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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11-Feb-1992 to 27-Apr-1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1-Dodecanol (Lorol C12-99)
- Substance type: fatty alcohol
- Physical state: colourless liquid, pasty
- Analytical purity: 100% (active substance)
- Lot/batch No.: A 06502:91
- Expiration date of the lot/batch: Apr-1992
- Stability under test conditions: not given (pure: at least 6 months)
- Storage condition of test material: at room temperature, dark
- Other:
Production date: 24-Oct-1991
Receipt of test material: 26-Nov-1991

Test animals

Species:
mouse
Strain:
other: albino mice, CFW 1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann
- Age at study initiation: 7-8 weeks
- Weight at study initiation: males 21-27 g, females 21-26 g
- Assigned to test groups randomly: yes, under following basis: allocated to treatment groups according to randomization table generated by computer programme or manually
- Fasting period before study: yes, overnight until 3-4 hours after dosing
- Housing: males, 1/cage, macrolon cages type I; females, <=3/cage, macrolon cages type II; filled with clean softwood bedding
- Diet (e.g. ad libitum): standard animal diet, Altromin No. 1314, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: >=6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 +- 3 (occasionally 20-25)
- Humidity (%): 40 - 50 (occasionally 45-70)
- Air changes (per hr): no data, except "air-conditioned room"
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES (main study): From: 25-Feb-1992 To: 28-Feb-1992

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: arachis oil
- Justification for choice of solvent/vehicle: test material easily soluble at required concentration
- Concentration of test material in vehicle: not stated, but provided a dose level of 5000 mg/kg bw, so 500 mg/ml
- Amount of vehicle (if gavage or dermal): 10 ml/kg bw (main study), 20 ml/kg bw (range finding study)
- Lot/batch no. (if required): no data
- Purity: no data
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 500 mg/ml in arachis oil (main study)
Duration of treatment / exposure:
single administration
Frequency of treatment:
single administration
Post exposure period:
evaluated at 24, 48, 72 hours after administration
Doses / concentrations
Remarks:
Doses / Concentrations:
5000 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Positive control(s):
cyclophosphamide
- Justification for choice of positive control(s): not stated
- Route of administration: oral
- Dose: 20 mg/kg bw

Examinations

Tissues and cell types examined:
bone marrow
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: maximum tolerated dose, based on range-finding study (effects seen at 5000 mg/kg were piloerection only)

TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields): single administration, animals sacrificed 24, 48 and 72 hours after administration

DETAILS OF SLIDE PREPARATION: bone marrow collected from femurs, using foetal calf serum applied via a syringe, into a siliconised centrifuge tube; after centrifugation at 1000 rpm and removal of all but one drop of supernatant, cells of sediment carefully mixed; drop of cell suspension placed on clean, degreased microscope slide and immediately spread; 3 slides/animal; slides air dried at least overnight; stained with Giemsa; air dried and dipped in xylol for 3 minutes

METHOD OF ANALYSIS: 1 slide/animal chosen and given a random code; microscopic evaluation of slides from 5 males and 5 females per treatment group at 1000x magnification; number of micronucleated cells counted in 1000 polychromatic erythrocytes (PCEs)/animal; ratio of
polychromatic to normochromatic erythrocytes determined by counting and differentiating the first 1000 erythrocytes

OTHER: means and standard deviations calculated
Evaluation criteria:
Statistically significant (p<0.05) increase in PCE compared to controls at any sampling time in either sex
Acceptability of test: positive controls induced statistically significant increase in frequency of micronucleated PCEs; solvent control incidence of micronuclei should reasonably fall within historical control range for the testing facility.
Statistics:
Method used: Kastenbaum & Bowman

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Remarks:
piloerection for 8 hours after administration; no mortality
Vehicle controls valid:
yes
Negative controls valid:
not examined
Positive controls valid:
yes
Additional information on results:
RESULTS OF RANGE-FINDING STUDY
- Dose range: 5000 mg/kg bw
- Solubility: used at 250 mg/ml
- Clinical signs of toxicity in test animals: piloerection
- Evidence of cytotoxicity in tissue analyzed: not examined
- Rationale for exposure: based on limit test in rats in which acute oral LD50 was >5000 mg/kg bw
- Harvest times: animals observed for 3 days

RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei (for Micronucleus assay): no statistically significant increase in micronucleus frequency in any treatment group
- Ratio of PCE/NCE (for Micronucleus assay): treated groups similar to controls
- Appropriateness of dose levels and route: maximum tolerated dose of 5000 mg/kg bw used; guideline recommends maximum dose of 2000 mg/kg bw; oral route selected "taking into account the possible route of human exposure during manufacture, handling and use"
- Statistical evaluation: no statistically significant increases in micronuclei in treated groups of either sex; positive control produced a statistically significant increase in micronuclei
- Control incidence of micronuclei: not reported but presumably therefore within historical control range

Any other information on results incl. tables

Lorol 12 did not increase the frequency of micronucleated erythrocytes or the PCE:NCE ratio in mice at any time interval after treatment (24, 48 or 72 hours) at dose levels up to 5000 mg/kg bw when compared to vehicle controls.

Mean values per group in the micronucleus test with 1-Dodecanol (Lorol C12-99)

a) Number of micronucleated cells per 1000 polychromatic erythrocytes (PCE)

b) Ratio of polychromatic to normochromatic erythrocytes (PCE/NCE)

Treatment group; (sampling time)

Species and sex

Dose mg/kg

Micronucleated cells 1000 PCE

Ratio of PCE/NCE

Mean

Range

Mean

Range

Negative control (24 hours) arachis oil

male mice

10 ml/kg

3.60

0 - 9

1.11

0.80 - 1.31

female mice

10 ml/kg

2.00

0 - 4

1.34

1.02 - 1.07

Positve control (24 hours) cyclophosphamide

male mice

20

13.40

10 - 16

1.21

0.90 - 1.72

female mice

20

10.80

7 - 14

0.95

0.67 - 1.28

1-Dodecanol (Lorol C12-99)

 

 

 

 

 

 

 

Limit dose (24 hours)

male mice

5000

2.60

0 - 5

1.08

0.94 - 1.26

female mice

5000

2.40

2 - 3

1.01

0.90 - 1.18

Limit dose (48 hours)

male mice

5000

3.00

1 - 4

0.89

0.48 - 1.16

female mice

5000

2.00

0 - 5

1.18

0.90 - 1.68

Limit dose (72 hours)

male mice

5000

2.60

2 - 4

1.65

0.91 - 2.14

female mice

5000

1.60

0 - 4

1.33

1.08 - 1.55

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Dodecan-1-ol has been tested a highly reliable study, conducted according to OECD guideline 474, no genotoxicity was seen in mice after a single oral dose of 5000 mg/kg bw. The study was performed in compliance with GLP. The test substance, dodecan-1-ol (CAS number ) is closely related to the registration substance, decan-1-ol, and it is considered that read-across is valid.