1-bromobutane

Endpoint summary

Description of key information

Read across to 1-bromopropane. Whole-body inhalation exposure of Sprague-Dawley CD rats to a vapour of 1-bromopropane for 6 hours each day, 5 days each week, for a 13-week period, at chamber concentrations of 0.5 to 3.0 mg/L produced no clinical observations which were considered to be related to treatment. Four mortalities occurred during bleeding procedures or anaesthesia but were not considered to be related to treatment. There were no obvious effects on body weight, food consumption, urinalysis, ophthalmology, functional observational battery or motor activity that could be attributed to treatment with 1-bromopropane. No treatment-related trends were evident in hematology, blood biochemistry analysis or gross pathology. There was a marginal increase in relative liver weights in Group 5 (3.0 mg/L- high dose) males. This effect was considered of questionable toxicological significance as intergroup differences were minimal and the effect was not observed in the Group 5 (3.0 mg/L-high dose) females. However, histopathological lesions were present in the liver (vacuolation of centrolobular hepatocytes) when exposed at concentrations of 2.0 mg/L (intermediate/high dose) and 3.0 mg/L (high dose). The No Effect Level was therefore identified as 1.0 mg/L.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10th July 1996 - 29th October 1996

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.

Qualifier:

no guideline available

Principles of method if other than guideline:

The study was a 90 day repeat dose inhalation study where animals were given full body exposure 5 days a week, for 6 hours.
Flow rate through the chamber was calculated to yield a t95 (the time required to build up 95% of the target concentration) of approximately 15 and/or 25 minutes. The t95 was calculated to be 15 minutes if based on a 400 L chamber size, and 25 minutes for a 650 L chamber size. From July 29 to September 25, 1996, inclusively a t95 of 15 minutes was used and commencing September 26, 1996 until study termination a t95 of 25 minutes was used. Although the incorrect t95 was used from July 29 to September 25, 1996, inclusively, this deviation was considered not to have influenced the outcome of the study. This was also demonstrated in the consistency obtained in the chamber concentrations.

At the onset of treatment, the animals were approximately 7 to 7½ weeks old with body weight ranges of 225-297 g and 167-209 g for males and females, respectively. Although the age differed from the one stated in the protocol (approximately 6 weeks) and the body weight ranges were outside those stated in the protocol for males (175-225 g) and females (125-175 g), these deviations were considered not to have impacted upon the outcome of the study.

Four days after arrival, all remaining animals (after health screen selection) were weighed and assigned to the study groups using a computer-based randomization procedure which ensured homogeneity of group means and variances for body weight. Although the time of randomization differed from the one stated in the protocol (approximately 1 week before treatment initiation), this deviation was considered not to have impacted upon the outcome of the study.

This level represented a minimum of 7.4 air changes an hour. Although the air changes differed from the one stated in the protocol (approximately 12 air changes an hour), this deviation was considered not to have influenced the outcome of the study since oxygen levels measured were considered to be adequate.

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Canada Inc., St. Constant, Québec
- Age at study initiation: 7 to 7.5 weeks old
- Weight at study initiation: 225-297 g and 167-209 g for males and females, respectively
- Fasting period before study: NDA
- Housing: Stainless steel wire mesh-bottomed cages
- Diet (e.g. ad libitum): rats had free access to pelleted commercial diet.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 18 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 50 ± 20 %
- Air changes (per hr): minimum of 7.4
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 11th July 1996 To: 29th October 1996

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: NDA

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Thirty-three inch cubed (650-L volume) stainless-steel and glass whole-body inhalation chambers.
- Method of holding animals in test chamber: The rats were housed in a stainless-steel wire mesh-compartmentalised cage with each compartment being approximately 7 inches x 3 inches x 4 inches.
- Source and rate of air: NDA
- Method of conditioning air: The test atmospheres were generated by a heated flow-through vapor generator consisting of a peristaltic pump, a glass column/J.-tube partially filled with glass beads; a heating tape and compressed air.
- System of generating particulates/aerosols: NDA
- Temperature, humidity and oxygen saturation in air chamber: 20 - 24 ºC, 30 - 70 % relative humidity and at least 19 % oxygen saturation.
- Air flow rate: 80 L/min
- Air change rate: 7.4 per hour.
- Method of particle size determination: N/A
- Treatment of exhaust air: A vacuum pump was used to exhaust the inhalation chamber at the required flow rate and draw the contaminated air through a purifying system consisting of a 5 µm coarse filter and an absolute filter (99.97% efficient at 0.3 µm) before expelling the air from the building.
- Air pressure: To prevent outward leakage of the test atmospheres, the chambers were operated under slight negative pressure maintained by means of a gate valve located in the exhaust line.

