Dimantine

Repeated dose toxicity: dermal

Administrative data

Endpoint:

chronic toxicity: dermal

Remarks:

combined repeated dose and carcinogenicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given: comparable to guidelines/standards. Justification for read-across see chemical safety report chapter 1.

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:

secondary source

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:

mouse

Strain:

CD-1

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: weanling animals
- Weight at study initiation: 16-20 g
- Housing: individually
- Diet: Zeigler NIH-07 diet, ad libitum
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 40-65
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: 2 x 3 cm, applied to clipped skin

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Constant volume used: yes

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:

once daily, three times per week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.05, 0.13, 0.26 corresponds to average daily doses of 0, 1.1, 2.8 or 5.6 mg/kg bw/day
Basis:
other: %

No. of animals per sex per dose:

75

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses were selected based on a 13 week study in which the high dose caused epidermal proliferative changes.
- Dose calculation according to SIDS.

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: each treatment period

DERMAL IRRITATION (if dermal study): Yes
- Time schedule: no data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the first 13 weeks of the study and monthly thereafter.

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: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Statistical evaluations were performed by one-way analysis of variance. Treated groups were compared against the control by least significant difference test, provided there was homogeneity of variances by the Bartlett´s test. In the case of heterogeneity of variances, group comparisons were performed ba Cochan´s modified t-test and Wilcoxon´s nonparametric two sample sum test. Whenever permitted, the non-parametric test was performed for group comparisons in the event of heterogeneity of variances. A linear regression on doses was performed which included F-tests for regression and lack of fit. Group comparisons were performed at a 5 % two- sided risk level.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

details see below

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

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:

Males in the high dose group had decreased overall survival. In contrast, females at the mid-dose group had increased survival rates compared to controls. These random values were within historical variability of controls and were not considered treatment related.
There were no statistical differences in group average body weights, organ weights, and organ to body weight ratios among treated animals compared to controls.
Compound related skin irritation (diffuse acanthosis and hyperkeratosis) was observed microscopically in the high dose group of mice. No skin tumors were observed in any group. There were no compound-related skin or systemic neoplasms in the study. There was no evidence of a carcinogenic response after chronic percutaneous administration.

HISTOPATHOLOGY:
Tissues examined microscopically included skin, mandibular lymph nodes, mammary gland, salivary gland, thigh muscle, sciatic nerve, bone marrow, costochondral junction, thymus, larynx, trachea, lungs and bronchi, heart, thyroid, parathyroid, esophagus, stomach, duodenum, jejunum, ileum, colon, mesenteric lymph nodes, liver, gallbladder, pancreas, spleen, kidneys, adrenals, bladder, seminal vesicles, prostate, testes or ovaries and uterus, eyes, brain, pituitary, and spinal cord.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 0.26 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There were no statistical differences in group average body weights, organ weights, and organ to body weight ratios among treated animals compared to controls.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test, the test substance does not show any effects on male and female CD-1 mice after dermal exposure for 104 weeks. An exeption is the compound related skin irritation (diffuse acanthosis and hyperkeratosis observed microscopically in the high dose group of mice. The NOAEL for chronic repeated dose toxicity after dermal application in mice is >= 0.26 % (5.6 mg/kg bw/day).

Executive summary:

Male and female CD-1 mice were exposed dermal against 0, 0.05, 0.13 or 0.26 % test substance for 104 wk. This corresponds to an average daily doses of 0, 1.1, 2.8 or 5.6 mg/kg bw/day. There were no statistical differences in group average body weights, organ weights, and organ to body weight ratios among treated animals compared to controls. Compound related No skin tumors were observed in any group. There were no compound-related skin or systemic neoplasms in the study. The NOAEL for chronic repeated dose toxicity after dermal application in mice is >= 0.26 % (5.6 mg/kg bw/day).