National Toxicology Program

National Toxicology Program
https://ntp.niehs.nih.gov/go/33575

Abstract for TR-561 - Tetralin (CASRN 119-64-2)

ABSTRACT

TR-561
Toxicology and Carcinogenesis Studies of Tetralin (CAS No. 119-64-2) in F344/N Rats and B6C3F1 Mice (Inhalation studies)

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Abstract

Chemical Formula: C10H12 -- Molecular Weight: 132.21  

Tetralin is used as an industrial solvent primarily for naphthalene, fats, resins, oils, and waxes; as a solvent and stabilizer for shoe polishes and floor waxes; as a solvent for pesticides, rubber, asphalt, and aromatic hydrocarbons (e.g., anthracene); as a dye solvent carrier in the textile industry; as a substitute for turpentine in lacquers, paints, and varnishes; in paint thinners and as a paint remover; in alkali-resistant lacquers for cleaning printing ink from rollers and type; as a constituent of motor fuels and lubricants; for the removal of naphthalene in gas distribution systems; and as an insecticide for clothes moths. Tetralin was nominated by the National Cancer Institute for carcinogenicity and disposition studies because of its structure, high production volume, and high potential for worker and consumer exposure. Male and female F344/N rats and B6C3F1 mice were exposed to tetralin (at least 97% pure) by inhalation for 2 weeks, 3 months, or 2 years; male NCI Black Reiter (NBR) rats were exposed to tetralin by inhalation for 2 weeks. Male NBR rats do not produce α2u-globulin; the NBR rats were included to study the relationship of α2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.

2-WEEK STUDY IN RATS

Groups of five male (F344/N and NBR) and five female (F344/N) rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 12 exposures. All rats survived to the end of the studies. The final mean body weight of female rats exposed to 120 ppm and mean body weight gains of female rats exposed to 30 ppm or greater were significantly less than those of the chamber controls. Final mean body weights of exposed groups of male NBR rats and mean body weight gains of all exposed groups of male rats were significantly less than those of the chamber controls. Dark-stained urine was observed in all 120 ppm rats. Squinting, weeping, or matted fur around the eyes were noted in the majority of F344/N rats exposed to 120 ppm. The α2u-globulin concentrations in the kidney of male F344/N rats were significantly greater in all exposed groups than in the chamber control group. The absolute kidney weight of 60 ppm females and the relative kidney weights of male F344/N rats exposed to 30 ppm or greater and female rats exposed to 15 ppm or greater were significantly increased. The absolute liver weight of 120 ppm NBR male rats and the relative liver weights of male and female rats exposed to 60 or 120 ppm were significantly increased. In the nose, the incidences of mononuclear cell cellular infiltration were generally significantly increased in all exposed groups of rats, and incidences of olfactory epithelium degeneration and glandular hypertrophy occurred in all male F344/N rats exposed to 120 ppm.

2-WEEK STUDY IN MICE

Groups of five male and five female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 13 exposures. All mice survived to the end of the study. Mean body weights of male and female mice were similar to those of the chamber controls. Dark-;stained urine was observed in most of the exposed mice. The absolute and relative liver weights of 60 and 120 ppm males and 30 and 120 ppm females and the relative liver weights of 60 ppm females were significantly greater than those of the chamber controls. In the nose, the incidences of olfactory epithelium atrophy were significantly increased in 60 and 120 ppm males and females. Glandular dilatation occurred in all 120 ppm females, and glandular hyperplasia occurred in all 120 ppm males and females.

3-MONTH STUDY IN RATS

Groups of 10 male and 10 female rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. The same exposure concentrations were given to additional groups of 10 male and 10 female clinical pathology study rats for up to 6 weeks and five male renal toxicity rats for 2 weeks. All rats survived to the end of the study. During the first 4 weeks of exposure, dark-stained urine was observed in the catch pans of rats exposed to 30, 60, or 120 ppm. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. Tetralin increased urine aspartate aminotransferase and urine lactate dehydrogenase activities (males and females) and glucose/creatinine ratio (males), suggestive of renal injury. The absolute kidney weights of 60 and 120 ppm females and the relative kidney weights of males and females exposed to 15 ppm or greater were significantly greater than those of the chamber controls. Concentrations of α2u-globulin in the kidney of exposed male rats were generally greater than those of the chamber controls at all time points and greater at 6 and 14 weeks than at 2 weeks. There were significantly increased incidences of olfactory epithelium necrosis in rats exposed to 30 ppm or greater and of olfactory epithelium regeneration in 60 and 120 ppm rats.

