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Abstract for TR-586 - CIMSTAR 3800

Abstract

Toxicology Studies of Cimstar 3800 in F344/NTac Rats and B6C3F1/N Mice and Toxicology and Carcinogenesis Studies of CIMSTAR 3800 in Wistar Han [Crl:WI (Han)] Rats and B6C3F1/N Mice (Inhalation Studies)

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Abstract

CIMSTAR 3800 is a metalworking fluid used as a lubricant and coolant liquid on the surface of the worked piece to remove heat and fine swarf and to provide corrosion inhibition at the newly cut surface. CIMSTAR 3800 is used in the general machining and grinding of automotive aluminum parts and on light to moderate machining and grinding of light steel, stainless steels, hardened steels, and other materials. CIMSTAR 3800 was nominated by the National Institute for Occupational Safety and Health for study by the National Toxicology Program because of its high production volume, the large number of occupationally exposed workers, the lack of carcinogenicity and chronic toxicology data, and because epidemiologic data indicate an increased incidence of laryngeal cancer in workers exposed to metalworking fluids. Male and female F344/NTac rats and B6C3F1/N mice were exposed to CIMSTAR 3800 by inhalation for 3 months, and male and female Wistar Han [Crl:WI (Han)] rats (referred to as Wistar Han rats) and B6C3F1/N mice were exposed to CIMSTAR 3800 by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and rat and mouse peripheral blood erythrocytes.

3-MONTH STUDY IN F344/NTac RATS

Groups of 10 male and 10 female F344/NTac rats were exposed by whole body inhalation to CIMSTAR 3800 aerosol at concentrations of 0, 25, 50, 100, 200, or 400 mg/m3 for 6 hours plus T90 (18 minutes) per day, 5 days per week for 14 weeks. All rats survived to the end of the study, and the mean body weights of all exposed groups were similar to those of the chamber controls. All exposed males and most exposed females had goblet cell hyperplasia, hyaline droplet accumulation, and suppurative inflammation of the olfactory epithelium and hyaline droplet accumulation and suppurative inflammation of the respiratory epithelium in the nose. In the larynx, there were significantly increased incidences of squamous metaplasia, hyperplasia of the squamous epithelium, and chronic active inflammation in all exposed groups. In the lung, there were significantly increased incidences of alveolus histiocytic cellular infiltration in males and females exposed to 200 or 400 mg/m3.

3-MONTH STUDY IN MICE

Groups of 10 male and 10 female mice were exposed by whole body inhalation to CIMSTAR 3800 aerosol at concentrations of 0, 25, 50, 100, 200, or 400 mg/m3 for 6 hours plus T90 (18 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. The final mean body weights and mean body weight gains of 400 mg/m3 males and females and the final mean body weight of 200 mg/m3 females were significantly less than those of the chamber controls. The absolute and relative lung weights of males exposed to 100 mg/m3 or greater were significantly greater than those of the chamber controls. In the nose, there were significantly increased incidences of hyaline droplet accumulation of the olfactory and respiratory epithelia in all exposed groups. In the larynx, there were significantly increased incidences of squamous metaplasia in all exposed groups, hyperplasia of the squamous epithelium in 200 and 400 mg/m3 males and females, chronic active inflammation in 50 mg/m3 males and males and females exposed to 100 mg/m3 or greater, and epiglottis dysplasia in 400 mg/m3 males and females. In the lung, there were significantly increased incidences of bronchiole hyperplasia in all exposed groups, perivascular chronic active inflammation in 200 and 400 mg/m3 males and 100 and 200 mg/m3 females, and arteriole hypertrophy in 400 mg/m3 males and 200 mg/m3 females.

2-YEAR STUDY IN WISTAR HAN RATS

Groups of 50 male and 50 female Wistar Han rats were exposed by whole body inhalation to CIMSTAR 3800 aerosol at concentrations of 0, 10, 30, or 100 mg/m3 for 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Survival of all exposed groups was similar to that of the chamber control groups. Mean body weights of exposed groups of male and female rats were similar to those of the chamber controls throughout the study.

In males, there were slightly increased incidences of prostate gland adenoma in the 100 mg/m3 group, and adenoma or carcinoma (combined) in the 30 and 100 mg/m3 groups.

In females, there was a positive trend in the incidences of squamous cell papilloma or keratoacanthoma (combined) of the skin. There was also a nonsignificant increase in the incidence of uterine adenocarcinoma or mixed malignant Müllerian tumor (combined) (original and residual longitudinal evaluation) in the 100 mg/m3 group.

In the nose, there were chemical-related, significantly increased incidences of goblet cell hyperplasia, hyperplasia of olfactory epithelium glands, and hyaline droplet accumulation of the olfactory and respiratory epithelia in all exposed groups of males and females.

There were significantly increased incidences of squamous metaplasia in the larynx in all exposed groups.

