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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
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: Comparable to guideline study with acceptable restrictions (without detailed documentation; raw data partly incomplete, prior to GLP)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1971
Report date:
1971

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
(documentation deficiencies)
Principles of method if other than guideline:
Groups of male and female rats were fed a diet containing the test substance in graduated doses on daily basis for a period of 90 days. During the period of administration the animals are observed closely for signs of toxicity. Animals which die or are killed during the test are subjected to necropsy and, at the conclusion of the test, necropsy is also performed on surviving animals.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Propionic acid
EC Number:
201-176-3
EC Name:
Propionic acid
Cas Number:
79-09-4
Molecular formula:
C3H6O2
IUPAC Name:
propionic acid
Details on test material:
- Name of test material (as cited in study report): Propionsaeure techn.
- Analytical purity: 100 % (acidimetric analysis)
- Stability in feed: up to 3 weeks

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Firma Gassner, Ottobrun
- Age at study initiation: no data
- Weight at study initiation: ♂ approx 135-136g, ♀ approx. 128-129g
- Fasting period before study: no data
- Housing: no data
- Diet: ad libitum
- Water: no data on drinking water
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): every three weeks
- Mixing appropriate amounts with (type of food): pulverised Altromin-R (Altrogge, Lage/L)
- Storage temperature of food: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
6200, 12500, 25000, 50000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
- Control: 20 (main study) + 10 (recovery group)
- 6200 ppm: 20 (main study) + 10 (recovery group)
- 12500 ppm: 20
- 25000 ppm 20
- 50000 ppm: 20 (main study) + 10 (recovery group)
Control animals:
yes, plain diet
Details on study design:
POST EXPOSURE PERIOD
- Post-exposure recovery period: 42 days
- Doses: control, 6200 and 50000 ppm
- Number of animals: 10/sex/dose
- Rationale for selecting satellite groups: determining reversibility of effects

DOSE SELECTION RATIONAL: no data

RATIONAL FOR ANIMAL ASSIGNMENT: no data

Examinations

Observations and examinations performed and frequency:

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: no data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: no data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 19-21 days and then 75-78 days after start of feeding
- Anaesthetic used for blood collection: No data
- Animals fasted: yes
- How many animals: 10/sex/time point
- Parameters checked: Leukocytes, erythrocytes, haemoglobin, hematocrit, BUN, differential blood count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 19-21 days and then 75-78 days after start of feeding
- Animals fasted: yes
- How many animals: 10/sex/time point
- Parameters checked: glutamat-pyruvate transaminase

URINALYSIS: Yes
- Time schedule for collection of urine: 14-17 days and then 70-73 days after start of feeding
- Metabolism cages used for collection of urine: No data
- Animals fasted: yes
- How many animals: 10/sex/time point
- Parameters checked: pH, protein, glucose, sediment, sugar
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Parameters examined: weight of the liver, kidneys and heart, testes and spleen. Organ weights in relation to the bodyweights and heart was computed and documented
HISTOPATHOLOGY: Yes
- Organs prepared: CNS (cerebrum and cerebellum), heart, lungs, thyroid, liver , kidneys, adrenals, spleen, stomach, intestines, lymph node of the stomach, genitals and bladder

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS
- During the entire study period, none of the animals showed signs that were related to the administration of the test substance.

MORTALITY: no data

BODY WEIGHT AND WEIGHT GAIN
Mild body weight loss was noticed in the male animals of the 12500 and 25000 ppm dose groups compared to controls. Males of the highest dose group (50000 ppm) experienced weight loss of a prolonged nature starting from the beginning of feeding and lasting till the end of the feeding period. Weight gain of animals fed with diets containing 12500, 25000 and 50000 ppm propionic acid was minimally reduced compared to control animals. In the recovery period, body weights of male and female rats fed a diet containing 50000 ppm propionic acid and female rats which had a diet containing 6200 ppm propionic acid did not quite attain the end body weight of the control animals

FOOD CONSUMPTION
Food consumption in all but the highest dose group (50000 ppm) was comparable to that of the animals in the control group. In the animals of the recovery group (50000 ppm), food consumption was comparable between males and females.

COMPOUND INTAKE (if feeding study): no data

HAEMATOLOGY and CLINICAL CHEMISTRY
- The haematological and clinical chemistry parameters of the treated animals were within physiological limits and comparable to that of the control animals.

URINALYSIS: no data

ORGAN WEIGHTS
- Absolute liver, kidney and heart weights of treated animals were comparable at all doses to that of control animals. In animals of the recovery groups, the absolute liver, kidney and heart weights were comparable between the treated animals and the control animals. Relative kidney to body weight of male animals in the highest dose group was slightly reduced compared to controls. In contrast, for females, the mean relative kidney to body weights was increased in all dose groups compared to control animals. The mean relative heart and liver to body weights were increased in the highest dose group only. This increase was no longer evident in animals of the recovery group. Liver and kidney weights of treated animals expressed relative to the corresponding heart weights were comparable at all doses (including the recovery groups) to that of the corresponding control animals.

GROSS PATHOLOGY
- No test substance dependent macroscopic changes were noticed in any of the treated groups


HISTOPATHOLOGY: NON-NEOPLASTIC
- A dose dependent increase in the incidence and severity of proliferation-acanthosis and retention-hyperkeratosis of the forestomach mucosa was seen from the 12500 ppm dose group and above. These effects were more distinctive in females than in males. Reversibility of these effects was noticed after the 42 day post-exposure-observation-period.

Effect levels

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Dose descriptor:
NOAEL
Remarks:
(local effects; 90 days)
Effect level:
6 200 ppm
Sex:
male/female
Basis for effect level:
other: Based on the dose dependent increase in the incidence and severity of proliferation-acanthosis and retention-hyperkeratosis of the forestomach mucosa seen from the 12500 ppm dose group and above.
Dose descriptor:
NOAEL
Remarks:
(systemic effects; 90 days)
Effect level:
50 000 ppm
Sex:
male/female
Basis for effect level:
other: Absence of adverse effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion