3-((C12-18)-acylamino)-N-(2-((2-hydroxyethyl)amino)-2-oxoethyl)-N,N-dimethyl-1-propanaminium chloride

Endpoint summary

Description of key information

Acute toxicity studies are performed on the notified chemical (i.e. 1-Propanaminium,3-(1-oxododecyl)-amino-N-(2-((2-hydroxyethyl)amino)-2-oxoethyl)-N,N-dimethyl) and the market name MONTALINE C 40. Either oral toxicity tests (OECD 401 and OECD 420) or dermal toxicity test (OECD 402) results in a same conclusion. The notified chemical doesn't required EU labelling (i.e. LD 50 > 2000 mg/kg).
Based on this weight of evidence, the acute inhalation test is not judged redundant and not performed. The DNEL for worker is then calculated by extrapolation. The calculated values are summarised as below:

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline, GLP study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

AnimaIs and Animal Husbandry
Male and female Sprague-Dawley CD (Crl:CD® (SD) IGS BR) strain rats supplied by Charles River (UK) Ltd, Margate, Kent, UK were used. At the start of the study the males weighed 202 ta 220g, and the females 208 to 225g, and were eight to twelve weeks old. After a minimum acclimatisation period of at least five days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card.
The animals were housed in groups of up to five by sex in solid-floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, Witham, Essex, UK) was allowed throughout the study.
The animal room was maintained at a temperature of 19 ta 21°C and relative humidity of 37 to 67%. The rate of air exchange was approximately
15 changes per hour and the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

dose level: 500 mg/kg
concentration: 50 mg/mL
dose volume: 10 mL/kg

Doses:

preliminery study:2000 and 500 mg/kg bw
main study: 500 mg/kg bw

No. of animals per sex per dose:

Preliminary sighting study: 1 (male)
Preliminary sighting study: 1 (female)
Main study: 5 (male)
Main study: 5 (female)

Preliminary study:

The female treated with 2000 mg/kg was found dead one day after dosing. Clinical signs of toxicity noted in the male treated with 2000 mg/kg were hunched posture, lethargy, pilo-erection, decreased respiratory rate, Iaboured respiration, diarrhoea, dehydration and emaciation. Signs of toxicity noted in animals treated with 500 mg/kg were hunched posture and lethargy.
The male treated with 2000 mg/kg recovered twelve days after dosing and the animals treated with 500 mg/kg recovered six days after dosing.
Based on this information, a dose level of 500 mg/kg bodyweight was selected for the main study.

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

500 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: Common clinical signs of toxicity noted during the study were hunched posture with incidents of noisy respiration. Animals recovered two to four days after dosing.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The discriminatory dose was identified as 500 mg/kg bodyweight.
The acute oral median lethal dose (LD50 of the test item in the Sprague-Dawley CD strain rat was estimated to be greater than 2000 mg/kg bodyweight. The test material may be of some concern if swallowed due to the nature of the toxic effects noted, but did not meet the criteria for classification under EU labelling regulations. No symbol or risk phrase are required.

Executive summary:

A study was performed to assess the acute oral toxicity of the test material in the Sprague-Dawley CD strain rat. The method complied with that described in the OECD Guidelines for Testing of Chemicals No. 420 "Acute Oral Toxicity - Fixed Dose Method" (adopted 1 7 July 1992) and Method B1 bis in Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC). The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (adapted to technical progress by Commission Directive 93/21/EEC) relating to the classification, packaging and labelling of dangerous substances.

 

Following a preliminary study at dose levels of 2000 and 500 mg/kg, a group of ten fasted animals (five males and five females) was given a single oral dose of test material, as a solution in distilled water at a dose level of 500 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed and subjected to gross necropsy.

 

There were no deaths. Clinical signs of toxicity noted during the study were hunched posture and noisy respiration. Animals recovered two to four days after dosing.

 

All animals showed expected gains in bodyweight during the 14-day study period.

 

No abnormalities were noted at necropsy.

 

The discriminatory dose was identified as 500 mg/kg bodyweight.

The acute oral median lethal dose (LD50 of the test material, notified substance (i.e. 100% active matter), in the Sprague-Dawley CD strain rat was estimated to be greater than 2000 mg/kg bodyweight. The test material may be of some concern if swallowed due to the nature of the toxic effects noted, but did not meet the criteria for classification under EU labelling regulations. No symbol or risk phrase are required.

