1-bromobutane

Carcinogenicity

Description of key information

Carcinogenicity and chronic toxicity examined by inhalation exposure using groups of F344/DuCrlCrlj (Fischer) rats.

There was no evidence of carcinogenic activity of 1-bromobutane in male or female rats.

Carcinogenicity and chronic toxicity examined by inhalation exposure using groups of B6D2F1/Crlj mice.

There was clear evidence of carcinogenic activity of 1-bromobutane in male mice. There was no evidence of carcinogenic activity of 1-bromobutane in females.

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is in accordance with GLP and OECD test guidelines, however, the information is not a full study report and is available in the public domain

Remarks:

The available report is appended below for clarity.

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

not specified

GLP compliance:

yes

Specific details on test material used for the study:

No further details specified in the study report

Species:

rat

Strain:

other: F344

Details on species / strain selection:

Not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

No further details specified in the study report.

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Remarks on MMAD:

Not specified

Details on exposure:

Stainless-steel inhalation exposure chambers (volume: 8500 L) were used throughout the 2-year exposure period. 1-Bromobutane vapor-air mixtures were generated by bubbling clean air through 1-bromobutane liquid and the mixtures supplied to the inhalation exposure chambers.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The identity of the 1-Bromobutane used in these experiments was confirmed by both infrared spectrometry and mass spectrometry, and it was analyzed by gas chromatography before and after its use to affirm its stability.
Air concentrations of 1-bromobutane vapor in the inhalation exposure chambers were monitored at 15 min intervals by gas chromatography.

Duration of treatment / exposure:

2 years

Frequency of treatment:

6 hours/day, 5 days/week

Post exposure period:

Not specified

Dose / conc.:

0 ppm (nominal)

Dose / conc.:

125 ppm (nominal)

Dose / conc.:

250 ppm (nominal)

Dose / conc.:

500 ppm (nominal)

No. of animals per sex per dose:

Each group of test animals consisted of either 50 male or 50 female rats.
Both sexes were exposed to each concentration of 1-bromobutane vapor.

Control animals:

yes, concurrent vehicle

Details on study design:

The highest dose level was chosen so as not to exceed the maximum tolerated dose (MTD), based on both growth rate and toxicity in the previous 13-week toxicity study.

Positive control:

Not required

Observations and examinations performed and frequency:

The animals were observed daily for clinical signs and mortality. Body weight and food consumption were measured once a week for the first 14 weeks and every 4 weeks thereafter.
Urinalysis was performed near the end of the exposure period. For hematology and blood biochemistry at the terminal necropsy, surviving animals were fasted overnight and bled under deep ether anesthesia.

Sacrifice and pathology:

All animals, including those found dead or in a moribund state as well as those surviving to the end of the 2-year exposure period, underwent complete necropsy.
Organs and tissues were removed, weighed and examined for macroscopic lesions at necropsy. The organs and tissues were then fixed and embedded in paraffin. Five μm thick tissue sections were prepared and stained with hematoxylin and eosin and examined microscopically.

Statistics:

Incidences of neoplastic lesions were statistically analyzed by Fisher’s exact test. Any positive dose-response trends of 1-Bromobutane induction of neoplastic lesions were analyzed by Peto’s test. Incidences of non-neoplastic lesions and urinalysis were analyzed by the Chi-square test. Changes in body weight, food consumption, hematological and blood biochemical parameters, and organ weights were analyzed by Dunnett’s test.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The body weights of the highest exposure groups, 500 ppm-exposed males and females, were slightly decreased: terminal body weights of the 500 ppm-exposed males and females were suppressed to 83% and 90% of their respective controls.

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:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not specified

Description (incidence and severity):

An increase in the incidence of eosinophilic change in the respiratory epithelium in males exposed to 500 ppm 1-bromobutane and an increase in the severity of eosinophilic change in the olfactory epithelium of males exposed to 250 ppm and 500 ppm 1-bromobutane.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not specified

Details on results:

The body weights of the highest exposure groups, 500 ppm-exposed males and females, were slightly decreased: terminal body weights of the 500 ppm-exposed males and females were suppressed to 83% and 90% of their respective controls. No other significant differences in survival rate or clinical symptoms were found between the 1-bromobutane-exposed groups of either sex and their controls.
No significant increase in the incidence of neoplastic lesions was found in any of the 1-bromobutane-exposed groups of either sex compared with their controls. There was, however, an increase in the incidence of eosinophilic change in the respiratory epithelium in males exposed to 500 ppm 1-bromobutane and an increase in the severity of eosinophilic change in the olfactory epithelium of males exposed to 250 ppm and 500 ppm 1-bromobutane.

Relevance of carcinogenic effects / potential:

There was no evidence of carcinogenic activity of 1-bromobutane in male or female rats.

Key result

Dose descriptor:

dose level:

Effect level:

500 ppm (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No significant effects noted in the parameters examined

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

500 ppm

Conclusions:

There was no evidence of carcinogenic activity of 1-bromobutane in male or female rats.

Executive summary:

The carcinogenicity and chronic toxicity of 1-bromobutane (greater than 99.7% pure) were examined by inhalation exposure using groups of F344/DuCrlCrlj (Fischer) rats.

 

The studies were conducted in accordance with the Organisation for Economic Co-operation and Development (OECD) Good Laboratory Practice and with reference to the OECD Guideline for Testing of Chemicals 451 “Carcinogenicity Studies”.

 

Each group of test animals consisted of either 50 male or 50 female rats. Test animals were exposed to 1-bromobutane vapor at target concentrations of 0 (clean air), 125, 250 or 500 ppm (v/v) for 6 hours/day, 5 days/week for 2 years (104 weeks). Both sexes were exposed to each concentration of 1-bromobutane vapor.

 

Stainless-steel inhalation exposure chambers (volume: 8500 L) were used throughout the 2-year exposure period. 1-Bromobutane vapor-air mixtures were generated by bubbling clean air through 1-bromobutane liquid and the mixtures supplied to the inhalation exposure chambers. Air concentrations of 1-bromobutane vapor in the inhalation exposure chambers were monitored at 15 min intervals by gas chromatography.

The animals were observed daily for clinical signs and mortality. Body weight and food consumption were measured once a week for the first 14 weeks and every 4 weeks thereafter.

All animals, including those found dead or in a moribund state as well as those surviving to the end of the 2-year exposure period, underwent complete necropsy. Urinalysis was performed near the end of the exposure period. For hematology and blood biochemistry at the terminal necropsy, surviving animals were fasted overnight and bled under deep ether anesthesia. Organs and tissues were removed, weighed and examined for macroscopic lesions at necropsy. The organs and tissues were then fixed and embedded in paraffin. Five μm thick tissue sections were prepared and stained with hematoxylin and eosin and examined microscopically.

 

Results

The body weights of the highest exposure groups, 500 ppm-exposed males and females, were slightly decreased: terminal body weights of the 500 ppm-exposed males and females were suppressed to 83% and 90% of their respective controls. No other significant differences in survival rate or clinical symptoms were found between the 1-bromobutane-exposed groups of either sex and their controls.

No significant increase in the incidence of neoplastic lesions was found in any of the 1-bromobutane-exposed groups of either sex compared with their controls. There was, however, an increase in the incidence of eosinophilic change in the respiratory epithelium in males exposed to 500 ppm 1-bromobutane and an increase in the severity of eosinophilic change in the olfactory epithelium of males exposed to 250 ppm and 500 ppm 1-bromobutane.

 

Conclusions

There was no evidence of carcinogenic activity of 1-bromobutane in male or female rats.

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is in accordance with GLP and OECD test guidelines, however, the information is not a full study report and is available in the public domain

Remarks:

The available report is appended below for clarity.

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

not specified

GLP compliance:

yes

Specific details on test material used for the study:

No further details specified in the study report

Species:

mouse

Strain:

other: B6D2F1/Crlj

Details on species / strain selection:

Not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

No further details specified in the study report.

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Remarks on MMAD:

Not specified

Details on exposure:

Stainless-steel inhalation exposure chambers (volume: 3900 L) were used throughout the 2-year exposure period. 1-Bromobutane vapor-air mixtures were generated by bubbling clean air through 1-bromobutane liquid and the mixtures supplied to the inhalation exposure chambers.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The identity of the 1-Bromobutane used in these experiments was confirmed by both infrared spectrometry and mass spectrometry, and it was analyzed by gas chromatography before and after its use to affirm its stability.
Air concentrations of 1-bromobutane vapor in the inhalation exposure chambers were monitored at 15 min intervals by gas chromatography.

Duration of treatment / exposure:

2 years

Frequency of treatment:

6 hours/day, 5 days/week

Post exposure period:

Not specified

Dose / conc.:

0 ppm (nominal)

Dose / conc.:

20 ppm (nominal)

Dose / conc.:

50 ppm (nominal)

Dose / conc.:

125 ppm (nominal)

No. of animals per sex per dose:

Each group of test animals consisted of either 50 male or 50 female mice.
Both sexes were exposed to each concentration of 1-bromobutane vapor.

