Butane-1,4-diol

Endpoint summary

Description of key information

Oral, rat: NOAEL: 225 mg/kg bw/day (subchronic, read-across) (NTP, 1992)

Oral, mouse: NOAEL: 525 mg/kg bw/day (subchronic, read-across) (NTP, 1992)

Oral, rat: NOAEL:200 mg/kg bw/day (subacute) (MHW, 1999)

Oral, rat: NOAEL: 500 mg/kg bw/day (subacute) (Jedrychowski, 1992)

Inhalation, rat: NOAEC 1 mg/L (subacute) (DuPont, 1984)

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Under GLP

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

According to the NTP protocol animals were treated for 5 days per week. No clinical pathology parameters were examined.

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female F344/N rats, obtained from Charles River Breeding Laboratories (Kingston, NY). The average age of rats was 51 days old at the beginning of the study. Animals were observed for 19 days before the study started. Rats were housed five to a solid-bottom polycarbonate cage and the light cycle was 12-hour light and dark. Temperature was maintained between 22-24 deg C with RH of 35-62%.

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days per week

Remarks:

Doses / Concentrations:
0, 56, 112, 225, 450, or 900 mg/kg bw
Basis:
other: by gavage in 5 mL corn oil

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

Animals were observed twice a day and clinical observations were recorded once a week. Animals were weighed at the start of the study and weekly thereafter.

Sacrifice and pathology:

Surviving animals were killed at the end of the 13-week studies. Necropsies were performed on all study animals. The brain, heart, right kidney, liver, lungs, and thymus of survivors were weighed at necropsy. Complete histopathology was performed on all animals killed or dying during the study, all control animals, rats receiving 900 mg/kg, male rats receiving 450 mg/kg. The liver and nose (nasal cavity and turbinates) were examined from rats in the 56, 112, and 225 mg/kg dose groups and from female rats in the 450 mg/kg dose groups. Tissues routinely examined include: adrenal gland, bone and marrow (femur), brain, clitoral gland, esophagus, epididymis, heart, kidney, large intestine, liver, lung with mainstem bronchi, lymph nodes (mesenteric, mandibular), mammary gland, nasal cavity and turbinates, ovary, pancreas, parathyroid gland, pituitary gland, prostate gland, salivary gland, seminal vesicle, skeletal muscle (thigh), skin, small intestine, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, uterus, and gross lesions and tissue masses (with regional lymph nodes).

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

males and females at 900 mg/kg became recumbent several minutes after dosing but were normal at next observation.

Mortality:

mortality observed, treatment-related

Description (incidence):

males and females at 900 mg/kg became recumbent several minutes after dosing but were normal at next observation.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

males given 450 mg/kg had decreased mean body weights and body weight gains.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

225 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Based on body weights. No specific target organs were identified.

Key result

Dose descriptor:

NOAEL

Effect level:

450 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Based on 1 death in the 900 mg/kg group. No specific target organs were identified.

Key result

Critical effects observed:

no

All high-dose males and one high-dose female died. Males receiving 450 mg/kg gained less body weight. There was no body-weight effect in females at any dose level. Other than inflammation of the nasal mucosa in all groups of dosed rats, there were no specific organ effects. The nasal mucosa irritation was considered to be a non-specific effect of gavage with a volatile agent. NTP reports that similar lesions have been observed in other NTP gavage studies with a variety of chemicals and that the lack of any histologically evident degenerative lesions may be attributed in part to the rapid absorption and metabolism of the chemical.

Rats at the higher dose levels (225 mg/kg and above) showed signs of sedation after dosing during the first 2-3 weeks of study that diminished in intensity with continued dosing, and rats showed no visible signs of sedation after three weeks of dosing. While this effect is clearly attributable to the test substance, it is not considered relevant to establishing a chronic NOAEL for workers or consumers except in cases of accidental poisoning.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

225 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Several subacute and subchronic studies on rats and mice were conducted in line with OECD guidelines or at an equivalent level. They are considered reliable for assessment of repeated dose toxicity of the test substance.

System:

central nervous system

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983-07-25 to 1983-08-19

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: Crl:CD

Sex:

male

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: Mass Mean Diameter of respirable particulte (% respirable; <10µm):
- 2.8µm to 2.9µm at 0.20 mg/L concentration (97% respirable)
- 2.3µm to 2.8µm at 1.1 mg/L concentration (94 to 98% respirable)
- 3.6µm 5.1 mg/L concentration (74 to 92% respirable)

Details on inhalation exposure:

DeVilbiss or Solosphere was used for generation of aerosols. Rats were restrained in perforated, stainless steel cylinders with conical nose pieces. Animals were exposed nose only 6 h/day, 5 days /wk for 2 weeks to design concentrations of 0.20, 1.0, or 5 mg/L of 1,4-butanediol in air. Control group was exposed simultaneously to air only.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Every 30 min samples were collected from each exposure chamber. Atmospheric concentration was determined from filter weight differential before and after sampling.

Duration of treatment / exposure:

2 weeks

Frequency of treatment:

6 h/day, 5 days/wk

Remarks:

Doses / Concentrations:
0.20, 1.0, or 5 mg/L
Basis:
nominal conc.

No. of animals per sex per dose:

10 male only

Control animals:

yes, concurrent no treatment

Details on study design:

Doses were selected based on the earlier acute LC50 study. The study was designed to determine the effects of repeated inhalation of sublethal concentrations of 1,4-butanediol.

Positive control:

no

Observations and examinations performed and frequency:

Rats were weighed and observed daily throughout the exposure and recovery periods, weekends excluded.

Sacrifice and pathology:

5 rats per group were sacrificed after 10th exposure, and 5 rats per group were sacrificed after recovery period of 14 days post exposure.
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Body weights, organ weights, clinical chemistry

Statistics:

Clinical results were statistically analyzed by one-way analysis of variance. Comparison of test rats with controls by least significant differences and Dunnett tests was considered valid only when the ratio of variance (F) indicated a significant among -to-within group variation. Significance was judged at 0.05 probability level.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

slight red nasal discharge in some animals. Effects were absent in animals allowed to recover for 14 days.

Mortality:

mortality observed, treatment-related

Description (incidence):

slight red nasal discharge in some animals. Effects were absent in animals allowed to recover for 14 days.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

reduced body weights at high dose from day 3 to 4 days post exposure

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had significantly increased hematocrits and erythrocyte counts. Effects were absent in animals allowed to recover for 14 days.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had significantly decreased serum cholesterol concentrations. Effects were absent in animals allowed to recover for 14 days.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had decreased osmolality and pH. Not present in animals allowed to recover for 14 days.

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had decreased mean heart weights. Not present in animals allowed to recover for 14 days.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had slight atrophy of lympoid cells in the thymus. Not present in animals allowed to recover for 14 days.

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
Some rats from all groups including control group had slight red nasal discharge during exposure. No other adverse clinical signs were seen.

BODY WEIGHT AND WEIGHT GAIN:
No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
For 5.2 mg/L group had significantly lower body weights than control.

FOOD CONSUMPTION
No data


FOOD EFFICIENCY
No data


WATER CONSUMPTION
No data

OPHTHALMOSCOPIC EXAMINATION
No data

HAEMATOLOGY
No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
For 5.2 mg/L group had significantly increased hematocrits and erythrocyte counts after 10 exposures

CLINICAL CHEMISTRY
No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
For 5.2 mg/L group had significantly decreased serum cholesterol after 10 exposures

URINALYSIS
Yes- once after 9th exposure. An overnight sample was collected to measure volume, osmololity, and pH. Presence of blood, sugar, protein, bilirubin, urobilinogen and ketone was analysed. Appearance of the specimen was recorded and sediment was examined microscopically.

NEUROBEHAVIOUR
No data

ORGAN WEIGHTS
No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
In rats exposed to 5.2 mg/L significantly decreased heart weight was observed after 10 exposures. This change was not significant on an organ-to-body weight basis. No significant organ weight changes were observed after 14 days recovery period.

GROSS PATHOLOGY
yes-No treatment related effects were observed that were biologically significant for all groups

HISTOPATHOLOGY: NON-NEOPLASTIC
yes - No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
Rats exposed to 5.2 mg/L had significantly decreased mean body weights from the third exposure day to 4 days post exposure.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
None noted.

HISTORICAL CONTROL DATA (if applicable)


OTHER FINDINGS

Key result

Dose descriptor:

NOEC

Effect level:

1 mg/L air

Sex:

male

Basis for effect level:

other: No treatment related effects were observed that were biologically significant.

Key result

Dose descriptor:

LOEC

Effect level:

5 mg/L air

Sex:

male

Basis for effect level:

body weight and weight gain

haematology

histopathology: non-neoplastic

other: see 'Remark'

Key result

Critical effects observed:

no

Conclusions:

No significant effects were noted for rats exposed to 0.2 and 1.0 mg/L.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

1 100 mg/m³

Study duration:

subacute

Experimental exposure time per week (hours/week):

30

Species:

rat

Quality of whole database:

NOAEC is based on data from two similar reports on a 14-d repeated exposure study with aerosols.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983-07-25 to 1983-08-19

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: Crl:CD

Sex:

male

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: Mass Mean Diameter of respirable particulte (% respirable; <10µm):
- 2.8µm to 2.9µm at 0.20 mg/L concentration (97% respirable)
- 2.3µm to 2.8µm at 1.1 mg/L concentration (94 to 98% respirable)
- 3.6µm 5.1 mg/L concentration (74 to 92% respirable)

Details on inhalation exposure:

DeVilbiss or Solosphere was used for generation of aerosols. Rats were restrained in perforated, stainless steel cylinders with conical nose pieces. Animals were exposed nose only 6 h/day, 5 days /wk for 2 weeks to design concentrations of 0.20, 1.0, or 5 mg/L of 1,4-butanediol in air. Control group was exposed simultaneously to air only.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Every 30 min samples were collected from each exposure chamber. Atmospheric concentration was determined from filter weight differential before and after sampling.

Duration of treatment / exposure:

2 weeks

Frequency of treatment:

6 h/day, 5 days/wk

Remarks:

Doses / Concentrations:
0.20, 1.0, or 5 mg/L
Basis:
nominal conc.

No. of animals per sex per dose:

10 male only

Control animals:

yes, concurrent no treatment

Details on study design:

Doses were selected based on the earlier acute LC50 study. The study was designed to determine the effects of repeated inhalation of sublethal concentrations of 1,4-butanediol.

Positive control:

no

Observations and examinations performed and frequency:

Rats were weighed and observed daily throughout the exposure and recovery periods, weekends excluded.

Sacrifice and pathology:

5 rats per group were sacrificed after 10th exposure, and 5 rats per group were sacrificed after recovery period of 14 days post exposure.
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Body weights, organ weights, clinical chemistry

Statistics:

Clinical results were statistically analyzed by one-way analysis of variance. Comparison of test rats with controls by least significant differences and Dunnett tests was considered valid only when the ratio of variance (F) indicated a significant among -to-within group variation. Significance was judged at 0.05 probability level.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

slight red nasal discharge in some animals. Effects were absent in animals allowed to recover for 14 days.

Mortality:

mortality observed, treatment-related

Description (incidence):

slight red nasal discharge in some animals. Effects were absent in animals allowed to recover for 14 days.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

reduced body weights at high dose from day 3 to 4 days post exposure

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had significantly increased hematocrits and erythrocyte counts. Effects were absent in animals allowed to recover for 14 days.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had significantly decreased serum cholesterol concentrations. Effects were absent in animals allowed to recover for 14 days.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had decreased osmolality and pH. Not present in animals allowed to recover for 14 days.

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had decreased mean heart weights. Not present in animals allowed to recover for 14 days.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

High dose animals had slight atrophy of lympoid cells in the thymus. Not present in animals allowed to recover for 14 days.

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
Some rats from all groups including control group had slight red nasal discharge during exposure. No other adverse clinical signs were seen.

BODY WEIGHT AND WEIGHT GAIN:
No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
For 5.2 mg/L group had significantly lower body weights than control.

FOOD CONSUMPTION
No data


FOOD EFFICIENCY
No data


WATER CONSUMPTION
No data

OPHTHALMOSCOPIC EXAMINATION
No data

HAEMATOLOGY
No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
For 5.2 mg/L group had significantly increased hematocrits and erythrocyte counts after 10 exposures

CLINICAL CHEMISTRY
No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
For 5.2 mg/L group had significantly decreased serum cholesterol after 10 exposures

URINALYSIS
Yes- once after 9th exposure. An overnight sample was collected to measure volume, osmololity, and pH. Presence of blood, sugar, protein, bilirubin, urobilinogen and ketone was analysed. Appearance of the specimen was recorded and sediment was examined microscopically.

NEUROBEHAVIOUR
No data

ORGAN WEIGHTS
No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
In rats exposed to 5.2 mg/L significantly decreased heart weight was observed after 10 exposures. This change was not significant on an organ-to-body weight basis. No significant organ weight changes were observed after 14 days recovery period.

GROSS PATHOLOGY
yes-No treatment related effects were observed that were biologically significant for all groups

HISTOPATHOLOGY: NON-NEOPLASTIC
yes - No treatment related effects were observed that were biologically significant for 0.2 and 1.1 mg/L.
Rats exposed to 5.2 mg/L had significantly decreased mean body weights from the third exposure day to 4 days post exposure.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
None noted.

HISTORICAL CONTROL DATA (if applicable)


OTHER FINDINGS

Key result

Dose descriptor:

NOEC

Effect level:

1 mg/L air

Sex:

male

Basis for effect level:

other: No treatment related effects were observed that were biologically significant.

Key result

Dose descriptor:

LOEC

Effect level:

5 mg/L air

Sex:

male

Basis for effect level:

body weight and weight gain

haematology

histopathology: non-neoplastic

other: see 'Remark'

Key result

Critical effects observed:

no

Conclusions:

No significant effects were noted for rats exposed to 0.2 and 1.0 mg/L.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Oral exposure

Repeated dose studies with the source substance

 

An oral 90-day subchronic toxicity study with the source substance GBL was performed on F344/N rats (NTP, 1992). Groups of 10 rats received GBL by gavage at doses of 0, 56, 112, 225, 450, or 900 mg/kg bw/day 5 days a week for 13 weeks. Animals were observed twice a day and clinical observations were recorded once a week. Animals were weighed at the start study and weekly thereafter. Necropsies were performed on all study animals. The brain, heart, right kidney, liver, lungs, and thymus of survivors were weighed at necropsy. Complete histopathology was performed on all animals killed or dying during the study, all control animals, rats receiving 900 mg/kg bw/day, and male rats receiving 450 mg/kg bw/day. All male rats and one female rat given GBL died by week 8. The final mean body weights and mean body weight gains of males in the 450 mg/kg bw/day group were significantly lower than those of the controls; final mean body weights and weight gains for males given 56, 112, or 225 mg/kg bw/day and for all female dose groups were similar to those of the controls. All rats in the 900 mg/kg bw/day dose groups became recumbent within several minutes after dosing, but appeared normal at the next observation period several hours later. Rats in the 225 and 450 mg/kg bw/day dose groups exhibited slight inactivity after dosing. After 2 to 3 weeks, all animals ceased to react visibly to the daily administration of GBL indicating some form of adaptation or tolerance to its 'anesthetic' and sedative properties. At necropsy there were no biologically significant differences in absolute or relative organ weights between dosed and control rats. No substance-related gross or microscopic lesions were observed at doses up to 900 mg/kg bw/day (rats) and 1050 mg/kg bw/day (mice), given 5 days per week. For male rats, a NOAEL of 225 mg/kg bw was reported based on decreased mean body weights and weight gains, and complete mortality of male rats at 900 mg/kg bw/day. For female rats, a NOAEL of 450 mg/kg bw/day was reported based on 1 death in the high dose group.

 

An additional oral 90-day subchronic toxicity study with the source substance GBL was performed on B6C3F1 mice (NTP, 1992). Groups of 10 mice received GBL by gavage at doses of 0, 65, 131, 262, 525, or 1050 mg/kg bw/day. Animals were observed twice a day and clinical observations were recorded once a week. Animals were weighed at the start study and weekly thereafter. Necropsies were performed on all study animals. The brain, heart, right kidney, liver, lungs, and thymus of survivors were weighed at necropsy. Complete histopathology was performed on all animals killed or dying during the study, all control animals, and mice receiving 1050 mg/kg bw/day. Deaths related to GBL administration occurred in three males from the 1050 mg/kg bw/day dose groups. Except for the final mean body weight of the 1050 mg/kg bw/day male dose group, which was approximately 11% lower than that of the controls, the final mean body control weights of male and female dose groups were similar to those of the controls. Mice in the 525 and 1050 mg/kg bw/day dose groups became recumbent several minutes after dosing, but were normal at the next observation period several hours later. Mice in the 262 mg/kg bw/day dose group exhibited moderate inactivity after dosing. In mice given 525 mg/kg or less, these acute reactions diminished after 3 to 4 weeks. There were no biologically significant differences in absolute or relative organ weights between dosed and control mice. No gross or microscopic lesions related to GBL administration were observed. A NOAEL of 525 mg/kg bw/day was reported based on decreased mean body weights and weight gains in males and increased mortality in males and females at the 1050 mg/kg bw/day dose.

