2-Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide

Endpoint summary

Description of key information

Oral toxicity

- Experimental acute oral toxicity test (OECD 423) on the substance itself ("2-Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide" (water and methanol free)).

Dermal toxicity

- Experimental acute dermal toxicity (OECD 402) on the analogue substance "Sodium N-(2 -carboxyethyl)-N-(2 -ethylhexyl)-β-alaninate, CAS 94441 -92 -6).

Toxicity by inhalation

- Experimental data on the substance itself ("2-Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide" (water and methanol free)) is not available. However, according to the chemical and physical properties of the substance and according to the Surfactants family, both the exposition and the toxicity by inhalation are not expected.

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:

24 September 2004 - 03 December 2004

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

The purity was taken into account for the preparation of the formulations

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Janvier (Le Genest-Saint-Isle, France)
- Females nulliparous and non-pregnant
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation: mean 193g (+/- 4g)
- Fasting period before study: animals were fasted for an overnight period of approximately 18 hours before dosing, but with free access to water
- Housing: in polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 30 to 70
- Air changes (per hr): aproximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

IN-LIFE DATES:
First treatment: 5 october 2004
Experimental completion date (necropsy of the last animal): 26 October 2004

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Purified water prepared by the Testing Faciilty (reverse osmosis)

DOSE VOLUME APPLIED: 20mL/kg

RATIONALE FOR THE SELECTION OF THE DOSE:
Based on the information on the toxic potential of the test item, mortality was not expected. Therefore a limit test at 2000 mg/kg was conducted.
After the first assay with 3 females, no death occurred at the dose level of 2000 mg/kg. Then the results were confirmed in three other females.

Doses:

Limit test at 2000 mg/kg

No. of animals per sex per dose:

6 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations (clinical sign and mortality): frequently during the hours following admiistration of the test item, and then, at least once a day
- Frequency of weighing: just before administration on Day 1, and then on day 8 and 15.
- Necropsy: on day 15
- Macroscopy examinations of the main organs as soon as possible after death (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any organs with obvious abnormalities)

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No death occurred during the study

Clinical signs:

other: Hypoactivity and piloerection in all animals, and dyspnea in 3/6 females, were noted on day 1 only. No other clinical signs were noted during the study.

Gross pathology:

No apparent abnormalities were observed

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions, the oral LD50 of the test item is higher than 2000 mg/kg in female rats.

Executive summary:

The test item was evaluated in 6 female rats according to the OECD 423 guideline.

The test item, prepared in water, was administered by gavage under a volume of 20 mL/kg, at the dose level of 2000 mg/kg.

Mortality, clinical signs and body weight gain were checked for a period of 14 days.

No death was observed during the study.

Hypoactivity and piloerection in all animals, and dyspnea in 3/6 females were noted on day 1 only. No other clinical signs were observed.

The body weight gain was slightly reduced in 4/6 females during the second week of the study compared to CIT historical control data.

At necropsy, no apparent abnormalities were observed in any animal.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

20 000 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

02 - 16 May 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No 8147, April 2011; including the most recent partial revisions.

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean (males: 271 grams; females: 186 grams).
- Housing: Individual housing in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle.

IN-LIFE DATES: From: 02 - 16 May 2012

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped.

The test substance was applied in an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D)*, successively covered with aluminum foil and Coban elastic bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only. *. Manufacturers: Laboratoires Stella s.a., Liege, Belgium (surgical gauze) and 3M, St. Paul, Minnesota, U.S.A. (Coban & Micropore).

Frequency: Single dosage, on Day 1.

Washing: Following application, dressings were removed and the skin cleaned of residual test substance using tap water.

Duration of exposure:

24 hours.

Doses:

2000 mg/kg (4.63 mL/kg) body weight. Dose levels were corrected for a purity of 40%.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Dose volume: 4.63 mL/kg

Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily.
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
- Necropsy of survivors performed: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
- Other examinations performed: none.

Statistics:

None.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture and/or chromodacryrrhoea were noted in all animals on Day 1 and/or 2. In addition, one female and one male showed piloerection on Day 1. No skin effects were noted on the treated skin during the observation period.

Gross pathology:

One female showed smaller spleen compared to normal. No further abnormalities were found at macroscopic post mortem examination of the animals.

Other findings:

none

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 value of Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-ß-alaninate in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results, Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-ß-alaninate does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011),
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across hypothesis is based on “different compounds which have similar properties”.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- The source substance is identified as Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, also known as Sodium 3-[(2-carboxyethyl)(2-ethylhexyl)amino]propanoate (CAS no. 94441-92-6 | EC no. 305-318-6). It is a UVCB substance whose major constituent is sodium 2-ethylhexylimino-di-propionate. Minor constituents are sodium 2-ethylhexylimino-mono-propionate, unreacted acrylic acid and unreacted 2-ethylhexylamine.
- The target substance is identified as Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide (methanol free) (CAS no. 68610-44-6| EC no. 271-865-1). It is a UVCB substance whose major constituents are sodium 2-ethylhexylimino-mono-propionate and sodium 2-ethylhexylimino-di-propionate. Minor constituents are unreacted acrylic acid and unreacted 2-ethylhexylamine.

3. ANALOGUE APPROACH JUSTIFICATION
The target and source substances are essentially the same: both are UVCB substances composed of the exact same constituents with the exact same functional groups (i.e. carboxylic acid groups and secondary/tertiary amine groups). They are expected to have the same ADME profile and to share common mode of action and breakdown products. The target and source substances only differ in the overlapping ranges of their constituents, the content of sodium 2-ethylhexylimino-mono-propionate being especially higher in the target substance. This difference is expected to have no or very limited impact on the potency of effects exerted on exposed living organisms.

4. DATA MATRIX
Cf. read-across justification document attached in §13. Assessment reports.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Justification for classification or non-classification

The substance "2-Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide" (water and methanol free) showed no adverse effects in an experimental acute oral toxicity test (OECD 423).

The analogue substance "Sodium N-(2 -carboxyethyl)-N-(2 -ethylhexyl)-β-alaninate" (CAS 94441 -92 -6) showed no adverse effects in an experimental acute dermal toxicity test (OECD 402).

According to the chemical and physical properties of the substance and according to the Surfactants family, both the exposition and the toxicity by inhalation are not expected.

In conclusion, the classification is not required for Acute toxicity whatever the exposition route.