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REACH

N,N-dimethyltetradecylamine N-oxide

EC number: 222-059-3 | CAS number: 3332-27-2

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

Acute oral toxicity: Two reliable studies are available for C14 AO, both performed on the commercial product as supplied. The reported LD50 values (rat) are > 5000 mg/kg bw and > 2000 mg/kg bw (based on test substance) equivalent to > 1495 mg AO/kg bw and > 500 mg AO/kg bw, respectively. Data are also available for other members of the category, where testing has also been performed on the commercial product as supplied. In a study for C12-14 AO the reported LD50 (rat) was 3800 mg/kg bw, equivalent to 1064 mg AO/kg bw. Other studies performed using C12-14 AO reported LD50 (rat) values of >300 and >600 mg AO/kg bw. In a study performed using C14-16 AO the reported LD50 (rat) was 5600 mg/kg bw, equivalent to 1680 mg AO/kg bw.
Acute dermal toxicity: No data are available for C14 AO, however two reliable studies are available for other members of the category. In the key study performed using C12-18 AO, the reported LD50 (rat) was > 2000 mg AO/kg bw.
Acute inhalation toxicity: No studies are available. The substance is a solid with very low vapour pressure. It is manufactured and supplied as an aqueous solution, therefore there is no possibility of exposure to dust. It is used in some spraying applications, but it is expected that inhalation exposure from these applications will be low and hence the dermal route is more relevant.

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:: 1997-10-29 to 1997-12-12
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: other: Guideline study to GLP, but report lacking some detail.
Qualifier:: according to guideline
Guideline:: OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:: yes
Test type:: acute toxic class method
Limit test:: yes
Species:: rat
Strain:: Sprague-Dawley
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Harlan Sprague-Dawley, Indianapolis, Indiana
- Age at study initiation: 6 to 10 weeks
- Weight at study initiation: 206 - 260 g
- Fasting period before study: Yes, overnight
- Housing: Individually in stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
Temperature, humidity and light controlled room (DHEW publication No. 86-23 (NIH))

IN-LIFE DATES: From: 1997-10-29 To: 1997-11-11
Route of administration:: oral: gavage
Vehicle:: unchanged (no vehicle)
Details on oral exposure:: Dosage volume: 5 g/kg
Metal dosing cannula
Doses:: 5 g/kg bw
No. of animals per sex per dose:: 5 male/5 female
Control animals:: no
Details on study design:: - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Frequently on day of dosing (1, 2.5 and 4 hours) and once daily thereafter
- Necropsy of survivors performed: yes
Statistics:: Calculations of the LC50 and 95% confidence limits: Method of moving averages, Weil CC (1952) table for convenient calculations of median effective dose (LD50 and ED50) and instruction in their use. Biometrics, 8.
Preliminary study:: Not performed
Sex:: male/female
Dose descriptor:: LD50
Effect level:: > 5 000 mg/kg bw
Based on:: test mat.
Sex:: male/female
Dose descriptor:: LD50
Effect level:: > 1 495 mg/kg bw
Based on:: act. ingr.
Mortality:: No mortalities
Clinical signs:: other: No clinical observations reported
Gross pathology:: No treatment related effects noted at gross necropsy
Interpretation of results:: Toxicity Category IV
Remarks:: Migrated information Criteria used for interpretation of results: EU
Conclusions:: The acute oral administration of the test material resulted in an LD50 >5000 mg/kg bw, equivalent to > 1500 mg AO/kg bw.
Executive summary:: The acute oral toxicity of C14 AO was assessed in male and female rats in accordance to OECD Guideline No. 401. Five male and five female rats were dosed by oral gavage with 5000 mg/kg bw test material (ca. 30% active). After a 14 day observation period there were no mortalities and no treatment related effects observed on bodyweight or at gross necropsy. The LD50 was > 1495 mg AO/kg bw.

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: discriminating dose
Value:: 1 495 mg/kg bw
Quality of whole database:: For C14 AO there are 2 Klimisch score 2 studies performed to OECD guidelines. There are 5 Klimisch score 2 studies for C12-14 AO and one for C14-16 AO.

Acute toxicity: via inhalation route

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:: migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:: key study
Study period:: 21/12/2009 - 19/02/2010
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: other: Guideline study conducted according to GLP;
Qualifier:: according to guideline
Guideline:: EU Method B.3 (Acute Toxicity (Dermal))
Deviations:: no
Qualifier:: according to guideline
Guideline:: OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:: no
GLP compliance:: yes (incl. QA statement)
Test type:: standard acute method
Limit test:: yes
Species:: rat
Strain:: other: CD/Crl: CD(SD)
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services Germany GmbH
- Age at study initiation: males 7 weeks; females 9 weeks
- Weight at study initiation: males 221-235 g; females 206-224 g
- Fasting period before study: 16 hours
- Housing: Housed singly during the 14 day observation period in Makrolon cages
- Diet (e.g. ad libitum): ssniff R/M-H V1534
- Water (e.g. ad libitum): ad libitum
- Acclimation period:at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 15
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 7/01/2010 - 3/02/2010
Type of coverage:: occlusive
Vehicle:: water
Details on dermal exposure:: TEST SITE
- Area of exposure: animals back, 5x6 cm
- % coverage: approx 10 % of body surface
- Type of wrap if used: 8 layers of gauze covered with a plastic sheet and secured with adhesive plaster

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not applicable
- Time after start of exposure: not applicable

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw
- Concentration (if solution): not stated
- Constant volume or concentration used: yes
Duration of exposure:: 24 hours
Doses:: 2000 mg AO/kg bw
No. of animals per sex per dose:: 5 animals/sex/dose
Control animals:: no
Details on study design:: - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations before and immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after administration. During the 14 day observation period observed at least once daily until all symptoms subsided and daily thereafter. Bodyweight recorded before administration and thereafter in weekly intervals up to the end of the study
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Preliminary study:: No preliminary study performed
Sex:: male/female
Dose descriptor:: LD50
Effect level:: > 2 000 mg/kg bw
Based on:: act. ingr.
Mortality:: No deaths seen during the study
Clinical signs:: other: No clinical signs seen during the study
Gross pathology:: No macroscopic changes were noted at necropsy
Other findings:: - Other observations: Erythema (grade 2-4) was observed at the application site in all 5 males and 5 females immediately after patch removal until test day 6 No oedema was observed in any animals. All reactions cleared by Day 7.
Interpretation of results:: not classified
Remarks:: Migrated information Criteria used for interpretation of results: EU
Conclusions:: The LD50 of C12-18 amine oxide is > 2000 mg AO/kg bw
Executive summary:: The acute dermal toxicity of the substance was investigated in a GLP study performed to OECD 402. The substance was applied as a solution in water to the skin of 5 male and 5 female rats (CD/Crl: CD(SD)) at a dose of 2000 mg AO/kg bw and covered with an occlusive dressing for 24 hours. After completion of the exposure period the dressing was removed. There were no deaths or signs of systemic toxicity during the 14 -day observation period and animals showed the expected bodyweight gains. Erythema (grade 2-4) was observed at the application site in all 5 males and 5 females immediately after patch removal until test day 6. No Oedema was noted at any time period. All reactions cleared after 7 days. Necropsy revealed no macroscopic findings. The LD50 was 2000 mg AO/kg bw.

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: discriminating dose
Value:: 2 000 mg/kg bw
Quality of whole database:: Both studies were performed to OECD guidlines and in addition, the selected study was performed undet GLP and has a Klimisch score of 1.

Additional information

Acute oral toxicity:

Two reliable studies are available using C14 AO. Both of these studies were performed using the commercial product as supplied. In the key study [Kukulinski M (1997a)] the acute oral toxicity of C14 AO was assessed in male and female rats in accordance to OECD TG 401. Five male and five female rats were dosed by oral gavage with 5000 mg test material/kg bw (equivalent to 1495 mg AO/kg bw). After a 14 day observation period there were no mortalities and no treatment related effects observed on bodyweight or at gross necropsy. The LD50 was >5000 mg/kg bw, equivalent to > 1495 mg AO/kg bw. In the supporting study [Hofmann T (1988)] the acute oral toxicity of C14 AO was also assessed in male and female rats in accordance to OECD Guideline No. 401. Five male and five female rats were dosed by oral gavage with 2000 mg test material/kg bw (equivalent to 500 mg AO/kg bw). After a 14 day observation period there were no mortalities and no treatment related effects observed on bodyweight or at gross necropsy. The LD50 was > 2000 mg/kg bw, equivalent to > 500 mg AO/kg bw.

In addition to these studies, data are available for other category members that contain significant percentages of C14 AO – C12-14 AO which may contain 20-53 %w/w C14 AO and C14-16 AO which may contain 40-75 %w/w C14 AO.

In a study performed according to OECD TG 401 using C12-14 AO [Fulfs JC (1978)] groups of rats (Sprague-Dawley, 5 animals/sex/dose) were dosed by gavage at 1500, 2100, 3000, 4100 or 5800 mg test material/kg bw (equivalent to 420, 588, 840, 1148 or 1624 mg AO/kg bw). There were no deaths at the lowest dose. Two females died at 2100 mg/kg bw, one male died at 3000 mg/kg bw, two males and four females died at 4100 mg/kg bw and five males and four females died at 5800 mg/kg bw. The gross toxic signs observed included decreased motor activity and salivation in all five test groups. Piloerection was observed in the 4100 and 5800 mg/kg bw dose groups. Blanching and nasal haemorrhaging were observed in the 2100, 3000, 4100 and 5800 mg/kg dose groups. Diarrhoea was observed in the 1500, 3000, 4100 and 5800 mg/kg dose groups. Bodyweight gain was seen in all dose groups except for the high dose group where a slight loss was observed. Necropsy revealed no remarkable observations at the low dose. At higher doses findings included tan discolouration, pale lungs, gas and fluid in stomach and intestines (2100 mg/kg bw), gas and fluid in stomach and intestines, petachiae on lungs (3000 mg/kg bw), tan discolouration on lungs, fluid filled stomach and intestines, bright red lungs, yellow fluid in small intestines (4100 mg/kg bw) and liver coloured lungs, fluid filled stomach and small intestines, tan discolouration and petachiae on lungs and gas in stomach (5800 mg/kg bw). The LD50 was 3800 mg/kg bw, equivalent to 1064 mg AO/kg bw. The LD50 values obtained from the other studies performed using C12-14 AO were >300 mg AO/kg bw [Gill CRB (1977)] and >600 mg AO/kg bw [Jones JR, Hewitt DS & Warner PA (1986); Hofmann T (1987); Gunn J & Goodwin M (1983)].

In the study performed using C14-16 AO [Bullens P (1984) ] performed according to the Consumer Product Safety Commission protocol, groups of rats (CD, 5 animals/sex/dose) were dosed by gavage at 4000, 5000 or 7000 mg/kg bw (equivalent to 1200, 1500 or 2100 mg AO/kg bw). Two males died at 4000 mg/kg bw, two males and two females died at 5000 mg/kg bw, whilst five males and two females died at 7000 mg/kg bw. The animals dosed at 4000 mg/kg bw appeared generally normal with slight diarrhoea. The animals dosed at 5000 mg/kg bw appeared normal, whilst those dosed at 7000 mg/kg bw exhibited severe diarrhoea and stomach swelling. The LD50 was 5600 mg/kg bw, equivalent to 1680 mg AO/kg bw.

Acute dermal toxicity:

No studies have been performed using C14 AO. Studies are available for two other category members, C12-14 AO and C12-18 AO. The results of these studies may be read across to C14 AO as both these substances contain between 20-53 and 10-25 %w/w respectively of C14 AO.

The key study [Haferkorn J (2010) ] was performed using C12 -18 AO. In this study, performed according to OECD TG 402 under GLP the test substance was applied as a solution in water to the skin of 5 male and 5 female rats (CD/Crl: CD(SD)) at a dose of 2000 mg AO/kg bw and covered with an occlusive dressing for 24 hours. After completion of the exposure period the dressing was removed. There were no deaths or signs of systemic toxicity during the 14 -day observation period and animals showed the expected bodyweight gains. Erythema (grade 2-4) was observed at the application site in all 5 males and 5 females immediately after patch removal until test day 6. No Oedema was observed in any animal at any time period. Erythema was not observed from day 7 onwards (Grade = 0). Necropsy revealed no macroscopic findings. The LD50 was > 2000 mg AO/kg bw.