3-MONTH STUDY IN MICE

Groups of 10 male and 10 female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of 120 ppm males were significantly less than those of the chamber controls. Dark;-stained urine was observed in the catch pans of mice exposed to 30, 60, or 120 ppm during the first month of the study. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. The relative liver weights of 120 ppm males and 30 ppm or greater females were significantly greater than those of the chamber controls. Incidences of olfactory epithelium metaplasia in 60 and 120 ppm males and females, respiratory epithelium hyaline droplet accumulation in 120 ppm males and 60 and 120 ppm females, cytoplasmic eosinophilic granules within the transitional epithelium lining the urinary bladder in all exposed groups of males and females, and ovarian atrophy and uterine atrophy in 60 and 120 ppm females were significantly increased.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female rats were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female rats were exposed to the same concentrations for 12 months. Survival of all exposed groups of rats was similar to that of the chamber controls. Mean body weights of 120 ppm females were 6% less than those of the chamber controls after week 29. Dark;-stained urine was observed in all exposed groups of rats. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females.

In the standard evaluation of the kidney, there were slightly increased incidences of cortical renal tubule adenoma in male rats. In the combined analysis of single and step sections, the incidence of cortical renal tubule adenoma was significantly increased in the 120 ppm group. In the combined analysis, there was also a significantly increased incidence of renal tubule hyperplasia in the 120 ppm group. In 120 ppm males in the standard evaluation, the severity of chronic nephropathy was increased and the incidence of transitional epithelial hyperplasia in the renal pelvis was significantly increased.

Three hepatocellular adenomas occurred in 120 ppm females, and one hepatocellular carcinoma each was observed in the 60 and 120 ppm groups.

The incidences of uterine stromal polyp and endometrium hyperplasia were significantly increased in 120 ppm females. Incidences of interstitial cell adenoma and germinal epithelium atrophy of the testis in 30 and 120 ppm males were significantly greater than those in the chamber controls.

The incidences of olfactory epithelium degeneration, metaplasia, basal cell hyperplasia, suppurative inflammation, and mineralization (except 30 ppm females) in the nose were significantly increased in all exposed groups of rats. The incidences of glandular dilatation were significantly increased in 120 ppm males and all exposed groups of females. The incidences of respiratory epithelium chronic inflammation were significantly increased in males exposed to 60 or 120 ppm and all exposed groups of females.

The incidences of lens cataract in 120 ppm females were significantly increased.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female mice were exposed to the same concentrations for 12 months. Survival of 60 and 120 ppm female mice was significantly greater than that of the chamber controls. The mean body weights of all exposed groups of male and female mice were similar to those of the chamber controls by the end of the study. Dark-;stained urine was observed in all exposed groups of male mice and in females exposed to 60 or 120 ppm. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females.

The incidence of hemangiosarcoma of the spleen was increased in 120 ppm females and exceeded the historical control range for inhalation studies.

The incidences of olfactory epithelium atrophy, respiratory metaplasia, glandular hyperplasia, and suppurative inflammation in exposed groups of mice were significantly greater than those in the chamber controls. Transitional epithelium cytoplasmic eosinophilic granules were present in the urinary bladder of all exposed mice. The incidence of corneal mineralization in 120 ppm females was significantly increased.

GENETIC TOXICOLOGY

Tetralin was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535 or in E. coli strain WP2 uvrA, with or without exogenous metabolic activation. No significant increases in the frequencies of micronucleated normochromatic erythrocytes, indicators of chromosomal damage, were observed in peripheral blood samples from male or female mice exposed to tetralin for 3 months. 

CONCLUSIONS

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 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.

