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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, available as unpublished report.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1993

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
Adopted 24 February 1987
Deviations:
no
Principles of method if other than guideline:
Similar to OECD TG 423 (Acute Oral Toxicity – Acute Toxic Class Method)
GLP compliance:
no
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
8-azaspiro[4,5]decane-8-{4-[4''-(2'''-pyrimidinyl)-1''-piperazinyl]-butyne/2/-yl}-7,9-dione /E/-2-butenedionate
EC Number:
947-290-3
Cas Number:
118286-97-8
Molecular formula:
C21H27N5O2 × C4H4O4
IUPAC Name:
8-azaspiro[4,5]decane-8-{4-[4''-(2'''-pyrimidinyl)-1''-piperazinyl]-butyne/2/-yl}-7,9-dione /E/-2-butenedionate
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Buspiron XI. fázistermék
- Physical state: white odourless powder
- Lot/batch No.: 1/1992
- Storage condition of test material: room temperature, protected from light

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Species: Rat
- Strain: Wistar
- Sex of animals: female and male rats
- Number of animals: 6 males and 6 females per dose group plus 6 males and 6 females in the control group - a total of 72 animals (including control animals)
- Source of test animals: Laboratóriumi Állatokat Tenyésztő és Takarmányellátó Kft. (LATI Kft., 2100 Gödöllő Táncsics Mihály utca 17.)
- Weights of study animals determined at the beginning of the study : 121-177 g (males), 126-162 g (females)

ENVIRONMENTAL CONDITIONS
- Housing conditions: Animals were kept in cages - group-caged by dose
- 6 animals per cage
- Size of boxes: 19.5 x. 45.5 x 29.0 cm
- Bedding: wood shavings
- Temperature in the experimental animal room: 22ºC +/- 3ºC
- Relative humidity: 50-70%
- Lighting: artificial - sequence: 12 hours light, 12 hours dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
concentration of methylcellulose solution: 1%
Details on oral exposure:
VEHICLE
- Substance formulation: test substance suspended in methylcellulose solution (cc: 1%)
- Physical form of the material administered: liquid
- Dosing volumes: 5 mL/kg (for all dose levels and for the control groups)
- Test solutions were administered to the test animals within 1 hour of their preparation

FEED AND DRINKING WATER
- Feed: conventional laboratory diet (standard rodent feed)
- Animals were fasted prior to dosing (food withheld for 12 hours)
- During the period of observations (the 2 weeks following the treatment) animals had feed and water ad libitum
- Microbiological status of the feed and drinking water were checked and found to be adequate

ADMINISTRATION OF THE TEST SUBSTANCE
- Single dose exposure
- Treatment: Day 0
- Observations: Day 1-14
- Necropsy: Day 15
Doses:
MALE RATS
0 mg/kg body weight (control)
600 mg/kg body weight
720 mg/kg body weight
860 mg/kg body weight
1040 mg/kg body weight
1250 mg/kg body weight

FEMALE RATS
0 mg/kg body weight (control)
500 mg/kg body weight
600 mg/kg body weight
720 mg/kg body weight
860 mg/kg body weight
1040 mg/kg body weight
No. of animals per sex per dose:
6
Control animals:
yes
Statistics:
LD50 calculation - probit analysis.
Body weight - mean and standard deviation values.
Difference between dose groups - Student's t test.

Results and discussion

Effect levelsopen allclose all
Key result
Sex:
male
Dose descriptor:
LD50
Remarks:
oral, 14 days
Effect level:
ca. 814.82 mg/kg bw
Based on:
act. ingr.
95% CL:
>= 728.82 - <= 910.96
Key result
Sex:
female
Dose descriptor:
LD50
Remarks:
oral, 14 days
Effect level:
ca. 822.36 mg/kg bw
Based on:
act. ingr.
95% CL:
>= 710.25 - <= 952.15
Mortality:
Lethal dose values:
males: LD50 (rat; 14ays) = 814.8 (728.8-911.0) mg/kg bw
females: LD50 (rat; 14 days) = 822.4 (710.3-952.2) mg/kg bw
Deaths occured within the first 6 hours (following the treatment/exposure). No deaths were observed in the 14-day period (observations) following the treatment.
Cause of death: respiratory arrest.
Clinical signs:
Following the treatment, animals showed:
- reduced movement
- ataxia
- clonic-tonic muscle spasm
- dyspnea

Animals surviving for 24 hours following the treatment showed signs of recovery and showed no clinical signs in the observational period.
Body weight:
The body weight value of animals measured on Days 7 and 14 did not differ from that of the control group's.
This was true for both male and female test animals and for every dose group.
Gross pathology:
No signs of macroscopic changes were found in post-mortem examinations.
This was true for both the animals that have died as a result of the treatment and the surviving animals euthanized after the observational period.

Any other information on results incl. tables

Mortality

 dose

(mg/kg bodyweight)

 mortality of males

(number of dead animals/number of animals in the treatment group)

 mortality of females  

(number of dead animals/number of animals in the treatment group)

 control  0/6  0/6
 500  no data  0/6
 600  0/6  1/6
 720 2/6  2/6
 860 4/6   3/6
 1040  5/5  5/5
 1250  6/6  no data

Clinical signs of toxicity observed in the 6-hour period following the administration

 Dose (mg/kg bw)

male rats (number of animals in which the clinical sign was detected/number of animals in the dose group)            

female rats  (number of animals in which the clinical sign was detected/number of animals in the dose group)  
   1  2  3  4  5  6  1  2  3  4  5  6
 control 6/6 0/6 0/6 0/6  0/6 0/6  6/6 0/6 0/6 0/6  0/6 0/6
 500  -  -  -  -  -  - 0/6 6/6 0/6 0/6 0/6 0/6 
 600 0/6 6/6 6/6 1/6 0/6 0/6 0/6 6/6 0/6 1/6 1/6 0/6
 720 0/6  6/6  6/6 2/6 2/6 0/6 0/6 6/6 0/6 0/6 2/6 3/6
 860 0/6  6/6  6/6  6/6  2/6  0/6  0/6 6/6  0/6  1/6  3/6  2/6 
 1040 0/6  6/6  6/6  6/6  0/6  4/6  0/6 5/6  0/6  3/6  3/6  2/6 
 1250 0/6 6/6  6/6  4/6  0/6  6/6   -  -  -  -  -  -

meaning of clinical signs:

1: test animal shows no signs of toxicity

2: reduced movement

3: ataxia

4: clonic muscle spasm

5: clonic-tonic muscle spasm

6: dyspnea

Body weight measurements - male rats

 Dose group    Body weight prior to treatment (g)  Body weight on Day 7 (g)  Body weight on Day 14 (g)
 control  number of data points  6  6  6
   mean  145.2  199.5  222.8
   standard deviation  12.5  29.9  28.1
 600 mg/kg bw number of data points  6  6
   mean  143.8  206.2  234.5
   standard deviation  10.7  13.3  31.9
720 mg/kg bw   number of data points  6  4  4
   mean  143.5  189.5  218.5
   standard deviation  13.9  14.4  22.5
 860 mg/kg bw  number of data points  6  2  2
   mean  146.5  228.5  273.0
   standard deviation  18.9  17.7  32.5
 1040 mg/kg bw  number of data points  6  1
   mean  144.3 162.0   250.0
   standard deviation  16.8

 no calculation

(number of data points lower than 3)

 no calculation

(number of data points lower than 3)

 1250 mg/kg bw  number of data points  6  -  -
   mean  145.2  -  -
   standard deviation  12.7  -  -

Body weight measurements - female rats

Dose group

 Body weight prior to treatment (g)  Body weight on Day 7 (g)  Body weight on Day 14 (g)
 control  number of data points  6  6  6
   mean  141.3  162.5  179.0
   standard deviation  10.1  11.2 12.6
500 mg/kg bw   number of data points  6  6  6
   mean  143.3  160.8  177.2
   standard deviation  11.4  11.1  12.8
 600 mg/kg bw  number of data points  6  5  5
   mean  140.2  159.4  176.6
   standard deviation  9.0  7.4  10.8
 720 mg/kg bw  number of data points  6  4  4
   mean  142.2 161.0   174.0
   standard deviation  10.0  10.8  13.8
 860 mg/kg bw  number of data points  6  3  3
   mean  140.7  143.0  166.3
   standard deviation  8.8  29.8  22.1
 1040 mg/kg bw  number of data points  6  1  1
   mean  141.2  144.0  151.0
   standard deviation  9.4

no calculation

(number of data points lower than 3)

no calculation

(number of data points lower than 3)

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The substance is harmful if swallowed (Acute Toxicity, Category 4) according to classification criteria laid down in Regulation EC No 1272/2008.