Registration Dossier

Administrative data

Description of key information

The available data on C16 TMAC and the read-across substance C12-18 TMAC indicate potential for acute oral (LD50 = 699 mg a.i./kg bw) and dermal toxicity (approximate LD50 = 528 mg a.i./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
Study period:
From June 27, 1984 to August 02, 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to OECD Guideline 401, in compliance with GLP.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG, Kastengrund
- Weight at study initiation: 176-201 g for males; 181-219 g for females
- Fasting period before study: 16 h
- Housing: up to 5 animals per cage in Macrolon cages
- Diet : Altromin 1324 (Altromin GmbH, Lage/Lippe) ad libitum
- Water : Tap water ad libitum
- Acclimation period: min 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 45 - 65
Route of administration:
oral: gavage
Vehicle:
water
Doses:
630, 1000, 1600, 2500, 3150 and 4000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of weighing: Days 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: Clinical signs, body weight and gross pathological examination
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 699 mg/kg bw
Based on:
act. ingr.
Remarks:
(based on ca. 29% a.i. in the preparation)
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 861 mg/kg bw
Based on:
act. ingr.
Remarks:
(based on ca. 29% a.i. in the preparation)
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 450 mg/kg bw
Based on:
act. ingr.
Remarks:
(based on ca. 29% a.i. in the preparation)
Mortality:
Mortalities occured from Day 1 to Day 13 of the study.
Clinical signs:
Clinical signs observed in the first days in male and female rats included: quiet behaviour, hunched posture, closed eyelids, retracted flanks, rough fur, paleness, noisy unregular breathing, myosis and slimy feces.
Body weight:
Reduced bodyweight compared to the other groups was seen in individual animals at most dosage groups, in particular after 7 days.
Gross pathology:
Animals dying during the study showed the following symptoms:
- Bleeding in the mucous membrane of the stomach, swollen stomach, stomach filled with liquid, slime or feed, glassy appearence of the small intestine, reddened small intestine mucous membrane, small intestine filled with yellowish-clear mass
- Darkened adrenal glands, very full bladder
- Bleeding in the lungs

Animals sacrificed at the end of the study did not present any significant macroscopic changes.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 of test substance was 2,410 mg/kg bw for males/females combined, 2,970 mg/kg bw for males and 1,550 mg/kg bw for females. This is equivalent to nominal concentrations of 699, 861 and 450 mg/kg bw based on active ingredient, respectively.
Executive summary:

An acute oral toxicity study was performed using Wistar rats according to OECD guidelines. A group of 10 fasted animals (five males and five females) were administered a single oral dose of C16 TMAC (containing 29% active substance) at nominal doses of 630, 1,000, 1,600, 2,500, 3,150 and 4,000 mg/kg bw. The animals were observed for 14 days following exposure. The animals were then sacrificed and subjected to gross pathological examination.

The acute oral LD50 was determined to be 2,410 mg/kg bw for males/females combined, 2,970 mg/kg bw for males and 1,550 mg/kg bw for females. This is equivalent to 699, 861 and 450 mg a.i./kg bw, respectively.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
699 mg/kg bw
Quality of whole database:
Guideline study with Klimisch score 1, meeting the tonnage information requirements.

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
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:
other: Study was conducted according to the OECD guideline 402 and EPA OPP 81-2 as well as in compliance with GLP.
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.
Sex:
male
Dose descriptor:
LD50
Effect level:
1 300 mg/kg bw
Based on:
test mat.
95% CL:
800 - 1 900
Sex:
female
Dose descriptor:
LD50
Effect level:
1 900 mg/kg bw
Based on:
test mat.
95% CL:
1 500 - 2 400
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 600 mg/kg bw
Based on:
test mat.
95% CL:
1 200 - 2 100
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 429 mg/kg bw
Based on:
act. ingr.
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 627 mg/kg bw
Based on:
act. ingr.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 528 mg/kg bw
Based on:
act. ingr.
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.
Interpretation of results:
Toxicity Category III
Remarks:
Migrated information Category 3 Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the test, the acute dermal LD50 of the test substance for male and female albino rabbits was found to be 1600 mg/kg bw (95% confidence limits of 1200 − 2100 mg/kg bw) or 528 mg a.i./kg bw.
Executive summary:

An OECD 402 study was conducted to determine the acute dermal toxicity of C12-18 TMAC (active ingredient 33%) in male or female albino rabbits. The test substance (0, 520, 1,020 or 2,000 mg/kg bw) was applied under semi-occlusive conditions for 24 hours 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 hours post-dosing. Following the 24 hour exposure period, animals were observed for mortality, clinical signs and skin response for 14 days. 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 was found to be 1,600 mg/kg bw (i.e., 528 mg a.i./kg bw) (95% confidence limits of 1,200 – 2,100 mg/kg bw).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
528 mg/kg bw
Quality of whole database:
Guideline study with Klimisch score 2, meeting the tonnage information requirements.

Additional information

Oral

In an acute oral toxicity study, five male and five female rats were administered a single oral dose of 5,000 mg/kg bw of C16 TMAC, equivalent to 250 mg a.i./kg bw (based on 5% active substance). The animals were observed for 14 days after dosing, then sacrificed and subjected to gross pathological examination. One animal died on Day 2; signs prior to death included lethargy, ano-gential staining and hunched posture. Several surviving animals exhibited transient diarrhoea, soft faeces and ano-genital staining, but were symptom-free from Day 4 post dosing. The acute oral LD50 was greater than 250 mg a.i./kg bw (Shapiro R, 1990).

In another acute oral toxicity study, C16 TMAC was administered to groups of 10 fasted Wistar rats (five males and five females) in a single oral dose at nominal concentrations of 630, 1,000, 1,600, 2,500, 3,150 and 4,000 mg/kg bw, equivalent to 183, 290, 464, 725, 914, 1160 mg a.i./kg bw (based on 29% active substance). The animals were observed for 14 days after dosing and then sacrificed and subjected to gross pathological examination. The acute oral LD50 of the test substance was 2,410 mg/kg bw for males/females combined, 2,970 mg/kg bw for males and 1,550 mg/kg bw for females; the latter appeared more sensitive to effects. This is equivalent to 699, 861 and 450 mg a.i./kg bw, respectively (Rupprich and Weigand, 1984).

Dermal

An OECD 402 study was conducted to determine the acute dermal toxicity of C12-18 TMAC (active ingredient 33%) in male or female albino rabbits. The test substance (0, 520, 1,020 or 2,000 mg/kg bw) was applied under semi-occlusive conditions for 24 hours 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 hours post-dosing. Following the 24 hour exposure period, animals were observed for mortality, clinical signs and skin response for 14 days. 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 was found to be 1,600 mg/kg bw (i.e., 528 mg a.i./kg bw) (95% confidence limits of 1,200 – 2,100 mg/kg bw) (Naas DJ, 1988).


Justification for selection of acute toxicity – oral endpoint
Study was performed with test substance with greater percentage of active ingredient and greater analytical purity. Therefore the study was considered as the key study for the chemical safety assessment

Justification for selection of acute toxicity – dermal endpoint
Reliable guidline study available on read-across substance.

Justification for classification or non-classification

The acute toxicity data (oral and dermal LD50 of 699 and 528 mg a.i./kg bw, respectively) indicates that C16 TMAC should be classified as follows: R22 (harmful if swallowed) and R21 (harmful in contact with skin), according to Directive 67/548/EEC and category 4, H302: harmful if swallowed and category 3, H311: toxic in contact with skin classification, according to Regulation EC 1272/2008.