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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: DNA damage and/or repair
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted to OECD guidelines and to GLP, and therefore meets the criteria for Klimisch code 1. However, as the study is used in a read-across approach, Klimisch 2 is assigned.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The test material was an analogue of CAS 70024-69-0 described as C20-24 alkaryl calcium salt derivative

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
Male and female swiss albino Crl: CD-1 (ICR) BR aged 50 days at initiation.

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
peanut oil
Details on exposure:
single dose via intraperitoneal injection followed by a 72 hr evaluation period
Dose volume: 5 ml/kg
Duration of treatment / exposure:
72 hours
Frequency of treatment:
Once
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
100 mg/kg
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
200 mg/kg
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
400 mg/kg
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
500 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
Peanut oil vehicle control: 18/sex;
triethylenemelamine positive control: 0.25 mg/kg, 5/sex;
100 and 500 mg/kg: 15/sex;
200 and 400 mg/kg: 18/sex
Control animals:
yes
Positive control(s):
triethylenemelamine positive control: 0.25 mg/kg, 5/sex; 100 and 500 mg/kg: l5/sex; 200 and 400 mg/kg: l8/sex

Examinations

Tissues and cell types examined:
erythrocytes evaluated for micronuclei and ratio of non chromatic and polychromatic determined
Evaluation criteria:
NCE/PCE ratio and % PCE versus total erythrocytes
Statistics:
Animal to animal variability in spontaneous frequency of micronucleated polychromatic erythrocytes were evaluated in vehicle controls. Statistically
significant differences were evaluated in the frequency of micronucleated polychromatic erythrocytes between treated groups and vehicle controls.
NCE/PCE (normochromatic erythrocytes/polychromatic erythrocytes) ratios in treated and control groups were compared. Tests included dispersion test of AmpWett and Delow, and Margolin, Fishers exact test, binomial approximation, Cochran-Artage test for trend, a one-way analysis of variance and Dunett's procedure.

Results and discussion

Test results
Key result
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid

Any other information on results incl. tables

During the main study, toxicity was observed at 400 and 500 mg/kg. at 500 mg/kg, 5 males and 4 females of 15/sex died prior to the scheduled sampling time. At 400 mg/kg, 1 of 18 treated females died on Day 3. Other clinical signs of toxicity included palpebral closure, decreased motor activity and weakness. Cytotoxicity was observed in both sexes. A statistically significant increase in NCE/PCE ratio was observed in individual animals of both sexes in other groups. Altered proportions of erythrocytes to nucleated cells were noted for both sexes in the treated groups. No biological or statistical significant increase in the number of micronucleated PCE/100 PCE expected for control animals. The variability in response observed in the vehicle controls. The positive control exhibited a statistically significant increase in micronuclei as expected. Chemical analysis confirmed that the dosing solution preparation procedure utilized for this study resulted in homogeneous solutions of appropriate concentration.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Under the conditions of this study the test substance was not genotoxic. Under the conditions of this study the test material did not induce micronuclei in bone marrow erythrocytes of mice. The genotoxicity NOEL was 500 mg/kg.
Executive summary:

In a mouse bone marrow micronucleus assay, animals were treated via the peritoneum with C20-24 alkaryl calcium salt derivatives at doses of 0, 100, 200, 400 and 500 mg/kg bw.  Bone marrow cells were harvested at 24, 48 and 72 hours post-treatment.  The vehicle was peanut oil. There were signs of toxicity during the study at 400 and 500 mg/kg.  The positive control induced the appropriate response.  There was not a significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time. This study is classified as acceptable. This study satisfies the requirement for Test Guideline OECD 474 for in vivo cytogenetic mutagenicity data.