This result is in compliance with those noted in the supporting study performed the diluted presentation the test item (i.e. LD 0 > 2000 mg/kg in a fixed dose).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: OECd guideline, GLP study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Species, strain, supplier : Albino Rat, Sprague Dawley OFA, IFFA-CREDO (69210 - L’ARBRESLE, FRANCE).
Reason for species selection : the Rat is the animal chosen by the regulatory authorities to evaluate the safety of drugs and chemicals.
- Number and sex: 10 animals: 5 males and 5 females
- Age, weight: about 6 weeks, weight between 195 g and 224 g (males) and 168 g and 185 g (females)
- Acclimatization: at least 5 days
- Housing, diet: 5 animals by sex in polypropylene cages (310 x 465 x 190) in accordance with the requirements of the 86/609/EEC guideline. Complete pelleted rat maintenance diet UAR A04-10 (91360 - EP1NAY SUR ORGE, FRANCE).

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

Animals have been fasted prior to substance administration by with holding food overnight.
They receive by gavage, according to the bodyweight, the product diluted in distilled water (Meram batch 62417) at the single dose of 2000 mg/kg under a constant volume of 5 ml/kg.
The administered preparation is kept up under magnetic stining during the treatments.
Reason for route of administration: Oral gavage is the route of choice for estimating potential adverse effects resulting from accidental oral ingestion.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Details on study design:

Observations
The animals are observed daily for 14 days afier the treatment.
Clinical examinations
- a clinical observation is carried out at least once a day in order to evaluate the general appearance, the behaviour and vegetative functions of the animals. An individual clinical observation is realized one hour after treatment. The continuous observations during the five following hours are renewed each following day.
- body weight are taken just prior to the test material administration (D1) and again on days 4, 8 and 15.
Macroscopic examinations
At termination of the 14 observation days, the rats are sacrificed after barbituric anaesthesia, then autopsied. All abnormalities are recorded.
No tissue is saved.

interpretation of the results
According to the 67/548/EEC directive, the classification of the test material is relied on the LD50 values:
• Very toxic : LD50 25 mg/kg body weight
• Toxic : 25 mg/kg • Harmful : 200 mg/kg • Unclassified : LD50 > 2000 mg/kg body weight

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Male: Number of animals: 5; Number of deaths: 0
Female:Number of animals: 5; Number of deaths: 0

Clinical signs:

other: No modification in the aspect, behaviour or vegetative functions is observed in the animals, 1 hour after the treatment or during the 5 following hours. However, at D2 and D3, soft faeces are observed in males and females, with an uro-genital area dirty i

Gross pathology:

The gross necropsy of the animals 14 days after the treatment does not show any visible organic or tissular lesions leading us to suspect a possible systemic toxicity of the product.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the experimental conditions adopted, the oral LD0 of the test item (containing 35.3 % of active matter) in male and female Rat is higher than 2000 mg/kg.
According to the 67/548/EEC directive, the test preparation is unclassified among the preparations dangerous if swallowed.

Executive summary:

The aim of this study was to assess the acute toxixity of the test item.

The protocol was designed according to the OECD guideline for the testing of Chemicals n°401.

This study was done in accordance with the GLP.

 

For this limit test, five males and five females were administrated (gavage) 2000 mg/ kg bw of the test item.

 

No mortality occures.

No modification in the aspect, behaviour or vegetative functions is observed in the animals, 1 hour after the treatment or during the 5 following hours. However, at D2 and D3, soft faeces are observed in males and females, with an uro-genital area dirty in some of them. From D4, the daily examinations which are repeated during all the observation period, fail to reveal any alteration in the general appearance and behaviour of the animals.

The individual growth weight of all the animals (males and females) is normal and regular. The mean weight gain 14 days after the treatment appears satisfactory for this animal species.

The gross necropsy of the animals 14 days after the treatment does not show any visible organic or tissular lesions leading us to suspect a possible systemic toxicity of the product.

 

Under the experimental conditions adopted, the oral LD0 of the test item (containing 35.3 % of active matter) in male and female Rat is higher than 2000 mg/kg.

According to the 67/548/EEC directive, the test preparation is unclassified among the preparations dangerous if swallowed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

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:

Justification for type of information:

In accordance with the column 2 of Annex VIII, the acute inhalation test (as required in section 8.5.2) does not need to be performed for the evaluation as acute oral and dermal toxicity data are available.

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: OECD guideline, GLP study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

Méthode B3

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Five male and five female Sprague-Dawley CD (Crl:CR® (SD) IGS BR) strain rats supplied by Charles River (UK) Ltd, Margate, Kent were used. At the start of the study the males weighed 290 to 300g, and the femaies 232 to 289g, and were approximateiy eight to twelve weeks old. After a minimum acclimatisation period of five days the animals were selected at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card.
The animals were housed in suspended polypropylene cages furnished with woodfiakes. The animals were housed individuaily during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (Rat and Mouse SQC Expanded Diet No.1, Speciai Diets Services Limited, Witham, Essex, UK) was ailowed throughout the study.
The animal room was maintained at a temperature of 19 to 21 °C and relative humidity of 44 to 66%. The rate of air exchange was approximateiy fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light and twelve hours darkness.

Type of coverage:

semiocclusive

Vehicle:

water

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

On the day before treatment the back and flanks of each animal were clipped free of hair using veterinary clippers.
The calculated volume of the test material formulation was applied uniformly to an area of shorn skin (approximating to 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. The animals were caged individually for the 24-hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.
The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material. The animals were returned to group housing for the remainder of the study period.
After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H (1977) “Dermal and Eye Toxicity Tests” .
Any other skin reactions, if present were also recorded.
Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
At the end of the study the animams were killed by cervical dislocation and subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0

Clinical signs:

other: Signs of toxicity related to dose levels: none during the 14-day observation period

Gross pathology:

Effects on organs:
none

Other findings:

Signs of toxicity (local):
Crust formation was noted in all females four to ten days after dosing. No signs of skin irritation were noted in males during the study.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute dermal median lethai dose (LD50) of the test item in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. No symbol and risk phrase are required according to EU labelling regulations.

Executive summary:

A study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley CD strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals No. 402 “Acute Dermal Toxicity” (adopted 24 February 1987) and Method B3 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 93/21/EEC) relating to the classification, packaging and labelling of dangerous substances.

 

A group of ten animals (five males and five females) was given a single 24-hour, semi-occluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination.

 

There were no deaths. No signs of systemic toxicity were noted during the study. Crust formation was noted in all females four to ten days after dosing. No signs of skin irritation were noted in males.

 

AIl animals showed an expected gain in bodyweight during the study except for one female which showed a loss in bodyweight during the first week of the study but expected gain in bodyweight during the second week.

 

No abnormalities were noted at necropsy.

 

The acute dermal median lethal dose (LD50) of the test material (i.e. the notified chemical), in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. No symbol and risk phrase are required according to EU labelling regulations.

Subsequently, the test item (i.e. a 35 -40% aqueouse solution) is concluded with LD50>2000 mg/kg

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

The following information is taken into account for any hazard / risk assessment:

The oral and dermal toxicity studies were performed under the regular bases. The results clearly classify 1-Propanaminium,3-(1-oxododecyl)-amino-N-(2-((2-hydroxyethyl)amino)-2-oxoethyl)-N,N-dimethyl as presenting a weak toxicity. Accordingly, the substance is not classified according to the current EU-CLP.

However, the acute inhalation toxicity of 1-Propanaminium,3-(1-oxododecyl)-amino-N-(2-((2-hydroxyethyl)amino)-2-oxoethyl)-N,N-dimethyl was not studied.

Justification for classification or non-classification

Based on the results observed in the acute oral toxicity study with rats, the notified substance do not have to be classified and have no obligation labelling requirement for acute oral toxicity according to the:
- Globally Harmonized System of Classification and Labelling of Chemical (GHS) of the United Nation (2007).
- Regulation (EC) n° 1272/02008 on classification, labelling and packaging of substances and mixtures.

Based on the results observed in the acute dermal toxicity study with rats, the notified substance do not have to be classified and have no obligation labelling requirement for acute dermal toxicity according to the:
- Globally Harmonized System of Classification and Labelling of Chemical (GHS) of the United Nation (2007).
- Regulation (EC) n° 1272/02008 on classification, labelling and packaging of substances and mixtures.