1-Octanamine, N,N-dimethyl-, N-oxide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

between 08 October 2008 and 05 November 2008.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Schedule 1 (Good Laboratory Practice Regulations 1999 (SI 1999/3106 as amended by 2004/0994))

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N-dimethyl-N-octylhydroxylamine

EC Number:

607-854-9

Cas Number:

2605-78-9

Molecular formula:

CH3(CH2)7N(CH3)2O

IUPAC Name:

N,N-dimethyl-N-octylhydroxylamine

Constituent 2

Reference substance name:

Water

EC Number:

231-791-2

EC Name:

Water

Cas Number:

7732-18-5

Molecular formula:

H2O

IUPAC Name:

Water

Test material form:

liquid

Specific details on test material used for the study:

- Analytical purity: 41.3%
- Purity test date: Not available
- Lot/batch No.: 95638
- Expiration date of the lot/batch: Not available
- Appearance: Clear colourless liquid
- Storage: In the dark at room temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

Female Sprague-Dawley strain rats were supplied by Harlan UK Limited, Bicester, Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non-pregnant. After an 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. At the start of the study the animals were eight to twelve weeks of age. The bodyweight variation did not exceed ± 20% of the initial/mean bodyweight of any previously dosed animal(s).
The animals were housed in groups of up to four in suspended 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 (2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: dosed neat at 5000 mg/kg

Details on oral exposure:

VEHICLE
None

MAXIMUM DOSE VOLUME APPLIED: Volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing.

DOSAGE PREPARATION (if unusual): not unusual

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not applicable

Doses:

doses used were at 750 mg/kg and 5000mg/kg

No. of animals per sex per dose:

1 female dosed at 750 mg/kg
5 females dosed at 5000 mg/kg

Control animals:

no

Details on study design:

Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for up to fourteen days. Morbidity and mortality checks were made twice daily.
Individual bodyweights were recorded on Day 0 (the day of dosing) and on Days 7 and 14 or at death.
Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Results and discussion

Preliminary study:

A preliminary study was used at a dose level of 750 mg/kg using 1 female rat. At dose Level 750 mg/kg there was no mortality, no signs of systemic toxicity were noted during the observation period and the animal showed an expected gain in bodyweight over the observation period.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

at dose Level 5000 mg/kg - One animal was found dead one hour after dosing.

Clinical signs:

other: at dose Level 5000 mg/kg - Signs of systemic toxicity noted in one animal were hunched posture and lethargy. No signs of systemic toxicity were noted in the remaining animals during the observation period.

Gross pathology:

Abnormalities noted at necropsy of the animal that died during the day of dosing were abnormally red lungs, drak liver and dark kidneys.
No abnormalities were noted at necropsy of animals that were sacrificed at end of test..

Other findings:

- Organ weights: Not determined.
- Histopathology: Not stated in report.
- Potential target organs: no
- Other observations: None

Any other information on results incl. tables

Dose level 750mg/kg

Individual clinical observations and mortality data are given in the table below:

Table 1                Individual Clinical Observations and Mortality Data - 750mg/kg (equivalent to 300 mg notifiable substance/kg)

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
750Å	1-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Å  = Equivalent to 300 mg notifiable substance/kg

0 = No signs of systemic toxicity

Individual bodyweights and bodyweight changes are given in the table below:

Table 2                Individual Bodyweights and Bodyweight Changes - 750mg/kg (equivalent to 300 mg notifiable substance/kg)

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
750Å	1-0 Female	177	182	200	5	18

Å  = Equivalent to 300 mg notifiable substance/kg

Necropsy findings are given in the table below:

No abnormalities were noted at necropsy.

Table 3                Necropsy Findings - 750 mg/kg (equivalent to 300 mg notifiable substance/kg)

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
750Å	1-0 Female	Killed Day 14	No abnormalities detected

Å  = Equivalent to 300 mg notifiable substance/kg

dose level 5000mg/kg: Based on the results at a dose level of 750 mg/kg bodyweight (equivalent to 300 mg notifiable substance/kg), and in conjunction with the results of SPL Project No. 1947/0011, a dose level of 5000 mg/kg bodyweight (equivalent to 2000 mg notifiable substance/kg) was investigated.

Individual clinical observations and mortality data are given in the table below:

Table 4                Individual Clinical Observations and Mortality Data - 5000mg/kg (equivalent to 2000 mg notifiable substance/kg)

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
5000Ä	2-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-3 Female	HL	X

Ä = Equivalent to 2000 mg notifiable substance/kg

0 = No signs of systemic toxicity

H = Hunched posture

L = Lethargy

X = Animal dead

Individual bodyweights and bodyweight changes are given in the table below:

Table 5                Individual Bodyweights and Bodyweight Changes - 5000mg/kg (equivalent to 2000 mg notifiable substance/kg)

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight (g) at Death	Bodyweight Gain (g) During Week
		0	7	14		1	2
5000Ä	2-0 Female	183	200	240		17	40
	3-0 Female	206	218	229		12	11
	3-1 Female	187	207	228		20	21
	3-2 Female	172	187	203		15	16
	3-3 Female	191	-	-	190	-	-

Ä = Equivalent to 2000 mg notifiable substance/kg

Surviving animals showed expected gains in bodyweight over the observation period.

Individual necropsy findings are given in the table below:

Table 6                Individual Necropsy Findings - 5000 mg/kg (equivalent to 2000 mg notifiable substance/kg)

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
5000Ä	2-0 Female	Killed Day 14	No abnormalities detected
	3-0 Female	Killed Day 14	No abnormalities detected
	3-1 Female	Killed Day 14	No abnormalities detected
	3-2 Female	Killed Day 14	No abnormalities detected
	3-3 Female	Found dead Day 0	Lungs: abnormally red Liver: dark Kidneys: dark

Ä = Equivalent to 2000 mg notifiable substance/kg

Abnormalities noted at necropsy of the animal that died during the day of dosing were abnormally red lungs, dark liver and dark kidneys.  No abnormalities were noted at necropsy of animals that were killed at the end of the test.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Sprague Dawley CD strain rat was estimated to be greater than 5000 mg/kg bodyweight (equivalent to 2000 mg notifiable substance/kg).

Executive summary:

Introduction.  The study was performed to assess the acute oral toxicity of the test material in the Sprague‑Dawley CD strain rat.  The method was designed to meet the requirements of the following:

§        OECD Guidelines for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (2001)

§        Method B1bisAcute Toxicity (Oral) of Commission Directive 2004/73/EC

Method. Following a sighting test at dose levels of 750 mg/kg and 5000 mg/kg (equivalent to 300 and 2000 mg notifiable substance/kg respectively), a further group of four fasted females was given a single oral dose of test material at a dose level of 5000 mg/kg bodyweight (equivalent to 2000 mg notifiable substance /kg).  Clinical signs and bodyweight development were monitored during the study.  All animals were subjected to gross necropsy.

Mortality.  One animal treated at a dose level of 5000 mg/kg (equivalent to 2000 mg notifiable substance /kg) was found dead one hour after dosing.

Clinical Observations.  Signs of systemic toxicity noted in one animal treated at a dose level of 5000 mg/kg (equivalent to 2000 mg notifiable substance /kg) were hunched posture and lethargy.  There were no signs of systemic toxicity noted in the remaining animals.

Bodyweight.  Surviving animals showed expected gains in bodyweight.

Necropsy.  Abnormalities noted at necropsy of the animal that died during the day of dosing were abnormally red lungs, dark liver and dark kidneys.  No abnormalities were noted at necropsy of animals that were killed at the end of the test.

Conclusion.  The acute oral median lethal dose (LD₅₀) of the test material in the female Sprague‑Dawley CD strain rat was estimated to be greater than 5000 mg/kg bodyweight (equivalent to 2000 mg notifiable substance/kg) (Globally Harmonised Classification System - Category 5).