Registration Dossier

Administrative data

Description of key information

No toxic effects were observed in a 2-year feeding study in rats receiving up to 5000 mg 1,3-butylene glycol/kg bw /d (Celanese, 1963a, Scala and Paynter, 1967) and in a chronic feeding study in dogs receiving up to 750 mg/kg bw /d (Celanese, 1963b, Scala and Paynter, 1967). In a subchronic feeding study in dogs the NOAEL was 6000 mg/kg bw and day and the LOAEL 9000 mg/kg bw and day (Reuzel et al., 1978).

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well performed study
Qualifier:
no guideline followed
Principles of method if other than guideline:
13-week feeding study in non-rodents
GLP compliance:
not specified
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals, CBP-TNO, Zeist, The Netherlands
- Age at study initiation: 7-8 weeks
- Weight at study initiation: males: 3.6 to 3.9 kg; females: 2.9 to 3.5 kg (mean body weights of animals per dose group)
- Fasting period before study: no data
- Housing: individually in indoor kennels
- Diet: restricted portion of food twice daily; either 40 g or 50 g food/kg bw/day on different days, but equal for the different dogs on one day
- Water: no data
- Acclimation period: no data
- all dogs had been immunized against distemper


Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet: once a week
- Mixing appropriate amounts with (Type of food): basel diet, diets were supplemented with an instant wheat product, glucose and soya bean oil and 1,3-butanediol in such a way that all diets were theoretically isocaloric
- Storage temperature of food: in closed containers at a temperature of 10-15°C


Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily, two times per day
Remarks:
Doses / Concentrations:
0, 3, 6, 12 g/kg bw/day
Basis:
other: nominal ingested
No. of animals per sex per dose:
4 animals per sex per dose group
Control animals:
yes, plain diet
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes (behaviour and health)
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- food consumption determined: daily

FOOD EFFICIENCY: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the beginning and at week 2, 6 and 12
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: in all dogs
- Parameters checked: hemoglobin content, packed cell volume, methaemoglobin content, erythrocyte fragility, erythrocytes counts, leucocytes counts, thrombocytes counts, differential white blood cell counts, reticulocytes, Heinz bodies


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the beginning and in week 6 and 12
- Animals fasted: No data
- How many animals: all animals
- Parameters checked: SGPT, SGOT, SAP, total serum protein, serum albumin, fasting blood glucose, blood urea-N, triglycerides, beta-hydroxybutyric acid, acetoacetic acid, plasma free fatty acids, lactate


URINALYSIS: Yes
- Time schedule for collection of urine: at the beginning and in week 6 and 12
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- How many animals: in all dogs
- Parameters checked: appearance, specific gravity, pH, sugar, protein, occult blood, ketones and microscopic examination of the sediment


NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
Analysis of 1,3-butylene glycol in feces was carried out in one male and one female of each group at week 4 by means of liquid chromatography
liver-function test: (bromosuophophthalein method), all dogs of the control and highest dose group at week 13
kidney-function test (phenolred excretion method), all dogs of the control and highest dose group at week 13
Sacrifice and pathology:
After 13 weeks all surviving dogs were anaesthetized by intravenous administratoin of Nembutal followed by exsanguination.

GROSS PATHOLOGY: Yes, each animal immediately after death

HISTOPATHOLOGY: Yes, all animals, Haematoxylin-eosin stained paraffin sections of the organs weighed and also of the following organs and tissues: spinal cord, sciatic nerve, salivary glands, skeletal muscle, thoracic aorta, skin, tonsils, bladder, oesophagus, stomach, duodenum, jejunum, ileum, caecum, colon, pancreas, trachea, circumanal glands, eyes, epididymis, prostate, uterus, gall bladder, tongue and thymus. Special attention was paid to possible occurence of lipofuscin in various tissues.
Other examinations:
ORGAN WEIGHTS: heart, kidneys, liver, spleen, lungs, testicles/ovaries, pituitary, thyroids, adrenals and brain
Statistics:
Wilcoxon test
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
An epileptic seizure was observed in one dog of the top-dose group during the third week. From that time the number of dogs with epilepsy-like symptoms and the frequency of the attacks increased gradually in the two highest dose groups both in males and females. The phenomen was easily induced by disturbing the animals.

