relatively limited observations on internal organs upon necropsis of the animals that died (Naas, 1988). Based on the results of the read across study, the acute dermal LD50 value of the test substance, C12 -14 TMAC, can also be considered to be 528 mg a.i./kg bw (429-627 mg a.i./kg bw for males and females).

Inhalation

The substance is a coarse grained solid with a low vapour pressure at room temperature. Due to its physical state and physical chemical properties it is unlikely that this substance will form inhalable dust, mist or fumes during normal processing and use conditions. In case inhalable forms of the substance are created under particular conditions (e.g. spraying, elevated temperature/pressure), appropriate risk management measures such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Under such conditions, the risk to humans following inhalation exposure can be considered minimal and further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation.

Justification for classification or non-classification

Based on the acute toxicity data (oral LD50 = 226 mg a.i./kg bw and dermal LD50 = 528 mg a.i./kg bw) of the read across substance, Coco TMAC, C12-14 TMAC is considered to be classified as 'Acute Tox.3, H301: toxic if swallowed' for oral route and 'Acute Tox.3, H311: toxic in contact with skin' for dermal route, according to EU CLP criteria (Regulation EC 1272/2008).