3-methylbutan-1-ol

Carcinogenicity

Description of key information

There are no indications of a carcinogenic potential from the available in vitro and in vivo genotoxicity and repeated dose toxicity study results. No carcinogenic potential was revealed for the category member pentan-1-ol in a 24 week pulmonary tumor screening assay performed using intraperitoneal injections in mice.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity

Remarks:

intraperitoneal

Type of information:

read-across based on grouping of substances (category approach)

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:

A read-across justification is provided in the IUCLID Chapter "Assessment reports"

Principles of method if other than guideline:

24 week carcinogenicity study in the strain A mouse pulmonary tumor assay

GLP compliance:

no

Species:

mouse

Strain:

other: A/He

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Institute for Cancer Research, Philadelphia, or obtained from the National Cancer Institute
- Age at study initiation: 6 to 8 w
- Weight at study initiation: 18 to 20 g
- Housing: in groups of 5 in plastic boxes
- Diet: Purina laboratory chow; ad libitum
- Water: water; ad libitum

Route of administration:

intraperitoneal

Vehicle:

other: tricaprylin

Details on exposure:

Dose: 0.1 mL/dose in vehicle tricaprylin (source: Eastman, Lot No.: X2097)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

8 weeks

Frequency of treatment:

3 times per week = 24 injections

Post exposure period:

not applicable

Remarks:

Doses / Concentrations:
50, 250 mg/kg/bw
Basis:
nominal conc.
dose per application

Remarks:

Doses / Concentrations:
1200, 6000 mg/kg bw
Basis:
nominal conc.
total amount received

No. of animals per sex per dose:

30

Control animals:

yes, concurrent no treatment

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
The MTD (maximally tolerated single dose) was determined in a preliminary toxicity study.
Serial 2-fold dilutions of the chemical were injected into groups of 5 mice. The MTD for that chemical was the maximum single dose that all 5 mice tolerated after receiving 6 i.p injections over a 2-week period. For evidence of delayed toxicity, particularly as occurred with the chemotherapeutic compounds, animals receiving 6 doses of the MTD were held for 1 to 2 months before experimental groups were initiated.

- Bioassay:
Groups of 15, 20 or 30 A/He mice per sex per dose received the test material 3 times per week for 8 weeks. The vehicle was tricaprylin. The mice were housed in groups of 5. The mice were 6-8 weeks old and initial body weights were 18 to 20 g. Sacrifice was 24 weeks after the start of dosing. The observations were survival, body weight, autopsy and microscopic examination of lungs. Liver, kidney, spleen, thymus, intestine and salivary and endocrine glands were also examined for abnormalities at necropsy. The positive control was 10 or 20 mg urethan. An untreated control group of 50 mice per sex was included.
Two series of base-line controls were maintained during the experimental period. One consisted of untreated mice killed along with the treated animals to determine the incidence of spontaneous pulmonary tumours. The other controls received injections of the vehicle.
Post-exposure period: 16 weeks

Positive control:

10, 20 mg/animal Urethan

Sacrifice and pathology:

GROSS PATHOLOGY: Yes: Liver, kidney, spleen, thymus, intestine, and salivary and endocrine gland
HISTOPATHOLOGY: Yes: lungs for the presence of tumours and other abnormalities, such as inflammatory reactions and adenomatosis

Statistics:

Tumour incidences in treated versus the appropriate vehicle control animals were compared by the standard Chi-Square test to determine whether each compound was positive. In addition, the method of Zweifel (1966), previously applied to pulmonary tumour data by Shimkin et al. (1966), was used to express the relative potency of the more reactive compounds.
Zweifel JR (1966). J. Nat l. Cancer Inst. 36: 937-946.
S himkin MB et al. (1969). Cancer Res. 29: 2184 -2190.

Details on results:

Result (carcinogenicity): negative

Dose descriptor:

NOEL

Effect level:

250 other: mg/kg bw/application

Sex:

female

Basis for effect level:

other: mortality; histopathology

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Results:

Treatment	Dose	Survivors/initial	Mice with lung tumours (%)	No. of tumours/animal
untreated		48/50	17	0.17 +/- 0.02
Tricaprylin 2097		22/25	45	0.59 +/- 0.13
Tricaprylin X2097		77/80	20	0.20 +/- 0.02
Urethan	10 mg	20/20	100	9.1 +/- 2.28
Urethan	20 mg	19/20	100	19.6 +/- 4.20
n-amyl alcohol	50 mg/kg bw/application	29/30	3	0.10 +/- 0.12
n-amyl alcohol	250 mg/kg bw/application	30/30	3	0.13 +/- 0.02

Data from female animals displayed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

mouse

Quality of whole database:

reliable publication

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available data are considered reliable and suitable for classification purposes under Regulation (EC) No 1272/2008 (CLP).

As a result, the substance is not classified for carcinogenicity under Regulation (EC) No 1272/2008, as amended for the seventh time in Regulation No (EC) 1297/2014.

Additional information

Based on reliable in vitro and in vivo genetic toxicity tests with 3-methylbutan-1-ol and its structural analogues, these substances are not considered to be genotoxic. In addition, there is no indication from repeated dose studies that the substances are able to induce hyperplasia or pre-neoplastic lesions. Thus, there is not concern regarding carcinogenicity for these substances.

No adequate experimental animal data according to or equivalent to the OECD guidelines 451/452/453 are available and no epidemiological studies investigating the carcinogenicity of 3-methybutan-1-ol or its structural analogues were identified. However, carcinogenicity of the read-across substance pentan-1-ol was investigated in a 24 week pulmonary tumor assay, where 30 female A/He mice per dose received 24 intraperitoneal injections of 50 or 250 mg/kg bw pentan-1-ol over 8 weeks. Thereby, survival, body weights and results from gross pathological and histological examinations of the lungs were assessed. 24 weeks after the start of dosing, animals were sacrificed and liver, kidney, spleen, thymus, intestine and salivary and endocrine glands were examined for abnormalities at necropsy. Positive control groups consisting of animals treated with 2 dose levels of urethane (10 or 20 mg urethane/animal) were also maintained. An untreated control group of 50 mice per sex was included. Data on untreated animals represent the spontaneous lung tumor incidence in A/He mice and according to the authors, were in close accord with earlier data on mice of equivalent age. Positive controls treated with urethane showed a dose-related increase in pulmonary tumor incidence. The result of this study was clearly negative, as the lung tumor rate was found to be lower in pentan-1-ol treated groups as compared to the untreated control group (3 % in treated versus 17 % in untreated mice). Thus, under the conditions of this study, pentan-1-ol did not show any carcinogenic potential.

3 -methylbutan-1 -ol (CAS No. 123 -51 -3) was evaluated in an invalid and badly documented carcinogenicity study which was described in two publications (Gibel et al. 1974, 1975). In these studies, 15 Wistar rats were dosed orally twice a week with 0.1 mL/kg bw 3-methylbutan-1-ol corresponding to 80.8 mg/kg bw/dose whereas 24 animals received an subcutaneous injection of 0.04 mL/kg bw corresponding to 32.3 mg/kg bw/dose once a week. The number of control animals was inconsistently reported as either 25 or 30. Postmortal examination after the average life time of 527 days included blood analysis as well as histopathological analysis of the organs, spinal segments and femurs. Severe chronic-toxic effects were reported. These were liver cirrhosis, myocard necrosis and effects on pancreas and haematopoietic organs. However, the number of affected animals was not given, nor could the effects be assigned to a specific dose group. The effects are especially surprising since no adverse effects were observed in two studies after daily treatment with a more than 10 times higher dose for 90 days, which leads to a higher cumulative dose (108 -119g/kg compared to 12g/kg p. o. and 2.7g/kg s. c.) in a much shorter time period. No tumours were seen in the control rats after two years, which is unlikely even considering the relatively low number of animals used. No historical control data were provided. A low overall number of tumours occured in the treated groups (4 after oral treatment, 10 after s.c. treatment) as single incidences of different tumour types in different organs, which are considered incidental. Due to severe deficits the study was disregarded for the assessment.

Justification for selection of carcinogenicity via oral route endpoint:
most reliable data available