1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-coco acyl derivs., hydroxides, inner salts

Endpoint summary

Description of key information

In an experimental study performed according to OECD Test Guideline 401 on a read-across substance, the oral LD50 in rats was calculated to be 3020 or 2950 mg active ingredient/kg bw, for females or both genders, respectively, at 24 hours and 14 days after administration. No deaths were observed at the lowest dose of 1000 mg/kg bw.

In a supporting epxerimental study not performed according to an OECD Test Guideline, the substance itself was determined to have an oral LD50 in rats of >5000 mg/kg bw, following 3 out of 10 mortalities after 14 days exposure to doses of 5 g/kg bw. No death or ill effects were observed in the 5 male rats.

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:

supporting study

Study period:

02 March, 1990 - 16 March, 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

other: Hagan (1959)

Version / remarks:

SOURCE:
Hagan, E.C. (1959) Acute Toxicity.
In: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, pp. 17-25.
Published: Austin, Tex., Association of Food & Drug Officials of the United States, 1959.

Principles of method if other than guideline:

SOURCE:
Hagan, E.C. (1959) Acute Toxicity.
In: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, pp. 17-25.
Published: Austin, Tex., Association of Food & Drug Officials of the United States, 1959.

GLP compliance:

no

Test type:

fixed dose procedure

Specific details on test material used for the study:

CROSULTAINE C-50
Cocamidopropyl hydroxysultaine
Lot: P-1439, 1/29/90

Species:

rat

Strain:

Wistar

Remarks:

albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data.
- Females nulliparous and non-pregnant: Yes.
- Age at study initiation: 6-9 weeks.
- Weight at study initiation: 190-220 grams.
- Fasting period before study: 18 hours.
- Housing: Stainless steel cages with indirect bedding.
- Diet: Agway ProLab Rat, Mouse and Hamster 1000 Feed, ad libitum.
- Water: ad libitum.
- Acclimation period: 7 days prior to test.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24.
- Humidity (%): Monitored but no data.
- Air changes (per hr): No data.
- Photoperiod (hrs dark / hrs light): 12/12.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Administered using a stainless steel intragastric feeding needle, of sufficient bore to allow even passage of the test item.

Doses:

Individual doses of 5 grams of test item per kilogram, calculated on the basis of bodyweight.

No. of animals per sex per dose:

Five (5) male and five (5) female rats.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.

- Frequency of observations and weighing: Animals were observed for pharmacologic activity and drug toxicity at 1, 3, 6 and 24 hours post-dosage. Observations were made at least once daily thereafter for a total of 14 days.

- Necropsy of survivors performed: Animals sacrificed at the end of the 14 day observation period, as well as non-survivors, were subject to complete gross necrospy, with all findings noted. Sacrificing was accomplished via carbon dioxide asphyxiation.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

Animals 8, 9 and 10 (all Female) died after 48 hours, 24 hours and 48 hours, respectively.

Clinical signs:

other: Animals 8 and 10: Entire gastro-intestinal tract distended and intestinal mucosa slightly reddened. Slight depression observed at 24 hours. Animal 9: Stomach distended, intestinal mucosa slightly reddened.

Interpretation of results:

GHS criteria not met

Conclusions:

3 out of 10 test animals (all female) died after 48 hours after intragastric feeding. No death or other clinical effects were observed in the male rats. Therefore, under the conditions of the test, the test item is not considered orally toxic to rats.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27 February, 1990 - 15 March, 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study (OECD 401 compliant), the test guideline being in force at the time of the study but deleted in 2002 and substituted by other test guidelines (not up-to-date).

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

other: OECD Test Guideline 401 ‘Acute Oral Toxicity’ deleted on 17th December 2002.

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany.
- Age at study initiation: No data.
- Weight at study initiation: 171-276 g (males), 164-216 g (females).
- Fasting period before study: from 16 hours before until 3-4 hours after administration.
- Housing: up to a maximum of 5 rats per cage (Macrolon type III cage).
- Diet (e.g. ad libitum): No data.
- Water (e.g. ad libitum): No data.
- Acclimation period: at least 7 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2.
- Humidity (%): 50-85.
- Air changes (per hr): No data.
- Photoperiod (hrs dark / hrs light): 12 / 12 (7.00 am-7.00 pm).

IN-LIFE DATES: No data.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
No vehicle used (solution administered as such with different dosing volumes).

MAXIMUM DOSE VOLUME APPLIED:
1000 mg/kg: 2.33 mL/kg bw;
2000 mg/kg: 4.65 mL/kg bw;
3000 mg/kg: 6.98 mL/kg bw.

Doses:

1000, 2000 and 3000 mg active component/ kg bw.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
- Examinations performed: mortality (over the 24-hour post-dosing period, and then daily), clinical signs (daily), body weights (just before dosing, on days 7 and 14).
- Necropsy of survivors performed: yes.

Statistics:

The method of Finney D.Y., Probit Analysis (3rd ed., Cambridge, 1971) was used for calculating the oral LD50.

Preliminary study:

One animal died within 24 hours of dosing at 2000 mg/kg.

Sex:

male

Dose descriptor:

LD50

Remarks on result:

other: Could not be calculated because only at the high dose pre-terminal deaths were lower than 100% and higher than 0%.

Sex:

female

Dose descriptor:

LD50

Effect level:

3 020 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other: at 24 h and 14 days after dosing.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 950 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other: at 24 h and 14 days after dosing.

Clinical signs:

other: Up to 3 days post-dosing, reduced general activity was observed at 3000 mg/kg, together with squatting position, reduced skin turgor, cyanosis, diarrhea and piloerection on some occasions.

Gross pathology:

- 2000 and 3000 mg/kg: animals killed in extremis within 24 hours post-dosing showed hemorrhagic and lytic alterations in the gatro-intestinal tract and/or yellow-orange discoloration of lungs and/or reddish pelvis at macroscopic examination.
- At terminal sacrifice (14 days post-dosing): no test-article abnormalities noted at necropsy.

Dose (mg/kg)	Post-treatment time
	Males			Females
	24 hours	7 days	14 days	24 hours	7 days	14 days
1000	0/5	0/5	0/5	0/5	0/5	0/5
2000	0/5	0/5	0/5	2/5	2/5	2/5
3000	3/5	3/5	3/5	2/5	2/5	2/5

Cumulative mortality over the 14-day observation period.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 in rats was calculated to be 3020 or 2950 mg active ingredient/kg bw, for females or both genders, respectively, at 24 hours and 14 days after administration. The oral LD50 in male rats could not be calculated because deaths occurred only in the high-dose group.

Executive summary:

Cocamidopropyl hydroxysultaine, as a 42% aqueous solution, has been tested for acute oral toxicity in Wistar rats. The test article was administered as such using different dosing volumes to reach the desired dose levels. Three groups of 5 rats per gender received a dose volume of 2.33, 4.65 and 6.98 mL/kg, equivalent to 1000, 2000 and 3000 mg active ingredient/kg, respectively. Examinations for mortality and clinical signs were performed daily during the 14-day study period. Body weights were measured just before dosing, and 7 and 14 after dosing. A macroscopic examination was performed at the necropsy of survivors on day 14.

 

A high incidence of pre-terminal deaths occurred at 2000 and 3000 mg/kg, whereas no death occurred at 1000 mg/kg: 3/5 male rats were found dead or sacrificed in extremis within 24 hours of dosing in the 3000 mg/kg dose group, and 2/5 female rats were found dead or sacrificed in extremis within 24 hours of dosing in each of the 2000 mg/kg and 3000 mg/kg dose groups. Marked clinical signs, such as general reduced activity together with diarrhea, squatting position, piloerection and/or reduced skin turgor were observed at 3000 mg/kg within 3 days post-dosing. Body weight gain was normal in surviving animals over the observation period. Hemorrhagic and lytic mucous membrane alterations in the gastro-intestinal tract, considered test-article related, were observed at necropsy in animals found dead or sacrificed in extremis within 24 hours of dosing in the 2000 mg/kg and 3000 mg/kg dose groups. At terminal sacrifice, no test-related macroscopic findings were observed in the other animals.

 

The oral LD50 in rats was calculated to be 3020 or 2950 mg active ingredient/kg bw, for females or both genders, respectively, at 24 hours and 14 days after administration. The oral LD50 in male rats could not be calculated because deaths occurred only in the high-dose group.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Overall, the identities of the major known constituents the source and target substances are the same or very closely with the exception of minor variations in the C18 constituents.
Based on the similarities of the composition of the target substance and the analogue, they are expected to share similar properties in regards to their capacity to be acutely toxic by oral exposure.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- Source: 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-(C8-18(even numbered) acyl) derivs., hydroxides, inner salts (EC 939-455-3)
- Target: 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-coco acyl derivs., hydroxides, inner salts (EC 268-761-3)

3. ANALOGUE APPROACH JUSTIFICATION
The source and target substances share a very similar composition in regards to the C8-C18 constituents they contain.
1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-coco acyl derivs., hydroxides, inner salts does not contain components above LOD known to be acutely toxic by oral exposure.
It can therefore be concluded that the source and target substances can be expected to share a similar potential to be acutely toxic, and that experimental data on the source substance can be used to fulfil the data requirements for the REACH Registration of the target substance for endpoints in accordance with Annex XI of REACH.