Synonyms: Benzocyclohexane; Δ5,7,9-naphthalene; naphthalene 1,2,3,4-tetrahydride; tetrahydronaphthalene; 1,2,3,4-tetrahydronaphthalene; tetraline
Trade name: Tetranap


 

Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Tetralin
  Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1 Mice
Female
B6C3F1 Mice
Concentrations in air 0, 30, 60, or 120 ppm 0, 30, 60, or 120 ppm 0, 30, 60, or 120 ppm 0, 30, 60, or 120 ppm
Body weights 120 ppm group 6% less than the chamber control group after week 29 120 ppm group 5% less than the chamber control group after week 29 120 ppm group 9% less than the chamber control group after week 29 Exposed groups generally similar to the chamber control group
Survival rates 20/50, 29/50, 25/50, 28/50 31/50, 36/50, 31/50, 38/50 36/50, 35/50, 38/50, 36/50 31/50, 38/50, 42/50, 43/50
Nonneoplastic effects Kidney: renal tubule, hyperplasia (standard evaluation - 1/50, 2/50, 0/50, 3/50; standard and extended evaluations combined - 1/50, 2/50, 1/50, 7/50); severity of nephropathy (2.6, 3.0, 3.0, 3.4); pelvis, transitional epithelium, hyperplasia (1/50, 1/50, 0/50, 7/50)
Testis: germinal epithelium, atrophy (32/50, 42/50, 34/50, 45/50)
Nose: glands, dilatation (0/50, 3/50, 3/49, 16/50); olfactory epithelium, degeneration (1/50, 40/50, 43/49, 42/50); olfactory epithelium, hyperplasia, basal cell (0/50, 38/50, 48/49, 48/50); olfactory epithelium, metaplasia (0/50, 17/50, 31/49, 37/50); olfactory epithelium, inflammation, suppurative (0/50, 12/50, 8/49, 10/50); olfactory epithelium, mineralization (0/50, 5/50, 12/49, 17/50); respiratory epithelium, inflammation, chronic (4/50, 4/50, 18/49, 16/50)
Uterus: endometrium, hyperplasia (2/50, 5/50, 7/50, 11/50)
Nose: glands, dilatation (0/50, 6/50, 10/50, 16/50); olfactory epithelium, degeneration (0/50, 47/50, 50/50, 46/50); olfactory epithelium, hyperplasia, basal cell (0/50, 48/50, 50/50, 49/50); olfactory epithelium, metaplasia (0/50, 41/50, 43/50, 49/50); olfactory epithelium, inflammation, suppurative (0/50, 16/50, 15/50, 19/50); olfactory epithelium, mineralization (0/50, 2/50, 8/50, 13/50); respiratory epithelium, inflammation, chronic (1/50, 7/50, 11/50, 12/50)
Nose: glands, olfactory epithelium, hyperplasia (14/49, 49/49, 50/50, 49/50); olfactory epithelium, atrophy (2/49, 49/49, 50/50, 50/50); olfactory epithelium, metaplasia, respiratory (2/49, 47/49, 50/50, 49/50); inflammation, suppurative (2/49, 26/49, 45/50, 45/50)
Urinary bladder: transitional epithelium, eosinophilic granules, cytoplasmic (0/49, 47/47, 50/50, 48/48)
Nose: glands, olfactory epithelium, hyperplasia (17/50, 50/50, 50/50, 49/49); olfactory epithelium, atrophy (1/50, 50/50, 50/50, 49/49); olfactory epithelium, metaplasia, respiratory (1/50, 49/50, 50/50, 49/49); inflammation, suppurative (3/50, 28/50, 48/50, 46/49)
Urinary bladder: transitional epithelium, eosinophilic granules, cytoplasmic (0/49, 50/50, 49/49, 49/49)
Neoplastic effects Kidney: cortical renal tubule adenoma (standard evaluation - 0/50, 1/50, 1/50, 2/50; standard and extended evaluations combined - 0/50, 3/50, 2/50, 6/50) Liver: hepatocellular adenoma (0/50, 0/50, 0/50, 3/50); hepatocellular adenoma or carcinoma (0/50, 0/50, 1/50, 4/50)
Uterus: stromal polyp (6/50, 10/50, 9/50, 17/50)
None None
Equivocal findings Testis: adenoma, interstitial cell (29/50, 39/50, 31/50, 41/50) None None Spleen: hemangiosarcoma (1/50, 0/50, 1/50, 4/50)
Level of evidence of carcinogenic activity Some evidence Some Evidence No Evidence Equivocal Evidence
Genetic Toxicology
Assay Results
Salmonella typhimurium gene mutations:
 
Negative in strains TA97, TA98, TA100, and TA1535 and in Escherichia coli strain WP2 uvrA/pKM101, with and without S9
Micronucleated erythrocytes
Mouse peripheral blood in vivo:
Negative in males and females

 


Date: April 2011

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies

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