N,N-Bis(2-hydroxyethyl)-C12-18(even numbered, C18 unsaturated) alkyl-1-amine oxides

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Remarks:

other: 7 days repeated dose; for the purpose of dose-range finding for the OECD 421 study

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

March 2012 - December 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

16 rats (2 per dose and sex) were treated daily for 7 days by oral gavage. The dose levels were 0, 62.5, 250 and 1000 mg/kg bw. The investigation parameters included clinical observation, body weight development, food consumption and macroscopic examination upon gross negropsy.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N-Bis(2-hydroxyethyl)-C12-18(even numbered, C18 unsaturated) alkyl-1-amine oxides

EC Number:

942-293-6

Molecular formula:

not applicable

IUPAC Name:

N,N-Bis(2-hydroxyethyl)-C12-18(even numbered, C18 unsaturated) alkyl-1-amine oxides

Test material form:

liquid: viscous

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

7 days

Frequency of treatment:

once per day

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

62.5 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

250 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

2

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:

other: Maximum Tolerated Dose

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Study results

At daily dose of 1000 mg/kg bw all animals (two males and two females) died after second or third application. The clinical signs observed prior to death included decreased activity, gasping respiration, salivation, piloerection, lethargy, hunched back and lacrimation. These animals exhibited severe body weight loss prior to death. At necropsy evaluation, the findings in dead animals were dark/red discoloratioin of the enlarged lungs, white foamy material in the trachea, enlarged adrenals, dark/red discoloration/focus on the thymus or glandular/non glandular stomach, mucoid material mixed with diet within the stomach, yellow/brown mucoid material in the digestive content of the duodenum, jejunum, ileum, cecum, colon and/or rectum. Additionally, clear liquid material at the perioral/periorbital area and/or red discoloration of the periorbital/perinasal area and yellow/brown discoloured nerinasal area, were also found.

At daily dose of 250 mg/kg bw all animals (two males and two females) survived the seven days application. One female exhibited sneezing, gasping respiration, piloerection, noisy respiration, salivation, decreased activity and incoordinated movement and one male exhibited increased respiration. In addition, reduced body weight gain and reduced food consumption were found, whereas the effect was more pronounced in the first three days. At necropsy at the end of the observation period, thickened/rough surface non glandular mucosa of the stomach was found in 3/4 rats.

At daily dose of 62.5 mg/kg bw all animals (two males and two females) survived the seven days application. The clinical signs observed were limited to noisy respiration in one female and increase respiration rate in one male. The body weight gain and the food consumption were also affected. No effect was found upon gross necropsy.

Tab: Body weight development [g]; individual values and mean
Dose group		Males			Females
		Day 0	Day 3	Day 6	Day 0	Day 3	Day 6
Control	Value 1	369	382	393	265	265	273
	Value 2	398	408	433	253	246	248
	Mean	384	395	413	259	256	261
62.5 mg/kg bw/day	Value 1	392	408	411	259	243	244
	Value 2	375	368	375	249	249	255
	Mean	384	388	393	254	246	250
250 mg/kg bw	Value 1	377	337	343	251	235	241
	Value 2	399	389	400	265	222	194
	Mean	388	363	372	258	229	218

Applicant's summary and conclusion

Conclusions:

The registration substance was investigated for its repeated dose toxicity by the oral application to rats for up to 7 days at doses of 62.5, 250 and 1000 mg/kg bw/day. The investigation parameters were limited to clinical signs, body weight development, food consumption and gross pathology. Rats treated with 1000 mg/kg bw died after 2-3 treatments and damages in the gastro-intestinal tract were evident upon gross necropsy. At doses of 250 and 62.5 mg/kg bw, body weight decrease, reduced food consumption were found in dose dependent manner and at 250 mg/kg bw the thickened/rough surface non glandular mucosa of the stomach was macroscopically observed. Considering that no macroscopic changes in the stomach was found at dose 62.5 mg/kg bw and that such effect was the NOAEL determining effect for the read-across supporting substance, the NOAEL in the range of 62.5 mg/kg bw for the registration can be reasonably derived.

Executive summary:

The registration substance was investigated for its repeated dose toxicity by the oral application to rats for up to 7 days at doses of 62.5, 250 and 1000 mg/kg bw/day. The study was performed for the purpose of dose-range finding for the main study (OECD 421).The investigation parameters were limited to clinical signs, body weight development, food consumption and macroscopic examination upon gross pathology. Rats treated with 1000 mg/kg bw died after 2-3 treatments and damages in the gastro-intestinal tract were evident upon gross necropsy. At doses of 250 and 62.5 mg/kg bw, body weight decrease and reduced food consumption were found in dose dependent manner and at 250 mg/kg bw the thickened/rough surface non glandular mucosa of the stomach was macroscopically observed.

Considering that no macroscopic changes in the stomach was found at dose 62.5 mg/kg bw and that such effect was the NOAEL determining effect for the read-across supporting substance, the NOAEL in the range of 62.5 mg/kg bw for the registration can be reasonably derived.

In view of the fact that comparable dose-range findings studies were performed for the registration substance and the proposed read-across substance, both studies are serving as crucial bridging evidence for the proposed read-across for the endpoint repeated dose toxicity. Both studies identified the gastro-intestinal tract as the target organ and were indicative of comparable potencies. Based on the similar findings under comparable study conditions, the proposed read-across is considered to be robust and reliable.