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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1976
Report date:
1976

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Preliminary toxicity studies to obtain skin irritation and mortality data on the test substance. In the first study, four dose levels were tested for each test substance with 15 males and 15 females at each dose level. Animals received 5 to 7 applications. Based on the results of the first study, three lower dose levels (n=15/sex/dose) were tested in the second study. Animals in the second study received 20 applications during a 4-week period. Only clinical observations, body weight, and mortality were recorded.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N,N-dimethyldecylamine N-oxide
EC Number:
220-020-5
EC Name:
N,N-dimethyldecylamine N-oxide
Cas Number:
2605-79-0
Molecular formula:
C12H27NO
IUPAC Name:
decyl(dimethyl)amine oxide
Details on test material:
- Name of test material (as cited in study report): UDL 1379 and UDL 1380 (dodecyl dimethyl amine oxide or DDAO)
- Molecular formula (if other than submission substance): N/A
- Molecular weight (if other than submission substance): N/A
- Smiles notation (if other than submission substance): N/A
- InChl (if other than submission substance): N/A
- Structural formula attached as image file (if other than submission substance): N/A
- Substance type: active
- Physical state: liquid
- Purity test date: N/A
- Radiochemical purity: N/A
- Specific activity: N/A
- Locations of the label: N/A
- Expiration date of radiochemical substance: N/A
- Stability under test conditions: N/A
- Storage condition of test material: N/A
- Other:N/A

Test animals

Species:
mouse
Strain:
other: Charles River ICR Swiss
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: N/A
- Age at study initiation: N/A
- Weight at study initiation: 23 to 29.7 grams
- Fasting period before study: N/A
- Housing:N/A
- Diet (e.g. ad libitum): N/A
- Water (e.g. ad libitum):N/A
- Acclimation period:N/A


ENVIRONMENTAL CONDITIONS
- Temperature (°C): N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light): N/A


IN-LIFE DATES: N/A

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: N/A
- % coverage: N/A
- Type of wrap if used: N/A
- Time intervals for shavings or clipplings: once prior to study and once weekly for 4 weeks


REMOVAL OF TEST SUBSTANCE
- Washing (if done): N/A
- Time after start of exposure:N/A


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution):0.5%, 1.0%, 2.0%, 5%, 10%, 15%, and 20%
- Constant volume or concentration used: yes
- For solids, paste formed: no


VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Amount(s) applied (volume or weight with unit):N/A
- Concentration (if solution):N/A
- Lot/batch no. (if required): N/A
- Purity: N/A


USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
N/A
Duration of treatment / exposure:
4 weeks / dermal for both studies
Frequency of treatment:
daily, for 5 days each week for both studies
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.5%, 1.0%, 2.0%, 5%, 10%, 15%, and 20% UDL-1379
Basis:
other: percent DDAO in solution
Remarks:
Doses / Concentrations:
0.5%, 1.0%, 2.0%, 5%, 10%, 15%, and 20% UDL-1380
Basis:
other: percent DDAO in solution
No. of animals per sex per dose:
15 males and 15 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: N/A
- Rationale for animal assignment (if not random): N/A
- Rationale for selecting satellite groups: N/A
- Post-exposure recovery period in satellite groups: N/A
- Section schedule rationale (if not random):N/A
Positive control:
N/A

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked:skin irritation, unkempt fur, arched spine, scaling, and scabs

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: No
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

FOOD EFFICIENCY: No
- 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

WATER CONSUMPTION: No
- Time schedule for examinations:No

OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:No
- Dose groups that were examined:No

HAEMATOLOGY: No
- Time schedule for collection of blood: No
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: No
- Parameters checked : No

CLINICAL CHEMISTRY: No
- Time schedule for collection of blood: No
- Animals fasted: No
- How many animals: No
- Parameters checked: No

URINALYSIS: No
- Time schedule for collection of urine: No
- Metabolism cages used for collection of urine: No
- Animals fasted: No
- Parameters checked: No

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations: No
- Dose groups that were examined: No
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No

OTHER:N/A
Sacrifice and pathology:
GROSS PATHOLOGY: No
HISTOPATHOLOGY: No
Other examinations:
N/A
Statistics:
N/A

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: Study 1- After five dermal applications all of the animals at the 5% and 10% dose levels of both test substances UDL-1379 and UDL-1380 showed slight to moderate irritation. The skin irritation was so severe at dosage levels of 15% and 20% for both test substances that the dermal applications were discontinued. After two additional dermal applications (total of 7 applications) all of the animals at the 5% and 10% dose levels of both test substances showed severe irritation and other signs of compound toxicity including arched spine and unkempt fur. Due to the severity and high incidence of the observations, dermal applications were discontinuted in these groups. Scar tissue was observed on 7 animals at 10%, 21 at 15%, and 19 at 20% for test substance UDL-1379 and 3 at 5%, 20 at 10%, 23 at 15%, and 23 at 20% for test substance UDL-1380.

None of the control group died during the study. The following mice died: 1 at 5%, 7 at 10%, 9 at 15%, and 11 at 20% for test substance UDL-1379 and 3 at 5%, 8 at 10%, 7 at 15%, and 7 at 20% for test substance UDL-1380.

