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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
analytical purity: separate certificate not enclosed
Purity test date: 21.08.1995
Lot/batch No.: 8/95
Expiration date of the lot/batch: 21.08.1996

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst Aktiengesellschaft, Kastengrund, SPF breeding colony
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: male: 108 g (mean), female: 114 g (mean)
- Housing: in groups of 5
- Diet: ssniff R/M-H (V 1534) ad libitum, except for the period in which the animals were kept in diuresis cages.
- Water: tap water in plastic bottles ad libitum, except for the period in which the animais were kept in diuresis cages.
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 50 ± 20 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The determination of the test substance was performed by spectrophotometrical detection (λ = 274 nm).
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily (7x week)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In a dose range finding study groups of 3 male and 3 female Wistar rats received 3-Dimethylaminopropylamin at dose levels of 50 and 250 mg/kg body weight per day over a period of 14 days. The animals of the 50 mg/kg body weight group showed no clinical signs. The animals of the of the 250 mg/kg body weight showed sporadically swollen abdomen during the study period.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: the animals were observed once daily.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weights of all animals were determined before the start of the study and then twice weekly throughout the study.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weekly
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the termination of the study
- Anaesthetic used for blood collection: Yes (intrapenitoneal injection of 50-100 mg Ketamin/kg body weight)
- Animals fasted: No data
- How many animals: all
- Parameters examined: Erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leucocyte count, thrombocyte count, differential leucocyte count and red ceII morphology, reticulocyte count*, heinz bodies*, coagulation time. *These parameters were scored in the control group and high dose group only.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the termination of the study
- Animals fasted: No data
- How many animals: all
- Parameters examined: Sodium, potassium, inorganic phosphorus, uric acid, bilirubin total, creatinine, glucose, urea, calcium, chloride, aspartate aminotransferase (ASAT/GOT), alanine aminotransferase (ALATIGPT), alkaline phosphatase (AP), gamma-glutamyltranspeptidase (GGT), cholesterol, triglycerides, total protein, albumin.

URINALYSIS: Yes
- Time schedule for collection of urine: overnight from day 26 to day 27
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: Appearance, color, pH-Value, hemoglobin, protein, glucose, ketone bodies, bilirubin, urobilinogen, specific weight, sediment, volume.

OTHERS: The animals were examined weekly for neurological disturbances, damage to the oral mucosa and impairment of dental growth.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. The autopsy included macroscopic examination of the skin, orifices, eyes, teeth, oral mucosa and internal organs.

HISTOPATHOLOGY: Yes. The necropsy included examination of the heart, stomach, liver, jejunum, kidneys, colon, adrenals, uterus, spleen, ovanies, testes, epididymides, lungs.
Statistics:
The following parameters were compared statistically with the control group values at the level of significance p = 0.05.
Body weights at the designated measurement times, hematological data, clinical chemistry parameters, urine analysis, absolute organ weights and organ to body weight ratios.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
Mortality occurred in four females of the 250 mg/kg body weight group. The animals were found dead on days 11, 18, 22 and 25 of the study.
One male animal of the high dose group showed irregular respiration as well as respiratory sounds at day 11 and 12 of the study. The following clinical signs were observed in female animals of the high dose group sporadically between day 11 and 24 of the study: decreased spontaneous activity, stilted gait, swollen abdomen, respiratory sounds, gasping and panting. The clinical signs were mainly seen in those females which died intercurrently. Behavior and state of health remained unaffected by the administration of the test compound in all other dose groups.
BODY WEIGHT AND WEIGHT GAIN
Body weight development was not impaired by the administration of the test compound and was comparable in all groups.

FOOD CONSUMPTION AND COMPOUND INTAKE
Absolute and relative food consumption remained unaffected by the administration of the test compound throughout the study.

WATER CONSUMPTION AND COMPOUND INTAKE
Likewise, the administration of the test compound did not alter the water consumption.

OPHTHALMOSCOPIC EXAMINATION
No abnormalities were observed

HAEMATOLOGY
Hematological examinations revealed statistically significant decreases in erythrocyte counts as weil as in hemoglobine and hematocrit values in males of the intermediate dose group. Haematocrit values were also decreased in males of the high dose group. Leukocyte counts were statistically significantly decreased in males of the intermediate and females of the low dose group. In all cases there was no dose dependency or the values were within the physiological range of rats. Therefore, a compound-related effect is not evident.

CLINICAL CHEMISTRY
Statistical evaluation revealed increases in aspartate aminotransferase and decreases in total protein values in females from the high dose group. lnorganic phosphorus values were decreased in females of the low dose group. Males of the intermediate dose group showed statistically significant decreases in total bilirubin values. In all dose groups of the females the uric acid values were statistically significantly decreased. In all cases there was no dose dependency or the values were within the physiological range of rats. Therefore, a compound-related effect is not evident.

URINALYSIS
Examination of the urine did not reveal any abnormalities.

ORGAN WEIGHTS
In males of the intermediate dose group statistical evaluation of the organ weights revealed increases in relative liver weights. As there was no dose dependency a compound-related effect is not evident.

GROSS PATHOLOGY
In terminally killed animals, no macroscopically visible organ alterations attributable to the compound administration were observed. Dilatation of renal pelvices was found in same male or female animals of all treatment groups and therefore was not considered to be compound-related but to be a strain specific alteration. In the four high dose females which died intercurrently gross findings included discoloration of Iungs with multiple red spots an its surfaces and foamy content. One female also showed a small spleen.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological examinations revealed lesions in the four females of the high dose group dying intercurrently. These lesions included congestion of organs, pulmanary hemorrhage, and edema, consistent with cardiorespiratory failure as cause of death. In addition, one of these females exhibited marked loss of lymphatic follicles of the spleen with massive marginal zone and periarteriolar lymphoid sheath atrophy, probably reflecting chronic stress due to treatment. In the one high dose male rat which had shown clinical signs, focal ballooning degeneration of the stratum corneum of the squamous epithellum of the forestomach with granulocytic infiltration of the submucosa was found, most likely due to the locally irritating effect of the compound.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment-related adverse effects were seen.
Key result
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 3-Dimethylaminopropylamin caused clinical symptoms and mortality in male and female Wistar rats when administered 28 times at the dose level of 250 mg/kg body weight. The female rats seem to be more sensitive.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion