1,2,3,4-tetrahydroisoquinoline

Repeated dose toxicity: other routes

Administrative data

Endpoint:

repeated dose toxicity: other route

Remarks:

other: short-term (4-day treatment period)

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, non-guideline study, available as unpublished report, restrictions in reporting (available report is a summary) but otherwise adequate for assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Principles of method if other than guideline:

Male mice were treated intraperitoneally with 1,2,3,4-Tetrahydroisoquinoline on 4 consecutive days at three different dose levels (10 mice/dose). A concurrent control group of the same size was treated similarly with the vehicle (physioligical saline) only. Hereafter, the animals were kept for a 9-day treatment-free observation period. Endpoints to assess toxicity included clinical observations, body weight, food consumption, motor activity, brain weight, necropsy and microscopic examination of the brain.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,2,3,4-tetrahydroisoquinoline

EC Number:

202-050-0

EC Name:

1,2,3,4-tetrahydroisoquinoline

Cas Number:

91-21-4

Molecular formula:

C9H11N

IUPAC Name:

1,2,3,4-tetrahydroisoquinoline

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): 1,2,3,4-Tetrahydroisoquinoline
- Stability of the test material in 0.9% saline solution at room temperature for a period of 5 days was demonstrated before the study (01Y0797/058062). No homogeneity and concentration control analyses in the carrier was carried out in this study.

Test animals

Species:

mouse

Strain:

other: C57BL/6 J Rj

Sex:

male

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

other: 0.9% saline solution

Details on exposure:

1,2,3,4-Tetrahydroisoquinoline was administered to groups of 10 male C57BL/6 J Rj mice via intraperitoneal application at dose levels of 0, 3, 50 and 200 mg/kg bw/d for 4 days followed by 9 days treatment-free observation period. The daily dosage was divided in two applications. One application was in the early morning, the second was in the afternoon.
Due to severe clinical findings the dose level in test group 3 was changed from 200 mg/kg bw/d to 100 mg/kg bw/d after the first administration on study day 0.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

4 days

Frequency of treatment:

daily dose was divided in two applications

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 3, 50 and 200 mg/kg bw/day (highest dose was reduced from 200 to 100 mg/kg bw/day after the first application)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: at least once daily

BODY WEIGHT: on days 0, 3 and 12.

FOOD CONSUMPTION: over 1-day periods on days 3 and 12.

MOTOR ACTIVITY: on days -1, 3 and 12 (12 time blocks)

Sacrifice and pathology:

Animals which died intercurrently and those that were sacrificed moribund were disposed of without any pathological examinations.
The first 5 surviving animals per test group were subjected to deep anesthesia with isoflurane and sacrificed by perfusion fixation.
The remaining 5 animals per test group were sacrificed by decapitation under isoflurane anesthesia. The exsanguinated animals were necropsied and the brains were removed, weighed and processed for microscopic examination (HE stained slides and neuronal cell count on tyrosine hydroxylase immunohistochemical stained slides).
The corpus striatum was dissected, shock-frozen with liquid nitrogen and stored at -70°C for further examination.

Results and discussion

Results of examinations

Details on results:

MORTALITY
In test group 3 (200 and 100 mg/kg bw/d) 3 animals were found dead, i.e. on day 0 one animal after the second treatment, on day 1 one animal before the second treatment, and on day 3 one animal after the second treatment.

CLINICAL SIGNS
- In test group 3 (200 and 100 mg/kg bw/d) severe signs of general toxicity were observed, i.e. all animals showed high stepping gait until the end of the administration period, 9 animals showed reduced attention until the end of the administration period, 7 animals had an unsteady gait until the end of the administration period, 4 animals had tremors after the first application on day 1, 3 animals showed moderate tonic-clonic convulsions after the first application on day 0, 2 animals with poor general condition (one animal on day 1 after the first application and one animal from day 7 onwards), one animal showed salivation after the first application on day 0, and one animal showed piloerection from day 7 onwards.
- In test group 2 (50 mg/kg bw/d) 5 animals showed reduced attention until the end of study day 1.
- In test group 1 (3 mg/kg bw/d) no test substance-related, adverse findings were observed.

BODY WEIGHT AND WEIGHT GAIN
On day 3 body weight loss of 5% was observed for animals of test group 3 (200 and 100 mg/kg bw/d). Body weight change values were also significantly decreased in this group on study day 3 (-271%).

FOOD CONSUMPTION
No test substance-related findings were observed.

MOTOR ACTIVITY
In test group 1 (3 mg/kg bw/d) the single interval 9 on study day 3 was significantly decreased. On study day 12 the single intervals 8, 9 and 12 were significantly decreased in test group 2 (50 mg/kg bw/d). These findings were assessed as being incidental and not test substance-related as no dose-response relationship was observed.

BRAIN WEIGHT
The mean absolute and relative weights of treated animals did not show relevant differences compared to the control group.

GROSS PATHOLOGY
No gross lesions were observed in all test animals.

HISTOPATHOLOGY OF THE BRAIN
The light microscopic examination of HE-stained slides as well as the neuronal cell count on tyrosine hydroxylase immunohistochemical stained slides revealed no differences between control animals and treated animals of test group 3.

Effect levels

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Based on clinical signs of toxicity (from 50 mg/kg bw/day) and reduced body weight (at 200/100 mg/kg bw/day)

Target system / organ toxicity

Critical effects observed:

not specified