TEST ATMOSPHERE
- Brief description of analytical method used: Chamber airflow was continuously monitored in the exhaust line by means of a precalibrated magnehelic gauge. Chamber vapour concentration was controlled by adjusting the rate of test article and airflow into the generator.
- Samples taken from breathing zone: NDA

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical verification was perfomed by GC. Nominal concentrations of 0.45 and 3.38 mg/L. The mean measured concentrations for these were determined as 0.436 mg/L and 3.604 mg/L respectively, corresponding to respective recoveries of 96.9% and 106.6%. This shows how the nominal concentrations are a good representation of the actual concentrations.

Duration of treatment / exposure:

For each test group, time zero was defined as that point in time at which approximately 95% of the desired concentration of test article had been established within the chamber.

Flow rate through the chamber was calculated to yield a t95 (the time required to build up 95% of the target concentration) of approximately 15 and/or 25 minutes.

The t95 was calculated to be 15 minutes if based on a 400 L chamber size, and 25 minutes for a 650 L chamber size.

During daily exposure, aerosol was actively generated for 360 minutes (for the duration of the t95 and a subsequest 335 and 345 minutes at a t95 of 25 and 15 minutes, respectively. Following 360 minutes of continuous operation, aerosol generation was stopped and the chamber concentration allowed to decay for the calculated t05 (approximately 15 and/or 25 minutes). The rats were then removed from the exposure chamber and returned to their home cages.

The air control group (Group 1) was restrained and handled in the same manner as the test article groups and was exposed to the conditioned room air for the same duration as the high dose test group (Group 5).

Frequency of treatment:

5 days per week.

Remarks:

Doses / Concentrations:
Control (group 1), 0.5 mg/L (group 2), 1.0 mg/L (group 3), 2.0 mg/L (group 4), 3.0 mg/L (group 5).
Basis:
nominal conc.

No. of animals per sex per dose:

15 per sex per dose

Control animals:

yes

Details on study design:

- Dose selection rationale: Based on results of previous 10 and 28 day studies on the test compound.
- Rationale for animal assignment (if not random): Four days after arrival, all remaining animals (after health screen selection) were weighed and assigned to the study groups using a computer-based randomization procedure which ensured homogeneity of group means and variances for body weight. Males and females were processed separately. Rats in poor health or at the extremes of the body weight range were not assigned to treatment groups.

Positive control:

No positive control substance.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were examined twice daily for mortality and signs of ill health or reaction to treatment during the pretreatment and treatment periods. On August 4, 1996 the animals were only examined once for signs of ill health. Each animal was also examined for signs of reaction to treatment before, during and after the exposure session.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A complete detailed examination was performed once pretreatment, and weekly during the treatment phase. Observed clinical signs and mortality were individually recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were measured weekly commencing the day of randomization and extending through the treatment period. In addition body weights were also measured prior to functional observational battery.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal: Yes

WATER CONSUMPTION: No
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Once prior to the start of treatment and again during Weeks 6 and 13 of treatment (before dosing).
- Dose groups that were examined: All dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to commencement of treatment, investigations were performed on the 10 male and 10 female health screen animals. Hematology was were performed on all animals at Week 6 and study termination.
- Anaesthetic used for blood collection: Yes (identity) isoflurane.
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: (using EDTA or Citrate* as anticoagulant)

activated partial thromboplastin time*
blood cell morphology
erythrocyte indices (MCV, MCH, MCHC and RDW) hematocrit
hemoglobin
mean platelet volume
platelet count
prothrombin time*
red blood cell count
reticulocyte count
white blood cell count (total, absolute and percent differential)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to commencement of treatment, investigations were performed on the 10 male and 10 female health screen animals. Clinical biochemistry was performed on all animals at Week 6 and study termination.
- Animals fasted: Yes
- How many animals: all
- Parameters checked:

AIG ratio (calculated)
alanine aminotransferase
albumin
alkaline phosphatase
aspartate aminotransferase
blood urea nitrogen
calcium
chloride
cholesterol
creatinine
globulin (calculated) glucose
inorganic phosphorus potassium
sodium
total bilirubin
total protein
triglycerides


URINALYSIS: Yes
- Time schedule for collection of urine: Prior to commencement of treatment, investigations were performed on the 10 male and 10 female health screen animals. Urine analysis was performed on all animals at Week 6 and study termination.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked:

bilirubin
blood
color and appearance
glucose
ketones
microscopy of centrifuged deposit
nitrite
pH
protein
specific gravity
urobilinogen
volume

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: All animals were tested prior to commencement of the treatment, and (for the first 10 animals/group only) once during each of Weeks 4, 8 and 13 (on the days without dosing).
- Dose groups that were examined: All dose groups.
- Battery of functions tested (qualitative):

Observations in Home Cage:
Body position
Tremors, twitches and convulsions
Bizarre-stereotypic behavior

Removal from Cage:
Ease of removal
Vocalization

Observations in Arena:
Rearing
Ataxic, hypotonic and impaired gait
Overall gait incapacity
Bizarre/Stereotypic behavior
Palpebral closure
Tremors, twitches and convulsions
Piloerection
Respiratory rate/pattern
Locomotor activity level
Arousal
Grooming
Defecation
Urination
Olfactory response

Handling Observations:
Lacrimation
Pupil size
Salivation
Urinary staining
Diarrhea
Body tone
Extensor thrust
Corneal reflex
Pinna reflex
Toe and tail pinch
Visual placing

On Surface:
Auricular startle
Air righting reflex

On Top of Box:
Positional passivity

- Battery of functions tested (quantitative):

Grip strength
Hindlimb splay
Body temperature


MOTOR ACTIVITY: YES

Following the FOB assessments the animals were transferred to a testing room where activity levels were measured individually in figure 8 enclosures. Animals were tested prior to commencement of treatment, and during Weeks 4, 8 and 13 (on the days without dosing). Animals from the control and treated groups were balanced across enclosures, where possible, using a preassigned distribution. The sessions were of 1-hour duration and activity counts were recorded by a microcomputer in 6 successive 10-minute intervals.

In the testing room, temperature and humidity were monitored and a background sound level of approximately 70 dBA and an illumination of approximately 900-1200 Lux maintained throughout testing. Light levels in the testing room were measured before the start of testing and following completion of testing on each day. The sound level were recorded on a continuous basis throughout testing on each day

In addition to the "diagnostic" function in the system, a check of each beam was made by manually "breaking" each beam a predetermined number of times and verifying that the "breaks" were properly recorded. These checks were made at least prior to the start of testing and at the completion of testing on each day.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

Prior to commencement of treatment, 10 male and 10 female health screen animals were euthanised by exsanguination from the abdominal aorta following anesthesia by intraperitoneal injection of sodium pentobarbital and blood sample collection from the abdominal aorta. These animals were subjected to external and internal gross examinations. Tissues were not retained.

All animals that died during orbital sinus bleeding procedure were subjected to necropsy and tissue samples were preserved. Prior to necropsy, the carcasses were stored at circa 4°C.

Those animals euthanised on completion of the treatment period, were euthanised by exsanguination following anesthesia by intraperitoneal injection of sodium pentobarbital and blood sample collection from the abdominal aorta. A similar proportion of animals from each group and sex, as appropriate, were euthanised on any one day. In order to avoid autolytic change, a complete gross pathology examination of the carcass was conducted immediately on all animals which were euthanised. All animals were fasted overnight before scheduled euthanasia. Terminal body weights were recorded at necropsy. All necropsies were conducted under the supervision of a pathologist and necropsy consisted of an external examination, including identification of all clinically recorded lesions, as well as a detailed internal examination.

ORGAN WEIGHT ASSESSMENT: Yes

For each animal euthanized during and at completion of treatment, the following organs were dissected free of fat and weighed:

adrenal glands
brain
heart
kidneys
liver
lungs
ovaries/testes
pituitary
prostate
spleen
thymus
thyroid lobes and parathyroid glands
uterus

Paired organs were weighed together. Organ weight ratios relative to body weights were calculated.

TISSUE PRESERVATION: Yes

On completion of the necropsy of each animal, the following tissues and organs were retained. Neutral buffered 10% formalin was used for fixation and preservation unless otherwise indicated.

abnormalities
animal identification ***
adrenals
aorta (thoracic)
bone and marrow (sternum)**
brain (cerebrum, cerebellum, midbrain and medulla oblongata)
bronchi
cecum
cervix
colon
duodenum
epididymides*
esophagus
eyes*
Harderian glands
heart (including section of aorta)
ileum
jejunum
kidneys
larynx
lacrimal glands
liver (sample of 2 lobes)
lungs (all lobes)++
lymph nodes (bronchial, mandibular and mesenteric)
mammary gland (inguinal)+++
nasal cavities and sinuses (3 levels)**++
optic nerves*+++
ovaries
pancreas
pharynx
pituitary
prostate
rectum***
salivary gland (submandibular)
sciatic nerve
seminal vesicles
skeletal muscle
skin (inguinal)
spinal cord (cervical)
spleen
stomach
testes*
thymus
thyroid lobes (and parathyroids)+++
tongue
trachea
urinary bladder
uterine horns
uterus
vagina

* Fixed in Zenker's fluid (euthanised animals only)
** Bone decalcified prior to sectioning.
++ Infused with neutral buffered 10% formalin. (Lungs and nasal cavities euthanised animals only)
*** Retained but not processed
+++ Examined histopathologically only if present in routine sections of eyes (optic nerves), thyroid lobes (parathyroid glands), or skin (mammary gland)

For all euthanised animals, 3 femoral bone marrow smears were prepared, one of which was stained with May-Grünwald-Giemsa but were not evaluated.

HISTOPATHOLOGY: Yes

Tissues were prepared for histopathological examination by embedding in paraffin wax, sectioning and staining with hematoxylin and eosin and examined as follows:

Groups 1 and 5: Tissues listed under Tissue Preservation.
Groups 2, 3 and 4: Respiratory tissues (lungs, larynx, pharynx, bronchi, trachea and nasal cavities and sinuses), liver and all gross lesions.

All tissues from Animal Nos. 1002, 3501 and 4504, which were found dead during orbital sinus bleeding procedure and Animal No. 5005, which was found dead during anaesthesia, were prepared and examined as Groups 1 and 5 above.

Statistics:

Numerical data obtained during the conduct of the study were subjected to calculation of group mean values and standard deviations. The data were analysed for homogeneity of variance using Bartlett's test. Homogeneous data were analysed using Analysis of Variance and the significance of differences between the control and treated groups were assessed using Dunnett's test. Heterogeneous data were analysed using Kruskal-Wallis test and the significance of differences between the control and treated groups were assessed using Dunn's test.

Motor activity counts were analysed using repeated measures analysis. Where appropriate, frequency data were analysed by comparing the control group to the treated groups using Fisher's exact probability test.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
There were no clinical signs that could be related to treatment with 1-bromopropane.

On Day 37, one animal died during the orbital sinus bleeding procedure and another died during anaesthesia.

On Day 39, 2 animals died during the orbital sinus bleeding procedure.

On Day 54, one animal was slightly dehydrated and abnormal breathing sounds were identified. Since this was only observed on one occasion and the animal did not have any other clinical signs that could be related to treatment, this was considered unrelated to treatment.

In Weeks 10 to 12 a mass was identified on the right side of the muzzle of a group 3 male, though in isolation, this was considered unrelated to treatment.

Other less significant clinical signs, that were considered to be incidental, included various localized skin conditions (staining, fur thin cover, scab and flaking).

BODY WEIGHT AND WEIGHT GAIN
The overall body weight gains of males exposed to 1-bromopropane at the high dose was marginally inferior to that of controls. The remaining male groups and treated females were unaffected in this respect. Although there was a slight decrease in body weights for some of the female animals in all groups on Day 57, this could not be attributed to treatment with 1-bromopropane and the slightly lower body weight values observed for all animals on Day 92, were considered to be due to food deprivation prior to necropsy.

Statistically significant differences were observed in body weight gains during pretreatment (Group 5 - males); during Week-3 (Groups 4 and 5 - males) and Week - 8 (Group 4 - males) compared with the control group. This difference was not considered significant as similar values are frequently observed in comparable populations.

FOOD CONSUMPTION
No effects on food consumption that could be confidently related to treatment were observed. Low, intermediate, intermediate/high and high dose males showed a food intake similar to the control group during the treatment period. However, there was a marginal increase in the food consumption for Group
4 and 5 females when compared to the control group.

Statistically significant differences were observed in food consumption during Weeks 3 and 4 (Group
5 - females) compared with the control group. This difference was not considered biologically significant as similar values are frequently observed in comparable populations.

OPHTHALMOSCOPIC EXAMINATION
No treatment-related ophthalmological findings were observed.

HAEMATOLOGY
There were no treatment-related changes evident at the hematological assessment.

The low white cell count and (absolute) lymphocytes evident in high dose females in Week 6 when compared with controls were statistically significantly different. At termination the white blood cell counts in high dose females were still low but were not statistically significantly different from controls and therefore considered of doubtful toxicological significance.

All other differences in hematology values, including any that achieved statistical significance, were incidental or represented expected variation in this age and strain of rat.

CLINICAL CHEMISTRY
There were no treatment-related changes evident at the clinical biochemical assessment.

However, on Week 6, decreased total bilirubin was observed for females and increased triglycerides were observed for some male and female animals in all groups.

At Week 6 (chlorine and total protein) and at termination (chlorine), values were statistically significantly different from controls, but these were considered not to be biologically significant.

All other differences in clinical biochemistry values listed in the tables, including any that achieved statistical significance, were incidental or represented expected biological variation in this age and strain of rat.

URINALYSIS
Urinalysis parameters were unaffected by treatment with 1-bromopropane.

NEUROBEHAVIOUR
No clear treatment-related findings were observed during functional observational battery on any occasion tested.

Occasional statistically significant differences between the control and treated groups were attributed to intergroup variation.

With respect to motor activity, no significant differences were detected between the control and treated groups during the study.

ORGAN WEIGHTS
It was considered that there were no effects on absolute or relative organ weights that could be confidently attributed to treatment. There was a marginal increase in relative liver weights in Group 5 males and statistically significant differences when compared with the control group. This effect was considered of questionable toxicological significance as intergroup differences were minimal and the effect was not observed in the Group 5 females.

The absolute adrenal weights of high dose males when compared with controls were statistically significantly different. This difference was not considered significant as similar values are frequently observed in comparable populations.

GROSS PATHOLOGY
Macroscopically, the most frequent finding was pale area in the liver and was considered to be a common incidental lesion. Other infrequent macroscopic findings appeared to be incidental or agonal.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological finding that was ascribed to exposure to 1-bromopropane was present in the liver (vacuolation of centrolobular hepatocytes) of 6 male animals from Group 5 (3.0 mg/L); 3 male and 1 female animals from Group 4 (2.0 mg/L).

Dose descriptor:

NOEL

Effect level:

1 mg/L air (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: histopathology

Critical effects observed:

not specified

Conclusions:

Whole-body inhalation exposure of Sprague-Dawley CD rats to a vapour of 1-bromopropane for 6 hours each day, 5 days each week, for a 13-week period, at chamber concentrations of 0.5 to 3.0 mg/L produced no clinical observations which were considered to be related to treatment. Four mortalities occurred during bleeding procedures or anaesthesia but were not considered to be related to treatment. There were no obvious effects on body weight, food consumption, urinalysis, ophthalmology, functional observational battery or motor activity that could be attributed to treatment with 1-bromopropane. No treatment-related trends were evident in hematology, blood biochemistry analysis or gross pathology. There was a marginal increase in relative liver weights in Group 5 (3.0 mg/L- high dose) males. This effect was considered of questionable toxicological significance as intergroup differences were minimal and the effect was not observed in the Group 5 (3.0 mg/L-high dose) females. However, histopathological lesions were present in the liver (vacuolation of centrolobular hepatocytes) when exposed at concentrations of 2.0 mg/L (intermediate/high dose) and 3.0 mg/L (high dose). The No Effect Level was therefore identified as 1.0 mg/L.

