2-Propanol, 1,1'-(tridecylimino)bis-

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

Report date:

1992

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

- Physical state: liquid
- Batch No.: Batch 704 / tank 328 from July 5, 1990
- Storage condition of test material: at a cool place (+4°C)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr . Karl Thomae GmbH, 7950 Biberach/Riss, Germany
- Age at study initiation: 42 days
- Weight at study initiation: male animals: 180 (166 - 192) g; female animals : 142 (134 - 155) g
- Housing: singly in type DK III stainless steel wire cages from Becker & Co., 4620 Castrop-Rauxel, Germany
- Diet: ad libitum Kliba rats/mice/hamsters maintenance diet, 343 meal, Klingentalmuehle AG, CH-4303 Kaiseraugst, Switzerland
- Water: e.g. ad libitum
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on oral exposure:

Administration volume: 5 ml/kg bw

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
25, 100, 300 mg/kg bw
Basis:

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day (Monday to Friday) and once a day (Saturdays, Sundays and public holidays).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The general state of health of the animals was checked twice a day (Monday to Friday) and once a day (Saturdays, Sundays and public holidays).

BODY WEIGHT: Yes
- Time schedule for examinations: on day 0 of the study and once a week thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE :
- The food consumption over a period of 7 days was determined weekly and calculated as mean food consumption in grams per animal and day.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: 14 days (erroneously not at the beginning of the study) and 90 days after the beginning of the study
- Dose groups that were examined: Control group and 300 mg/kg bw /day test group

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 29 and 85 days after the start of the administration period
- Anaesthetic used for blood collection: No
- Animals fasted: No
- Parameters checked: leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 29 and 85 days after the start of the administration period
- Animals fasted: No
- Parameters checked:
Enzymes: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase,serum-gamma-glutamyltransferase
Blood chemistry: sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, magnesium

Sacrifice and pathology:

- animals were fasted 16-20 h prior to sacrifice
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Organs examined: Brain, Pituitary Gland, Thyroid and Parathyroid Glands, Thymus, Trachea, Lungs, Heart, Aorta, Salivary Glands (Mandibular & Sublingual), Liver, Spleen, Kidneys, Adrenal Glands, Pancreas, Testes, Ovaries, Uterus, Oesophagus, Stomach (Forestomach and Glandular Region), Duodenum, Jejunum, Ileum, Caecum, Colon, Rectum, Urinary, Bladder, Mesenteric Lymph Node, Sciatic Nerve, Sternum with Marrow, Femoral Bone Marrow

Statistics:

Statistical significance were determined by analysis of variance (ANOVA) followed by a DUNNETT's test

Results and discussion

Results of examinations

Details on results:

In the lowest dose group (25 mg/kg bw) no substance related effects in any of the endpoints assessed were observed.

MORTALITY
Four animals died or were sacrificed before the end of the treatment period; two control males and two females given the highest dosage. The death of one of the controls was due to accidental trauma inflicted with the gavage. Although no cause of death was established for the other decedents there was no histopathological evidence to indicate that the two females given the highest dosage had died as a result of the administration of the test compound.

CLINICAL SIGNS
-100 mg/ kg bw group: no substance related changes
-300 mg/ kg bw group:
All male and females showed salivation, predominantly after test substance administration. Genital region smeared with urine in 9 male and 10 female animals.

BODY WEIGHT:
-100 mg/ kg bw group: There was a statistically significant (p ≤ 0.05) increase in the body weight of males between day 56 and day 84 (max + 9.1 %), however this difference was statistically not significant at day of sacrifice.
-300 mg/ kg bw group: A statistically significant reduction of terminal body weight of males (10.4 % reduction; p ≤ 0.05).

FOOD CONSUMPTION AND COMPOUND INTAKE:
-100 mg/ kg bw group: no substance related changes
-300 mg/ kg bw group: food consumption was of females was statistically significantly increased at the end of the study (+18% on day 91; p ≤ 0.01), but there was no corresponding effect seen in the body weight.

OPHTHALMOSCOPIC EXAMINATION
-No substance related effect in any group

HAEMATOLOGY
-100 mg/ kg bw group: no substance related changes
-300 mg/ kg bw group: increase of polymorphonuclear neutrophiles (8% females, 74% males; statistically not significant). This increase in polymorphonuclear neutroptphils is treatment-related and might be due to the changes seen in the forestomach of these animals (see histology)


CLINICAL CHEMISTRY
-100 mg/ kg bw group: no substance related changes
-300 mg/ kg bw group:
In males alkaline phosphatase was statistically significant increased (32% ; p ≤ 0.01 ) at day 29 but not at the end of the study
alanine aminotransferase was statistically significant increased in both sexes (55% females, 68% males; p ≤ 0.01)
cholesterol was statistically significant decreased in both sexes (24% females, 36% males; p ≤ 0.01)

ORGAN WEIGHTS
-100 mg/ kg bw group: no substance related changes
-300 mg/ kg bw group:
Statistically significant increased absolute (+21.7%) and relative liver weights (+23.7%) of females (p ≤ 0.01)
Statistically significant increased relative weights of the kidneys (8.3% females, 13.6% males; p ≤ 0.05)
Statistically significant increased relative weights of the adrenal glands (20.9% females, 21% males; p ≤ 0.05 )
Statistically significant increased absolute adrenal weights in females (19.9%; p ≤ 0.05)

HISTOPATHOLOGY
-100 mg/ kg bw group (effects in males only):
Stomach: slight or moderate focal thickening of the forestomach wall, diffuse hyperplasia of the keratinised epithelium, focal epithelial hyperplasia.

-300 mg/ kg bw group:
Stomach: Both sexes had have slight or moderate focal thickening of the forestomach wall, afocal or diffuse hyperplasia of the keratinised epithelium of the forestomach; in few animals hyperkeratosis, submucosal inflammation, submucosal oedema, oedema of the lamina propria and focal ulceration or erosion.
Liver: The amount of fat within centriacinar hepatocytes of males was less than in controls. This change may have resulted from lower calorific intake rather than a direct effect of the test compound since bodyweight was lower in males given the highest dosage than in controls.
Adrenal Glands: Two females had a marked or moderate focal cortical necrosis with fibrosis and mineralisation and a further female from this group had slight cortical fibrosis. No such changes were noted in any of the other animals on study. It is possible that all three lesions had a similar pathogenesis, possibly infarction. However, since these changes can occur spontaneously in rats, the low incidence was considered insufficient to provide clear evidence of a treatment-related effect.

OTHER DEVIATIONS
Some differences in clinicochemical statistically significant inter-group the results of the hematological and clinicochemical examinations. These deviations are marginal, inconsistent,sporadic or lacking dosage-relationship. Accordingly, these changes are considered to be of no toxicological significance.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

25 mg/kg bw/day (actual dose received)

Sex:

male

2

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Sex:

female

Target system / organ toxicity

Critical effects observed:

not specified