BODY WEIGHT AND WEIGHT GAIN
In the two highest dose groups weight gain was clearly less than in the controls. This effect was statistically significant at 9000 and 12000 mg/kg bw/day in males and at 12000 mg/kg bw/day in females.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The daily portion was consumed completely by all dogs.

HAEMATOLOGY
Hematological effects were only seen in thrombocyte counts and methaemoglobin. Thrombocyte counts were increased in the groups receiving 9000 and 12000 mg/kg bw/day at all stages, although in the group receiving 9000 mg/kg bw/day the increase was not statistically significant at week 12. The increased thrombocyte counts observed with 6000 mg/kg bw/day at weeks 6 and 12 were regarded as not treatment-related. Increased levels of methaemoglobin were observed at the high dose group at all stages. The effect was statistically significant at week 12.

CLINICAL CHEMISTRY
Biochemistry changes consisted of a slight, but dose-related increase in SGPT at the two highest doses, increased SGOT in the top dose group at 6 weeks but not at week 12, and a dose-related increase in free fatty acid that was statistically significant only at the high dose. Blood levels of beta-hydroxy butyric acid, acetoacetic acid and lactate increased with increasing feeding levels of BD. Small quantities of BD were recovered from faeces of dogs fed 9000 or 12000 mg/kg bw/day.

URINALYSIS
Values for pH in urine of dogs of the two highest dose groups were lower than in the other groups at week 7. Slight ketonuria was observed in dogs of the top-dose group at week 12.

ORGAN WEIGHTS
The relative weights of the kidneys, liver, brain, adrenals and lungs were statistically significantly increased in dogs of the top-dose group, the relative weights of the thymus and spleen were decreased. The relative weights of the liver and kidneys were also increased at 9000 mg/kg bw/day.

GROSS PATHOLOGY
Gross examination of the female dog from the 9000 mg/kg bw/day dose group that died during the study revealed a congenital heart defects (persistent ductus arteriosis). No other treatment attributable effects were observed.

HISTOPATHOLOGY
No treatment related histopathological effects were observed.

Dose descriptor:
NOAEL
Effect level:
6 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: changes in behaviour, haematology, blood biochemistry, organ weights and growth rate
Dose descriptor:
LOAEL
Effect level:
9 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: changes in behaviour, haematology, blood biochemistry, organ weights and growth rate
Critical effects observed:
not specified
Conclusions:
In this subchronic feeding study in dogs treatment-related effects occurred only at 9000 and 12000 mg/kg bw/day. It is therefore concluded that 6000 mg/kg bw/day was a no-toxic effect level in the present study.
Executive summary:

In a subchronic (13-week) feeding study dogs were fed with a diet containing 1,3-butylene glycol, resulting in intake levels of 0, 3000, 6000, 9000 and 12000 mg/kg bw/d (Reuzel et al., 1978). Epilepsy-like seizures were frequently observed in dogs fed 9000 or 12000 mg of the test item/kg bw/d. Body weight gain was depressed in dogs fed 9000 or 12000 mg/kg bw/d. Thrombocyte counts were increased at 6000 mg/kg bw/d and above. Methaemoglobin was elevated in dogs of the top-dose group only. Blood levels of free fatty acids, beta-hydroxy butyric acid, aceto-acetic acid and lactate increased with increasing feeding levels of the test item. Kidney and liver function was not affected. Slight ketonuria was observed in dogs of the top-dose group at week 12. Small quantities of the test item were recovered from feces of dogs fed 9000 or 12000 mg/kg bw/d. The relative weights of the liver and adrenals showed dose-related increases in the two highest dose groups. In addition, the top-dose group showed increased relative weights of the kidneys, brain and lungs and decreased relative weights of the thymus and spleen. Gross and microscopic examination failed to reveal any changes that could be ascribed to treatment. The NOAEL in the present study was 6000 mg/kg bw/d.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
31 August 1960 to 29 August 1962
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
insufficient number of animals per dose group, no analytical validation of test substance concentration in diet
Qualifier:
no guideline followed
Principles of method if other than guideline:
chronic feeding study in rodents
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 72 to 115 g (males); 68 to 109 g (females)
- Housing: individually in wire mesh cages
- Diet: ad libitum
- Water: ad libitum

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet: weekly
- Mixing appropriate amounts with basal laboratory diet of Purina Laboratory Chow
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 1.0, 3.0, 10.0%
Basis:
nominal in diet
No. of animals per sex per dose:
60 per sex in the control group; 30 per sex in the treatment groups
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: none
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 26 weeks, biweekly from week 27 through week 52, and every four weeks from week 53 through week 104


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
- Time schedule for examinations: weekly for the first 26 weeks, biweekly from week 27 through week 52, and every four weeks from week 53 through week 104


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4, 13, 26, 52, 78, and 104 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: five animals of each sex from each group
- Parameters checked: erythrocyte count, total and differential leukocyte counts, hemoglobin, hematocrit

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: fter 4, 13, 26, 52, 78, and 104 weeks
- Metabolism cages used for collection of urine: Yes (individual housing overnight in metabolism cages)
- How many animals: pooled samples from five rats of each sex 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, five males and five females from the control and each test group were sacrificed by exsanguination and autopsies performed. After 104 weeks all surviving test and control rats were sacrificed and autopsied.

Organs preserved from sacrificed animals in 10% formalin:
brain, pituitary, thyroid, lung, heart, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intestines, urinary bladder, gonads, bone and bone marrow, unusual lesions found at autopsy, mandibula

HISTOPATHOLOGY:
Histopathological evaluation was performed on the preserved tissues (brain, pituitary, thyroid, lung, heart, liver, spleen, kidney, adrenal, pancreas, stomach, small and large intstines, urinary bladder, gonads, bone and bone marrow, mandibula) from each control and high level test rat (10% level) sacrificed. after 52 weeks and from five male and five female control and five male and four female high level test rate (10% level) sacrificed after 104 weeks. The tissue masses found in one female control rat and in one male rat of Group No. 4 (10% level) were also evaluated histopathologically.
Other examinations:
ORGAN WEIGHT: heart, liver, kidneys, spleen, testes; thyroids and adrenals were weighed after fixation in 10% formalin
Statistics:
The parameters chosen for statistical evaluation at 52 weeks were growth, total food consumption, over-all food efficiency, survival, and hematological values. No attempt was made to analyze terminal body weights, organ weights, or organ/body weight ratios because of the wide variation in them.
The criteria evaluated statistically at 104 weeks were terminal body weights, organ weights, organ/body weight ratios, hematological values,and survival. No statistical evaluation was made of growth, food consumtion, and food efficiency.
Survival was analyzed by the life-table technique. All other criteria were examined by the analysis of variance or F-test at the 5% probability level. Body weights were prepared for analysis by the method of Rao. Before completing each F-test, Bartlett's test was applied to assure homogeneity of the variances. If the variances were homogeneous the F-test was completed in the normal Fashion. Whenever a significant F-value was obtained those groups significantly different from the controls were determined by Scheffe's test. Whenever heterogeneous variances were obtained, comparisons were made by the Fisher-Behrens modified "t"-technique. A more detailed description of these methods may be found in publications by Ostle, B., Statistics in Research, Ames, Iowa, Iowa State College Press, 1956; Snedecor, G. W., Statistical Methode, Ames, Iowa, Iowa State College Press, 1956; Rao, C. R., Biometrics 14, 1, 1958; and Sachs, R., Toxicol. Appl. Pharmacol. 1, 203, 1959.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
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
Details on results:
Chronic application 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.

CLINICAL SIGNS AND MORTALITY
Rats of the control and various test groups showed signs of respiratory involvement (wheezing, rapid or labored respiration, nasal dischare, and inflamed eyes) with equal frequency. These signs were slight during the first six month of the study and became more frequent and severe as the study proceeded. Mass treatments with antibiotics were institued, however, were of only transient value. There were no differences between control and test animals with respect to mortality due to respiratory disease. Incidence increased during the latter part of the first year and remained high throughout the second year of the study. Incidence of subcutaneous tissue masses is described in chapter 7.7

BODY WEIGHT AND WEIGHT GAIN
During the first year of the study, growth rate for the males and females in dose group No. 2 (1.0% level, 500 mg/kg/d) and dose group No. 3 (3.0% level, 1500 mg/kg/d) was not significantly different from that of the corresponding control groups. In Group No. 4 (10% level, 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 Group No. 4, the higher growth rate was not significant.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption for the males in Group No. 4 for the first 13 weeks and from the 28th through the 52nd week was significantly
lower than that for the male controls. Food consumption was comparable among the other test groups and the respective controls.

FOOD EFFICIENCY
Food efficiency was significantly higher in Group No. 4 during the first 13 weeks (males and females) and from the 27th through the 52nd week (females).


OPHTHALMOSCOPIC EXAMINATION
no data

HAEMATOLOGY
During the first year of the study all hematological values remained generally within normal limits and were comparable among the control and test groups. At 52 weeks the percentages for the segmented neutrophils were somewhat elevated for the rats in all groups including the controls. At 78 and 104 weeks the segmented neutrophil percentages were even more elevated and in some cases exceeded the lymphocyte percentages. Furthermore, at the 545-day interval and even more so at termination, low hematocrit, hemoglobin, and erythrocyte values and/or elevated leukocyte counts
were obtained for a number of rats in all groups including the controls. An additional finding at termination was moderate or marked polychromia or hypochromia in several rats of all groups. One male rat in Group No. 2 (1.0% level, 1000 mg/kg/d) exhibited one nucleated erythrocyte per 100 White blood cells. All above mentioned abnormal findings probably were due to the high incidence of pulmonary disease among the rats and in some instances also to the presence of tissue masses.


URINALYSIS
The results of the urine analyses were comparable among the control and test groups throughout the study. No particular significance can be attached to the increased protein content in the urine of the male and female test rats at termination because of the poor health of the rats and the small number of survivors in some of the groups.


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

GROSS PATHOLOGY
Findings at autopsy in the rats which were sacrificed at 52 and 104 weeks or which died or were sacrificed in moribund condition during the course of the study did not reveal any consistent gross changes in the tissues or viscera of the test rats that could be associated with the ingestion of the test material. Infected lungs (consolidation, abscesses, emphysema and in some cases, adhesions to the thoracic wall or areas of firm white tissue) were found in the majority of the control and test rats sacrificed after 52 and 104 weeks and in all animals which died or were sacrificed in moribund condition during the course of the study. Subcutaneous tissue masses, primarily in female control and test rats, were observed. For details see chapter 7.7.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic examination of tissue sections from the high level test rats (10% level, 5000 mg/kg/d) sacrificed after 52 weeks did not reveal any consistent alterations. The cellular structure of the sections from the test rats was generally similar to that observed in the sections from the controls. Slight to moderate vacuolation of liver cells, present in some of the high level rats at 104 weeks, was considered to be of no significance. The only lesions consistently present in both the control and test animals were due to chronic inflammatory disease and neoplasia.

HISTOPATHOLOGY: NEOPLASTIC
Several subcutaneous tissue masses were identified as mammary fibromas, fibroadenomas, and carcinomas, or adenomas and melanomas. For details see chapter 7.7.


Key result
Dose descriptor:
NOAEL
Effect level:
>= 5 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: calculated (10% in diet, food factor 0.05; see: Guidance on Information requirements R.8)
Critical effects observed:
not specified

No adverse effects compared to control

Conclusions:
No treatment related adverse effects were observed in a chronic feeding-study in rats which received up to 10% (5000 mg/kg/d) 1,3-butylene glycol in food.
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) (Celanese, 1963a, Celanese, 1961, Scala and Paynter, 1967). 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. Signs of respiratory involvement were observed with equal frequency among the control and various test groups. None of the test rats showed any sign of compound effect.