Executive summary:

Four groups of Sprague Dawley rats, each comprising 15 males and 15 females (weighing between 225-297 g and 167-209 g for males and females, respectively), were subjected to 6 hour "whole-body" exposures daily (5 days/week) of a vapour formulation of 1 -bromopropane for 13 weeks at target concentrations of 0.5 mg/L (Group 2), 1.0 mg/L (Group 3), 2.0 mg/L (Group 4) and 3.0 mg/L (Group 5). A similarly constituted control group (Group 1) was similarly restrained, but exposed to room air. The mean overall chamber concentration of 1 -bromopropane, determined by Miran infrared gas analyzer, was 0.5, 1.01, 2.01 and 3.0 mg/L for Groups 2, 3, 4 and 5, respectively. The mean overall analytical chamber concentration for the 4 treated groups was 0.51, 1.01, 2.00 and 2.98 mg/L for Groups 2, 3, 4 and 5, respectively. The mean concentrations obtained were within 2% of the targeted concentrations whether determined by either Miran gas analysis or by gas chromatography.

Whole-body inhalation exposure of Sprague-Dawley CD rats to a vapour of 1-bromopropane for 6 hours each day, 5 days each week, for a 13-week period, at chamber concentrations of 0.5 to 3.0 mg/L produced no clinical observations which were considered to be related to treatment. Four mortalities occurred during bleeding procedures or anaesthesia but were not considered to be related to treatment. There were no obvious effects on body weight, food consumption, urinalysis, ophthalmology, functional observational battery or motor activity that could be attributed to treatment with 1-bromopropane. No treatment-related trends were evident in hematology, blood biochemistry analysis or gross pathology. There was a marginal increase in relative liver weights in Group 5 (3.0 mg/L- high dose) males. This effect was considered of questionable toxicological significance as intergroup differences were minimal and the effect was not observed in the Group 5 (3.0 mg/L-high dose) females. However, histopathological lesions were present in the liver (vacuolation of centrolobular hepatocytes) when exposed at concentrations of 2.0 mg/L (intermediate/high dose) and 3.0 mg/L (high dose). The No Effect Level was therefore identified as 1.0 mg/L.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read across to structural analogue.

Justification for type of information:

Please see attached justification for read across in Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOEL

Effect level:

1 mg/L air (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: histopathology

Key result

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

1 000 mg/m³

Study duration:

subchronic

Species:

rat

Organ:

liver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Read across to 1-bromopropane. Whole-body inhalation exposure of Sprague-Dawley CD rats to a vapour of 1-bromopropane for 6 hours each day, 5 days each week, for a 13-week period, at chamber concentrations of 0.5 to 3.0 mg/L produced no clinical observations which were considered to be related to treatment. Four mortalities occurred during bleeding procedures or anaesthesia but were not considered to be related to treatment. There were no obvious effects on body weight, food consumption, urinalysis, ophthalmology, functional observational battery or motor activity that could be attributed to treatment with 1-bromopropane. No treatment-related trends were evident in hematology, blood biochemistry analysis or gross pathology. There was a marginal increase in relative liver weights in Group 5 (3.0 mg/L- high dose) males. This effect was considered of questionable toxicological significance as intergroup differences were minimal and the effect was not observed in the Group 5 (3.0 mg/L-high dose) females. However, histopathological lesions were present in the liver (vacuolation of centrolobular hepatocytes) when exposed at concentrations of 2.0 mg/L (intermediate/high dose) and 3.0 mg/L (high dose). The No Effect Level was therefore identified as 1.0 mg/L.

Justification for classification or non-classification

STOT-RE 2, H373 is applied on the basis that histopathological lesions in the liver (vacuolation of centrolobular hepatocytes) were observed in the mid- and high dose groups