In the lung, there were exposure concentration-related, significantly increased incidences of lymphohistiocytic inflammation in all exposed groups and of lymphohistiocytic hyperplasia of bronchus-associated lymphoid tissue in 30 mg/m3 males and 100 mg/m3 males and females. There was also a significantly increased incidence of alveolar epithelium hyperplasia in 100 mg/m3 males.

In the bronchial lymph nodes, there were exposure concentration-related, significantly increased incidences of lymphohistiocytic hyperplasia in 30 and 100 mg/m3 males and females. In the mediastinal lymph nodes, there were exposure concentration-related, significantly increased incidences of lymphohistiocytic hyperplasia in 100 mg/m3 males and females.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were exposed by whole body inhalation to CIMSTAR 3800 aerosol at concentrations of 0, 10, 30, or 100 mg/m3 for 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Survival of all exposed groups was similar to that of the chamber control groups. Mean body weights of exposed groups of male and female mice were similar to those of the chamber controls throughout the study.

There was a positive trend in the incidences of follicular cell carcinoma in the thyroid gland of females. There were also exposure concentration-related increased incidences of follicular cell hyperplasia.

In the lung, there was a positive trend in the incidences of alveolar/bronchiolar adenoma or carcinoma (combined) in females, and the incidence was significantly increased in the 100 mg/m3 group. There was also a positive trend in the incidences of alveolar/bronchiolar carcinoma in females. Significantly increased incidences of bronchiole hyperplasia occurred in 30 and 100 mg/m3 males and females. The incidences of alveolar epithelium hyperplasia were slightly increased in 30 mg/m3 males and females and 100 mg/m3 males. The incidences of histiocytic cellular infiltration were slightly increased in 100 mg/m3 males and females. In 100 mg/m3 females, there was a significantly increased incidence of chronic active perivascular inflammation.

In the nose, there were significantly increased incidences of hyaline droplet accumulation of the olfactory and respiratory epithelia in all exposed groups of mice and respiratory metaplasia of the olfactory epithelium in all exposed groups of males and 30 and 100 mg/m3 females. There were increased incidences of olfactory epithelium atrophy in 100 mg/m3 males and chronic active inflammation in 10 and 100 mg/m3 males.

In the larynx, the incidences of squamous metaplasia were significantly increased in all exposed groups of males and females. There were significantly increased incidences of chronic active inflammation in 100 mg/m3 males and females.

GENETIC TOXICOLOGY

CIMSTAR 3800 was mutagenic in E. coli strain WP2 uvrA/pKM101 in the absence of exogenous metabolic activation (S9); no mutagenic activity was observed in S. typhimurium strains TA98 and TA100, with or without S9, or in the E. coli strain with S9.

In vivo, no increases in the frequencies of micronucleated reticulocytes or erythrocytes were observed in peripheral blood samples from male and female F344/NTac rats or B6C3F1/N mice exposed to CIMSTAR 3800 via inhalation for 3 months.

CONCLUSIONS

Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of CIMSTAR 3800 in male Wistar Han rats based on the incidences of prostate gland adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of CIMSTAR 3800 in female Wistar Han rats based on the incidences of squamous cell papilloma or keratoacanthoma (combined) of the skin and adenocarcinoma or mixed malignant Müllerian tumor (combined) of the uterus. There was no evidence of carcinogenic activity of CIMSTAR 3800 in male B6C3F1/N mice exposed to 10, 30, or 100 mg/m3. There was some evidence of carcinogenic activity of CIMSTAR 3800 in female B6C3F1/N mice based on the incidences of follicular cell carcinoma of the thyroid gland and alveolar/bronchiolar adenoma or carcinoma (combined) of the lung.

Exposure to CIMSTAR 3800 resulted in increased incidences of nonneoplastic lesions of the nose, larynx, and lung in male and female rats and mice, lymph nodes in male and female rats, and thyroid gland in female mice.

 


Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of CIMSTAR 3800
  Male
Wistar Han Rats
Female
Wistar Han Rats
Male
B6C3F1/N Mice
Female
B6C3F1/N Mice
Concentrations in air 0, 10, 30, or 100 mg/m3 0, 10, 30, or 100 mg/m3 0, 10, 30, or 100 mg/m3 0, 10, 30, or 100 mg/m3
Body weights Exposed groups similar to the chamber control group Exposed groups similar to the chamber control group Exposed groups similar to the chamber control group Exposed groups similar to the chamber control group
Survival rates 33/50, 34/50, 34/50, 33/50 35/50, 33/50, 36/50, 30/50 39/50, 31/50, 36/50, 40/50 39/50, 37/50, 37/50, 33/50
Nonneoplastic effects Nose: goblet cell, hyperplasia (0/50, 20/50, 25/50, 34/50); glands, olfactory epithelium, hyperplasia (1/50, 39/50, 47/50, 50/50); olfactory epithelium, accumulation, hyaline droplet (19/50, 50/50, 50/50, 50/50); respiratory epithelium, accumulation, hyaline droplet (0/50, 17/50, 25/50, 29/50)
Larynx: metaplasia, squamous (1/50, 47/50, 50/50, 50/50)
Lung: inflammation, lymphohistiocytic (6/50, 14/50, 41/50, 47/50); bronchus-associated lymphoid tissue, hyperplasia, lymphohistiocytic (0/50, 1/50, 5/50, 19/50); alveolar epithelium, hyperplasia (4/50, 6/50, 11/50, 13/50) Lymph node, bronchial: hyperplasia, lymphohistiocytic (0/42, 0/40, 10/37, 28/35)
Lymph node, mediastinal: hyperplasia, lymphohistiocytic (0/46, 0/45, 4/50, 29/49)
Nose: goblet cell, hyperplasia (0/50, 25/50, 34/50, 42/50); glands, olfactory epithelium, hyperplasia (1/50, 32/50, 48/50, 49/50); olfactory epithelium, accumulation, hyaline droplet (16/50, 50/50, 50/50, 50/50); respiratory epithelium, accumulation, hyaline droplet (1/50, 24/50, 31/50, 34/50)
Larynx: metaplasia, squamous (1/50, 50/50, 50/50, 50/50)
Lung: inflammation, lymphohistiocytic (3/50, 20/50, 42/50, 50/50); bronchus-associated lymphoid tissue, hyperplasia, lymphohistiocytic (0/50, 0/50, 0/50, 5/50)
Lymph node, bronchial: hyperplasia, lymphohistiocytic (0/38, 0/35, 7/32, 30/35)
Lymph node, mediastinal: hyperplasia, lymphohistiocytic (0/49, 0/46, 4/45, 23/47)
Lung: bronchiole, hyperplasia (11/50, 11/50, 32/50, 44/50); alveolar epithelium, hyperplasia (4/50, 4/50, 6/50, 7/50); infiltration cellular, histiocyte (5/50, 5/50, 1/50, 9/50)
Nose: olfactory epithelium, accumulation, hyaline droplet (4/50, 31/50, 43/50, 49/50); respiratory epithelium, accumulation, hyaline droplet (7/50, 36/50, 50/50, 50/50); olfactory epithelium, metaplasia, respiratory (7/50, 15/50, 25/50, 37/50); olfactory epithelium, atrophy (1/50, 0/50, 0/50, 4/50); inflammation, chronic active (6/50, 8/50, 4/50, 12/50)
Larynx: metaplasia, squamous (0/50, 50/50, 49/49, 50/50); inflammation, chronic active (0/50, 2/50, 3/49, 8/50)
Thyroid gland: follicular cell, hyperplasia (1/50, 1/48, 2/50, 3/50)
Lung: bronchiole, hyperplasia (7/50, 4/50, 22/50, 41/50); alveolar epithelium, hyperplasia (4/50, 2/50, 5/50, 4/50); infiltration cellular, histiocyte (4/50, 1/50, 1/50, 6/50); perivascular, inflammation, chronic active (4/50, 3/50, 0/50, 11/50)
Nose: olfactory epithelium, accumulation, hyaline droplet (25/50, 40/49, 50/50, 49/50); respiratory epithelium, accumulation, hyaline droplet (34/50, 48/49, 50/50, 50/50); olfactory epithelium, metaplasia, respiratory (3/50, 4/49, 12/50, 23/50)
Larynx: metaplasia, squamous (1/49, 49/49, 50/50, 50/50); inflammation, chronic active (0/49, 0/49, 0/50, 10/50)
Neoplastic effects None None None Thyroid gland: follicular cell carcinoma (0/50, 0/48, 0/50, 3/50)
Lung: alveolar/bronchiolar carcinoma (4/50, 1/50, 4/50, 8/50); alveolar/bronchiolar adenoma or carcinoma (4/50, 5/50, 6/50, 12/50)
Equivocal findings Prostate gland: adenoma (1/50, 1/50, 1/50, 3/50); adenoma or carcinoma (1/50, 1/50, 2/50, 3/50) Skin: squamous cell papilloma or keratoacanthoma (0/50, 0/50, 0/50, 4/50)
Uterus: adenocarcinoma or mixed malignant Müllerian tumor (original and residual longitudinal evaluation combined) (1/50, 4/50, 5/50, 6/50)
None None
Level of evidence of carcinogenic activity Equivocal evidence Equivocal evidence No evidence Some evidence
Genetic Toxicology of CIMSTAR 3800
Assay Test System Results
Bacterial gene mutations Salmonella typhimurium Positive in E. coli strain WP2 uvrA/pKM101 without S9; negative in S. typhimurium strains TA98 and TA100 with and without S9; negative in E. coli with S9
Micronucleated erythrocytes Rat peripheral blood in vivo: Negative in males and females
Micronucleated erythrocytes Mouse peripheral blood in vivo: Negative in males and females

 


Date: September 2015 

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

Target Organs & Incidences from 2-year Studies