Registration Dossier

Administrative data

Description of key information

Acute toxicity oral: LD50 = approx. 5697 mg/kg body weight; read-across

Acute toxicity inhalation (similar to OECD TG 403): LC50 < 1 mg/L air, only nominal concentration determined

Acute toxicity dermal (similar to OECD TG 402): LD50 > 3000 mg/kg body weight

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:
test procedure in accordance with national standard methods with acceptable restrictions
Remarks:
no detailed information on conduct of the study available; purity of the test substance not specified
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: The test substance was applied via stomach intubation (single dose). No further details on the conduct of the study available.
- Short description of test conditions: no information availble
- Parameters analysed / observed: mortality, clinical signs, body weight changes, gross pathology of died animals and survivors
GLP compliance:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch No. of test material: 03788
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: testing facility
- Age at study initiation: 3 - 4 weeks
- Weight at study initiation: 90 - 120 g
- Fasting period before study: no
- Diet: Wayne diet, ad libitum
- Water: ad libitum
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 8 mL/kg bodyweight
Doses:
8, 4 and 2 mL/kg body weight (corresponding to approx. 9264, 4632 and 2316 mg/kg body weight; based on a density of 1.158 g/mL (lit.))
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: not specified
- Frequency of observations and weighing: not specified
- Necropsy of survivors performed: yes + necropsy of died animals
Sex:
male
Dose descriptor:
LD50
Effect level:
4.92 mL/kg bw
Remarks on result:
other: corresponding to approx. 5697 mg/kg bodyweight (based on the density of 1.158 g/mL (lit.))
Mortality:
- in the 8 mL/kg bw group 5/5 animals died (4 on 1st day and 1 after 5 days)
- in the 4 mL/kg bw group 1/5 animals died (on 1st day)
- in the 2 mL/kg bw group no mortality was observed
Clinical signs:
- 8 mL/kg bw group: sluggish, slow breathing 15 min; prostrate 1.5 h
- 4 mL/kg bw group: sluggish, slow breathing 30 min; piloerection, legs stiffened within 2 h; prostrate at 2.5 h; convulsions, foaming at mouth at 4 h
- 2 mL/kg bw group: sluggish, slow breathing 30 min; prostrate 3 h
Body weight:
- decrease of 6,7 - 15 % in the 4 mL/kg bw group and 2.2 - 3.3 % in the 2 mL/kg bw group
- bodyweight changes in the 8 mL/kg bw group could not be determined due to the death of all animals
Gross pathology:
- in died animals petechial hemorrhages and congestion in the lungs; livers burned; livers, spleens and kidneys mottled; kidneys pale; adrenals congested; stomachs distended, containing a hard mass, opaque and gas-filled; intestines opaque, gas-filled and yellow
- nothing remarkable in survivors
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
5 697 mg/kg bw
Quality of whole database:
Read-across from structural analogue (CAS 57116-45-7)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating conc.
1 000 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
3 000 mg/kg bw

Additional information

Acute toxicity oral:

There are no data on the acute oral toxicity of 2-[(3-aziridin-1-ylpropionyl)methyl]-2-ethylpropane-1,3- diyl bis(aziridine-1-propionate) available. However, a structural analogue substance (CAS 57116-45-7) was assessed for this toxicological endpoint:

A single dose of 8, 4 or 2 mL/kg body weight of  Pentaerythritol tris(3-(1-aziridinyl)propionate) (CAS 57116-45-7) was administered to male Wister rats (5 animals per dose) via stomach intubation. Following administration, mortality, clinical signs and body weight changes were recorded for all animals. Survivors as well as died animals were necropsied.

In the high dose group (8 mL/kg bw) alle animals died within 5 days after treatment. In the mid dose group (4 mL/kg bw) 1 animal died within 1 day after treatment. No mortality was observed in the low dose group (2 mL/kg bw). Clinical signs observed in all groups were sluggish, slow breathing and prostrate. In the mid dose group piloerection, stiffened legs, convulsions and foaming at mouth were observed additionally.

Futhermore, body weights were reduced in the mid and low dose group (decrease of 6,7 - 15 % and 2.2 - 3.3 %, respectively). Body weight changes in the high dose group could not be determined due to the death of all animals. Gross pathology revealed the following findings in died animals: petechial hemorrhages and congestion in the lungs; livers burned; livers, spleens and kidneys mottled; kidneys pale; adrenals congested; stomachs distended, containing a hard mass, opaque and gas-filled; intestines opaque, gas-filled and yellow. No gross pathological changes were found in the survivors.

Based on the results of this study, a LD50 of 4.92 mL/kg bw, corresponding to approx. 5697 mg/kg bw, based on the relative density of 1.158 mg/mL (lit.)), was calculated.

Due to the structural and physico-chemical similarity of both substances, this LD50 is assumed for 2-[(3-aziridin-1-ylpropionyl)methyl]-2-ethylpropane-1,3- diyl bis(aziridine-1-propionate) as well.

Acute toxicity inhalation:

The acute vapor inhalation toxicity of the test substance was evaluated in Sprague Dawley albino rats. A total of 30 rats was used in the experiment. 10 males and 10 females were exposed (nose only) to vapors of the test compound, and 5 males and 5 females served as controls. Vapors of the test substance were generated by passing a stream of air over the surface of the liquid at a rate of 6 liters/minute. The nominal concentration of the test substance vapor was approx. 1 mg/L air (determined by weighing the flask containing the test material before and after the exposure and dividing the difference in weights by the total volume of air bubbled through the test material). The exposure was conducted over 4 hours. During this time, the animals were observed frequently for adverse reactions.

The body weight of each rat was recorded before initation of the exposure. Surviving animals were weighed on the first, second, seventh, and fourteenth days after exposure. The general condition of the animals was checked visually daily during the 14-day observation period. Necropsies were performed on selected animals that died after the exposure as well as on survivors sacrificed at the end of the observation period. In addition, brain, heart, liver, lungs, spleen, kidneys, and testes from survivors were weighed at necropsy.

No deaths or adverse effects were noted during the exposure. However, the exposed rats became inactive within 1 hour of the end of exposure, and 14 (8 males and 6 females) of the 20 exposed rats died between 1 and 6 days after inhaling the test substance vapors. During the period when deaths occurred, the exposed animals were inactive. Activity among all but one of the survivors appeared to be normal after the sixth day.

Gross pathologic findings among animals that died included hemorrhagic and emphysemic lungs in four of the five rats examined. In addition, the spleens of two of these animals were pale.

The exposed animals lost weight during the first 24 hours after inhalation of test substance vapors. Although most of the survivors had regained the lost weight by the end of the observation period, a marked difference in weights between exposed and control animals was still evident.

Gross pathologic examination of survivors revealed hydronephrosis of the kidneys in one male and one female from the exposed group. The female also had enlarged adrenal glands. No other abnormalities were noted among either exposed or control rats.

Based on these results it was concluded, that the LC50 of the test substance (4-h exposure) was less than 1.0 mg/liter air.

Acute toxicity dermal:

To assess the acute toxicity of the test substance after dermal exposure, the test material (3 g/kg bodyweight) was applied to the back of 6 young-adult male New Zealand White rabbits (3 with intact and 3 with abraded skin) and spread over approximately 10% of the body surface. The application site was covered with gauze pads and the entire torso was overwrapped with rubber dam. 24 hours later, the wraps were removed. After treatment, all the animals were observed daily for physiological and behavioral responses. Body weights were determined initially and then weekly. At the end of the 2-week observation period, all animals were sacrificed and examined for evidence of gross pathological changes.

None of the 6 male rabbits died after dermal treatment with the test substance. On removal of the wraps 24 hours after compound application, two rabbits (one each with intact and abraded skin) had slight erythema. No differences were noted between intact and abraded skin groups. All the rabbits had dry, wrinkled skin from Day 4 after treatment; eventually the skin flaked and peeled. By Day 11 all had slight erythema, most likely resulting from scratching and grooming. No other abnormal physiological or behavioral responses were noted. Three rabbits lost weight during the first week after treatment, but regained and exceeded their initial weight by Day 14.

Necropsy on Day 14 revealed slight to moderate mottling of the kidneys of two intact-skin rabbits. No other gross abnormalities were found.

The acute dermal LD50 of the test substance in male New Zealand White rabbits was found to be greater than 3 g/kg bodyweight.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for acute oral and dermal toxicity, but has to be classified for acute inhalative toxicity under Regulation (EC) No. 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776. On the basis of the results obtained in the acute inhalation toxicity study (LC50, 4h < 1 mg/L air) the substance has to be classified as fatal if inhaled (Cat. 2) at least.