Registration Dossier

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:
1992-02-24 to 1992-05-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Qualifier:
according to
Guideline:
EPA OTS 798.5395 (In Vivo Mammalian Cytogenics Tests: Erythrocyte Micronucleus Assay)
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Dodecanedioic acid of Du Pont Chemicals, purity 100 %, Haskell ID: H-19,272.

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ORGANISMS: 
- Source: Charles River Canada Inc., Montreal (Quebec, Canada)
- Age: 56 days (49+6+1)
- Weight at study initiation:   males 27.6 - 34.0 g, mean 30.6 g   females 22.6 - 28.2 g, mean 25.2 g
- No. of animals per dose: 5 males + 5 females per sampling time

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
0.5 % methyl cellulose in deionized water
Details on exposure:
ADMINISTRATION: 
- Vehicle: 0.5 % methyl cellulose in deionized water
- Control groups and treatment:    
negative: vehicle   
positive: 20 mg cyclophosphamide (CPA)/kg bw/day (in sterile water for  irrigation)
- Total volume applied: 15 ml/kg bw/administration on 2 days each in all  groups
- Duration of test: 72 hours
- Sampling times and number of samples: 24 hours (all dose levels) and 48  hours (all except positive control) after last treatment
Duration of treatment / exposure:
2 equal exposures separated by approx. 24 hours
Post exposure period:
Clinical observations: First 3-5 hours after administration; once daily  thereafter
Doses / concentrations
Remarks:
Doses / Concentrations:
5000; 2000; 1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
20 mg cyclophosphamide (CPA)/kg bw/day (in sterile water for  irrigation)

Examinations

Details of tissue and slide preparation:
EXAMINATIONS: 
- Clinical observations: First 3-5 hours after administration; once daily  thereafter
- Organs examined at necropsy: femur bone marrow   1000 PCE (polychromatic erythrocytes) per animal were analysed for  micronuclei
- Criteria for selection of M.T.D.: Initial study with 2 applications  each of 1250; 2500; 5000 mg/kg bw separated by 1 day; 
2 males + 2 females  / dose level; 2 days post dose observation.   
The top dose for the cytogenetic test was selected as the maximal  non-lethal dose.
Evaluation criteria:
- Criteria for evaluating results: Statistically significant (p<=0.05)  and biologically relevant increase in frequency of micronucleated  polychromatic 
erythrocytes of at least one test group as compared to the  negative control group
Statistics:
Following transformation using the arcsine method data were analysed by one-way ANOVA. In case of significance individual dose groups were compared to the negatiove control using Dunnett's test.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
MORTALITY: 
No deaths occurred during dose finding and main study.
CLINICAL SIGNS: No significant changes in body weight were observed in  any treated group at any sacrifice. Ruffled fur was exhibited by several  
treated and negative control animals. No other clinical signs were  observed. 
EFFECT ON MITOTIC INDEX OR PCE/NCE RATIO:    No significant reduction in PCE/NCE ratio was present in the positive  control group or in any test 
group when compared with the negative  control animals.
GENOTOXIC EFFECTS:    For the positive control a significant and clear increase in the  frequency of micronucleated polychromatic erythrocytes was 
observed.   The mean frequencies of micronucleated polychromatic erythrocytes in  the groups treated with the test item were equivalent to those of 
the  vehicle control group. 

Any other information on results incl. tables

--------------------------------------------------------
Treatment     Sex   Time   % Micron. in PCE    PCE/NCE
--------------------------------------------------------
Vehicle        m    24 h    0.10 +- 0.03    1.24 +- 0.20
Vehicle        f    24 h    0.10 +- 0.03    1.19 +- 0.21
1000 mg TS     m    24 h    0.02 +- 0.02    1.37 +- 0.17
1000 mg TS     f    24 h    0.16 +- 0.07    1.26 +- 0.08
2000 mg TS     m    24 h    0.10 +- 0.03    0.85 +- 0.15
2000 mg TS     f    24 h    0.08 +- 0.04    1.15 +- 0.07
5000 mg TS     m    24 h    0.14 +- 0.07    1.01 +- 0.14
5000 mg TS     f    24 h    0.08 +- 0.06    1.09 +- 0.18
Vehicle        m    48 h    0.20 +- 0.13    1.34 +- 0.27
Vehicle        f    48 h    0.10 +- 0.03    1.21 +- 0.24
1000 mg TS     m    48 h    0.04 +- 0.02    1.18 +- 0.28
1000 mg TS     f    48 h    0.06 +- 0.04    1.24 +- 0.20
2000 mg TS     m    48 h    0.08 +- 0.04    1.14 +- 0.20
2000 mg TS     f    48 h    0.16 +- 0.05    1.61 +- 0.28
5000 mg TS     m    48 h    0.12 +- 0.04    0.87 +- 0.05
5000 mg TS     f    48 h    0.06 +- 0.02    1.57 +- 0.17
20 mg CPA      m    24 h    0.96 +- 0.22 *  0.81 +- 0.10
20 mg CPA      f    24 h    0.76 +- 0.13 *  1.03 +- 0.12
--------------------------------------------------------
TS = test substance; CPA = cyclophosphamide; 
doses in mg/kg bw/day; * p<0.05

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Under the conditions of this study there was no indication for genotoxicity of the test substance dodecanedioic acid (DDDA) in vivo.
Executive summary:

The ability of Dodecanedioic acid (DDDA) to induce micronuclei in bonemarrow polychromatic erythrocytes (PCEs) was tested in male and female mice according to OECD TG 474.

Doses of 5000, 2000, or 1000 mg/kg bodyveightwere administered twice, approximately 24 hrs apart, by oral intubation. For all groups,bone marrow smears were prepared approximately 24 and 48 hrs after the final dose. Five males and five females per dose group were sacrificedat each sampling time. One thousand polychromatic erythrocytes per animal were evaluated for the presence of micronuclei.

No statistically significant increases in the frequency of micronucleated PCEs were observed in DDDA-treated animals at any sampling time. Nosignificant depression in the ratio of young, polychromatic erythrocytesto mature, normochromatic erythrocytes was observed. Under the conditions of this assay, DDDA did not induce micronuclei; the test material is negative.