Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Start: September 9, 1980. Ended: October 14, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not applicable
Principles of method if other than guideline:
The LC50 of rats exposed to TK-12824 was determined in an acute toxicity inhalation study. Animals were exposed (nose only) for four hours to 1.2, 3.0 and 6.0 mL/hr. A control goup was also provided. Animals were observed for 14 days for any adverse effects, at the end of which animals were sacrificed and underwent necropsy. An LC50 value was calculated based on the observed mortality of the treated animals.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: TK-12824
- Physical state: liquid, dark brown
- Analytical purity: 84 % dibutyltin bis(2-ethylhexylthioglycollate)
- Impurities: 16 % monobutyltin tris(2-ethylhexylthioglycollate)
- Trade name: IRGASTAB 17M
- Batch number: 543

Test animals

Species:
rat
Strain:
other: Tif:RAIF
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Bred in house
- Weight at study initiation: Please refer to table 3 under Any other information on results incl. tables
- Housing: Males and females were segregated and kept in Marcolon cages, type 4 (10 animals to a cage).
- Diet : ad libitum, MAFAG, Gossau SG, Switzerland
- Water : ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 55 + 10 %
- Photoperiod (hrs dark / hrs light): 10 hour light cycle day

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Remarks:
filtered
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation cylinder (with a THERM 2104 contact thermometer, a VERSELA Humidity Indicator HM 11 and a DRAEGER E 15 stationary control system to determine oxygen content)
- Method of holding animals in test chamber: Animals were kept in seperate PVC tubes positioned radially around the exposure chamber such that snouts and nostrils of the animals only were exposed to the aerosols.
- System of generating particulates/aerosols: The aerosol was generated by injecting the liquid test material at a rate of 1.2, 3.0 and 6.0 mL/hr into an air stream which was discharged into the exposure chamber through a spray nozzle under a pressure of 2 atm. at a rate of 10 L/min.
- Temperature, humidity, pressure in air chamber: Please refer to table 1 under section Any other information on material and methods incl. tables.

TEST ATMOSPHERE
- Brief description of analytical method used: The concentration and the particle size distribution of the aerosol in the vicinity of the animals were monitored at regular intervals throughout the aerosol exposure. The concentrations was determined 5 times gravimetrically by sampling the test atmosphere through a selection filter of 50 mm diameter and with a pore size of 0.2 µm at an air flow at an air flow rate of 10 L/min. The size distribution of the particles was measured twice with a four stage cascade Impactor with selectron filters of 25 mm and with a pore size of 0.2 µm at an air flow rate of 17.5 L/min.
- Samples taken from breathing zone: No, measured within the vicinity of the animals.

VEHICLE
A vehicle control was employed for comparison
- Composition of vehicle (if applicable): 50% acetone-ethanol (W/W) diluted 1:1 in distilled water.

TEST ATMOSPHERE
Please refer to table 1 under Any other information on results incl. tables
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
247 ± 9, 561 ± 19 and 1068 ± 46 mg/m^3
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Bodyweights measured on days 1, 7 and 14. After exposure, animals were observed for clinical signs during the 14 day observation period.
- Necropsy of survivors performed: yes
Statistics:
LC50 including 5 % confidence limits were calcualted by the logit model

