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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
This endpoint study record is the experimental source record for the registered target substance.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
This endpoint study record is the experimental source record for the registered target substance.
Reason / purpose:
reference to same study
Related information:
Composition 1
Reason / purpose:
reference to same study
Related information:
Composition 1
Reference:
Composition 0
Principles of method if other than guideline:
chronic feeding study in dogs
GLP compliance:
no
Remarks:
Study pre-dates GLP requirements
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
The sample of 1,3-butanediol used in this study was supplied by the Celanese Corporation of America, New York, New York
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
Purebred beagles 6-16 months of age were inoculated against distemper, hepatitis, and rabies and acclimated to the laboratory for 4-6 weeks prior to initiation of the study. The dogs received a basal diet of laboratory meal (Wayne Dog Food, Allied Mills, Inc.,) supplemented with horse meat.
Route of administration:
oral: feed
Details on route of administration:
Appropriate amounts of 1,3-butanediol were mixed with basal laboratory diet of Wayne Dog Food supplemented with horse meat
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Dose / conc.:
0 other: % dry-weight bases
Dose / conc.:
0.5 other: % dry-weight bases
Dose / conc.:
1 other: % dry-weight bases
Dose / conc.:
3 other: % dry-weight bases
No. of animals per sex per dose:
4 male and 4 female dogs per dose
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Data on body weight were recorded regularly, values reported for initial, 4 weeks, 20 weeks, and 104 weeks.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule for examinations: Data on food and compound consumption were recorded regularly (no data reported)

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 8 intervals during the two-year feeding period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: each animals in each group
- Parameters checked: erythrocyte count, total and differential leukocyte counts, blood urea nitrogen, bromosulphalein retention, and hemoglobin, hematocrit, and determination of sedimentation rate

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: 8 intervals during the two-year feeding period
- Metabolism cages used for collection of urine: Not reported
- How many animals: each animals in each group
- Animals fasted: No data
- Parameters checked: appearance, pH, specific gravity, sugar, acetone, protein, bilirubin, urobilinogen, occult blood, microscopic examination of the sediment

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
After 52 weeks,10 animals from each group were sacrificed and autopsies performed. After 104 weeks, all surviving test and control rats were sacrificed and autopsied.
Organs: brain, pituitary, thyroid, lung, heart, lymph node, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intestine, gall bladder, urinary bladder, gonads, bone, and bone marrow.

HISTOPATHOLOGY: Histopathological evaluation was performed on brain, pituitary, thyroid, lung, heart, lymph node, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intestine, gall bladder, urinary bladder, gonads, bone, and bone marrow
Other examinations:
ORGAN WEIGHT: liver, kidneys, testes, thyroids and adrenals were weighed
Statistics:
Survival was analysed by the life table technique. The other criteria examined were subjected to an analysis of variance or F-test at the 5% probability level.
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Some focal chronic nephritis characterized by radial scarring, mild lymphocytic and plasmocytic infiltration, cast formation, and tubular atrophy as well as mild to moderate glomerulitis were seen in control and test animals.
Details on results:
Chronic admiinstration of 0, 0.5, 1.0 or 3.0% 1,3-butylene glycol in the diet (0, 125, 250 or 750 mg/kg/d ) did not induce adverse effects in dogs.
Key result
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: calculated (3% in diet, food factor of 0.025)
Key result
Critical effects observed:
no
Conclusions:
On the basis of this study, 1,3-butanediol is considered to be without deleterious effect at the highest levels fed to experimental animals for 2 years, namely, 3% (750 mg/kg/d) in the diet of dogs.
Executive summary:

Dogs received 1,3-butylene glycol in the diet at levels of 0.5%, 1.0%, and 3.0%, for two years (125, 250 and 750 mg/kg/d). The control group was fed the basal laboratory diet supplemented with horse meat. The physical appearance and behavior of the test dogs generally was comparable with those of the corresponding controls. Organ weights and ratios were within comparable with the controls. None of the test dogs showed any sign of compound related effect.

Reason / purpose:
reference to same study
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
This endpoint study record is the experimental source record for the registered target substance.
Reason / purpose:
reference to same study
Related information:
Composition 1
Reason / purpose:
reference to same study
Related information:
Composition 1
Reference:
Composition 0
Principles of method if other than guideline:
2-year feeding study in rodents
GLP compliance:
no
Remarks:
Study pre-dates GLP requirements
Test material information:
Composition 1
Specific details on test material used for the study:
The sample of 1,3-butanediol used in this study was supplied by the Celanese Corporation of America, New York, New York
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Weanling rats of the Sprague-Dawley strain were individually housed in metal cages and provided with free access to the diet and drinking water.
The control group of 60 male and 60 female rats received a basal diet of laboratory chow.
Test group of 30 male and 30 female rats each received a diet containing 1.0, 3.0, or 10% of 1,3-butanediol by weight.
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Appropriate amounts of 1,3-butanediol were mixed with basal laboratory diet of Purina Rat Chow
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Dose / conc.:
0 other: % basis in diet
Dose / conc.:
1 other: % basis in diet
Dose / conc.:
3 other: % basis in diet
Dose / conc.:
10 other: % basis in diet
No. of animals per sex per dose:
The control group of 60 male and 60 female
Test group of 30 male and 30 female rats per dose
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Data on body weight were recorded regularly, values reported for initial, 4 weeks, 20 weeks, 52 weeks, and 104 weeks.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule for examinations: Data on food and compound consumption were recorded regularly (no data reported)

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6 intervals during the two-year feeding period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: not specified; reported as representative animals in each group
- Parameters checked: erythrocyte count, total and differential leukocyte counts, and hemoglobin, hematocrit

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: 6 intervals during the two-year feeding period
- Metabolism cages used for collection of urine: Not reported
- How many animals: pooled samples from rats of each group
- Animals fasted: No data
- Parameters checked: appearance, pH, specific gravity, sugar, acetone, protein, bilirubin, urobilinogen, occult blood, microscopic examination of the sediment

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
After 52 weeks, 10 animals from each group were sacrificed and autopsies performed. After 104 weeks, all surviving test and control rats were sacrificed and autopsied.
Organs: brain, pituitary, thyroid, lung, heart, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intestines, urinary bladder, gonads, bone and bone marrow

HISTOPATHOLOGY: Histopathological evaluation was performed on brain, pituitary, thyroid, lung, heart, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intestines, urinary bladder, gonads, bone and bone marrow.
Other examinations:
ORGAN WEIGHT: liver, kidneys, testes, thyroids and adrenals were weighed
Statistics:
Survival was analysed by the life table technique. The other criteria examined were subjected to an analysis of variance or F-test at the 5% probability level.
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Experimental findings, not attributable to long-term ingestion of butanediol, included chronic inflammatory disease of the lungs, spleen, and kidneys of rats, and spontaneous subcutaneous neoplasms distributed among the control (16) and test (11) rats. These findings are common among laboratory animals of this age and strain.
Details on results:
Chronic administration of 0, 1.0, 3.0 or 10.0% 1,3-butylene glycol in the diet (0, 500, 1500 or 5000 mg/kg/d ) did not induce adverse effects in rats.

BODY WEIGHT AND WEIGHT GAIN
During the first year of the study, growth rate for the males and females in the 1.0% dose group (500 mg/kg/d) and the 3.0% dose group (1500 mg/kg/d) was not significantly different from that of the corresponding control groups. In the 10% dose group (5000 mg/kg/d), the growth rate was significantly higher than that for the male controls. While this trend was also present in the females of 10% dose group , the higher growth rate was not significant. (see table below).

ORGAN WEIGHTS
Organ weights and weight ratios showed a wide variation within normal limits. Statistical analysis revealed no significant difference between the control data and the high-level test data.
Relevance of carcinogenic effects / potential:
The study was judged to be relevant for the evaluation of carcinogenicity of 1,3-butylene glycol after chronic oral application. There was no treatment related increase in tumor incidence or any other adverse effect as compared to control. One shortcoming of this study is the selection of dose: the highest concentration tested did not reveal any adverse effect. Therefore, it cannot be excluded, that adverse (including carcinogenic) effects might occur at higher dose levels.
Key result
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: calculated (10% in diet, food factor 0.05; see: Guidance on Information requirements R.8)

Mean Survival Time and Body Weight of Rats receiving Various Dietary Concentrations of 1,3-Butanediol

Criterion

Controls

Dietary concentration of 1,3-butanediol

1.0%

3.0%

10%

Male

Female

Male

Female

Male

Female

Male

Female

Mean body weight (g)

Initial

90

81

89

80

91

80

88

80

4 weeks

270

192

266

190

269

192

255

159

20 weeks

511

299

515

293

500

298

524

306

52 weeks

565

347

560

320

511

347

578

370

Survival (a)

Initial

60/60

60/60

30/30

30/30

30/30

30/30

30/30

30/30

4 weeks

60/60

60/60

30/30

30/30

30/30

30/30

30/30

30/30

20 weeks

59/60

60/60

30/30

30/30

30/30

30/30

29/30

30/30

52 weeks

46/60

54/60

27/30

26/30

26/30

27/30

24/30

29/30

104 weeks

12/55

14/55

2/25

3/25

2/25

8/25

8/25

4/25

Mean survival time

(days) (b)

521

521

511

521

513

553

553

587

(a) Survival is expressed as the ratio of the number of animals alive at the indicated time from beginning of the study, divided by the number with which the study commenced. The denominator at 104 weeks is adjusted to reflect the sacrifice of 5 animals at one year.

(b) Adjusted to compensate for interval sacrifice at one year.

Conclusions:
On the basis of this study, 1,3-butanediol is considered to be without deleterious effect (carcinogenic and non-carcinogenic) at the highest levels fed to experimental animals for 2 years, namely, 10% (5000 mg/kg/d) in the diet of rats.
Executive summary:

Rats received 1,3-butylene glycol in the diet at levels of 1.0, 3.0, and 10%, for two years (500, 1500 and 5000 mg/kg/d). The control group was fed the basal laboratory diet. The physical appearance and behavior of the test rats generally was comparable with those of the corresponding controls. Organ weights and ratios were within normal limits and comparable with the controls. None of the test rats showed any sign of compound related effect (carcinogenic and non-carcinogenic).

Data source

Reference
Reference Type:
publication
Title:
Chronic oral toxicity of 1,3-butanediol
Author:
Scala RA, Paynter OE
Year:
1967
Bibliographic source:
Scala RA, Paynter OE (1967). Chronic oral toxicity of 1,3-butanediol. Toxicol Appl Pharmacol 10(1):160-164.

Materials and methods

Principles of method if other than guideline:
chronic feeding study in rodents
GLP compliance:
no
Remarks:
Study pre-dates GLP requirements
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
no impurities described
Specific details on test material used for the study:
The sample of 1,3-butanediol used in this study was supplied by the Celanese Corporation of America, New York, New York

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Weanling rats of the Sprague-Dawley strain were individually housed in metal cages and provided with free access to the diet and drinking water.
The control group of 60 male and 60 female rats received a basal diet of laboratory chow.
Test group of 30 male and 30 female rats each received a diet containing 1.0, 3.0, or 10% of 1,3-butanediol by weight.

Administration / exposure

Route of administration:
oral: feed
Details on route of administration:
Appropriate amounts of 1,3-butanediol were mixed with basal laboratory diet of Purina Rat Chow
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 other: % basis in diet
Dose / conc.:
1 other: % basis in diet
Dose / conc.:
3 other: % basis in diet
Dose / conc.:
10 other: % basis in diet
No. of animals per sex per dose:
The control group of 60 male and 60 female
Test group of 30 male and 30 female rats per dose
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Data on body weight were recorded regularly, values reported for initial, 4 weeks, 20 weeks, 52 weeks, and 104 weeks.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule for examinations: Data on food and compound consumption were recorded regularly (no data reported)

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6 intervals during the two-year feeding period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: not specified; reported as representative animals in each group
- Parameters checked: erythrocyte count, total and differential leukocyte counts, and hemoglobin, hematocrit