Control animals:

yes, concurrent vehicle

Details on study design:

The highest dose level was chosen so as not to exceed the maximum tolerated dose (MTD), based on both growth rate and toxicity in the previous 13-week toxicity study.

Positive control:

Not required

Observations and examinations performed and frequency:

The animals were observed daily for clinical signs and mortality. Body weight and food consumption were measured once a week for the first 14 weeks and every 4 weeks thereafter.
Urinalysis was performed near the end of the exposure period. For hematology and blood biochemistry at the terminal necropsy, surviving animals were fasted overnight and bled under deep ether anesthesia.

Sacrifice and pathology:

All animals, including those found dead or in a moribund state as well as those surviving to the end of the 2-year exposure period, underwent complete necropsy.
Organs and tissues were removed, weighed and examined for macroscopic lesions at necropsy. The organs and tissues were then fixed and embedded in paraffin. Five μm thick tissue sections were prepared and stained with hematoxylin and eosin and examined microscopically.

Statistics:

Incidences of neoplastic lesions were statistically analyzed by Fisher’s exact test. Any positive dose-response trends of 1-Bromobutane induction of neoplastic lesions were analyzed by Peto’s test. Incidences of non-neoplastic lesions and urinalysis were analyzed by the Chi-square test. Changes in body weight, food consumption, hematological and blood biochemical parameters, and organ weights were analyzed by Dunnett’s test.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

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:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The incidence of bronchiolar-alveolar carcinomas in the lung was increased in males exposed to 50 ppm and 125 ppm 1-bromobutane. No significant increases in the incidence of neoplastic lesions was found in any of the 1-bromobutane-exposed female groups. There was, however, an increase in the incidence of eosinophilic change in the olfactory epithelium of females exposed to 125 ppm 1-bromobutane.

Other effects:

not specified

Relevance of carcinogenic effects / potential:

There was clear evidence of carcinogenic activity of 1-bromobutane in male mice. There was no evidence of carcinogenic activity of 1-bromobutane in females.

Key result

Dose descriptor:

dose level:

Effect level:

50 ppm (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

50 ppm

System:

respiratory system: lower respiratory tract

Organ:

alveoli

bronchi

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

There was clear evidence of carcinogenic activity of 1-bromobutane in male mice. There was no evidence of carcinogenic activity of 1-bromobutane in females.

Executive summary:

The carcinogenicity and chronic toxicity of 1-bromobutane (greater than 99.7% pure) were examined by inhalation exposure using groups of B6D2F1/Crlj mice.

 

The studies were conducted in accordance with the Organisation for Economic Co-operation and Development (OECD) Good Laboratory Practice and with reference to the OECD Guideline for Testing of Chemicals 451 “Carcinogenicity Studies”.

 

Each group of test animals consisted of either 50 male or 50 female mice. Test animals were exposed to 1-bromobutane vapor at a target concentration of 0 (clean air), 20, 50 or 125 ppm (v/v) for 6 hours/day, 5 days/week for 2 years (104 weeks). Both sexes were exposed to each concentration of 1-bromobutane vapor.

Stainless-steel inhalation exposure chambers (volume: 3900 L) were used throughout the 2-year exposure period. 1-Bromobutane vapor-air mixtures were generated by bubbling clean air through 1-bromobutane liquid and the mixtures supplied to the inhalation exposure chambers. Air concentrations of 1-bromobutane vapor in the inhalation exposure chambers were monitored at 15 min intervals by gas chromatography.

The animals were observed daily for clinical signs and mortality. Body weight and food consumption were measured once a week for the first 14 weeks and every 4 weeks thereafter.

All animals, including those found dead or in a moribund state as well as those surviving to the end of the 2-year exposure period, underwent complete necropsy. Urinalysis was performed near the end of the exposure period. For hematology and blood biochemistry at the terminal necropsy, surviving animals were fasted overnight and bled under deep ether anesthesia. Organs and tissues were removed, weighed and examined for macroscopic lesions at necropsy. The organs and tissues were then fixed and embedded in paraffin. Five μm thick tissue sections were prepared and stained with hematoxylin and eosin and examined microscopically.

 

Results

No significant difference in survival rate, clinical symptoms, body weight or food consumption was found between any 1-bromobutane-exposed group of either sex and their respective controls.

The incidence of bronchiolar-alveolar carcinomas in the lung was increased in males exposed to 50 ppm and 125 ppm 1-bromobutane. No significant increases in the incidence of neoplastic lesions was found in any of the 1-bromobutane-exposed female groups. There was, however, an increase in the incidence of eosinophilic change in the olfactory epithelium of females exposed to 125 ppm 1-bromobutane.

 

Conclusions

There was clear evidence of carcinogenic activity of 1-bromobutane in male mice. There was no evidence of carcinogenic activity of 1-bromobutane in females.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

50 mg/m³

Study duration:

chronic

Species:

mouse

Quality of whole database:

K2

System:

respiratory system: upper respiratory tract

Organ:

lungs

Additional information

Carcinogenicity and chronic toxicity of 1-bromobutane examined by inhalation exposure using groups of F344/DuCrlCrlj (Fischer) rats.

Each group of test animals consisted of either 50 male or 50 female rats. Test animals were exposed to 1-bromobutane vapor at target concentrations of 0 (clean air), 125, 250 or 500 ppm (v/v) for 6 hours/day, 5 days/week for 2 years (104 weeks). Both sexes were exposed to each concentration of 1-bromobutane vapor.

Stainless-steel inhalation exposure chambers (volume: 8500 L) were used throughout the 2-year exposure period. .

The animals were observed daily for clinical signs and mortality. Body weight and food consumption were measured once a week for the first 14 weeks and every 4 weeks thereafter.

All animals, including those found dead or in a moribund state as well as those surviving to the end of the 2-year exposure period, underwent complete necropsy. Urinalysis was performed near the end of the exposure period. For hematology and blood biochemistry at the terminal necropsy, surviving animals were fasted overnight and bled under deep ether anesthesia. Organs and tissues were removed, weighed and examined for macroscopic lesions at necropsy.

 

Results

The body weights of the highest exposure groups, 500 ppm-exposed males and females, were slightly decreased: terminal body weights of the 500 ppm-exposed males and females were suppressed to 83% and 90% of their respective controls. No other significant differences in survival rate or clinical symptoms were found between the 1-bromobutane-exposed groups of either sex and their controls.

No significant increase in the incidence of neoplastic lesions was found in any of the 1-bromobutane-exposed groups of either sex compared with their controls. There was, however, an increase in the incidence of eosinophilic change in the respiratory epithelium in males exposed to 500 ppm 1-bromobutane and an increase in the severity of eosinophilic change in the olfactory epithelium of males exposed to 250 ppm and 500 ppm 1-bromobutane.

 

Conclusions

There was no evidence of carcinogenic activity of 1-bromobutane in male or female rats.

Carcinogenicity and chronic toxicity of 1-bromobutane examined by inhalation exposure using groups of B6D2F1/Crlj mice.

Each group of test animals consisted of either 50 male or 50 female mice. Test animals were exposed to 1-bromobutane vapor at a target concentration of 0 (clean air), 20, 50 or 125 ppm (v/v) for 6 hours/day, 5 days/week for 2 years (104 weeks). Both sexes were exposed to each concentration of 1-bromobutane vapor.

Stainless-steel inhalation exposure chambers (volume: 3900 L) were used throughout the 2-year exposure period.

The animals were observed daily for clinical signs and mortality. Body weight and food consumption were measured once a week for the first 14 weeks and every 4 weeks thereafter.

All animals, including those found dead or in a moribund state as well as those surviving to the end of the 2-year exposure period, underwent complete necropsy. Urinalysis was performed near the end of the exposure period. For hematology and blood biochemistry at the terminal necropsy, surviving animals were fasted overnight and bled under deep ether anesthesia. Organs and tissues were removed, weighed and examined for macroscopic lesions at necropsy.

 

Results

No significant difference in survival rate, clinical symptoms, body weight or food consumption was found between any 1-bromobutane-exposed group of either sex and their respective controls.

The incidence of bronchiolar-alveolar carcinomas in the lung was increased in males exposed to 50 ppm and 125 ppm 1-bromobutane. No significant increases in the incidence of neoplastic lesions was found in any of the 1-bromobutane-exposed female groups. There was, however, an increase in the incidence of eosinophilic change in the olfactory epithelium of females exposed to 125 ppm 1-bromobutane.

 

Conclusions

There was clear evidence of carcinogenic activity of 1-bromobutane in male mice. There was no evidence of carcinogenic activity of 1-bromobutane in females.