Decahydronaphthalene

Endpoint summary

Description of key information

Subacute studies on oral repeated dose toxicity in rats are available. Subcaute and subchronic repeated dose toxicity studies in rats, mice, dogs and guinea pigs with inhalation exposure to decahydronaphthalene are available (see below "Additional information"). No data available on repeated dermal exposure with the test item. A data waiver is claimed.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

daily oral dosing up to 28 days

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

no data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 10, 100, 1000 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

30 male
5 female

Control animals:

yes, concurrent vehicle

Details on study design:

5 males each were sacrificed on days 1, 3, 7, 14, 28 and 14 days post -treatment
5 females were sacrificed on day 28

Positive control:

no data

Observations and examinations performed and frequency:

no data

Sacrifice and pathology:

no data

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

kidney toxicity in male rats at dose levels >10 mg/kg bw/d

Histopathological findings: neoplastic:

not specified

Details on results:

Increased incidences of hyaline droplets in the renal proximal tubule cells of male rats, increased cell turnover, and focal renal tubule damage were seen in the 100 and 1,000 mg/kg groups.

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no adverse effects were seen up to the highest dose level

Key result

Dose descriptor:

NOAEL

Effect level:

> 10 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Kidney toxicity, hyaline droplets

Critical effects observed:

not specified

Conclusions:

Male specific kidney toxicity was observed upon oral administration of decahydronaphthalene at dose levels of 100 and 1000 mg/kg bw/d administered by gavage. Hystology of kidneys identified possible mechanism for this sex and species specific toxicity.

Executive summary:

Kidneys from male and female Wistar rats dosed with Decalin, were examined by light and electron microscopy. Paraffin histology showed hyaline droplet accumulation in the renal proximal tubular cells of the male rats. Resin histology at both the light and electron microscope level, along with cytochemical procedures for acid phosphatase and the protein 'alpha 2U globulin', helped further in the characterisation of these cytoplasmic inclusions. These techniques confirmed that the accumulation of hyaline droplets seen by paraffin histology represented an increase in the size and number of secondary lysosomes which have been shown to be involved in protein uptake and metabolism. Time course studies showed that increased numbers of small dense lysosomes appear first, which then increase in size, presumably by fusion. Crystalloid bodies form in these large lysosomes eventually giving rise to rectilinear bodies. The accumulation of these protein laden secondary lysosomes took place primarily in the cells of the S1 and S2 segments of the proximal tubules. In extreme cases of lysosomal accumulation however, loading of the S3 segments was noted. In tubules where cellular inclusion loading was heavy, there was evidence of increased cell turnover. The kidneys of female rats appeared normal.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Klimisch 2 (reliable with restrictions)

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

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

Principles of method if other than guideline:

Repeated Dose Toxicity, U.S. NTP

GLP compliance:

no

Limit test:

no

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

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

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

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

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.

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'

Critical effects observed:

not specified

 

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 % **

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

143 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Klimisch 1 (reliable without restrictions)

System:

urinary

Organ:

kidney

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

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

Principles of method if other than guideline:

Repeated Dose Toxicity, U.S. NTP

GLP compliance:

no

Limit test:

no

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

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

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

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

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.

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'

Critical effects observed:

not specified

 

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 % **

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Klimisch 1 (reliable without restrictions)

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No adverse effects were observed upon repeated oral exposure at dose levels up to 1000 mg/kg bw/day.

In the 90-day inhalation study (NTP 2005) 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 (143 mg/m3) is determined to be the no observed effect concentration (NOAEC) in female rats in this 90-day study.

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.

Furthermore, increase liver weight even at the lowest dose level (LOAEC) of 25 ppm (143 mg/m³) in rats was observed in a 16-day inhalation study with rats. As this effect was not observed in the 90-day inhalation study (NTP 2005) it indicates that this effect is rather reversible and hence the LOAEC was not used as starting point for the derivation of the DNEL (see chapter 5.11. of CSR).

 

 

Summary of repeated dose toxicity studies with decahydronaphthalene

Route	Type of study	NOAEL/NOAEC	LOAEL/LOAEC	Effect	Reference
oral	Rat 30 days	1000 mg/kg bw/d	-	-	Read 1988
	Rat, male 30 days	10 mg/kg bw/d	100 mg/kg bw/d	Males:Kidney, hyaline droplets	Read 1988
inhalation	Rat 14-days	-	25 ppm 143 mg/m³	Liver weight	NTP 2005
	Rat 90-days	25 ppm 143 mg/m³	> 25 ppm > 143 mg/m³	Increase in lactate dehydrogenase/creatinine ratio in males and females	NTP 2005
	Mouse 14-days	50 ppm 285 mg/m³	100 ppm 570 mg/m³	Liver weight	NTP 2005
	Mouse 90-days	25 ppm 143 mg/m³	50 ppm 285 mg/m³	Liver cytomegaly	NTP 2005
	Rat, male, 30 days		50 ppm 285 mg/m³	Reduced body weight	MacEwen 1978
	Mouse, female 30 days	50 ppm 285 mg/m³	250 ppm 1425 mg/m³	Liver, vacuolisation	MacEwen 1978
	Guineapig, male, 30 days	-	50 ppm 285 mg/m³	Reduced body weight	MacEwen 1978
	Rat, female, 90 days	-	50 ppm 285 mg/m³	-	MacEwen 1979
	Rat, male, 90 days	5 ppm 28.5 mg/m³	-	Males:Kidney, hyaline droplets	MacEwen 1979
	Mouse, female 90 days	-	50 ppm 285 mg/m³	-	MacEwen 1979
	dog, male+female 90 days	-	50 ppm 285 mg/m³	-	MacEwen 1979
	Rat 20 days	-	200 ppm 1148 mg/m³	-	Gage 1970
	Rat female 28 days	-	125 ppm 710 mg/m³	increased relative liver weight	Stone 1987
	Rat female 35 days	-	25 ppm 143 mg/m³	Males:Kidney, hyaline droplets	Stone 1987

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

According to the criteria of CLP Regulation 1272/2008 the test item is not classified because it has a low oral repeated dose toxicity.

Effects observed in a repeated inhalation toxicity study (findings in liver and kidney) do not meet the criteria for classification and labelling.