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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
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: Study well documented, although some data are missing (purity for example
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Studies of the Safety of Azodicarbonamide as a Flour-Maturing Agent
Author:
Oser BL, Oser M, Morgareidge K
Year:
1965
Bibliographic source:
TOXICOLOGY AND APPLIED PHARMACOLOGY 7, 445-472 (1965)
Reference Type:
publication
Title:
Nutritional studies on rats on diets containing high levels of partial ester emulsifiers. IGeneral plan and procedures; Growth and food utilisation
Author:
Oser BL, Oser M
Year:
1956
Bibliographic source:
Journal of Nutrition 60, 367-390

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rats were treated with biurea in diet for 1 years and were evaluated for carcinogenicity and chronic effects.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
No data on purity
- Name in the article: HADA

Test animals

Species:
rat
Strain:
other: : FDRL albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: weanling
- Weight at study initiation: 50-70 g
- Fasting period before study: no
- Housing: individually
- Diet (e.g. ad libitum): ad libitum Purina Laboratory Chow
- Water (e.g. ad libitum):ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS:
No data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: bread made with untreated flour
Details on oral exposure:
HADA (Biurea) was added as supplement to the basal diet of Purina Laboratory Chow.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
1 year
Frequency of treatment:
in diet
Doses / concentrations
Remarks:
Basis:nominal in diet
No. of animals per sex per dose:
2 tested groups 25 males and 25 females each
1 control group 10 males and 10 females
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: In view of Ihe innocuous effects of HADA in bread diets at levels up to 1000 times that resulting from the intended use level of ADA in flour, it was decided to test dietary levels of 5 and 10%.
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

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

WATER CONSUMPTION: Yes, but no further data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 12, 26, 44, and 52 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: in representative animals
- Parameters examined: hemoglobin, hematocrit, total and differential leukocytes counts, glucose and non-protein nitrgen levels.

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: at 12, 26, 44, and 52 weeks
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: albumin, sugar, and pH, and the sediment was examined microscopically

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
Necropsies were performed on all rats.
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Five major organs were weighed, and microscopic examinations were made of 16 organs and tissues of approximately 10 rats of each sex per test group, and 5 per sex of the control rats.
Other examinations:
-
Statistics:
-

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not specified
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 adverse effects on the behavior or appearance of the rats, and all but one animal at the 10% HADA level survived the entire year.

BODY WEIGHT AND WEIGHT GAIN - FOOD CONSUMPTION
Food intake was normal, and the efficiency of food utilization was approximately the same in the control and both test groups (19.7, 19.1, and 19.3 for males and 13.8, 13.1, and 12.7 for females, respectively). Growth responses of females at both levels of dosage approximated that of the controls although in the males, growth was slightly depressed during the initial 12 weeks but equal to the controls thereafter.

HAEMATOLOGY
In rats the hemoglobin and hematocrit values were essentially normal. The total leukocyte counts of both species were within normal limits.
A slight elevation in NPN of the rats fed 5% HADA is not considered significant in view of its normality in the 10% HADA group. Blood sugar levels were normal. Methemoglobin levels in all groups were below the limit of sensitivity of the analytical procedure (0.2 mg/100 ml).

GROSS PATHOLOGY
Gross findings at autopsy, including pulmonary changes, such as are commonly seen In rats, were few and scattered randomly among the groups.

ORGAN WEIGHTS
Weights of the liver, kidneys, spleen, heart, and adrenals were normal.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopically, no dose-related findings were disclosed in the examinations of organs from rats that received the high HADA dosage.

Effect levels

Dose descriptor:
NOAEL
Effect level:
10 other: % in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Survival and growth responses of rats fed high levels of HADA for 1 year
Group Diet code No and sex Survival (%) Mean body weight (g)
week 12 52 0 12 52
H Control 10M 100 100 62 354 458
10F 100 100 58 209 277
F 5% HADA 25M 100 100 62 334 438
25F 100 100 60 207 278
G 10% HADA 25M 100 96 62 333 431
25F 100 100 59 211 272

Applicant's summary and conclusion

Executive summary:

To investigate the safety of azodicarbonamide (ADCA) as a flour maturing agent, studies in rats were conducted in two stages. In the first phase, a 2-year feeding study in rats was carried out in which the principal ingredient in- the diet was bread made either from flour over-treated (10 times) with ADCA, or from untreated flour to which graded levels of biurea (HADA) (to which ADCA is converted in the prebaking stage), were added up to 1000 times the level of use. Assuming food consumption of 20 g/day and a mean body weight of 350 g, the dietary inclusion levels correspond to approximately 45, 140, and 450 mg biurea/kg body weight per day (CICAD 1999).

 

Observations were made of appearance, behaviour, growth, food efficiency, hematologic, blood chemical and urine changes, survival and gross and microscopic pathology.

In the rats, evaluations were made of reproduction and lactation performance and similar observations were also made in three descendant generations maintained on the same diets.

No adverse dose-related effects with respect to any of these criteria were noted in rats.

 

Hence, the second phase of the study was inaugurated in which HADA was fed at 5% and 10% levels in a basal diet for one year to rats. In the rats, the only effect-noted was a slight growth depression with a corresponding diminution of food intake in the males.

Authors concluded that use of azodicarbonamide (ADCA) as a flour maturing agent is safe.