(R)-(-)-butane-1,3-diol

Repeated dose toxicity: oral

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-reference

Cross-reference 1

Reason / purpose for cross-reference:

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 for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

chronic feeding study in dogs

GLP compliance:

no

Remarks:

Study pre-dates GLP requirements

Limit test:

no

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 or test system 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.

Cross-reference 2

Reason / purpose for cross-reference:

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 for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

2-year feeding study in rodents

GLP compliance:

no

Remarks:

Study pre-dates GLP requirements

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 or test system 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

Test material information

Constituent 1

Reference substance name:

Butane-1,3-diol

EC Number:

203-529-7

EC Name:

Butane-1,3-diol

Cas Number:

107-88-0

Molecular formula:

C4H10O2

IUPAC Name:

butane-1,3-diol

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 or test system 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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 other: % basis in diet

Doses / concentrations 2

Dose / conc.:

1 other: % basis in diet

Doses / concentrations 3

Dose / conc.:

3 other: % basis in diet

Doses / concentrations 4

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.