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
941 mg/m³ air
Based on:
test mat.
95% CL:
750 - 1 283
Exp. duration:
4 h
Mortality:
No deaths occurred in the control, vehicle control of the 247 mg/m^3 exposure group. One male died on Day 10 of the observation period after exposure to 1060 mg/m^3, whereas, 7 females were found dead between 6 hours and 7 days after exposure to the same concentration.
Clinical signs:
The surviving animals recovered within 9 to 13 days after the exposure period. Exposure to 247 mg/m^3 elicited slight to moderate sedation and dysponea as well as slight ruffled fur and curved body position. The same symptoms were noted after exposure to 561 mg/m^3 except ruffled fur graded as slight to moderate was noted and slight ventral body position. Identical signs were observed with rats exposed to 1068 mg/m^3 as ascribed to the rats exposed to 561 mg/m^3. All rats were submitted to a necropsy whenever they died, survivors at the end of the observation period.
Body weight:
Because of the initial body weight differences, it was not possible to make a meaningful statistical comparison between control and exposure groups in regard to body weight difference. Body weight gains were not within normal limits for control rats only exposed to air. Body weight gains for animals exposed to 247 mg/m^3 were comparable to the acetone-ethanol control group. However, Day 1 to 7, body weight gains were significantly depressed for rats of both sexes for rats of both sexes exposed to 561 mg/m^3 compared to vehicle control animals (P < 0.05). Although body weight gains for male rats exposed to 561 mg/m^3 exposure groups was not equal to the acetone-ethanol exposed rats. Significant mortality in the 1068 mg/m^3 test group prevented meaningful comparisons.
Gross pathology:
No gross pathology was noted in the control or acetone-ethanol control groups at necropsy. Although no gross lesions were noted in males exposed to 247 mg/m^3, 3 females exhibited a reddish colouration of the lungs. Areas of discolouration of the lungs were noted in one male exposed to 561 mg/m^3 of the test material. No changes were noted in the lungs of females exposed to this concentration however, a lump was observed in the liver of 1 female as well as areas of discolouration in the liver of another.
Areas of discolouration of the lungs were noted in 3 males and 3 females exposed to 1068 mg/m^3.
In addition, several changes in the liver were noted, described as multiple lumps (1 male and 1 female) and a small mass with areas of dicolouration (1 male) in the liver of this exposure group. One female was also noted to have areas of discolouration of the bladder as well as 2 females exhibiting enlargement of the adrenal glands. All rats of this group exhibited loss of hair around the muzzle.
Other findings:
No further details reported

Any other information on results incl. tables

Table 1: Mortality

Conc mg/m3

Sex

Total Number Animals in Group

Total Number Animals Dead

Death Ratio %

Time of Death After Exposure

Hours After Exposure

Days After Exposure

1

2

4

6

24

2

3

4

5

6

7

8

9

10

11

12

13

14

Control

Male

10

0

0

Vehicle control

10

0

0

247.9

10

0

0

561.19

10

1

10

1

1068

10

6

60

4

1

1

Control

Female

10

0

0

Vehicle control

10

0

0

247.9

10

0

0

561.19

10

0

0

1068

10

7

70

2

2

1

2

 

Table 2: Bodyweight change

Concentration (mg/m3)

Control

Acetone-ethanol control

247 ± 9

561 ± 19

1068 ± 46

Day 1 (male)

Mean Bodyweight/SD (g)

274/14

208/14

195/5

214/6

266/14

Day 1 (female)

220/13

191/6

183/6

185/4

208/13

Day 7 (male)

271/14

250/18

230/10

216/ 251

219/29

Day 7 (female)

220/17

203/11

191/9

164/ 201

153/16

Day 14 (male)

315/19

298/25

282/13

265/ 241

258/44

Day 14 (female)

239/16

220/11

212/11

191/ 141

189/21

1 Body weight gain signifcantly different from the vehicle control group at P>0.05 for the 1-7 and 1-14 day intervals for rats of both sexes and for the 7-14 day interval for the females

 

Applicant's summary and conclusion

Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LC50 of a 4 hour aerosol exposure for rats of both sexes is 941 (758-1283) mg/m^3 air, when evaluated for a 14 day post-treatment observation period.
Executive summary:

Male and female rats, Tif:RAIF strain, were exposed to TK-12824 for 4 hours as an aerosol, nose only inhalation. Animals were observed for the following 14 days for mortality, clinical signs and changes in bodyweight. The LC50 of a 4 hour aerosol exposure for rats of both sexes is 941 (758-1283) mg/m3 air, when evaluated for a 14 day post-treatment observation period.