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Diss Factsheets

Toxicological information

Genetic toxicity: in vivo

Currently viewing:

Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996-09-16 to 1996-12-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2005

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
yes
Remarks:
subchronic exposure
Principles of method if other than guideline:
NTP mouse peripheral blood micronucleus test protocol
MacGregor, J. T., Wehr, C. M., Henika, P. R., Shelby, M. D.(1990) Fund. Appl. Toxicol. 14, 513.
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Constituent 1
Chemical structure
Reference substance name:
Decahydronaphthalene
EC Number:
202-046-9
EC Name:
Decahydronaphthalene
Cas Number:
91-17-8
Molecular formula:
C10H18
IUPAC Name:
decahydronaphthalene
Details on test material:
Decahydronaphthalene, purity > 99 %

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS: 
- Source: Taconic Laboratory Animals and Services, Germantown (NY, USA)
- Age: 6 weeks at study initiation
- Weight at study initiation: males mean 21.9 g, females mean 19.6 g
- Number of animals: 10 males + 10 females per exposure concentration

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
Vehicle: clean air
Details on exposure:
ADMINISTRATION:   
- Concentration in vehicle: established within 12 minutes, monitored  every 24 minutes   At 72 +- 3 °F (22.2 °C) the ppm concentrations 
correspond to: 143, 285,  570, 1141, 2282 mg/m3
- Frequency of treatment: 6 hours (+ 12 minutes concentration  buildup)/day, 5 days/week
- Control groups and treatment: concurrent vehicle
EXAMINATIONS: 
CLINICAL OBSERVATIONS AND FREQUENCY: 
- Clinical signs: observed twice daily
- Mortality: observed twice daily
- Clinical findings: weekly
- Body weight: initially + weekly + end of study
- Hematology: Blood sampling at end of study. Determination of  hematocrit; packed red cell volume; hemoglobin; erthrocyte, reticulocyte,  nucleated  erythrocyte, and platelet counts; mean cell volume; mean cell  hemoglobin; mean cell hemoglobin concentration; and leukocyte count and  
differentials.
- Biochemistry: None
- Urinalysis: Sampling during week 12. Determination of creatinine,  glucose, glucose/creatinine ratio, protein, protein/creatinine ratio,  alkaline
phosphatase, alkaline phosphatase/creatinine ratio, alkaline  aminotransferase, aspartate aminotransferase, aspartate  aminotransferase/creatinine  ratio, lactate dehydrogenase, lactate  dehydrogenase/creatinine ratio, gamma-glutamyltransferase,  gamma-glutamyltransferase/creatinine ratio,   N-acetyl-beta-D-glucosaminidase, N-acetyl-beta-  D-glucosaminidase/creatinine ratio, volume, and specific gravity.
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Weights: heart, right kidney, liver, lung, right testis, thymus
- Macroscopic: yes, no details reported
- Microscopic: 0 and 400 ppm animals: gross lesions, adrenal gland, bone  with marrow, brain, clitoral gland, esophagus, gall bladder, heart, large  
intestine (cecum, colon, rectum), small intestine (duodenum, jejunum,  ileum), kidney, larynx, liver, lung, lymph nodes (mandibular, mesenteric,  
bronchial, and mediastinal), mammary gland (females only), nose, ovary,  pancreas, parathyroid gland, pituitary gland, preputial gland, prostate  
gland, salivary gland, skin, spleen, stomach (forestomach and glandular),  testis with epididymis and seminal vesicle, thymus, thyroid gland,  
trachea, urinary bladder, and uterus.
- Sampling times and number of samples: end of 3-month toxicity study,  peripheral blood samples   2000 NCEs (normochromatic erythrocytes) 
per animal were analysed for  micronuclei in up to 10 animals per exposure group.   1000 erythrocytes were counted to determine the percentage 
of  polychromatic (immature) erythrocytes (PCEs) among the total erythrocyte  population.
- Criteria for evaluating results:    
(1) one-tailed Cochran-Armitage trend test, followed by pairwise  comparisons between each exposed group and the control, for determination  
of concentration-response relationship   
(2) adjustment in case of excess binomial variation (binomial  dispersion test)   
(3a) P <= 0.025 in trend test OR   
(3b) single group with P <= 0.025/number of exposed groups   
(4) expert judgment by scientific staff
- Criteria for selection of M.T.D.: Low mortality and low impairment of  body weight development in preceding two-week study
Duration of treatment / exposure:
14 weeks; 1 additional day before end of study
Frequency of treatment:
6 hours (+ 12 minutes concentration  buildup)/day, 5 days/week
Post exposure period:
Post-exposure period: none
Doses / concentrations
Remarks:
Doses / Concentrations:
25, 50, 100, 200, 400 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed

Examinations

Evaluation criteria:
In the micronucleus test, an individual trial is considered positive if the trend test P value is less than or equal to 0.025 or
if the P value for any single exposed group is less than or equal to 0.025 divided by the number of exposed groups.
A final call of positive for micronucleus induction is preferably based on reproducibly positive trials.
Statistics:
The frequency of micronucleated cells among NCEs was analyzed by a statistical software package that tested for increasing trend over exposure groups with a one-tailed Cochran- Armitage trend test, followed by pairwise comparisons between each exposed group and the chamber control group
(ILS, 1990). In the presence of excess binomial variation, as detected by a binomial dispersion test, the binomial variance of the Cochran-Armitage test was adjusted upward in proportion to the excess variation.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
not applicable
Additional information on results:
MORTALITY: All mice survived to the end of the study.
CLINICAL SIGNS: There were no clinical findings related to exposure. 
NECROPSY FINDINGS: see subchronic toxicity study
BODY WEIGHT CHANGES: see subchronic toxicity study
GENOTOXIC EFFECTS: 
- males: small but statistically significant (P=0.001) increase in  frequency of micronucleated NCEs with exposure concentration
- female: no induction of micronuclei (P=0.917)
- both: slight increase over exposure range in percentage of PCEs,  however, all values were within the normal range
NOAEL (NOEL) (C) / LOAEL (LOEL) (C): see subchronic toxicity study

Any other information on results incl. tables

EFFECT ON MITOTIC INDEX OR PCE/NCE RATIO: 
--------------------------------------------------------
Treatment  Mice scored  Sex  % Micron. in PCE   PCEs (%)
--------------------------------------------------------
    0 ppm          10       m       5.5 +/- 1.6       1.8
   25 ppm        10       m       4.5 +/- 1.6       1.8
   50 ppm         10       m     10.0 +/- 1.5       2.0
  100 ppm       10       m     10.0 +/- 2.2       1.9
  200 ppm       10       m     12.5 +/- 2.0       1.9
  400 ppm         9       m     13.3 +/- 2.0       2.6
--------------------------------------------------------
    0 ppm          9       f      6.7 +/- 2.0       1.6
   25 ppm         10       f      5.0 +/- 1.1       1.8
   50 ppm        10       f      7.0 +/- 1.9       1.6
  100 ppm       10       f      3.5 +/- 1.3       1.5
  200 ppm       10       f      3.0 +/- 0.8       2.0
  400 ppm       10       f      4.0 +/- 1.2       2.0
--------------------------------------------------------
GENOTOXIC EFFECTS: 
- males: small but statistically significant (P=0.001) increase in  frequency of micronucleated NCEs with exposure concentration
- female: no induction of micronuclei (P=0.917)
- both: slight increase over exposure range in percentage of PCEs,  however, all values were within the normal range
NOAEL (NOEL) (C) / LOAEL (LOEL) (C): see subchronic toxicity study

Applicant's summary and conclusion

Conclusions:
No effects were noted in females, a slight statistically significant increase in micronucleated normochromatic erythrocytes was observed in males but the values were within the normal range.
Executive summary:

As part of the repeated dose study, following inhalation exposure to decahydronaphthalene for 5 days per week, 4 hours per day for a period of 3 months blood smears from 10 male and ten female mice were obtained. Dose levels were 0, 25, 50, 100, 200, 400. A slight but statistically significant increase in micronucleated normochromatic erythrocytes was observed in males ppm. However the values were within the normal range. No effects were noted in female mice.