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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:
From Jan. 6, 1986 to Mar. 3, 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study conduct was in principal similar to the OECD guideline 474 (1997), and GLP compliant. The Chinese hamster was used as test system; the OECD guideline recommends primarily the use of either mice or rats if bone marrow is considered, however any appropriate other mammalian species also may be used. According to OECD guideline 474, at least 2000 immature erythrocytes per animal have to be scored for the incidence of micronucleated immature erythrocytes. In the present study, 1000 immature erythrocytes per animal were scored. However, since the study was conducted prior to the implementation of the OECD guideline mentioned above and since the method and results were well-documented, the study is considered as fully reliable.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Version / remarks:
(1997)
Deviations:
yes
Remarks:
Instead of 2000 immature erythrocytes 1000 erythrocytes per animal were scored for micronuclei.
GLP compliance:
no
Type of assay:
micronucleus assay

Test material

Constituent 1
Reference substance name:
A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)
EC Number:
400-830-7
EC Name:
A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)
Cas Number:
104810-48-2
IUPAC Name:
14-({3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoyl}oxy)-3,6,9,12-tetraoxatetradecan-1-yl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate; 14-hydroxy-3,6,9,12-tetraoxatetradecan-1-yl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate; tris(17-({3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoyl}oxy)-3,6,9,12,15-pentaoxaheptadecan-1-yl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate); tris(17-hydroxy-3,6,9,12,15-pentaoxaheptadecan-1-yl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate); 2-(2-hydroxyethoxy)ethan-1-ol; 2-({3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoyl}oxy)ethyl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate; 2-[2-(2-hydroxyethoxy)ethoxy]ethan-1-ol; 2-[2-(2-hydroxyethoxy)ethoxy]ethyl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate; 2-hydroxyethyl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate; 2-methoxyethan-1-ol; 2-{2-[2-({3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoyl}oxy)ethoxy]ethoxy}ethyl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate; 20-({3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoyl}oxy)-3,6,9,12,15,18-hexaoxaicosan-1-yl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate; 20-hydroxy-3,6,9,12,15,18-hexaoxaicosan-1-yl 3-[3-(2H-1,2,3-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl]propanoate; 3,6,9,12,15,18,21-heptaoxatricosane-1,23-diol; 3,6,9,12,15-pentaoxaheptadecane-1,17-diol; 3,6,9,12-tetraoxatetradecane-1,14-diol; bis(ethane-1,2-diol)
Details on test material:
- Lot/batch No.: EN 20043.42
- Stability: Ensurd by sponsor
- Purity: Commercial grade
Substance of the same batch number was used in the 90 d repeated dose toxicity study (CIT 874232) were analytical analysis was given in the study report.

Test animals

Species:
hamster, Chinese
Strain:
other: randomly outbred
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CIBA-Geigy Tierfarm, Sisseln
- Age at study initiation: 6 to 10 weeks (females) and 4 to 9 weeks (males)
- Weight at study initiation: 20 to 28 g (females) and 21 to 29 g (males) for the mutagenicity experiment
- Housing: Individual caging
- Diet ad libitum: NAFAG No. 924
- Water ad libitum: tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 23 °C
- Humidity (%): 47 to 51 %
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle used: 0.5% CMC (carboxymethyl cellulose)
- Amount of vehicle: 20 ml
Duration of treatment / exposure:
Single dose administration
Frequency of treatment:
Single dose administration
Post exposure period:
Animals were sacrificed 16, 24, and 48 hours (treatment and negative control) and 24 hours (positive control) after treatment.
Doses / concentrations
Remarks:
Doses / Concentrations:
2940 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
24 animals/sex/treatment and negative control group (equals 8 animals/sex/group per investigated time point)
8 animals/sex/positive control group
Control animals:
yes, concurrent vehicle
Positive control(s):
64 mg/kg bw of cyclophosphamide in 0.5% Carboxymethylcellulose (CMC) was used as positive control.

Examinations

Tissues and cell types examined:
Bone marrow was harvested from the femurs. 1000 polychromatic erythrocytes (PCE) each were scored for the incidence of micronuclei per animal. The ratio of polychromatic to normochromatic erythrocytes (NCE) was determined for each animal by counting a total of 1000 erythrocytes. The slides of five female and five male animals each of the negative control group and of the dosage group sacrificed at 16, 24 and 48 hours post-treatment were examined.
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION
A preliminary toxicity test was performed with a single dose of 5000 mg/kg bw and doses corresponding to 2/3 and 1/3 of the high dose. Since no mortality occured at 2940 mg/kg bw/d, this dose was used as the highest dose in the mutagenicity experiment.
DETAILS OF SLIDE PREPARATION
Bone marrow was harvested from the shafts of femurs. Preparations were air-dried and stained with May-Gruenwald and Giemsa's. Cover slips were mounted in Eukitt.
Statistics:
The significance of difference was assessed by a chi-square test.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Remarks:
The mean percentage of PCE with micronuclei was 0.16 and 0.23, 0.1 and 0.26 as well as 0.19 and 0.24 for control and treatment after 16, 24 and 48 h. 6.1 % of PCE showed micronuclei after 24 h treatment with the positive control.
Toxicity:
no effects
Remarks:
The PCE/NCE-Ratio was 1.27 and 1.23, 1.75 and 1.47 as well as 1.58 and 1.01 for control and treatment after 16, 24 and 48 h.
Vehicle controls validity:
valid
Negative controls validity:
not examined
Positive controls validity:
valid
Additional information on results:
Toxic effects on bone marrow cells were seen in animals treated with the positive control (PCE/NCE-Ratio of 1.75 at control versus 0.8). The slight reduction of PCE/NCE- Ratio at 2940 mg/kg bw after 48 h (1.58 and 1.01 for control and treatment group) indicates that the substance reached the bone marrow cells.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative