1-bromobutane

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19 March to 10 April 1997 and 14 May to 6 June 1997.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

not specified

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

not specified

GLP compliance:

yes

Test type:

traditional method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-bromobutane

EC Number:

203-691-9

EC Name:

1-bromobutane

Cas Number:

109-65-9

Molecular formula:

C4H9Br

IUPAC Name:

1-bromobutane

Test material form:

liquid

Details on test material:

Identity: n-butyl bromide
Batch no.: 5-254-1
Appearance: Colourless liquid
Storage: Room temperature and in the dark
Purity: >99.6%
Amount received: 1 litre
Expiry: January 1998

Specific details on test material used for the study:

No further details specified on the study report.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Fifteen male and 15 female albino rats (Sprague-Dawley) were selected from two consignments of rats obtained from Charles River UK Ltd, Manston Road, Margate, Kent, England on 19 March 1997 (10 male and 10 female) and 14 May (5 male, 5 female). The rats were selected so that males and females would be between 8 weeks and 9 weeks old on the day of exposure. The weight ranges were 182 - 213 g for males and 170 - 187 g for females when placed on the study.
On arrival the rats were allocated to 1 of 3 groups, each of 5 males and 5 females and were identified individually by a number tattooed on the ears. The rats were housed by sex in groups of 5 and acclimatised to laboratory conditions for at least 5 days before the day of exposure.
The holding cages (size 35 cm x 53 cm x 25 cm height) were made of stainless steel sheet and wire mesh and were suspended on a movable rack. While in their cages all rats had free access to a measured excess amount of food (SDS RMI) and tap water. Food and water supplies were analysed routinely to determine the levels of chemical or microbiological contaminants. Room lighting was by artificial light between 8 am and 8 pm daily.
The rats remained in a holding room except for the 4-hour exposure period and an overnight post exposure period when the rats in the test groups were kept in a ventilated cabinet to allow dispersal of any residual test substance.
The temperature and relative humidity of the holding room air was monitored continuously using a Kent Clearspan thermohygrograph. The temperature of the holding area during the study generally remained within the range of 21 °C± 2°C and the relative humidity was normally within the range 55% ± 10%. On one occasion and for a period of less than I hour the temperature and relative humidity of the room air fell to 16.5°C and 37% repectively. The extremes of temperature and relative humidity were considered unlikely to have influenced the results of the study.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

clean air

Remark on MMAD/GSD:

Not specified

Details on inhalation exposure:

Atmosphere generator
The atmosphere generator, was designed to produce and maintain an atmosphere containing vapour by evaporation of the test substance from a fritted glass disc with a counter current of air. All parts of the generator in contact with the test substance were made of glass. The test substance was delivered to the generator at a constant flow rate from a syringe driven by a syringe pump and the air supplied to the generator was dried, filtered and oil free.

Exposure chambers
The snout-only exposure chambers were of cylindrical form (30 cm id, 45 cm height) and made of aluminium alloy. The chambers had an enclosed volume of approximately 30 litres. The rats were held for exposure in moulded polycarbonate tubes which were attached at evenly spaced ports in the cylindrical section of the chamber. The tubes were tapered at one end to allow the snout only to project into the chamber. The other end was closed by insertion of an expanded plastic bung. A push rod passed through the centre of the bung and was adjusted to maintain the position of a rat during exposure. The tubes were attached to the chamber at parts in the mid-section of the chamber.
The test atmosphere entered the chamber through a port at the top centre of the chamber and was extracted at the base centre below the level of the rats. Each chamber was installed in a large fume cupboard exhausting through an absolute filter.

PROCEDURE
A supply of clean dried air was connected to the vapour generator and the supply pressure was adjusted to give a flow rate of 10 litres per minute measured at the generator outlet tube. An in-line flow meter was used to monitor air flow throughout the exposure.
A syringe filled with the test substance was fitted to the syringe pump and connected to the generator with PTFE tubing. A flow rate of 0.18 ml/minute (Group 2) or 0.22 ml/minute (Group 3) was selected for the exposure. These flow rates were expected to give a vapour concentration of approximately 20 mg/l and in excess of 20 mg/l respectively.
The rats to be exposed were placed into restraining tubes. The tubes were attached to the ports in the mid section of the chamber.
The syringe pump and air supply were switched on and the exposure timed for 4 hours, following a
7-minute equilibration period.
After 4 hours, the supply of test substance was discontinued and the exposure chamber was allowed to clear before the rats were removed for examination.
Following exposure, the rats were returned to the holding cages and food and water supplies were restored. The test rats were kept in a ventilated cabinet overnight and then returned to the holding room for the remainder of the observation period.
The control group was treated similarly but exposed to clean dried air only.
The control rats were returned to the holding room at the end of the exposure procedure.

CHAMBER AIR TEMPERATURE
The air temperature in the exposure chamber was measured with a thermometer and recorded at the start of exposure and then at 30-minute intervals during the 4-hour exposure.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

18.0 mg/l or 25.4 mg/l of air.

No. of animals per sex per dose:

One control group and 2 test groups each of 5 male and 5 female rats.

Control animals:

yes

Details on study design:

OBSERVATIONS
Clinical signs
The rats were observed continuously for signs of reaction to the test substance during exposure and at least twice daily throughout the observation period. The clinical signs were recorded at the end of the chamber equilibration period, at 0.25, 0.5 and 1.0 hours and then at hourly intervals during the exposure. During the observation period, the clinical signs were recorded once in the morning and then as necessary following a later check for clinical signs.
Bodyweight
All rats were weighed daily from the day of delivery to the Huntingdon Life Sciences up to and including the day of exposure. During the observation period rats were weighed on Days 7 and 14.
Food and water consumption
The amount of food and water consumed by each cage of rats was measured daily from the day of arrival. The daily mean intakes of food and water for each rat were calculated from the recorded data.
TERMINAL STUDIES
At the end of the 14-day observation period, the rats were killed by intraperitoneal injection of pentobarbitone sodium and exsanguinated when clinically dead.
All rats were subjected to a detailed macroscopic examination. The lungs were infused with, and preserved in, buffered 10% formalin together with samples of the liver and kidneys and retained until the study completion date.

Statistics:

Not specified

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LCLo

Effect level:

> 25.4 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

There were no deaths following exposure to the vapour of n-butyl bromide at a concentration of 18.0 mg/l or 25.4 mg/l of air.

Clinical signs:

other: During the exposure During exposure, signs seen in rats exposed to n-butyl bromide at 18.0 mg/l or 25.4 mg/l were exaggerated respiratory movements and shallow breathing. In addition, irregular respiration was seen in rats exposed at 25.4 mg/l. During th

Body weight:

The rate of bodyweight gain for the test rats was similar to that of the control rats.

Gross pathology:

Minimal congestion of all lobes of the lung and a small dark focus on the left lung were seen in 1 male test rat at 18.0 mg/l. There were no other macroscopic abnormalities in any rat.

Other findings:

Food consumption
Food consumption for test rats was slightly reduced on the day following exposure ton-butyl bromide. Otherwise food consumption for test rats was similar to that of the controls.

Water consumption
Water consumption in test rats (except for females at 25.4 mg/l) was slightly reduced on the day following exposure to n-butyl bromide. Otherwise water consumption for test rats was similar to that of the control rats.

Any other information on results incl. tables

Concentration of n-butyl bromide

Chemical analysis

Group	Sample	Time taken (h:min)	Amount in air (mg/l)	Nominal concentration^1 (mg/l)
2	1 2 3 4 5	0:30 1:00 2:00 3:00 3:50	15.3 17.2 17.5 19.8 20.3
		Mean sd	18.0 2.04	24.3

¹Calculated from the weight of test substance dispersed and the total volume of air supplied to the exposure system

sd Standard deviation

 

Chemical analysis

Group	Sample	Time taken (h:min)	Amount in air (mg/l)	Nominal concentration^1 (mg/l)
3	1 2 3 4 5	0:30 1:00 2:00 3:00 3:50	25.0 27.3 25.0 25.2 24.7
		Mean sd	25.4 1.05	26.1

¹Calculated from the weight of test substance dispersed and the total volume of air supplied to the exposure system

sd Standard deviation

 

Clinical signs during exposure

Group	Signs	Number showing signs
		Time in hours
		0*	0.25	0.5	1.0	2.0	3.0	4.0
1M (Control)	Normal appearance and behaviour Fur soiled with excreta	5	5	5	5	5	5	5
1F (Control)	Normal appearance and behaviour Fur soiled with excreta	5	5	5	5	5	5	5
2M (18.0 mg/l)	Normal appearance and behaviour Fur soiled with excreta Shallow respiration Exaggerated respiratory movements	5	5	4     1	5 4 1	5 4 1	5 4 1	5   5
2F (18.0 mg/l)	Normal appearance and behaviour Fur soiled with excreta Shallow respiration Exaggerated respiratory movements	5	5	5	5 4 1	5 4 1	5 4 1	5   5
3M (25.4 mg/l)	Normal appearance and behaviour Fur soiled with excreta Irregular respiration Exaggerated respiratory movements Shallow respiration	5	3     2	4 1	2 3	5	5   5	5   5
3F (25.4 mg/l)	Normal appearance and behaviour Fur soiled with excreta Irregular respiration Exaggerated respiratory movements Shallow respiration	5	5	5	5	5	5   5	5   5