Mortality in the various groups increased markedly during the second half of the first year and remained high during the second year of the study due to respiratory diseases. Hematological values and the results of urine analyses for treated rats were generally within normal limits and comparable with those of the controls. Minor abnormalities in hematological parameters, encountered in control and test animals alike during the second year, were compatible with inflammatory disease and neoplasia.

Organ weights and ratios were within normal limits and comparable with the controls. Subcutaneous and internal neoplasms were encountered in a number of control and test animals, primarily in females. Microscopic examination of tissue sections did not reveal any consistent alterations.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
24 October 1960 to 1 November 1962
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
well performed study with some minor restrictions, pre-GLP
Qualifier:
no guideline followed
Principles of method if other than guideline:
chronic feeding study in non-rodents
GLP compliance:
not specified
Remarks:
pre-GLP
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Lu-Nor Farms, Kalamazoo, Michigan
- acclimation period: at least one month; during this period dogs received a vermifuge and were vaccinated against canine distemper, infectious canine hepatitis, and rabies.
- Age at study initiation: 6-16 month
- housing conditions: individually in metal cages
- Diet: ground Wayne dog food ad libitum; five days weekly the diet for each dog was supplemented with a 100 g ration of canned horsemeat
- Water: ad libitum

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
- the compound was added to both the dry dog food and the meat rations
- the compound was thoroughly incorporated into the ground dog food
- the basic diets were prepared weekly
- preparation of meat rations: appropriate amounts of the test compound were injected into the individual meat rations, which were then offered to the dogs. Dietary levels were computed on a moisture free basis.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 0.5, 1.0, 3.0%
Basis:
nominal in diet
No. of animals per sex per dose:
4 animals per sex per dose
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: none
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: initially, at two and four weeks, at three, six, 12, 18 and 24 month
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all dogs
- Parameters checked: erythrocyte count, total and differential leukocyte counts, hematocrit, hemoglobin, sedimentation rate determinations


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: initialla, at two and four weeks, at three, six, 12, 18 and 24 month
- Animals fasted: No data
- How many animals: all dogs
- Parameters checked: bromsulphalein liver function tests, blood urea nitrogen determination


URINALYSIS: Yes
- Time schedule for collection of urine: initialla, at two and four weeks, at three, six, 12, 18 and 24 month
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: appearance, specific gravity, pH, sugar, acetone, ptrotein, bilirubin, occult blood, microscopic examination of the sediment

NEUROBEHAVIOURAL EXAMINATION: No


Sacrifice and pathology:
After the study had completed one year, one female and one male from each group, including the controls, were sacrificed by exsanguination under thiamylal (Surital) sodium anesthesia, and complete autopsies were performed. The remaining animals were sacrificed after the study had completed two years.

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
- all tissues from the control and high level dogs sacrificed at one year plus bone marrow slides of the low and intermediate levels

SECTIONS PRESERVED in 10% formalin:
- all dogs: brain, pituitary, thyroid, lung, heart, mesenteric lymph node, stomach, small and large intestines, pancreas, spleen, liver, gallbladder, kidney, adrenal, urinary bladder, gonads, bone and bone marrow (rib junction)
-sections of the lower jaw bone were taken from selected animals of all dose groups at terminal sacrifice and stored in 10% formalin
Other examinations:
ORGAN WEIGHT: thyroid, heart, liver, spleen, kidneys, adrenals, gonads (males only)
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
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
Details on results:
In general, no treatment related effects were observed during this study. Effects seen in single animals were not regarded as treatment related, they are reported below.

One female of the 0.5% dose group (125 mg/kg bw/d) showed several periods of emesis. The effects were not connected with the dietary feeding of the test compound. The remaining animals showed normal behaviour during the first year.

One male dog of the 1% dose group (250 mg/kg bw/d) lost weight (up to 1.1 kg) during the study. At the end of the study the dog had nearly gained back its initial body weigth within 0.3 kg.

One female of the high dose group (3%; 750 mg/kg bw/d) was pregnant and delivered four healthy pups during the 10th week of the study. Fourteen weeks after birth an abdominal hernia was noted in this animal which was surgically repaired during the 25th week.

Hematological determinations, biochemical studies and urine analyses were within normal limits.

Some single cross pathological findings, which were not treatment related, were recorded:
- lowest dose (0.5%; 125 mg/kg bw/d): female dog: scar around teh anterior end of the right kidney
- mid dose (1.0%; 250 mg/kg bw/d): male dog: scar shaped cicatrix on the renal surface of one kidney; another male dog: thickening in the center of the spleen with a small necrotic area in the center; female dog: congested kidneys
- high dose (3.0%; 750 mg/kg bw/d): male dog: spleen with thickened margins and blue-black coloration, slightly congested kidneys; another male dog: mildly congested medulla in the kidney; female dog: lightly mottled liver

Organ weights were within the normal limits, a trend toward increased thyroid/body weigth ratios was not accompanied by histopathological findings.

The histopathological evaluation did not reveal any compound related effects.

Both, control and treated animals showed some focal chronic nephritis and tubular atrophy as well as mild to moderate glomerulitis.
Dose descriptor:
NOAEL
Effect level:
>= 750 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: calculated assuming a food factor of 0.025 (Gold et al., 1984)
Critical effects observed:
not specified

No adverse effects compared to control.

Calculation of dose in mg/kg bw/d is based on food consumption data of dogs as given in Gold et al (1984): A carcinogenic potency database of the standardized results of animal bioassays. Environmental Health Perspectives 58: 9 -319.

Conclusions:
No treatment related adverse effects were observed in a chronic feeding-study in dogs which received up to 3% 1,3-butylene glycole in food.
Executive summary:

1,3-butylene glycol was fed to adult male and female beagles at dietary level of 0, 0.5, 1.0, and 3.0% (0, 125, 250, and 750 mg/kg bw/d) for a period of two years (Celanese, 1963b; Scala and Paynter, 1967). The physical appearance, behavior, and total food consumption of the test dogs were comparable with those of the control dogs throughout the study. No definite signs of compound effect were observed in any of the test dogs. The results of the hematological, biochemical, and urine studies showed comparable values for the control and test groups. Organ weights and organ/body weight ratios of the test animals were generally within normal limits. Gross and microscopic evaluation of tissues from dogs sacrificed at one and two years of feeding revealed no consistent findings. The test dogs were considered to be within normal limits and comparable with the controls.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
limitations of the individual studies, but sufficient information for a WoE assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

In the absence of information on species specific effects or metabolism the results are regarded as relevant for humans.

Additional information

No repeated dose toxicity data for the submission substance is available. However, adequate and reliable data are reported here for a structural analogue (source substance 1,3 -butanediol). Please also refer to the read-across justification document.

Repeated-dose oral toxicity of the source substance butane-1,3 -diol has been investigated in a 2 -year feeding study in rats (up to 5000 mg/kg bw/d; Celanese, 1963a; Scala and Paynter, 1967) and a 2 -year feeding study in dogs (Celanese, 1963b, Scala and Paynter, 1967), which received up to 750 mg/kg bw/d. In both studies no substance related effects were observed, even in the highest dose group tested. These data are supported by the findings of a subchronic feeding study in dogs (Reuzel et al., 1978). Dogs of the two highest dose groups (9000 and 12000 mg/kg bw/d) revealed toxic effects like changes in behaviour (epilepsy-like seizures), haematology, blood biochemistry, organ weights and growth rate, but no treatment related effects occurred at 6000 mg/kg bw/d. This study was well performed and judged to be reliable with minor restrictions (RL2). In contrast, the 2-year feeding studies in rats and dogs have some methodological deficiencies (e.g. insufficient number of animals per dose group, no analytical verification of dose), but contribute to the overall picture of (no) effects of the substance after repeated exposure.

Justification for classification or non-classification

The substance has not to be classified for toxicity after repeated exposure according to Regulation (EC) No 1272/2008, because no toxic effects were observed in a chronic study in rats (NOAEL 5000 mg/kg bw/day). Effects in a subchronic study in dogs were only observed at doses above 6000 mg/kg bw/day (NOAEL 6000 mg/kg bw/day).


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