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Abstract for TR-456 - 1,2-Dihydro-2,2,4-Trimethylquinoline (CASRN 147-47-7)

Abstract

Toxicology and Carcinogenesis Studies of 1,2-Dihydro-2,2,4-Trimethylquinoline (CAS No. 147-47-7) in F344/N Rats and B6C3F 1 Mice (Dermal Studies) and the Dermal Initiation/Promotion Study in Female Sencar Mice

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Chemical Formula : C 12 H 15 N

1,2-Dihydro-2,2,4-trimethylquinoline (monomer) is used as an antioxidant in styrene-butadiene and nitrile-butadiene rubbers and latexes. It was nominated by the National Cancer Institute as part of a review of chemicals used in the manufacture and processing of rubber, during which potential occupational and consumer exposure to this compound can occur. It was selected for evaluation because it is a derivative of quinoline, a known rodent carcinogen, and was regarded as having potential carcinogenic activity. Because of the pattern of use and exposure, dermal administration was considered most appropriate.

Male and female F344/N rats and B6C3F 1 mice received topical applications of 1,2-dihydro-2,2,4-trimethylquinoline in acetone (greater than 90% pure) for 13 weeks or 2 years. Groups of female SENCAR mice received 1,2-dihydro-2,2,4-trimethylquinoline (greater than 90% pure) during a 1-year dermal initiation/promotion study to determine the tumor initiation or promotion potential of the chemical. Genetic toxicology studies were conducted in Salmonella typhimurium , cultured Chinese hamster ovary cells, and mouse peripheral blood cells.

13-WEEK STUDY IN RATS

Groups of 10 male and 10 female F344/N rats were topically administered 0, 5, 20, 50, 100, or 200 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 13 weeks. In addition, there were 10 male and 10 female untreated controls. All rats survived to the end of the study. Final mean body weights and mean body weight gains of treated male and female rats were similar to those of the vehicle controls except those of 200 mg/kg males, which were significantly lower than those of the vehicle controls. The only notable clinical observation was skin discoloration of treated rats. In the 200 mg/kg groups, absolute and relative liver weights of males and absolute liver weights of females were significantly greater than those of the vehicle controls. There were no significant differences in hematology or clinical chemistry parameters, reproductive tissue parameters, or estrous cycle characterization between treated and control groups. Histopathologic lesions of the skin at the site of application included acanthosis and hyperkeratosis in 100 and 200 mg/kg males and 200 mg/kg females. Cytoplasmic vacuolization of hepatocytes of mild to moderate severity was observed in the livers of all 200 mg/kg males and was considered treatment related. Based on the incidence and severity of skin and liver lesions observed in 200 mg/kg rats in the 13-week study, 100 mg/kg was selected as the high dose for the 2-year rat study.

13-WEEK STUDY IN MICE

Groups of 10 male and 10 female B6C3F 1 mice were topically administered 0, 2.5, 5, 10, 20, or 50 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 13 weeks. In addition, there were 10 male and 10 female untreated controls. All mice except one 2.5 mg/kg female survived to the end of the study. Final mean body weights and mean body weight gains of male and female mice were similar to those of the vehicle controls. There were no treatment-related clinical observations. There were no significant differences between treated and control groups in organ weights, hematology and clinical chemistry parameters, reproductive tissue parameters, or estrous cycle characterization. Histopathologic lesions of the skin at the site of application included acanthosis (epidermal hyperplasia), hyperkeratosis, and parakeratosis, all ranging from minimal to mild in severity. Minimal to mild fibrosis and subchronic inflammation were observed in the dermis. Based on the incidences and severities of skin lesions observed in 20 and 50 mg/kg mice in the 13-week study, 10 mg/kg was selected as the high dose for the 2-year mouse study.

2-YEAR STUDY IN RATS

Groups of 60 male and 60 female F344/N rats were topically administered 0, 36, 60, or 100 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 103 (males) or 104 (females) weeks. Ten rats per group were evaluated after 15 months of treatment.

Survival and Body Weights
Survival of treated rats was similar to that of controls. Mean body weights of 60 mg/kg males and 100 mg/kg males and females were slightly lower than those of the controls after week 21. Mean body weights of 36 mg/kg males and females and 60 mg/kg females were generally similar to those of the controls throughout the study.

Pathology Findings
No skin neoplasms were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. Several nonneoplastic skin lesions were determined to be treatment related. Incidences of acanthosis at the site of application in all treated groups of males and in 100 mg/kg females at the 15-month interim evaluation were significantly greater than those in the controls. At the end of the 2-year study, incidences of acanthosis at the site of application in 60 and 100 mg/kg males and females and hyperkeratosis at the site of application in 60 mg/kg females were significantly greater than those in the controls. Absolute and relative right kidney weights of 60 and 100 mg/kg male rats were significantly greater than those of the controls at the 15-month interim evaluation. Incidences of renal tubule adenoma and adenoma or carcinoma (combined) in all treated groups of males were significantly greater than those in the controls. These incidences exceeded the range from the historical controls in 2-year NTP feed studies. An extended (step section) evaluation of the kidneys of male rats did not reveal an additional increase in neoplastic response because additional adenomas and hyperplasias were observed in the controls as well as in treated groups.

2-YEAR STUDY IN MICE

Groups of 60 male and 60 female B6C3F 1 mice were topically administered 0, 3.6, 6, or 10 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 103 (males) or 104 (females) weeks. Nine or ten mice per group were evaluated after 15 months of treatment.

Survival and Body Weights
Survival of treated mice was similar to that of controls. Mean body weights of treated male and female mice were similar to those of the controls throughout the study.

Pathology Findings
No neoplasms or nonneoplastic lesions were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline.

1-YEAR INITIATION/PROMOTION STUDY IN FEMALE SENCAR MICE

Groups of 30 female SENCAR mice were topically administered varying initiation/promotion treatments as outlined in the table below.

Survival, Body Weights, and Clinical Findings
Survival in all treated groups was similar to that of the respective controls, except in the 2.5 m g 7,12-dimethylbenz(a)anthracene (DMBA)/0.5 m g 12- O -tetradecanoylphorbol-13-acetate (TPA) group in which survival was significantly lower than that of the controls. Mean body weights of all treated groups were similar to those of the respective controls throughout the study. No clinical observations were associated with 1,2-dihydro-2,2,4-trimethylquinoline treatment; however, mice promoted with TPA showed signs of irritation and papilloma at the site of application.

Pathology Findings
Initiation and promotion with acetone alone was not associated with any skin lesions at the site of application. The incidences of acanthosis and chronic inflammation were increased in all groups promoted with TPA regardless of the initiator treatment; however, the incidences of nonneoplastic lesions were low in all other groups. Incidences of squamous cell papillomas and squamous cell carcinomas were markedly increased in the DMBA/TPA positive control group; however, no response was observed in groups initiated with DMBA and promoted with 5, 10, or 25 mg/kg 1,2-dihydro-2,2,4-trimethylquinoline or in the group initiated with 1,2-dihydro-2,2,4-trimethylquinoline and promoted with TPA.

 

Design of the 1-Year Initiation/Promotion Dermal Study of 1,2-Dihydro-2,2,4-trimethylquinoline
in Female SENCAR Mice a
Treatment b
Initiator c Promoter d Treatment Group
Acetone Acetone e Vehicle Control
2.5 m g DMBA Acetone DMBA Initiation Control
Acetone 0.5 m g TPA f TPA Promotion Control
2.5 m g DMBA 0.5 m g TPA Initiation/Promotion Control
50 mg/kg TMQ 0.5 m g TPA TMQ Initiation
2.5 m g DMBA 5 mg/kg TMQ g TMQ Promotion
2.5 m g DMBA 10 mg/kg TMQ TMQ Promotion
2.5 m g DMBA 25 mg/kg TMQ TMQ Promotion
Acetone 5 mg/kg TMQ TMQ Promotion Control
Acetone 10 mg/kg TMQ TMQ Promotion Control
Acetone 25 mg/kg TMQ TMQ Promotion Control
a Thirty mice per treatment group
b DMBA = 7,12-dimethylbenz(a)anthracene,TPA = 12- O -tetradecanoylphorbol- 13-acetate,   TMQ = 1,2-dihydro-2,2,4-trimethylquinoline
c Initiators were applied once during week 1 of the study in a volume of 0.1 mL
d Promoters were applied in a volume of 0.1 mL
e Acetone promotion: three times per week
f TPA promotion: one time per week
g 1,2-Dihydro-2,2,4-trimethylquinoline promotion: three times per week


 

GENETIC TOXICOLOGY

1,2-Dihydro-2,2,4-trimethylquinoline was not mutagenic in any of several strains of Salmonella typhimurium , with or without S9 metabolic activation. 1,2-Dihydro-2,2,4-trimethylquinoline induced sister chromatid exchanges in cultured Chinese hamster ovary cells in the absence of S9, but not in the presence of S9. However, no increase in the frequency of chromosomal aberrations was observed in cultured Chinese hamster ovary cells treated with 1,2-dihydro-2,2,4-trimethylquinoline, with or without S9. No increase in the frequency of micronucleated erythrocytes was noted in peripheral blood of male or female mice exposed topically to 1,2-dihydro-2,2,4-trimethylquinoline for 13 weeks.

CONCLUSIONS

Under the conditions of these 2-year dermal studies, there was some evidence of carcinogenic activity of 1,2-dihydro-2,2,4-trimethylquinoline in male F344/N rats, based on increased incidences of renal tubule adenoma and adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of 1,2-dihydro-2,2,4-trimethylquinoline in female F344/N rats receiving 36, 60, or 100 mg/kg, or in male or female B6C3F 1 mice receiving 3.6, 6, or 10 mg/kg.
 

Exposure of rats to 1,2-dihydro-2,2,4-trimethylquinoline by dermal application in acetone for 2 years resulted in acanthosis in males and females and hyperkeratosis in females at the site of application. No nonneoplastic lesions in male or female mice were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline.

Synonyms: 2,2,4-Trimethyl-1,2-dihydroquinoline; acetone anil; methylquinoline
Trade names: Agerite Resin D; Flectol A; Flectol H; Flectol Pastilles; Vulkanox HS/LG; Vulkanox HS/Powder

Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of 1,2-Dihydro-2,2,4-trimethylquinoline
  Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F 1 Mice
Female
B6C3F 1 Mice
Doses

0, 36, 60, or 100 mg/kg applied topically in acetone

0, 36, 60, or 100 mg/kg applied topically in acetone

0, 3.6, 6, or 10 mg/kg applied topically in acetone

0, 3.6, 6, or 10 mg/kg applied topically in acetone

Body weights

60 and 100 mg/kg groups slightly lower than controls

100 mg/kg group slightly lower than controls

Treated groups similar to controls

Treated groups similar to controls

2-Year survival rates

5/50, 2/50, 4/50, 1/50

19/50, 21/50, 22/50, 22/50

39/50, 37/50, 41/50, 37/50

34/50, 40/50, 40/51, 40/50

Nonneoplastic effects

Skin (site of application) : acanthosis (1/50, 4/50, 14/49, 21/50) Skin (site of application) : acanthosis (0/50, 1/50, 9/50, 22/50); hyperkeratosis (0/50, 1/50, 7/50, 1/50)

None

None

Neoplastic effects

Kidney : renal tubule adenoma (standard evaluation - 1/50, 7/50, 10/50, 7/50; extended evaluation - 6/50, 5/50, 6/50, 8/50; standard and extended evaluations - 7/50, 11/50, 14/50, 14/50); renal tubule adenoma or carcinoma (standard evaluation - 1/50, 8/50, 10/50, 7/50; extended evaluation - 6/50, 6/50, 6/50, 8/50; standard and extended evaluations - 7/50, 12/50, 14/50, 14/50)

None

None

None

Level of evidence of carcinogenic activity

Some evidence

No evidence

No evidence

No evidence

Genetic Toxicology
Assay Results
Salmonella typhimurium gene mutations: Negative in strains TA98, TA100, TA1535, and TA1537 with and without S9
Sister chromatid exchanges
Cultured Chinese hamster ovary cells in vitro:

Negative with S9; positive without S9
Chromosomal aberrations
Cultured Chinese hamster ovary cells in vitro:

Negative with and without S9
Micronucleated erythrocytes
Mouse peripheral blood in vivo:

Negative

Report Date: February 1997

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

Target Organs & Incidences from 2-year Studies


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