*Clinical signs recorded during the 7-minute equilibration period

 

Clinical signs during observation period

Group	Signs	Number showing sign
		Day of observation period
		0hr*	1hr*	2hr*	1	2	3	4	5	6	7	8	9	10	11	12	13	14
1M (Control)	Normal appearance and behaviour Fur soiled with excreta	5	5	5	5	5	5	5	5	5	5	5	5	5	5	5	5	5
1F (Control)	Normal appearance and behaviour Fur soiled with excreta	5	5	5	5	5	5	5	5	5	5	5	5	5	5	5	5	5
2M (18.0 mg/l)	Normal appearance and behaviour Fur soiled with excreta Staggering Wet fur around the snout and/or jaws Peripheral vasodilation Exaggerate respiratory movements Matted fur Brown staining around snout and/or jaws	5 5 5 5 4	5   4 3 5	1 1 1 1 1 5 1	3         1   2	5	5	5	5	5	5	5	5	5	5	5	5	5
2F (18.0 mg/l)	Normal appearance and behaviour Fur soiled with excreta Staggering Wet fur around the snout and jaws Peripheral vasodilation Exaggerated respiratory movements Clear secretion from the eyes Matted fur Staining around the uro-genital region Brown staining on the head	5 5 5 5 5 2	5   5 4 5	4     1     1	1       5 3	4                 1	4                 1	5	5	5	5	5	5	5	5	5	5	5
3M (25.4 mg/l)	Normal appearance and behaviour Fur soiled with excreta Whole body tremors Staggering Wet fur around the snout and/or jaws Peripheral vasodilation Clear discharge from the eyes	5 1 5 5 5 2	5   1 5	5   1 5	5	5	5	5	5	5	5	5	5	5	5	5	5	5
3F (25.4 mg/l)	Normal appearance and behaviour Fur soiled with excreta Staggering Wet fur around the snout and/or jaws Peripheral vasodilation Clear discharge from the eyes Red discharge from the eyes Lethargy Whole body tremors	5 5 4 5 4 1 1 2	5 1 5       1 1	5 1 5       1 1	5	5	5	5	5	5	5	5	5	5	5	5	5	5

*Clinical signs recorded after exposure on the day of exposure

 

Individual and group mean bodyweights (g)

Group	Rat	Day of observation
		-5	-4	-3	-2	-1	0	7	14
1M (Control)	21 22 23 24 25	234 232 228 230 227	248 253 242 240 240	260 263 251 255 250	273 278 258 262 259	280 287 264 275 266	287 297 269 280 274	354 368 310 334 321	407 419 337 378 356
	Mean	230	245	356	266	274	281	337	379
1F (Control)	26 27 28 29 30	190 197 197 192 203	198 191 195 203 198	199 210 201 208 203	202 211 208 216 208	199 208 213 219 212	208 201 203 221 209	228 225 224 243 230	239 244 235 265 244
	Mean	196	197	204	209	210	209	230	245
2M (18.0 mg/l)	31 32 33 34 35	242 240 231 221 242	261 254 242 234 256	273 268 256 248 266	278 282 269 259 278	290 293 276 271 285	298 300 285 272 294	335 259 327 314 335	379 419 376 343 382
	Mean	235	249	262	273	283	290	334	380
2F (18.0 mg/l)	36 37 38 39 40	205 192 205 189 193	212 187 196 201 198	217 201 209 205 202	223 204 209 208 209	219 204 217 206 210	223 198 209 216 205	233 217 230 231 224	251 223 243 243 243
	Mean	197	199	207	211	211	210	227	241
3M (25.4 mg/l)	1 2 3 4 5	227 252 229 231 250	239 262 239 247 262	243 268 246 254 268	251 274 254 265 276	262 283 263 274 283	269 288 271 282 292	210 322 309 332 320	364 364 349 389 359
	Mean	238	250	256	264	273	280	319	365
3F (25.4 mg/l)	6 7 8 9 10	211 199 208 196 208	217 204 220 203 213	218 209 228 203 213	220 206 232 200 209	225 216 239 211 222	223 217 240 214 222	244 233 244 223 242	257 248 254 234 251
	Mean	204	211	214	213	223	223	237	249

0 = Day of exposure

 

Group mean daily food consumption (g/rat)

Group	Days
	Pre-exposure					Post-exposure
	-5	-4	-3	-2	-1	1	2	3	4	5	6	7	8	9	10	11	12	13	14
1M (Control)	35	35	34	34	34	29	35	35	32	36	34	35	37	36	35	35	35	34	32
2M (18.0 mg/l)	35	37	36	35	36	22	32	34	35	35	35	36	37	36	37	36	37	36	37
3M (25.4 mg/l)	33	33	34	34	34	16	31	33	33	33	33	33	33	33	35	33	36	34	33
1F (Control)	21	24	22	22	22	22	28	24	21	25	24	23	25	24	26	24	22	24	22
2F (18.0 mg/l)	23	26	26	23	24	13	23	24	24	27	29	25	23	24	27	26	22	24	25
3F (25.4 mg/l)	25	25	22	26	25	15	23	24	25	23	23	25	24	21	24	26	25	23	22

 

Group mean daily water consumption (g/rat)

Group	Days
	Pre-exposure					Post-exposure
	-5	-4	-3	-2	-1	1	2	3	4	5	6	7	8	9	10	11	12	13	14
1M (Control)	36	34	35	35	35	34	36	35	33	36	33	34	36	33	36	37	35	34	33
2M (18.0 mg/l)	26	35	36	34	35	23	36	34	28	33	33	33	33	34	32	34	35	36	37
3M (25.4 mg/l)	34	33	34	35	34	21	34	35	33	34	36	34	33	34	35	32	35	33	32
1F (Control)	21	27	24	23	22	25	27	24	21	28	25	24	24	26	28	28	23	28	26
2F (18.0 mg/l)	32	30	28	25	32	17	26	31	23	32	32	33	33	33	34	37	28	34	34
3F (25.4 mg/l)	30	30	26	32	29	26	28	37	35	31	29	33	31	29	31	32	31	27	28

 

Macroscopic pathology

Group	Rat	Region/organ affected	Observation
1M (Control)	21 22 23 24 25		No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
1F (Control)	26 27 28 29 30		No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
2M (18.0 mg/l)	31 32 33 34 35	Lungs	No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Minimal congestion all lobes Small dark subpleural foci left lung
2F (18.0 mg/l)	36 37 38 39 40		No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
3M (25.4 mg/l)	1 2 3 4 5		No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
3F (25.4 mg/l)	6 7 8 9 10		No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected

 

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The LCLO (4 hour) for n-butyl bromide is in excess of 25.4 mg/l in air.

Executive summary:

Test substance

A colourless liquid identified as n-butyl bromide (Batch No. 5-254-1).

 

Test animals

Albino rats, (Sprague-Dawley). One control group and 2 test groups each of 5 male and 5 female rats.

 

Route of administration

By inhalation of a test atmosphere containing a vapour generated from the test substance.

 

Duration of exposure

4 hours continuous snout only exposure.

 

Observation period

14 days post exposure.

 

Results

Exposure levels and mortality

           Group Level                        Mortality

                       (mg/l)             M        F         Total

           1         control           0/5      0/5      0/10

           2         18.0 mg/l        0/5      0/5      0/10

           3         25.4 mg/l        0/5      0/5      0/10

 

Clinical signs

Clinical signs seen in rats during exposure to n-butyl bromide were exaggerated respiratory movements and shallow breathing. Irregular respiration was also noted in rats exposed at 25.4 mg/l.

 

Signs seen in the test rats during a 2 hour post-exposure observation period were staggering, wet fur around the snout and jaws and peripheral vasodilatation. Exaggerated respiratory movements and matted fur were seen in rats exposed at 18.0 mg/1. Lacrimation was observed in 2 female rats. A clear (lacrimation) or red secretion from the eyes was observed in the rats exposed at 25.4 mg/l. On Day 1 of observation, staining around the urogenital region and brown staining on the head were also noted in female rats exposed at 18.0 mg/l.

 

Additional signs noted in rats exposed at 25.4 mg/l were whole body tremors and lethargy.

 

Male and female test rats exposed at 18.0 mg/l were normal in appearance and behaviour by Days 2 and 4 of the observation period respectively. Males and females exposed at 25.4 mg/l were normal in appearance and behaviour by Days 1 and 2 of the observation period respectively.

 

Fur soiled with excreta was evident in all test and control rats during and immediately following exposure. The sign was attributed to the method of restraint.

 

Bodyweight

The rate of bodyweight gain for the test rats was similar to that of the control rats.

 

Food and water consumption

Food consumption for test rats was slightly reduced on the day following exposure to n-butyl bromide. Otherwise food consumption for test rats was similar to that of the controls.

Water consumption in test rats (except for females exposed at 25.4 mg/l) was slightly reduced on the day following exposure ton-butyl bromide. Otherwise water consumption for test rats was similar to that of the control rats.

 

Macroscopic pathology

Minimal congestion of all lobes of the lung and a small dark focus on the left lung were seen in 1 male test rat at 18.0 mg/l. There were no other macroscopic abnormalities in any rat.

 

CONCLUSION

The LC_LO(4 hour) for n-butyl bromide as a vapour is in excess of 25.4 mg/l in air.