 

Repeated dose studies with the target substance

 

In an OECD 422 combined repeated dose toxicity study with the reproduction / developmental toxicity screening test guideline study with BDO, the NOAEL was found to be 200 mg/kg bw/day for male and female rats (MHW, 1999). Male and female Sprague Dawley rats were administered daily oral doses of 200, 400 or 800 mg/kg over a study period of 42 days for male rats and from 14 days prior to mating to day 3 of lactation for female rats. Acute and transient toxic signs in central nervous system were observed after daily administration of 1,4-butanediol in both sexes, and severity of the sign increased with dosage levels. The transient hyperactivity was observed during a short period after administration at 200 mg/kg/day. At 400 mg/kg, activities were rather suppressed than increased although hyperactivity was also observed after a few doses. At 800 mg/kg, toxic signs observed were more severe and some animals were even comatose after showing hypoactivity and recumbency. By 5 hours after dosing these signs disappeared and animals recovered to normal. Body weight gains were suppressed at 400 and 800 mg/kg during the early period of administration. The weight gains were not further suppressed thereafter, the difference in body weight produced during the early period of administration remained until termination of the study. Food consumption also decreased accordingly. In hematological and blood chemistry findings of males, there were slightly but statistically significant and dose-related decrease of blood glucose at all treated groups. At terminal necropsy, no compound-related lesions were noted macroscopically. In the histopathological examination, very slight diffuse transitional epithelial hyperplasia and fibrosis in the lamina propria of the urinary bladder were observed in the 400 and 800 mg/kg groups, but there were no significant changes in other tissues examined, such as liver, kidney, and thymus.

 

In a 28-day subacute toxicity study with BDO a NOAEL for male and female rats was found to be 50 mg/kg/bw/d and the LOAEL for male and female rats was found to be 500 mg/kg bw/day (Jedrychowski, 1990). Male and female Wistar rats were administered oral doses of 5, 50 or 500 mg/kg over a study period of 28 days. The subacute oral administration of the test substance resulted in an overall low degree of systemic toxicity. There were no changes in body weight, food consumption, and absolute and relative organ weights. Slightly higher activities of sorbitol dehydrogenase and alanine aminotransferase were observed in male rats given the test substance at the highest dose of 500 mg/kg/day. Some disturbances in hematological parameters, characterized by macrocytosis and thrombocytopenia were observed in treated rats. Mild to moderate inflammation of the liver, characterized by proliferation of bile ducts and periportal infiltrations with fibroblasts and mononuclear cells, were found in treated animals. A statistically significant difference for histopathological changes was found in animals treated with the test substance at the dose of 500 mg/kg/day only in the case where both sexes were jointly taken for comparison.

 

Respiratory exposure

 

In a 14-day inhalation study with 1,4-butanediol, the NOAEC for male rats was 1.1 mg/L air (DuPont, 1989). Male rats were offered aerosol concentrations of 0.2, 1.1 or 5.2 mg/L for 2 weeks (nose-only exposure). The inhalation of aerosol concentrations by rats of up to 5.2 mg/L was well tolerated. No adverse effects were detected at concentrations of 0.2 and 1.1 mg/L. Rats exposed to 5.2 mg/L had slight atrophy of the lymphoid cells in the thymus. This was seen in three of five rats and was considered to be slight in degree of change. This was not seen in rats of this group following the 14-d recovery period. All other tissues and organs from rats exposed to 5.2 mg/L showed no histopathologic changes. No changes were seen in rats exposed to either 0.2 or 1.1 mg/L.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on oral repeated dose toxicity, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the seventeenth time in Regulation (EU) 2021/849.