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Description of key information

Based on the results of the read across study, the oral and dermal LD50 values for the test substance is considered at 207 and 429 mg a.i./kg bw respectively; indicative of moderate acute toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
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:
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.
Qualifier:
according to
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:
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:
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 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: Category 3 as per CLP
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
226 mg/kg bw
Based on:
act. ingr.
95% CL:
ca. 207 - ca. 245
Remarks on result:
other: Category 3 as per CLP
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:
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 mouth, respiratory distress, ataxia, lethargy, salivation and hypothermia. Animals in the 908 mg/kg bw also showed clear ocular discharge and tremors.
Body weight:
No effect
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.

Mortality and other observations

Table 1.                           Table for Acute Toxicity

Dose [mg a.s./kgbw]

Number of dead /
number of investigated

Time of death (range)

Observations

0

0/10

 

No findings

169

0/10

 

Four females had wet yellow anogenital staining early in the study period. One of these also had diarrhea and one male had slight dried brown staining around the mouth. There were no other findings.

205

3/10

Found dead day 3

Anogenital staining, diarrhea, brown staining around the mouth, evidence of respiratory distress (respiratory rales and/or bradypnea), ataxia, lethargy, salivation, and hypothermia

248

7/10

Found dead day 1-3

Similar, but higher incidence.

300

5/5

Found dead day 1-3

diarrhea, wet yellow and/or brown urogenital staining, and respiratory distress (rales and bradypnea).

Ataxia and lethargy were noted for three of the five rats.

Other findings in this group included clear ocular discharge, hypothermia, tremors and various stains around the mouth

LD50 value

Male & female combined: 226 (207-245) mg a.i./kgbw

 

Interpretation of results:
other: Category 3 based on CLP criteria
Conclusions:
Based on the results of the read across study, the acute oral LD50 of the read across substance in Sprague-Dawley rats is considered to be 684 mg test substance/kg bw (i.e., 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 (33% active in water), 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 read across substance (i.e., equivalent to 0, 169, 205, 248 and 300 mg a.i./kg bw) 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 (or 169 mg a.i./kg bw) group while 3 out of 10 and 7 out of 10 rats died in the 620 mg/kg bw (or 205 mg a.i./kg bw) and 750 mg/kg bw (or 248 mg a.i./kg bw) groups, respectively. All five animals in the highest dose group (908 mg/kg bw or 300 mg a.i./kg bw) died. Under the study conditions, the acute oral LD50 of the read across substance in Sprague-Dawley rats was determined to be 684 mg/kg bw (or 226 mg a.i./kg bw) with 95% confidence limits of 629 -743 mg/kg bw (or 207-245 mg a.i./kg bw) (Naas, 1987). Based on the results of the read across study, similar LD50 value is expected for the test substance.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
207 mg/kg bw
Quality of whole database:
The information requirement for this tonnage band is sufficiently met with the available data.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
the study does not need to be conducted because the substance is classified as corrosive to the skin
other:
Reason / purpose:
data waiving: supporting information
Clinical signs:
other:
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.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
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 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.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
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
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
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:
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 528 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:
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.
Body weight:
Treatment-related body weight loss in one animal each at two higher doses throughout the 14 d. For other eight rabbits body weight was decreased during first wk with a subsequent recovery in the second wk and net gain in the entire 14 d study period.
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.

Mortality and other observations

Table 1.                           Table for Acute Toxicity

Dose [mg a.s./kg bw]

Number of dead /
number of investigated

Time of death (range)

Observations

0

0/6

 

Pale kidneys were observed for one female in the control group. No other changes were noted for control group.

172

0/10

 

Eschar and thickening on the application site.

Decreased defecation primarily early in the study period(7/10). Also observed in one or two animals: clear wet matting around the mouth, clear wet ventral abdominal matting, clear nasal discharge, diarrhea, scabbing on the right hind leg and hair loss and desquamation in the urogenital area.

337

2/10

Found dead morning 1stand 2ndday

Eschar, subcutaneous hemorrhage, blanching and thickening were noted on the application sites of rabbits that died, and Eschar and thickening on the application site of the other animals.

Decreased defecation primarily early in the study period(4/10). Also observed in one or two animals: clear wet matting around the mouth, clear wet ventral abdominal matting, clear nasal discharge, diarrhea, scabbing on the right hind leg and hair loss and desquamation in the urogenital area.

660

7/10

Found dead morning 1stday.

Lethargy, ataxia, laboured respiration, purulent nasal discharge on day 1, emaciated appearance.

Necrosis, desquamation, scabbing, eschar, exfoliation, fissuring and blanching. Also, subcutaneous hemorrhage was present on the application sites of one rabbit in the 2000 mg/kg group that survived and all animals that died.
No internal abnormalities were observed among rabbits that died which could be Attributed to the test material.