Also see attachment.

Reason / purpose for cross-reference:

read-across source

Preliminary study:

One animal died within 24 hours of dosing at 2000 mg/kg.

Sex:

male

Dose descriptor:

LD50

Remarks on result:

other: Could not be calculated because only at the high dose pre-terminal deaths were lower than 100% and higher than 0%.

Sex:

female

Dose descriptor:

LD50

Effect level:

3 020 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other: at 24 h and 14 days after dosing.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 950 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other: at 24 h and 14 days after dosing.

Clinical signs:

other: Up to 3 days post-dosing, reduced general activity was observed at 3000 mg/kg, together with squatting position, reduced skin turgor, cyanosis, diarrhea and piloerection on some occasions.

Gross pathology:

- 2000 and 3000 mg/kg: animals killed in extremis within 24 hours post-dosing showed hemorrhagic and lytic alterations in the gatro-intestinal tract and/or yellow-orange discoloration of lungs and/or reddish pelvis at macroscopic examination.
- At terminal sacrifice (14 days post-dosing): no test-article abnormalities noted at necropsy.

Dose (mg/kg)	Post-treatment time
	Males			Females
	24 hours	7 days	14 days	24 hours	7 days	14 days
1000	0/5	0/5	0/5	0/5	0/5	0/5
2000	0/5	0/5	0/5	2/5	2/5	2/5
3000	3/5	3/5	3/5	2/5	2/5	2/5

Cumulative mortality over the 14-day observation period.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 in rats was calculated to be 3020 or 2950 mg active ingredient/kg bw, for females or both genders, respectively, at 24 hours and 14 days after administration. The oral LD50 in male rats could not be calculated because deaths occurred only in the high-dose group.

Executive summary:

Based on similarities in chemical composition, 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-(C8-18(even numbered) acyl) derivs., hydroxides, inner salts (EC 939 -455 -3) was identified as a suitable read-across substance to assess the capacity of the 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-coco acyl derivs., hydroxides, inner salts to be acutely toxic by oral exposure.

Cocamidopropyl hydroxysultaine, as a 42% aqueous solution, has been tested for acute oral toxicity in Wistar rats. The test article was administered as such using different dosing volumes to reach the desired dose levels. Three groups of 5 rats per gender received a dose volume of 2.33, 4.65 and 6.98 mL/kg, equivalent to 1000, 2000 and 3000 mg active ingredient/kg, respectively. Examinations for mortality and clinical signs were performed daily during the 14-day study period. Body weights were measured just before dosing, and 7 and 14 after dosing. A macroscopic examination was performed at the necropsy of survivors on day 14.

 

A high incidence of pre-terminal deaths occurred at 2000 and 3000 mg/kg, whereas no death occurred at 1000 mg/kg: 3/5 male rats were found dead or sacrificed in extremis within 24 hours of dosing in the 3000 mg/kg dose group, and 2/5 female rats were found dead or sacrificed in extremis within 24 hours of dosing in each of the 2000 mg/kg and 3000 mg/kg dose groups. Marked clinical signs, such as general reduced activity together with diarrhea, squatting position, piloerection and/or reduced skin turgor were observed at 3000 mg/kg within 3 days post-dosing. Body weight gain was normal in surviving animals over the observation period. Hemorrhagic and lytic mucous membrane alterations in the gastro-intestinal tract, considered test-article related, were observed at necropsy in animals found dead or sacrificed in extremis within 24 hours of dosing in the 2000 mg/kg and 3000 mg/kg dose groups. At terminal sacrifice, no test-related macroscopic findings were observed in the other animals.

 

The oral LD50 in rats was calculated to be 3020 or 2950 mg active ingredient/kg bw, for females or both genders, respectively, at 24 hours and 14 days after administration. The oral LD50 in male rats could not be calculated because deaths occurred only in the high-dose group.

Based on these results, it is concluded that 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-coco acyl derivs., hydroxides, inner salts does not meet the criteria for classification in accordance with CLP Regulation (EC) 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed