Registration Dossier

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:
1993-04-26 to 1993-05-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

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:
Produced by Hüls AG, sampled 02 Feb. 1993; Sample ID 3633/81495, purity 98.5 % w/w (GD)

Test animals

Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals and environmental conditions:
TEST ORGANISMS: 
- Age: young adults
- Source: Winkelmann, Borchen (Germany)
- Weight at study initiation:    
test group, male: 32.2 +/- 6.4 g   
test group, female: 27.2 +/- 5.4 g
- No. of animals per dose: 5 males, 5 females per test duration

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn-oil
Details on exposure:
ADMINISTRATION: 
- Vehicle: corn oil
- Duration of test: 24 hours; 48 hours
- Sampling times and number of samples: 24 hours; 48 hours
- Control groups and treatment:   
positive control cyclophosphamide (vehicle physiol. NaCl),   dose 100 mg/kg bw, 24 hours   
negative control corn oil (= vehicle)
Duration of treatment / exposure:
one single application (10 ml/kg bw)
Frequency of treatment:
one time
Post exposure period:
24 and 48 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
2000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
5 animals per sex
cyclophosphamide (vehicle physiol. NaCl),   dose 100 mg/kg bw, 24 hours   

Examinations

Details of tissue and slide preparation:
EXAMINATIONS: 
- Clinical observations: yes
- Organs examined at necropsy: femur bone marrow
- Criteria for selection of M.T.D.: maximum dose <= 2000 mg/kg bw  without  mortalities within 48 hours
Evaluation criteria:
- Criteria for evaluating results: statistically significant and  biologically relevant increase in frequency of micronucleated  polychromatic 
erythrocytes of at least one test group as compared to the  negative control group of the same sampling time

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Remarks:
MORTALITY: No mortality in dose finding test within 48 hours at 2000  mg/kg bw. Two females from the satellite group died within 30 hours  post  treatment. CLINICAL SIGNS: piloerection, apathy, dark coloured urine; normality  within 48 hours
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
MORTALITY: No mortality in dose finding test within 48 hours at 2000  mg/kg bw. Two females from the satellite group died within 30 hours 
post  treatment.
CLINICAL SIGNS: piloerection, apathy, dark coloured urine; normality  within 48 hours

A significant decrease in the PCE/NCE (NCE = normochromatic erythrocytes)  relation in the treated animals proved that the test substance or its  
metabolites had reached the bone marrow.

Any other information on results incl. tables

EFFECT ON MITOTIC INDEX OR PCE/NCE RATIO: 
---------------------------------------------------------
- positive control, 24 h: PCE statistically significant
  males   362 micronuclei / 10,011 PCE (3.62 +- 1.49 %)
           43 micronuclei / 47,756 NCE (0.11 +- 0.05 %)
           PCE/NCE = 0.24 +- 0.08
  females 350 micronuclei / 10,005 PCE (3.50 +- 0.33 %)
           24 micronuclei / 45,909 NCE (0.06 +- 0.04 %)
           PCE/NCE = 0.27 +- 0.16
- negative control, 24 h:
  males    18 micronuclei / 10,030 PCE (0.18 +- 0.07 %)
           24 micronuclei / 17,855 NCE (0.13 +- 0.05 %)
           PCE/NCE = 0.59 +- 0.13
  females  13 micronuclei / 10,023 PCE (0.13 +- 0.07 %)
           11 micronuclei / 17,407 NCE (0.07 +- 0.07 %)
           PCE/NCE = 0.66 +- 0.23
- test substance, 24 h: PCE not statistically significant
  males    16 micronuclei / 10,013 PCE (0.16 +- 0.15 %)
           89 micronuclei / 66,679 NCE (0.13 +- 0.05 %)
           PCE/NCE = 0.17 +- 0.06
  females   7 micronuclei / 10,009 PCE (0.07 +- 0.07 %)
           30 micronuclei / 42,428 NCE (0.07 +- 0.03 %)
           PCE/NCE = 0.26 +- 0.08
- negative control, 48 h:
  males    20 micronuclei / 10,019 PCE (0.20 +- 0.12 %)
           24 micronuclei / 28,511 NCE (0.09 +- 0.05 %)
           PCE/NCE = 0.39 +- 0.12
  females  16 micronuclei / 10,023 PCE (0.16 +- 0.07 %)
           10 micronuclei / 15,394 NCE (0.07 +- 0.05 %)
           PCE/NCE = 0.67 +- 0.12
- test substance, 48 h: PCE not statistically significant
  males    13 micronuclei / 10,006 PCE (0.13 +- 0.04 %)
           66 micronuclei / 89,554 NCE (0.08 +- 0.05 %
           PCE/NCE = 0.19 +- 0.14
  females   7 micronuclei / 10,009 PCE (0.07 +- 0.06 %)
           19 micronuclei / 45,881 NCE (0.05 +- 0.01 %)
           PCE/NCE = 0.23 +- 0.07

---------------------------------------------------------

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
In a murine micronucleus test tetrahydronaphthalene exhibited no genotoxic activity in vivo.
Executive summary:

In a micronucleus assay in NMRI mice according to OECD TG 474 (1983) five mice per sex and test duration received one single application with 2,000 mg 1,2,3,4- tetrahydronaphthalene/kg bw in corn oil (10 ml/kg bw) by gavage. The selected dose was the maximum dose without mortalities within 48 hours. Sampling times were 24 and 48 hours after test substance administration. 1,2,3,4-Tetrahydronaphthalene treatment did not result in an increase in the frequency of micronucleated polychromatic erythrocytes (PCE), but it significantly reduced the PCE/NCE ratio in male and female animals at both sampling times. This clearly indicates that the

target organ (the bone marrow) had been reached in this test.