Study 2- After four weeks of the dermal applications the control group, three out of thirty animals were observed with unkempt fur. For the 0.5% UDL-1379 test group two out of thirty animals were observed with unkempt fur. Scabs on the dorsal skin and unkempt fur were observed in the remaining test groups (1.0% & 2.0% UDL-1379 and 0.5%, 1.0% & 2.0% UDL-1380).

None of the control group or 0.5% and 1.0% test groups for UDL-1379 and UDL 1380 died during the study. The following animals died: 1 at 2.0% for test substance UDL-1379 and 4 at 2.0% for test substance UDL-1380.

BODY WEIGHT AND WEIGHT GAIN: Study 1- After the first week the negative control group gained weight and all of the test groups lost weight. Over the next two weeks there was a slight weight gain in the negative control and test groups.

Study 2- After the first week the negative control group and test groups gained weight except for the male animals in group 6 (1.0% UDL-1380). Over the next three weeks all groups had a slight weight gain.

FOOD CONSUMPTION: No data

FOOD EFFICIENCY: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOUR: No data

ORGAN WEIGHTS: No data

GROSS PATHOLOGY: No data

HISTOPATHOLOGY- NON-NEOPLASTIC: No data

HISTOPATHOLOGY - NEOPLASTIC: No data

HISTORICAL CONTROL DATA: No data

OTHER FINDINGS: No data

Effect levels

open allclose all
Dose descriptor:
LOEL
Effect level:
2 other: %
Sex:
male/female
Basis for effect level:
other: UDL 1379 - induced minimal effects on the dorsal skin and possibly the death of one animal. UDL1380 - caused mortality in 4 mice and some dermal and systemic effects in 10/30 mice
Dose descriptor:
NOAEL
Effect level:
1 other: %
Sex:
male/female
Basis for effect level:
other: UDL 1379 and UDL 1380 - Scabs on the dorsal in 2/30 animals were identified from each group but this was not considered significant.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Gonadal tissues were not examined for gross pathology or histopathology for this study.

Applicant's summary and conclusion

Conclusions:
Based on the observations of compound effects induced at dosage levels of 5%, 10%, 15%, and 20% of UDL-1379 and UDL-1380 it was concluded that a second study would be performed using lower concnetrations of each compond. The second study indicated that UDL-1379 at concentrations of 2.0% induced minimal effects in the treatment area of dorsal skin. The death of one animal in this group may have been caused by the compound. UDL-1380 at concentrations of 2.0% caused mortality in 4 mice and some dermal and systemic effects in 10 of 30 mice. UDL 1379 - induced minimal effects on the dorsal skin and possibly the death of one animal. A LOEL of 2% and a NOAEL of 1% was determined for the study.
Executive summary:

This preliminary study was conducted to obtain toxicity and mortality data on two test substances (UDL-1379 and UDL-1380, dodecyl dimethyl amine oxide) for use in setting dose levels in a subsequent chronic study. In the first study the test substances were administered dermally to four groups of Charles River ICR Swiss mice at dosage levels of 5%, 10%, 15%, and 20% dodecyl dimethyl amine oxide for three weeks. Based on the severity and high incidence observations from the first study a second study was conducted with three groups of Charles River ICR Swiss mice at dosage levels of 0.5%, 1.0%, and 2.0% for four weeks.

The parameters monitored were body weight, mortaility, and clinical observations. In the first study, after the first week the negative control group gained weight and all of the test groups lost weight. Over the next two weeks there was a slight weight gain in the negative control and all of the test groups. After five dermal applications all of the animals at the 5% and 10% dose levels of both test substances UDL-1379 and UDL-1380 showed slight to moderate irritation. The skin irritation was so severe at dosage levels of 15% and 20% for both test substances that the dermal applications were discontinued. After two additional dermal applications (total of 7 applications) all of the animals at the 5% and 10% dose levels of both test substances showed severe irritation and other signs of compound toxicity including arched spine and unkempt fur. Due to the severity and high incidence of the observations, dermal applications were discontinuted in these groups. Scar tissue was observed at dosage levels 10%, 15%, and 20% for test substance UDL-1379 and all dosage levels for test substance UDL-1380. None of the control group died during the study. Several mice died at all dosage levels for both test substances.

In the second study, after the first week the negative control group and test groups gained weight except for the male in group 6 (1.0% UDL-1380). Over the next three weeks all groups had a slight weight gain. After four weeks of the dermal applications the control group, three out of thirty animals were observed with unkempt fur. For the 0.5% UDL-1379 test group two out of thirty animals were observed with unkempt fur. Scabs on the dorsal skin and unkempt fur were observed in the remaining test groups (1.0% & 2.0% UDL-1379 and 0.5%, 1.0% & 2.0% UDL-1380). None of the control group or 0.5% and 1.0% dose UDL-1379 and UDL 1380 test groups died during the study. One animal died at 2.0% for test substance UDL-1379 and 4 at 2.0% for test substance UDL-1380. The second study indicated that UDL-1379 at concentrations of 2.0% induced minimal effects in treatment area of dorsal skin. The death of one animal in this group may have been caused by the compound. UDL-1380 at concentrations of 2.0% caused mortality in 4 mice and some dermal and systemic effects in 10 of 30 mice.

A LOEL of 2% and a NOAEL of 1% dodecyl dimethyl amine oxide was determined for the study.

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