In the second study, performed according to OECD TG 402 [Dean WP (1978a) ] C12-14 AO was applied as a solution in water to the skin of 3 male and 3 female rabbits (New Zealand White) at a dose of 2000 mg/kg bw (equivalent to 560 mg AO/kg bw) and covered with an occlusive dressing for 24 hours. One rabbit died during the observation period. This death was attributed to pneumonia and was not considered to be related to treatment. One female rabbit showed hypoactivity, decreased limb tone ataxia and anorexia. Surviving animals showed expected bodyweight gains. Necropsy revealed pale green fluid and white mucoid material adhering to mucosa in the stomach, severe congestion, consolidation and white film adhering in the lungs of the animal that died of pneumonia. In the surviving animals no gross lesions were noted except mottled colouration in the kidneys of one male. The LD50 >2000 mg/kg bw (equivalent to > 560 mg AO/kg bw).

Acute inhalation toxicity:

No data are available for the inhalation route. The substance is a solid with very low vapour pressure. It is manufactured and supplied as an aqueous solution therefore there is no possibility of exposure to dust. It is used in some spraying applications, but it is expected that inhalation exposure from these applications will be low and hence the dermal route is more relevant.

Justification for selection of acute toxicity – oral endpoint
All the available acute oral toxicity studies were performed on products containing approximately 30 %w/w AO. Kukulinski M (1997a) was selected as this study was performed on C14 AO itself and used the highest dose levels out of the two C14 AO studies.

Justification for selection of acute toxicity – inhalation endpoint
The substance is a solid with very low vapour pressure. It is used in some spraying applications, but it is expected that inhalation exposure from these applications will be low. The most likely route of exposure for consumers and professionals is the dermal route. Testing for acute toxicity via the inhalation route is, therefore, not required.

Justification for selection of acute toxicity – dermal endpoint
Both acute dermal toxicity studies were performed on commercial grades of amine oxides, typically containing approximately 30 % AO in aqueous solution. The study performed using C12-18 AO was selected because it was performed at a sufficiently high dose level to allow the discriminating dose to be elucidated.

Justification for classification or non-classification

Acute oral toxicity: Both studies for C14 AO were performed using commercial grades of the substance (normally an approximately 25-30 % aqueous solution of the amine oxide). In both cases, the LD50 of the test substance was > 2000 mg/kg bw, indicating that the commercial product as supplied should not be classified. Classification for the pure substance is derived from read across to a study performed using C12-14 AO [Fulfs JC (1978)] where the LD50 (rats) = 1064 mg AO/kg bw. Based on this result the classification of the pure amine oxide is Acute Toxicity 4, with the Hazard Statement H302: Harmful if swallowed.

Acute dermal toxicity: No data are available for C14 AO however two reliable studies are available for other members of the category. An OECD TG 402 study performed using C12 -18 AO resulted in a LD50 > 2000 mg AO/kg bw [Haferkorn J (2010)]. This is supported by a limit test performed with C12-14 AO which resulted in a LD50 > 560 mg AO/kg bw [Dean WP (1978a)]. On the basis of these two studies classification for acute dermal toxicity is not required.

Acute inhalation toxicity: No data are available. Testing was not performed as the dermal route was considered to be the most likely route of exposure.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Animal No. & sex	Skin reactions on test day
	1	2	3	4	5	6	7
		E/Oe/N	E/Oe/N	E/Oe/N	E/Oe/N	E/Oe/N	E/Oe/N
1 m		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0
2 m		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0
3 m		2/0/0	0/0/0	3/0/0	4/0/0	4/0/0	0/0/0
4 m		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0
5 m		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0
6 f		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0
7 f		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0
8 f		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0
9 f		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0
10 f		2/0/0	2/0/0	3/0/0	4/0/0	4/0/0	0/0/0

Animal No. & sex	Skin reactions on test day
	8	9	10	11	12	13	14
		E/Oe/N	E/Oe/N	E/Oe/N	E/Oe/N	E/Oe/N	E/Oe/N
1 m	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
2 m	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
3 m	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
4 m	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
5 m	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
6 f	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
7 f	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
8 f	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
9 f	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0
10 f	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0	0/0/0