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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996-09-16 to 1996-12-18
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

Principles of method if other than guideline:
Repeated Dose Toxicity, U.S. NTP
GLP compliance:
no
Limit test:
no

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, mixed lots 07347LG and 12426EN of Sigma Aldrich Fluka Bulk Chemicals (St. Louis, MO, USA), purity > 99 %

Test animals

Species:
rat
Strain:
Fischer 344
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 97 g, females mean 90 g (core  study)  
Number of animals: total 25 males + 20 females per exposure  concentration
- Food a(d libitum except during exposure and urine collection periods), irradiated: NTP-2000 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA)
- Water (ad libitum): tap water
- Housing: individually in Stainless-steel wire bottom (Hazleton System, Inc., Aberdeen, MD)

ENVIRONMENTAL CONDITIONS (CHAMBER)
- Temperature: 72° ± 3° F
- Relative humidity: 50% ± 15%
- Room fluorescent light: 12 hours/day
- Chamber air changes: 15/hour

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: clean air
Details on inhalation exposure:
ADMINISTRATION / EXPOSURE 
- Duration of exposure:    
2 weeks:  5 male renal toxicity rats   
6 weeks:  10 male + 10 female clinical pathology rats  
14 weeks: 10 male + 10 female core study rats
- Type of exposure: whole-body inhalation
- Vehicle: clean air
- 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
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations in the exposure chambers were monitored every 24  minutes by an on-line gas chromatograph
Duration of treatment / exposure:
2, 6, or 14 weeks; 1 additional day before end of study
Frequency of treatment:
6 hours (+ 12 minutes concentration buildup)/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
25, 50, 100, 200, 400 ppm
Basis: analytical conc.
No. of animals per sex per dose:
25 male and 20 female rats
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
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 on days 3 and 23 (clinical pathology group) or at end of study (core
study group). 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: Urea nitrogen, creatinine, total protein, albumin, globulin, albumin/globulin ratio, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids
- 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

OTHER EXAMINATIONS: 
- Sperm motility: Collection of sperm samples from 0, 100, 200, and 400  ppm males at the end of the study. Evaluation of: spermatid heads per  
testis, per gram testis, per cauda, and per gram cauda and epididymal  spermatozoal motility. The left cauda, left epididymis, and left testis  were 
weighed. 
- Vaginal cytology: Collection of vaginal samples for up to 12  consecutive days prior to the end of the study from 0, 100, 200, or 400  ppm females. 
The percentage of time spent in the various estrous cycle  stages and estrous cycle length were evaluated. 
- Renal effects:   16 hour-urine samples (all exposure concentrations) from   
- 2 weeks: 5 male renal toxicity + 5 female clinical pathology rats:  volume and decalol excretion;   
- 6 weeks: 5 male + 5 female clinical pathology rats: volume and  decalol excretion;   
- 12 weeks:10 male + 10 female core study rats: volume.   
Urine analysis (all exposure groups) for  
- weeks 2 and 6: decalol and creatinine   
- week 12: creatinine   Right kidney sample analysis (all male groups) for   
- weeks 2, 6, and 14: cis- and trans-decahydronaphthalene, cis- and  trans-decahydro-2-naphthalone, a2u-globulin   Right kidney sample analysis 
(females) for   
- week 14: cis- and trans-decahydronaphthalene   Calculation of several concentration ratios.
- Assessment of cell proliferation: Analysis of left kidney sections and  duodenum from   
- 5 male renal toxicity rats (2 weeks),   
- 5 male clinical pathology rats (6 weeks),   
- 5 or 10 male core study rats (14 weeks)
Sacrifice and pathology:
SACRIFICE
Carbon dioxide asphyxiation

PATHOLOGY
Necropsy was performed on all core study animals. Organs weighed were the heart, right kidney, liver, lung, right testis, and thymus.
- Weights: heart, right kidney, liver, lung, right testis, thymus
- Macroscopic: yes, no details reported
- Microscopic: 0 and 400 ppm core study rats: gross lesions, adrenal gland, bone with marrow, brain, clitoral gland, esophagus, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lung, lymph nodes (mandibular, mesenteric, bronchial, and mediastinal), mamary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and semial vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus
Other groups: kidney of male rats.
Statistics:
STATISTICAL METHODS: not specifically reported; general data compiled  with carcinogenicity study data in chapter 5.7

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical findings related to exposure. 
Mortality:
no mortality observed
Description (incidence):
All rats survived to the end of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weights of exposed groups were similar to  those of the control groups. 
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Several transient observations were minimal and not considered  toxicologically relevant
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Several transient observations were minimal and not considered  toxicologically relevant
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Significant findings were consistent with the renal  toxicity data and the renal lesions observed microscopically:  
increase in glucose/creatinine ratio (males >= 25 ppm: 20-93 %)   
increase in protein/creatinine ratio (males >= 25 ppm: 19-44 %)  
increase in aspartate aminotransferase/creatinine ratio (males >= 25  ppm: 4.9-6.7fold, females >= 50 ppm: 1.7-2.3fold)   
increase in lactate dehydrogenase/creatinine ratio (males and females  >= 25 ppm: 3.0-4.2fold and 1.5-2.1fold, respetively)
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and/or relative kidney and liver weights of male rats exposed  to >= 50 ppm were increased, s. "Any other information on results incl. tables"
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Incidences and/or severities of hyaline droplet accumulation and renal tubule regeneration in the kidney generally increased with increasing  exposure concentration. Granular casts were seen in the kidney at 6 weeks and at terminal sacrifice. 
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
Concentrations of a2u-globulin in the kidney as well as the  a2u globulin/soluble protein ratios were significantly increased in the  200 and 400 ppm males at weeks 2, 6, and 14.  Sperm motility and vaginal cytology parameters were not affected by  exposure.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
25 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
urinalysis
Dose descriptor:
LOAEC
Effect level:
> 25 ppm
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 

Concentration Kidney Liver
  absolute relative absolute relative
25 ppm +5.8 % +4.5 % *  +5.5 %   +3.9 %
50 ppm +5.3 % +7.9 % ** +5.1 %  +8.0 % **
100 ppm +3.3 % +7.7 % **  +1.2 % +5.5 % **
200 ppm +15.0 % ** +11.5 % ** +12.1 % ** +8.7 % **
400 ppm +19.8 % ** +19.6 % ** +11.2 % ** +10.9 % **

Applicant's summary and conclusion

Conclusions:
Urinalysis showed significant findings (increase in lactate dehydrogenase/creatinine ratio and in aspartate aminotransferase/creatinine ratio) in male and female rats exposed to 25 ppm and greater. Absolute and/or relative kidney and liver weights of male rats exposed to 50 ppm were increased. Females were not affected. So the changes in enzyme urine levels in female rats are not adverse effects, because they are not related to any simultaneous increase of kidney weight damage and therefore, 25 ppm is determined to be the no observed effect concentration (NOAEC) in female rats in this 90 day study.
Furthermore, Decahydronaphthalene causes male rat-specific alpha2u-globulin nephropathy. This type of kidney toxicity characterised by increased formation of hyaline droplets, increased concentration of alpha2u-globulin results in increased cell proliferation and may increase renal adenoma and carcinoma rates. Because the mechanism has been established as species and sex-specific for the male rat it is generally considered to be of no relevance for human health, endpoints resulting from male nephrotoxicity are not considered as relevant.
Executive summary:

Groups of 25 male and 20 female F344/N rats were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 2 (five male renal toxicity rats), 6 (10 male and 10 female clinical pathology rats), or 14 (10 core study rats) weeks. All rats survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Urinalysis results indicated that decalin exposure caused increases in urine glucose and protein concentrations and enzyme activities that were consistent with the renal lesions observed microscopically. Renal toxicity studies were performed on rats sacrificed at 2 and 6 weeks and at the end of the study. In kidney tissue examined for cell proliferation, the numbers of PCNA-labeled cells and labeling indices were generally significantly greater than those of the chamber controls in exposed groups of rats at all three time points. Concentrations of alpha2u-globulin in the kidney as well as the alpha2u-globulin/soluble protein ratios were significantly increased at week 2 in all exposed groups and in the 200 and 400 ppm groups at week 6 and at the end of the study. Absolute and/or relative kidney and liver weights of male rats exposed to 50 ppm or greater were increased. Females were not affected. Incidences of renal tubule regeneration and granular casts in the medulla of the kidney in exposed male rats were increased, and the severities of hyaline droplets generally increased with increasing exposure concentration.