Amines, C16-18-alkyldimethyl

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given: comparable to guidelines/standards.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Toxicological Evaluation of Commercial Alkyldimethylamine oxides: Two-Year Chronic Feeding and Dermal Studies

Author:

Cardin, C.W.; Domeyer, B.E. and Bjorkquist, L.

Year:

1985

Bibliographic source:

Fundamental and Applied Toxicology 5, 869-878

Reference 2

Reference Type:

review article or handbook

Title:

SIDS Initial Assessment Report for SIAM 22

Author:

OECD

Year:

2006

Bibliographic source:

OECD Existing Chemicals Database

Report date:

2006

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

no

Remarks:

original study performed in 1979, prior to the adoption of GLP compliance standards. However, it was reviewed and found acceptable by the laboratory´s Quality Assurance Department in accordance with US FDA´s GLP Regulation of June 20, 1979.

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Amines, C10-16-alkyldimethyl, N-oxides

EC Number:

274-687-2

EC Name:

Amines, C10-16-alkyldimethyl, N-oxides

Cas Number:

70592-80-2

IUPAC Name:

dimethyl(tridecyl)amine oxide

Test animals

Species:

rat

Strain:

other: Charles River

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding laboratories Inc., Portage, Michigan, USA
- Age at study initiation: 4 weeks
- Housing: individually
- Diet: Zeigler NIH-07diet containing test substance, ad libitum
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 46-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: feed

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Zeigler NIH-07

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

not indicated

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

daily with the food

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.01, 0.1 and 0.2 % of the test compound (100% (w/v) active basis)
Basis:
nominal in diet

No. of animals per sex per dose:

60

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses were selected based on the results from a 13 week study which showed the high dose causing about a 5 to 8 % reduction in body weight.
- Concentrations in the diet of 0, 0.01, 0.1 and 0.2 % test compound (100% (w/v) active basis) correspond to 0, 4.24, 42.3, or 87.4 mg/kg bw/day for males and 0, 5.23, 52.6, or 107 mg/kg bw/day for females according to OECD (2006).

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 14 weeks of study, biweekly for the next 12 weeks and monthly thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/week: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once during pretest and at 3,6,12,16,19,22 and 24 months
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: all rats to be sacrificed at 52 weeks of the study and all rats at study termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: all rats to be sacrificed at 52 weeks of the study and all rats at study termination
- Animals fasted: No data
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: all rats to be sacrificed at 52 weeks of the study and all rats at study termination
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Body weights, feed consumption, efficiency of feed utilization, clinical chemistry parameters and absolute and relative organ weights were compared by analysis of variance (one way classification), Bartlett´s test for homogeneity of variances, and at least significant differences criterion. If Bartlett´s test were significant, then pairwise comparisons were made by the Mann-Whitney U test. All statistical analyses were conducted at a 5 %, two-sided risk level, and each treatment group was compared with the main control group by sex.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

details see below

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
There were no significant differences in survival at 104 weeks. There were no significant, compound-related differences in mean feed consumption, clinical chemistry or ophthalmology.

BODY WEIGHT AND WEIGHT GAIN
The high dose animals demonstrated >10% decreases in mean body weight. Animals in the 0.1% test substance group also showed reduced body weight, but the reduction was not as strong as in the high dose group.

HISTOLOGY
There were no compound-related effects on histopathic examination. There was no evidence of a carcinogenic response after chronic dietary administration of the test substance.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

42.3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: based on decreased mean body weight in the highest dose group.

2

Dose descriptor:

NOAEL

Effect level:

52.6 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: based on decreased mean body weight in the highest dose group.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test, no substance related effects were observed in male and female rats after oral exposure for 104 weeks. The NOAEL is 42.3 (males) or 52.6 (females) mg/kg bw/day.

Executive summary:

Male and female Charles River rats were given a diet containing 0, 0.01, 0.1 or 0.2 % test substance ad libitum for 104 weeks. No substance related effect was observed in any concentration tested. The NOAEL is 42.3 (male) or 52.6 (female) mg/kg bw/day based on decreased mean body weight in the highest dose group.