LD50value

Male & female combined: 528 (396 – 693) mg a.s/kg bw

 

For further details on result tables, kindly refer to the attached background material section of the IUCLID.

Interpretation of results:
other: Category 3 based on CLP criteria
Conclusions:
Based on the results of the read across study, 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 was determined to be 1,600 mg/kg bw (i.e., equivalent to 528 mg a.i./kg bw).
Executive summary:

A study was conducted to determine the acute dermal toxicity of the read across substance, Coco TMAC (33% active in water), in albino rabbits according to OECD 402 Guideline, in compliance with GLP. Semi-occlusive patches of the read across substance at 0, 520, 1,020 or 2,000 mg/kg bw (i.e., equivalent to 0, 172, 337 and 660 mg a.i./kg bw) was applied to the shaved, intact skin of groups of 10 rabbits (five per sex) for 24 h. 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 (or 172 mg a.i./kg bw) group. Two males died in the 1,020 mg/kg bw (or 337 mg a.i./kg bw) group while 4 males and 3 females died in the 2,000 mg/kg bw (or 660 mg a.i./kg bw) group. Under the study conditions, 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 read across 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, similar LD50 can be expected for the test substance.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
429 mg/kg bw
Quality of whole database:
The information requirement for this tonnage band is sufficiently met with the available data.

Additional information

Oral

A study was conducted to determine the acute oral toxicity of the read across substance, Coco TMAC (33% active in water), 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 read across substance (i.e., equivalent to 0, 169, 205, 248 and 300 mg a.i./kg bw) 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 (or 169 mg a.i./kg bw) group while 3 out of 10 and 7 out of 10 rats died in the 620 mg/kg bw (or 205 mg a.i./kg bw) and 750 mg/kg bw (or 248 mg a.i./kg bw) groups, respectively. All five animals in the highest dose group (908 mg/kg bw or 300 mg a.i./kg bw) died. Under the study conditions, the acute oral LD50 of the read across substance in Sprague-Dawley rats was determined to be 684 mg/kg bw (or 226 mg a.i./kg bw) with 95% confidence limits of 629 -743 mg/kg bw (or 207-245 mg a.i./kg bw) (Naas, 1987). Based on the results of the read across study, similar LD50 value is expected for the test substance.

Based on the above study, the biocide assessment report available from RMS Italy on Coco TMAC (ECHA assessment report, 2016), selected the lowest acute oral LD50 value at 207 mg a.i./kg bw. They further stated that the clinical signs were mainly due to gastrointestinal disturbance, respiratory distress, ataxia, lethargy, salivation and hypothermia. Therefore, in line with the biocides assessment report, the oral LD50 value of 207 mg a.i./kg bw has been considered further for hazard/risk assessment.

Dermal

A study was conducted to determine the acute dermal toxicity of the read across substance, Coco TMAC (33% active in water), in albino rabbits according to OECD 402 Guideline, in compliance with GLP. Semi-occlusive patches of the read across substance at 0, 520, 1,020 or 2,000 mg/kg bw (i.e., equivalent to 0, 172, 337 and 660 mg a.i./kg bw) was applied to the shaved, intact skin of groups of 10 rabbits (five per sex) for 24 h. 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 (or 172 mg a.i./kg bw) group. Two males died in the 1,020 mg/kg bw (or 337 mg a.i./kg bw) group while 4 males and 3 females died in the 2,000 mg/kg bw (or 660 mg a.i./kg bw) group. Under the study conditions, 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 read across 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, similar LD50 can be expected for the test substance.

Based on the above study the biocide assessment report available from RMS Italy on Coco TMAC (ECHA assessment report, 2016), selected the lowest acute dermal LD50 value at 429 mg a.i./kg bw. They further stated that all concentrations applied induced moderate to severe erythema and oedema; the clinical signs and the observed lethality are secondary to the severe local tissue damage, rather than the result of systemic toxicity through percutaneously absorbed material. Therefore, in line with the biocides assessment report, the dermal LD50 value of 429 mg a.i./kg bw has been considered further for hazard/risk assessment.

Inhalation

In accordance with Annex VII, Section 8.5, Column 2, of the REACH regulation, the study does not need to be conducted because the substance is classified as corrosive to the skin. Further, the substance has a low vapour pressure (VP = 0.0058 Pa at 25 °C), which is below the cut-off of 0.01 Pa set for defining low volatility substances, as per the ECHA Guidance R.7a (2017). Therefore, due to the low VP, it is unlikely that the test substance will form inhalable dust, mist or fumes when handled and used in solid form. In case inhalable forms of the substance (either pure or in aqueous solutions) 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 oral and dermal LD50 values from the read across studies, the test substance C12-18 TMAC warrants an ‘Acute Tox. 3; H301: toxic if swallowed’ classification for the oral route and ‘Acute Tox. 3; H311: toxic in contact with skin’ for the dermal route according to EU CLP criteria (Regulation EC 1272/2008).