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: 6 intervals during the two-year feeding period
- Metabolism cages used for collection of urine: Not reported
- How many animals: pooled samples from each group
- Animals fasted: No data
- Parameters checked: appearance, pH, specific gravity, sugar, acetone, protein, bilirubin, urobilinogen, occult blood, microscopic examination of the sediment

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
After 52 weeks, 10 animals from each group were sacrificed and autopsies performed. After 104 weeks, all surviving test and control rats were sacrificed and autopsied.
Organs: brain, pituitary, thyroid, lung, heart, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intestines, urinary bladder, gonads, bone and bone marrow

HISTOPATHOLOGY: Histopathological evaluation was performed on brain, pituitary, thyroid, lung, heart, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intestines, urinary bladder, gonads, bone and bone marrow.
Other examinations:
ORGAN WEIGHT: liver, kidneys, testes, thyroids and adrenals were weighed
Statistics:
Survival was analysed by the life table technique. The other criteria examined were subjected to an analysis of variance or F-test at the 5% probability level.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Experimental findings, not attributable to long-term ingestion of butanediol, included chronic inflammatory disease of the lungs, spleen, and kidneys of rats, and spontaneous subcutaneous neoplasms distributed among the control (16) and test (11) rats. These findings are common among laboratroy animals of this age and strain.
Details on results:
Chronic administration of 0, 1.0, 3.0 or 10.0% 1,3-butylene glycol in the diet (0, 500, 1500 or 5000 mg/kg/d) did not induce adverse effects in rats.

BODY WEIGHT AND WEIGHT GAIN
During the first year of the study, growth rate for the males and females in the 1.0% dose group (500 mg/kg/d) and the 3.0% dose group (1500 mg/kg/d) was not significantly different from that of the corresponding control groups. In the 10% dose group (5000 mg/kg/d), the growth rate was significantly higher than that for the male controls. While this trend was also present in the females of 10% dose group, the higher growth rate was not significant. (See table below).

ORGAN WEIGHTS
Organ weights and weight ratios showed a wide variation within normal limits. Statistical analysis revealed no significant difference between the control data and the high-level test data.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: calculated (10% in diet, food factor 0.05; see ECHA Guidance on Information requirements R.8)

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Mean Survival Time and Body Weight of Rats receiving Various Dietary Concentrations of 1,3-Butanediol

Criterion

Controls

Dietary concentration of 1,3-butanediol

1.0%

3.0%

10%

Male

Female

Male

Female

Male

Female

Male

Female

Mean body weight (g)

Initial

90

81

89

80

91

80

88

80

4 weeks

270

192

266

190

269

192

255

159

20 weeks

511

299

515

293

500

298

524

306

52 weeks

565

347

560

320

511

347

578

370

Survival (a)

Initial

60/60

60/60

30/30

30/30

30/30

30/30

30/30

30/30

4 weeks

60/60

60/60

30/30

30/30

30/30

30/30

30/30

30/30

20 weeks

59/60

60/60

30/30

30/30

30/30

30/30

29/30

30/30

52 weeks

46/60

54/60

27/30

26/30

26/30

27/30

24/30

29/30

104 weeks

12/55

14/55

2/25

3/25

2/25

8/25

8/25

4/25

Mean survival time

(days) (b)

521

521

511

521

513

553

553

587

(a) Survival is expressed as the ratio of the number of animals alive at the indicated time from beginning of the study, divided by the number with which the study commenced. The denominator at 104 weeks is adjusted to reflect the sacrifice of 5 animals at one year.

(b) Adjusted to compensate for interval sacrifice at one year.

Applicant's summary and conclusion

Conclusions:
On the basis of this study, 1,3-butanediol is considered to be without deleterious effect at the highest levels fed to experimental animals for 2 years, namely, 10% (5000 mg/kg/d) in the diet of rats.
Executive summary:

Rats received 1,3-butylene glycol in the diet at levels of 1.0, 3.0, and 10%, for two years (500, 1500 and 5000 mg/kg/d). The control group was fed the basal laboratory diet. The physical appearance and behavior of the test rats generally was comparable with those of the corresponding controls. Organ weights and ratios were comparable with the controls. None of the test rats showed any sign of compound related effect.