Registration Dossier

Administrative data

Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976-03-24 to 1979-01-04
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Methods and results adequately documented and scientifically defensible. Pre-GLP
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
N/A
GLP compliance:
no
Remarks:
Pre-GLP
Type of method:
in vivo
Endpoint addressed:
repeated dose toxicity: oral

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): dodecyl dimethyl amine oxide (DDAO)
- Molecular formula (if other than submission substance): N/A
- Molecular weight (if other than submission substance): 235.7
- 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): see Fig. N/A
- Substance type: Active
- Physical state: Powder (pure test substance) no data for the commercial grade

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: N/A
- Age at study initiation: young adult and adult
- Weight at study initiation: young adult mean values (149 g for males and 131 g for females), adult mean values (288 g for males and 256 g for females)
- Fasting period before study: N/A
- Housing: The animals were housed individually in stainless steel cages with wire mesh bottoms.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approx. 1 week


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: From: N/A To: N/A

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: Laboratory diet for commercial grade test substance and pure grade test substance was prepared in an aqueous solution and then added to the diet.
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The procedure used in phase II was to prepare a 26.8% aqueous solution of pure DDAO, then add this solution to ground Purina Chow to obtain the correct percent (0.35) or pure-DDAO in the diet.


DIET PREPARATION
- Rate of preparation of diet (frequency): 2 week intervals
- Mixing appropriate amounts with (Type of food): N/A
- Storage temperature of food: N/A

VEHICLE
- Justification for use and choice of vehicle (if other than water): N/A
- Concentration in vehicle: N/A
- Amount of vehicle (if gavage): N/A
- Lot/batch no. (if required): N/A
- Purity: N/A
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The commercial grade and pure grade test substances were analyzed for the percent of amine oxide in the diet. See below in additional information section for measured values.
Duration of treatment / exposure:
up to 30 weeks
Frequency of treatment:
daily
Post exposure period:
N/A
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.35 %AO given to young adult rats using a commercial grade of C12-14 amine oxide
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.5 %AO given to both young adult and adult rats using a commercial grade of C12-14 amine oxide
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.35 %AO given to young adult rats using a pure grade of amine oxide (water and impurities removed prior to testing)
Basis:
nominal in diet
No. of animals per sex per dose:
25 males and 25 females in the control groups and the commercial grade test substance groups. 15 males and 15 females in the pure test substance group.
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: The highest treatment level selected represented a level that produced cataracts in rats in previous studies. The lowest treatment level fed represented a no-effect level established in a chronic rat feeding study conducted with commercial amine oxide paste.
- Rationale for animal assignment (if not random): The rats were randomly distributed on the basis of body weight, sex, and eye examination.
- Rationale for selecting satellite groups: N/A
- Post-exposure recovery period in satellite groups: N/A
- Section schedule rationale (if not random): N/A

Examinations

Examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly
- Cage side observations included- gross abnormalities


DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: N/A


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes, but no data on how it was calculated was given
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day:No data
- 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, but no data on how it was calculated was given


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: N/A


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: The eyes of all the animals were examined during the acclimation period and at approximately four-week intervals throughout the study.
- Dose groups that were examined: N/A


HAEMATOLOGY: No data
- Time schedule for collection of blood:N/A
- Anaesthetic used for blood collection: N/A
- Animals fasted: N/A
- How many animals: N/A
- Parameters checked in table [No.?] were examined.N/A


CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood:N/A
- Animals fasted: N/A
- How many animals: N/A
- Parameters checked in table [No.?] were examined.N/A


URINALYSIS: No data
- Time schedule for collection of urine:N/A
- Metabolism cages used for collection of urine: N/A
- Animals fasted: N/A
- Parameters checked in table [No.?] were examined.N/A


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


OTHER: N/A

Positive control:
N/A

Results and discussion

Details on results:
CLINICAL SIGNS AND MORTALITY-N/A


BODY WEIGHT AND WEIGHT GAIN- Both male and female young adult animals that received 0.5 % commercial grade test substance exhibited significantly lower final body weight gain compared with all other groups. Both adult males and females in the 0.5 % commercial grade test substance group had significantly lower body weight gain than the controls. Both males and females from the 0.35 % commercial grade and 0.35 % pure grade test substance groups were significantly lower in body weight gain compared to the control group.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)-Both male and female young adult animals that received 0.5 % commercial grade test substance exhibited significantly lower feed consumption compared with all other groups. Both adult males and females in the 0.5 % commercial grade test substance group had significantly lower food consumption than the controls. Both males and females from the 0.35 % commercial grade and 0.35 % pure grade test substance groups were significantly lower in feed efficiency compared to the control group except in the female group that received 0.35 % pure test substance.



FOOD EFFICIENCY-Both male and female young adult animals that received 0.5 % commercial grade test substance exhibited significantly lower feed efficiency compared with all other groups. Both adult males and females in the 0.5 % commercial grade test substance group had significantly lower feed efficiency than the controls. Both males and females from the 0.35 % commercial grade and 0.35 % pure grade test substance groups were significantly lower in feed efficiency compared to the control group.



WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)-N/A


OPHTHALMOSCOPIC EXAMINATION-
The incidence of cataracts in the treatment groups was greater than that seen in the control animals. Cataracts was not reported in either the young or adult control animals. In the 0.35% commerical test substance exposure group, the incidence of cataracts in the young male and female animals was 11/25 and 12/25, respectively. In the 0.5% commercial test substance exposure group the incidence of cataracts in the young male and female animals was 14/25 and 19/25, respectively. In the 0.35% pure test substance exposure group, the incidence of cataracts in the young male and female animals was 0/15 and 3/15, respectively. In the 0.5% commercial test substance exposure group the incidence of cataracts in the adult male and female animals was 18/25 and 11/25, respectively.

HAEMATOLOGY-N/A


CLINICAL CHEMISTRY-N/A


URINALYSIS-N/A


NEUROBEHAVIOUR-N/A


ORGAN WEIGHTS-N/A


GROSS PATHOLOGY-N/A


HISTOPATHOLOGY: NON-NEOPLASTIC-N/A


HISTOPATHOLOGY: NEOPLASTIC (if applicable)-N/A


HISTORICAL CONTROL DATA (if applicable)-N/A


OTHER FINDINGS-N/A

Applicant's summary and conclusion

Conclusions:
Groups of young adult male and female rats were treated with one of three treatments, 0.35 % commercial test substance, 0.5 % commercial test substance, or 0.35 % pure test substance and one group of adult male and female rats was treated with 0.5 % commercial test substance daily for 16 weeks by oral feed. The body weight gain, feed consumption, and feed efficiency of both young adult and adult animals treated with 0.5 % commercial test substance were significantly lower than control or other test groups. The two groups of young adult animals that received either 0.35 % commercial test substance or 0.35 % pure test substance had lower values for body weight gain, feed consumption, and feed efficiency compared to control animals except for the feed consumption of the females that received 0.35 % pure test substance. The incidence of cataracts in the treatment groups was greater than that seen in the control animals. Cataracts was not reported in either the young or adult control animals. In the 0.35% commerical test substance exposure group, the incidence of cataracts in the young male and female animals was 11/25 and 12/25, respectively. In the 0.5% commercial test substance exposure group the incidence of cataracts in the young male and female animals was 14/25 and 19/25, respectively. In the 0.35% pure test substance exposure group, the incidence of cataracts in the young male and female animals was 0/15 and 3/15, respectively. In the 0.5% commercial test substance exposure group the incidence of cataracts in the adult male and female animals was 18/25 and 11/25, respectively.
Executive summary:

Groups of young adult male and female rats were treated with one of three treatments: 0.35 % commercial test substance (25 per sex), 0.5 % commercial test substance (25 per sex), or 0.35 % pure test substance (25 per sex) and one group of adult male and female rats was treated with 0.5 % commercial test substance (25 per sex) daily for 16 weeks by oral feed. Two additional groups receiving only laboratory diet were included as controls. The commercial grade test substance was added directly to the food, while the pure test substance was formed in an aqueous solution and then added to the food.

The eyes of all the animals were examined during the 1 week acclimation period, followed by being randomly distributed into groups on the basis of body weight, sex, and eye examination. Body weights and feed consumption were measured weekly. The animals were observed weekly and gross abnormalities recorded. Ocular examinations were performed at approximately 4 -week intervals throughout the study. Results from the ocular examinations were reported in a separate report. Upon completion of the final eye examination, the animals were sacrificed. Gross pathology and histopathology of gonadal tissues and all other tissues were examined in the study.

Both male and female young adult animals that received 0.5 % commercial test substance exhibited significantly lower final body weight gain, feed consumption, and feed efficiency compared with all other groups. The groups that received 0.35 % commercial test substance or 0.35 % pure test substance were similar in growth characteristics. However, both groups were significantly lower in body weight gain, feed consumption, and feed efficiency compared to the control group except for feed consumption in the female group that received 0.35 % pure test substance. In both male and female adult animals that received 0.5 % commercial test substance, body weight gain, feed consumption, and feed efficiency were significantly lower than their control group.

The incidence of cataracts in the treatment groups was greater than that seen in the control animals. Cataracts was not reported in either the young or adult control animals. In the 0.35% commerical test substance exposure group, the incidence of cataracts in the young male and female animals was 11/25 and 12/25, respectively. In the 0.5% commercial test substance exposure group the incidence of cataracts in the young male and female animals was 14/25 and 19/25, respectively. In the 0.35% pure test substance exposure group, the incidence of cataracts in the young male and female animals was 0/15 and 3/15, respectively. In the 0.5% commercial test substance exposure group the incidence of cataracts in the adult male and female animals was 18/25 and 11/25, respectively.

No NOAEL was identified.