Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2-Methylimidazol
- Substance no.: XXIII/189
- Analytical purity: > 99%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Firma WIGA (Sulzfeld)
- Age at study initiation: 36 days
- Weight at study initiation: 137 g (males) and 125 g (females)
- Housing: V2A-wire cages with a bottom surface of ca. 900 cm2
- Diet: Altromin-R (Firma Altrogge, Lage/Lippe), ad libitum
- Water: ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 1 to 8%
- Amount of vehicle: 10 mL
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
4 weeks (28 days)
Frequency of treatment:
5 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
800 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: no
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: no

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): no

OPHTHALMOSCOPIC EXAMINATION: no

HAEMATOLOGY: yes
- Schedule for collection of blood: at study initiation and after the 28-day exposure period
- How many animals: 5 males and 5 females per exposure group
- Parameters examined: haemoglobin, erythrocytes, haematocrit, mean cell volume, mean corpuscular haemoglobin concentration, leukocytes and differential blood count.

CLINICAL CHEMISTRY: yes
- Schedule for collection of blood: at study initiation and after the 28-day exposure period
- How many animals: 5 males and 5 females per exposure group
- Parameters examined: sodium, potassium, carbon dioxide, chloride, calcium, phosphate, glucose, urea, total protein, total lipids, total bilirubin, creatinine, serum glutamic pyruvic transaminase and alkaline phosphatase .

URINALYSIS: yes
- Time schedule for collection of urine: after 3 weeks of exposure
- Metabolism cages used for collection of urine: yes
- Parameters examined: pH value, protein, glucose, urobilinogen and sediment

NEUROBEHAVIOURAL EXAMINATION: no
Sacrifice and pathology:
HISTOPATHOLOGY: heart, liver, kidneys, spleen, testicles/ovaries, thyroid glands, suprarenal glands, hypophysis, brains, lungs, pancreas, stomach, small intestine, large intestine, lymph nodes, urinary bladders, skin, eyes with optic nerve, rhinitis and pharyngitis, tongue, skull with teeth, salivary gland, skeletal muscles, thymus gland, tracheae, oesophagus, thoracic aorta, prostate/uterus, seminal vesicles, epididymis and adipose tissue.
Other examinations:
Weight of: heart, liver, kidneys, spleen, thyroid glands, suprarenal glands and testicles
Statistics:
A variance analysis was perform with all exposure groups, when one or more of the doses showed a statistically significant effect (p ≤ 0.05) a mean t-test was performed for between the dose group and the control group.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY: no mortality observed, slight ruffled fur at 200 mg/kg bw dose; 400 and 800 mg/kg bw: yellow urine, ruffled fur and increased salivation.

BODY WEIGHT AND WEIGHT GAIN: normal body weight gain in all exposure groups, except for males at 800 mg/kg bw.

HAEMATOLOGY: no changes.

CLINICAL CHEMISTRY: decreases in total protein in males and females in all dose groups (not dose related in males) and increased creatinine at 800 mg/kg bw in males.

URINALYSIS: no changes.

ORGAN WEIGHTS:
Increased absolute weights for:
- liver: females in 800 mg/kg bw exposure group
- thyroid glands: males of the 200 to 800 mg/kg bw exposure groups and females of the 800 mg/kg bw exposure group
Increased relative weights for:
- liver: females in 400 and 800 mg/kg bw exposure group
- thyroid glands: males of the 200 to 800 mg/kg bw exposure groups and females of the 800 mg/kg bw exposure group
- kidneys: females of the 800 mg/kg bw exposure group

MACROSCOPY: no substance treatment related effects

MICROSCOPY: no substance treatment related effects

Effect levels

Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion