Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

No carcinogenic effects were observed in a 2-year feeding study in rats receiving 10% butane- 1,3 -diol in food (5000 mg/kg bw/day)

and in a 2-year feeding study with dogs, which received 3% butane- 1,3 -diol in food (750 mg/kg bw/day) .

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
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
Reason / purpose:
reference to same study
Principles of method if other than guideline:
2-year feeding study in rodents
GLP compliance:
not specified
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 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
Post exposure period:
post exposure period: none
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
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.

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:
CLINICAL SIGNS AND MORTALITY
Signs of respiratory involvement (wheezing, rapid or labored respiration, nasal dischare, and inflamed eyes) were noted with equal frequency among the rats in the control and various test groups. These signs were slight during the first six month of the study and became more frequent and severe as teh study proceeded. Mass treatments with antibiotics were institued, however, were of only transient value. Mortality because of respiratory disease, in the control and test animals alike, increased during the latter part of the first year and remained high throughout the second year of the study.

Subcutaneous tissue masses of varying size and location were observed predominantly in the female animals and especially in the controls. The incidence of such tissue masses is described below. Frequent locations of the tissue masses were the axillary and the inguinal areas. In two rats large tissue masses adhered to the body sides. Three animals exhibited nodules in the perianal region. One rat had a wart-like growth at one ear, and three other rats displayed one tissue node each at the throat, lip and vagina. Several rats showed two tissue masses at different locations. The
majority of the subcutaneous tissue growths were of firm consistency, loosely attached to the underlying tissue, and therefore easily movable.
Others were softer, of fatty consistency. The growths varied in size, the smaller ones being pea sized and the larger ones reaching the size and shape of an Idaho potato. In many instances the skin cover was intact. In some rats, however, the growths were ulcerated, partly necrotic, and exuded a foul odor. The earliest incidence of a subcutaneous growth was observed in a female control rat, where a firm tissue mass at the right hip was noted beginning with the 19th week; the mass became ulcerated and the animal died in the 37th week. During the latter part of the first year (40 weeks) tissue masses became apparent in three more rats. The other tissue masses developed during the second year of the study.


BODY WEIGHT AND WEIGHT GAIN
No substance related effects, for details see chapter 7.5.1.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No substance related effects, for details see chapter 7.5.1.

FOOD EFFICIENCY
No substance related effects, for details see chapter 7.5.1.


OPHTHALMOSCOPIC EXAMINATION
no data

HAEMATOLOGY
All in chapter 7.5.1 mentioned abnormal findings (e.g. somewhat elevated segmented neutrophils, low hematocrit, hemoglobin and erythrocyte values, elevated leukocyte counts, polychromia in all groups ) 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
no adverse effects


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.

The subcutaneous tissue masses observed in a number of female and a few male control and test rats in the course of the study varied in weight from one gram to 291 grams. In most cases these growths were encapsulated, nodular, of firm consistency; the cut surface was nodular or homogeneous, gray dull or glistening white, sometimes showing hemorrhagic pockets of caseous, necrotic masses. A few tissue masses were of softer consistency and of predominantIy homogeneous structure, some of them showing a dark black cut surface. Internal tissue masses, concealed in the body cavities, were detected at autopsy in four male and eight female control and test rats, and are described below. Two of these animals also showed subcutaneous tissue masses.

HISTOPATHOLOGY: NON-NEOPLASTIC
The microscopic examination did not reveal any consistent alterations in the cellular or tissue structure of the test animals that could be associated with the ingestion of the test material. The only lesions consistently present in both the control and test animals were due to chronic inflammatory disease and neoplasia.

HISTOPATHOLOGY: NEOPLASTIC
Several of the subcutaneous tissue masses encountered, primarily in female control and test rate were identified as mammary fibromas,
fibroadenomas, and carcinomas. The abdominal tumor in a male high level rat (10% level), described as replacing the left kidney and the left adrenal, was identified as a cortical carcinoma. The wart-like nodule observed at the ear of a female control was diagnosed as a melanoma.

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 up to the highest dose tested which is well above the recommended limit dose.
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)
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
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)
Remarks on result:
other: Effect type: toxicity (migrated information)

There was no treatment related increase in carcinogenic and non-carcinogenic effects in treated animals compared to the control.

The incidence of subcutaneous tissue masses was as follows:

 Dietary level (%) male  female 
 0  1  15
 1  1  0
 3  0  6
 10  1  3

The internal tissue masses, concealed in the body cavities, and detected at autopsy in four male and eight female rats are described in the following:

 dietary level (%)  sex  gross autopsy findings
 0  M  Red tissue mass attached to left lung lobe.
 0  F  Abdominal, cherry-sized, dark red nodule attached to the uterus at the bifurcation.
 0  F  Tissue masses involving both ovaries.
 F  Nodular, firm, gray-white tissue mass containing hemorrhagic pockets, closely attached to and partly penetrating spleen.
1  F  Several large hemorrhagic nodules attached to pancreas and spieen, and a large, irregularly nodular mass involving cecum and upper colon.
 3  F  Diffuse nodular tissue mass involving ileum and cecum and spreading through the lower abdominal cavity.
 3  F  Firm, congested node at right uterine horn.
 10  M  Large, abdominal tissue mass, encapsulated, soft, with hemorrhagic pockets, involving left kidney and left adrenal; the cut surface of the growth revealed the indistinct outline of a pale, greatly enlarged kidney; the left adrenal could not be located.
 10  M  Firm, irregularly shaped tissue mass involving the thymus.
 10  M  Cherry-sized, dark brown, firmly elastic nodule between the liver lobes.
 10  F  Encapsulated, greatly hemorrhagic, friable tissue mass enclosing the left ovary.
 10  F  Large tissue mass adhering to the left lung lobe.
Conclusions:
No treatment related adverse effects (carcinogenic and non-carcinogenic) were observed in a chronic feeding-study in rats which received up to 10% (5000 mg/kg bw/d) 1,3-butylene glycol in the diet.

Executive summary:

Albino rats received 1,3 -butylene glycol in the diet at levels of 1.0, 3.0, and 10.0% (500, 1500, and 5000 mg/kg bw/d) for two years. The control group was fed the basal laboratory diet (Celanese, 1963a, Scala and Paynter, 1967). The physical appearance and behaviour of the 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. No compound related adverse effects were observed. Subcutaneous and internal neoplasms were encountered in a number of control and test animals, primarily in females. Some of the neoplasms found at autopsy were identified as fibromas, fibrosarcomas, carcinomas, or adenomas and melanomas.

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:
sufficient for evaluation of endpoint

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

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

In a chronic feeding study in rats (Celanese, 1963a, Scala and Paynter, 1967), which had methodological deficiencies - number of animals per dose group too low, no analytical verification of doses - no cancer and non-cancer effects were observed in the tested dose range (up to 10% 1,3 -butylene glycol in food; 5000 mg/kg bw/d). These data are supported by a two year feeding study in dogs which received up to 3% 1,3-butylene glycol in the diet (750 mg/kg bw/d; Celanese, 1963b, Scala and Paynter, 1967). As the dog study did not fulfill the guideline requirements, especially the number of dogs tested was to low, it was judged not to be reliable (RL3).

Justification for classification or non-classification

In the absence of carcinogenic effects in chronic studies with rats and dogs and the negative findings in the available mutagenicity assays 1,3 -butylene glycol has not to be classified as carcinogenic according to the criteria of Regulation (EC) No 1272/2008.