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Description of key information

In two NTP inhalation studies groups of fifty F344/N rats and fifty B6C3F1 mice of each sex were exposed to tetrahydronaphthalene for 6 h per day for 5 days per week at levels of 0, 30, 60 and 120 ppm (NTP 2011). For non-neoplastic local effects the LOAEC was 30 ppm (165 mg/m³; nasal effects) in rats, for systemic non-neoplastic effects the NOAEC was 30 ppm (165 mg/m³; cardiomyopathy at higher dose levels) in rats. Increased incidence of hepatocellular adenoma and carcinoma and stromal polyps of the uterus in female rats was observed. A NOAEC for carcinogenicity was noted at 60 ppm (330 mg/m³). Based on the lack of genotoxic activity in an array of genotoxicity studies THN is not considered to be a genotoxic cancerogen.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 2003 - June 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted according to NTP Protocol
Qualifier:
according to guideline
Guideline:
other: NTP protocol
Deviations:
not applicable
GLP compliance:
yes
Species:
mouse
Strain:
other: B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic Frams, Inc(Germantown, NY, USA)
- Age at study initiation: 5-6 weeks
- Weight at study initiation:no data
- Fasting period before study: no
- Housing: individually
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 12 days

Environment
Temperature: 72° ± 3° F (22.2° ± 1.6° C)
Relative humidity: 55% ± 15%
Room fluorescent light: 12 hours/day
Chamber air changes: 15/hour

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
not specified
Vehicle:
air
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance concentrations in the exposure chambers were monitored by an online gas chromatograph.
Duration of treatment / exposure:
6 hours plus T90 (12 minutes) per day
Frequency of treatment:
5 days per week for 105 weeks
Remarks:
Doses / Concentrations:
0, 30, 60, or 120 ppm= 0, 165; 330; 660 mg/m³
Basis:
analytical conc.
No. of animals per sex per dose:
50
Control animals:
yes, sham-exposed
Positive control:
no
Observations and examinations performed and frequency:
Observed twice daily; clinical findings were recorded every 4 weeks through week 93, every 2 weeks thereafter, and at the end of the studies. Animals were weighed initially, weekly for the first 13 weeks, then every 4 weeks through week 93, every 2 weeks thereafter, and at the end of the studies
Sacrifice and pathology:
Following sacrifice by carbon dioxide asphyxiation necropsies were performed on all animals.
Complete histopathology was performed on all rats and mice. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, eyes, gallbladder (mice), Harderian gland, heart and aorta, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lung (with mainstem bronchus), lymph nodes (mandibular, mesenteric, bronchial, mediastinal), mammary gland, 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
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958) . Animals found dead of other than natural causes were censored from the survival analyses; animals dying from natural causes were not censored. Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.
The Poly‑k test (Bailer and Portier, 1988; Portier and Bailer, 1989; Piegorsch and Bailer, 1997) was used to assess neoplasm and nonneoplastic lesion prevalence.
Organ and body weight data, which historically have approximately normal distributions, were analyzed with Dunnett's and Williams' parametric multiple comparison procedures. Hematology, clinical chemistry, urinalysis, renal toxicity, urine metabolites spermatid, and epididymal spermatozoal data, which have typically skewed distributions, were analyzed using Shirley's nonparametric multiple comparison methods. Jonckheere’s test was used to assess the significance of the dose-related trends and to determine whether a trend-sensitive test (Williams’ or Shirley’s test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic dose-related trend (Dunnett’s or Dunn’s test). Prior to statistical analysis, extreme values identified by the outlier test of Dixon and Massey (1957) were examined.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
mean body weights of all exposed groups of mice were similar to those of the chamber controls at the end of the study
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
spleen
Histopathological findings: neoplastic:
no effects observed
Details on results:
Mortality and body weights were not adversely affected.
Dark-stained urine was observed in all exposed groups of male mice and in females exposed to 60 or 120 ppm but was more frequent in males (males: 0 ppm, 0/50; 30 ppm, 8/50; 60 ppm, 36/50; 120 ppm, 45/50; females: 0/50, 0/50, 3/50, 8/50).
Spleen: There was a positive trend in the incidences of hemangiosarcoma in female mice, and the incidence in 120 ppm females exceeded the historical control range for inhalation studies but not for all routes of administration.
Nose: The incidences of glandular hyperplasia, olfactory epithelium atrophy, and respiratory metaplasia in exposed groups of mice were significantly greater than those in the chamber controls.
Urinary Bladder: The incidences of minimal transitional epithelium cytoplasmic eosinophilic granules were significantly increased in all exposed groups of male and female mice with unclear biological significance.
The incidence of minimal corneal mineralization was significantly increased in 120 ppm females.
Relevance of carcinogenic effects / potential:
Not carcinogenic
Dose descriptor:
LOAEC
Effect level:
165 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Nose: The incidences of glandular hyperplasia, olfactory epithelium atrophy, and respiratory metaplasia in exposed groups of mice were significantly greater than those in the chamber controls.
Remarks on result:
other:
Remarks:
Effect type: other: local effect: nose (migrated information)
Dose descriptor:
NOAEC
Effect level:
> 660 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no evidence of carcinogenicity
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
LOEC
Effect level:
165 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: urinary bladder
Remarks on result:
other: Effect type: toxicity (migrated information)
Conclusions:
There was no evidence of carcinogenic activity of tetralin in male B6C3F1 mice exposed to 30, 60, or 120 ppm. There was equivocal evidence of carcinogenic activity of tetralin in female B6C3F1 mice based on the increased incidence of splenic hemangiosarcoma.
Exposure to tetralin resulted in nonneoplastic lesions of the nose in male and female mice, and urinary bladder in male and female mice.
Executive summary:

In a 2 -year inhalation study groups of fifty B6C3F1 mice of each sex were exposed to tetrahydronaphthalene for 6 h per day for 5 day per week at levels of 0, 30, 60 and 120 ppm (corresponding to 165, 330 and 660 mg/m³).

Mortality and body weights were not adversely affected.

Dark-stained urine was observed in all exposed groups of male mice and in females exposed to 60 or 120 ppm but was more frequent in males (males: 0 ppm, 0/50; 30 ppm, 8/50; 60 ppm, 36/50; 120 ppm, 45/50; females: 0/50, 0/50, 3/50, 8/50); this observation was not related to toxicological effects.

There was a positive trend in the incidences of hemangiosarcoma in female mice, and the incidence in 120 ppm females exceeded the historical control range for inhalation studies but not for all routes of administration.

Urinary Bladder: The incidences of minimal transitional epithelium cytoplasmic eosinophilic granules were significantly increased in all exposed groups of male and female mice with unclear biological significance.

The incidence of minimal corneal mineralization was significantly increased in 120 ppm females.

The incidences of nose glandular hyperplasia, olfactory epithelium atrophy, and respiratory metaplasia in exposed groups of mice were significantly greater than those in the chamber controls.

Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 2003 - June 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted according to NTP Protocol
Qualifier:
according to guideline
Guideline:
other: NTP protocol
Deviations:
not applicable
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic Frams, Inc(Germantown, NY, USA)
- Age at study initiation: 5-6 weeks
- Weight at study initiation:no data
- Fasting period before study: no
- Housing: individually
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 12 days

Environment
Temperature: 72° ± 3° F (22.2° ± 1.6° C)
Relative humidity: 55% ± 15%
Room fluorescent light: 12 hours/day
Chamber air changes: 15/hour
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
nose only
Vehicle:
air
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance concentrations in the exposure chambers were monitored by an online gas chromatograph.
Duration of treatment / exposure:
6 hours plus T90 (12 minutes) per day,
Frequency of treatment:
5 days per week for 105 weeks
Remarks:
Doses / Concentrations:
0, 30, 60, or 120 ppm= 0, 165, 330, 660 mg/m³
Basis:
analytical conc.
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Positive control:
no
Observations and examinations performed and frequency:
Observed twice daily; clinical findings were recorded every 4 weeks through week 93, every 2 weeks thereafter, and at the end of the studies. Animals were weighed initially, weekly for the first 13 weeks, then every 4 weeks through week 93, every 2 weeks thereafter, and at the end of the studies.
Sacrifice and pathology:
Following sacrifice by carbon dioxide asphyxiation necropsies were performed on all animals.
Complete histopathology was performed on all rats and mice. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, eyes, gallbladder (mice), Harderian gland, heart and aorta, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lung (with mainstem bronchus), lymph nodes (mandibular, mesenteric, bronchial, mediastinal), mammary gland, 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
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958) . Animals found dead of other than natural causes were censored from the survival analyses; animals dying from natural causes were not censored. Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.
The Poly‑k test (Bailer and Portier, 1988; Portier and Bailer, 1989; Piegorsch and Bailer, 1997) was used to assess neoplasm and nonneoplastic lesion prevalence.
Organ and body weight data, which historically have approximately normal distributions, were analyzed with Dunnett's and Williams' parametric multiple comparison procedures. Hematology, clinical chemistry, urinalysis, renal toxicity, urine metabolites spermatid, and epididymal spermatozoal data, which have typically skewed distributions, were analyzed using Shirley's nonparametric multiple comparison methods. Jonckheere’s test was used to assess the significance of the dose-related trends and to determine whether a trend-sensitive test (Williams’ or Shirley’s test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic dose-related trend (Dunnett’s or Dunn’s test). Prior to statistical analysis, extreme values identified by the outlier test of Dixon and Massey (1957) were examined.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Survival not affected, dark stained urine was observed in all treated animals
Mortality:
mortality observed, treatment-related
Description (incidence):
Survival not affected, dark stained urine was observed in all treated animals
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
nose, lung, kidney, heart, eye, uterus
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
kidney, uterus, liver
Details on results:
Survival of all exposed groups of rats was similar to that of the chamber controls.
Mean body weights of 660 mg/m³ females were less than those of the chamber controls after week 29 mean body weights of exposed groups of males were similar to those of the chamber controls throughout the study. Although more prevalent in females, dark-stained urine was observed in all exposed groups of rats, and the incidences increased with increasing exposure concentration (males: 0 ppm, 0/50; 30 ppm, 20/50; 60 ppm, 33/50; 120 ppm, 50/50; females: 2/50, 40/50, 48/50, 50/50).

Kidney:
One renal tubule adenoma and one renal tubule carcinoma occurred in female rats exposed to 120 ppm.
The incidences of cortical renal tubule adenoma were increased in all exposed male groups, and the incidence was significantly increased in the 120 ppm group. There was also a significantly increased incidence of cortical renal tubule hyperplasia in the 120 ppm group.

Liver:
Three hepatocellular adenomas occurred in 660 mg/m³ females, and one hepatocellular carcinoma each was observed in the 60 and 120 ppm groups

Uterus:
Incidences of stromal polyp and endometrium hyperplasia in 660 mg/m³ female rats were significantly greater than those in the chamber controls, and the severity of endometrium hyperplasia was increased in 660 mg/m³ females.

Testis:
Incidences of interstitial cell adenoma and germinal epithelial atrophy in 330 and 660 mg/m³ males were significantly greater than those in the chamber controls but were within the range of historical controls.

Nose:
The incidences of olfactory epithelium degeneration, basal cell hyperplasia, metaplasia, and suppurative inflammation in all exposed groups of male and female rats were significantly greater than those in the chamber controls.

Heart:
The incidences of cardiomyopathy in 330 mg/m³ and 660 mg/m³ ppm females were significantly increased (0 ppm, 22/50; 30 ppm, 24/50; 60 ppm, 32/50; 120 ppm, 34/50).

Eye:
The incidence of lens cataract in 660 mg/m³ females was significantly increased (2/49, 6/50, 7/49, 11/50).

Relevance of carcinogenic effects / potential:
Neoplastic effects in the kidney based at least in parts on a mechanism with no relevance for humans.
Dose descriptor:
LOAEC
Effect level:
165 mg/m³ air (analytical)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: The incidences of olfactory epithelium degeneration, basal cell hyperplasia, metaplasia, and suppurative inflammation in all exposed groups of male and female rats were significantly greater than those in the chamber controls.
Remarks on result:
other:
Remarks:
Effect type: other: non-neoplastic local effects: nose (migrated information)
Dose descriptor:
NOAEC
Effect level:
330 mg/m³ air (analytical)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEC
Effect level:
165 mg/m³ air (analytical)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: The incidences of cardiomyopathy in 330 mg/m³ and 660 mg/m³ ppm females were significantly increased
Remarks on result:
other: Effect type: toxicity (migrated information)

Incidences of Neoplasms and Nonneoplastic Lesions of the Kidney in Rats in the 2-Year Inhalation Study of Tetralin

Combined single and Step sections

Control

30 ppm

60 ppm

120 ppm

Male n

50

50

50

50

Cortex renal tubule hyperplasia

1

2

1

7*

Pelvis transit. epithelium, hyperplasia

1

1

0

7*

Nephropathy chronic

48

50

48

50

Cortex renal tubule adenoma

0

3

2

6

 

 

 

 

 

Female n

50

50

50

50

Renal tubule adenoma

0

0

0

1

Renal tubule carcinoma

0

0

0

1

 Incidences of Neoplasms in female rats in the 2-Yyear inhalation study of tetralin

 

Control

30 ppm

60 ppm

120 ppm

n

50

50

50

50

hepatocellular adenoma or carcinoma

0

0

1

4

Uterus: stromal polyp

6

10

9

17

Conclusions:
Under the conditions of these 2-year inhalation study, there was some evidence of carcinogenic activity of tetrahydronaphthalene in male F344/N rats based on the increased incidence of cortical renal tubule adenoma. There was some evidence of carcinogenic activity of tetrahydronaphthalene in female F344/N rats based on the increased incidences of hepatocellular neoplasms and uterine stromal polyp.
Exposure to tetrahydronaphthalene resulted in nonneoplastic lesions of the nose in male and female rats, kidney and testis in male rats, uterus in female rats.
Executive summary:

In a 2 -year inhalation study groups of fifty F344/N rats of each sex were exposed to tetrahydronaphthalene for 6 h per day for 5 day per week at levels of 0, 30, 60 and 120 ppm (corresponding to 165, 330 and 660 mg/m³).

Survival of all exposed groups of rats was similar to that of the chamber controls.

Dark-stained urine was observed in all exposed groups of rats, and the incidences increased with increasing exposure concentration (males: 0 ppm, 0/50; 30 ppm, 20/50; 60 ppm, 33/50; 120 ppm, 50/50; females: 2/50, 40/50, 48/50, 50/50).

The incidences of olfactory epithelium degeneration, basal cell hyperplasia, metaplasia, and suppurative inflammation in all exposed groups of male and female rats were significantly greater than those in the chamber controls.

120 ppm

Mean body weights of females were less than those of the chamber controls after week 29.

One renal tubule adenoma and one renal tubule carcinoma occurred in female rats exposed to 120 ppm.

The incidences of cortical renal tubule adenoma were increased in all exposed male groups, and the incidence was significantly increased in the 120 ppm group. There was also a significantly increased incidence of cortical renal tubule hyperplasia in the 120 ppm group. Three hepatocellular adenomas occurred in 120 ppm females, and one hepatocellular carcinoma each was observed in the 60 and 120 ppm groups

Incidences of stromal polyp and endometrium hyperplasia in 120 ppm female rats were significantly greater than those in the chamber controls, and the severity of endometrium hyperplasia was increased in 120 ppm females.

The incidences of cardiomyopathy in 60 and 120 ppm females were significantly increased (0 ppm, 22/50; 30 ppm, 24/50; 60 ppm, 32/50; 120 ppm, 34/50). The incidence of lens cataract in 120 ppm females was significantly increased (2/49, 6/50, 7/49, 11/50).

For local effects the LOAEC was 30 ppm (165 mg/m³, nasal effects), for systemic non-neoplastic effects the NOAEC was 30 ppm ( 165 mg/m³, cardiomyopathy at higher dose levels). For systemic neoplastic effects NOAEC: 60 ppm (330 mg/m³, Liver adenoma or carcinoma, uterus stroma polyp)

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
330 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
2 (reliable with restrictions)

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on mechanistic considerations renal tubule adenoma observed in male rats are considered not relevant for human cancer risk.

No carcinogenic effects were noted in mice. Increased incidence of hepatocellular adenoma and carcinoma and stromal polyps of the uterus in female rats was observed.

A NOAEC for carcinogenicity was noted at 60 ppm (330 mg/m³).

Based on the lack of genotoxic activity in an array of genotoxicity studies THN is considered to be not a genotoxic cancerogen.

According to CLP regulation 1272/2008 THN is classified to be a Carcinogen Cat. 2 substance with H351.

Additional information

Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of tetralin in male F344/N rats based on the increased incidence of cortical renal tubule adenoma.

The increased incidence of testicular interstitial cell adenoma may have been related to tetralin exposure. There was some evidence of carcinogenic activity of tetralin in female F344/N rats based on the increased incidences of hepatocellular neoplasms (adenomas and adenomas or carcinomas combined) and uterine stromal polyp.

There was no evidence of carcinogenic activity of tetralin in male B6C3F1 mice exposed to 30, 60 or 120 ppm.

There was equivocal evidence of carcinogenic activity of tetralin in female B6C3F1 mice based on the increased incidence of splenic hemangiosarcoma.

Exposure to tetralin resulted in nonneoplastic lesions of the nose in male and female rats and mice, kidney and testis in male rats, uterus in female rats, and urinary bladder in male and female mice

For systemic non-neoplastic effects the NOAEC was 30 ppm (165 mg/m³) based on increased incidence of cardiomyopathy in female rats at higher dose levels was noted.

Increased incidence of hepatocellular adenoma and carcinoma and stromal polyps of the uterus in female rats was observed. A NOAEC for carcinogenicity was noted at 60 ppm (330 mg/m³).

Based on the lack of genotoxic activity in an array of genotoxicity studies THN is considered to be not a genotoxic cancerogen.

Carcinogenicity: via inhalation route (target organ): renal, liver, urogenital: uterus

.