Share This:
https://ntp.niehs.nih.gov/go/37197

Abstract for TR-574 Pyrogallol

Abstract

Toxicology and Carcinogenesis Studies of Pyrogallol (CASRN 87-66-1) in F344/N Rats and B6C3F1/N Mice (Dermal Studies)

Link to the full study report  in PDF. If you have difficulty accessing the document, please send email to the NTP Webmaster [ Send Email ] and identify documents/pages for which access is required.

Abstract

The current main commercial use of pyrogallol is the production of pharmaceuticals and pesticides. In analytical chemistry, pyrogallol is used as a complexing agent, reducing agent, and, in alkaline solution, as an indicator of gaseous oxygen. Pyrogallol was nominated for testing by private individuals based on its frequent occurrence in natural and manufactured products, including hair dyes, and the apparent lack of carcinogenicity data. Male and female F344/N rats and B6C3F1/Nmice were administered pyrogallol (99% pure) dermally for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, mouse bone marrow cells, and mouse peripheral blood erythrocytes.

3-MONTH STUDY IN RATS

Groups of 10 male and 10 female rats received dermal applications of pyrogallol in 95% ethanol at doses of 0, 9.5, 18.75, 37.5, 75, or 150 mg pyrogallol/kg body weight, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female special study rats were administered the same doses, 5 days per week for 23 days. All rats survived until the end of the study except for one vehicle control female. Mean body weights of dosed groups of males and females were generally similar to those of the vehicle controls. Chemical-related clinical findings included brown staining and irritation of the skin at the site of application. There were no changes in the hematology, serum clinical chemistry, thyroid hormone values, or organ weights attributable to the dermal administration of pyrogallol. The incidences of squamous hyperplasia, hyperkeratosis, and chronic active inflammation of the skin at the site of application were significantly increased in all dosed groups of males and females.

3-MONTH STUDY IN MICE

Groups of 10 male and 10 female mice received dermal applications of pyrogallol in 95% ethanol at doses of 0, 38, 75, 150, 300, or 600 mg pyrogallol/kg body weight, 5 days per week for 14 weeks. All mice survived until the end of the study. Mean body weights of dosed groups of males and females were similar to those of the vehicle controls. Chemical-related clinical findings included brown staining and irritation at the site of application. There were no changes in the hematology values or organ weights attributable to the dermal administration of pyrogallol. The incidences of squamous hyperplasia, hyperkeratosis, and chronic active inflammation of the skin at the site of application were significantly increased in all dosed groups of males and females. The incidence of hematopoietic cell proliferation of the spleen in 600 mg/kg males was significantly greater than that in the vehicle control group.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female rats received dermal applications of pyrogallol in 95% ethanol at doses of 0, 5, 20, or 75 mg pyrogallol/kg body weight, 5 days per week for up to 104 weeks. Survival of dosed groups of male and female rats was similar to that of the vehicle control groups. Mean body weights of dosed male and female rats were similar to those of the vehicle control groups throughout the study. Irritation of the skin at the site of application was the only chemical-related clinical finding and occurred in the 20 and 75 mg/kg groups.

In the skin at the site of application, there were significant increases in the incidences of hyperplasia in all dosed groups of males and females, hyperkeratosis in 20 and 75 mg/kg males and all dosed groups of females, inflammation in 75 mg/kg males and 20 and 75 mg/kg females, and sebaceous gland hyperplasia in 20 and 75 mg/kg males and females.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice received dermal applications of pyrogallol in 95% ethanol at doses of 0, 5, 20, or 75 mg pyrogallol/kg body weight, 5 days per week for up to 105 weeks. Survival of dosed groups of male mice was similar to that of the vehicle control group. Survival was significantly decreased in 75 mg/kg females; most early deaths in this group were due to ulcers at or adjacent to the site of application. The mean body weights of 75 mg/kg female mice were generally over 10% less than those of the vehicle controls during year 2 of the study. Irritation and/or ulceration of the skin at the site of application were the only chemical-related clinical findings and occurred predominantly in the 20 and 75 mg/kg groups.

In the skin at the site of application, the incidence of squamous cell carcinoma in 75 mg/kg females was significantly greater than that in the vehicle control group. Two 75 mg/kg males had squamous cell papillomas; squamous cell papillomas have not been observed in historical control male mice in four ethanol dermal studies.

Increased incidences of nonneoplastic lesions at the site of application included hyperplasia and hyperkeratosis in all dosed groups; inflammation, fibrosis, and pigmentation in the 20 and 75 mg/kg groups; and sebaceous gland hyperplasia and ulcer in the 75 mg/kg groups. Similar lesions in the skin of the neck and back immediately adjacent to the site of application were observed; the incidences of hyperplasia, hyperkeratosis, ulcer, inflammation, and fibrosis at these sites were significantly increased in 75 mg/kg male and female mice, and the incidence of sebaceous gland hyperplasia was significantly increased in 75 mg/kg female mice.

Dermal application of pyrogallol also resulted in significant increases in the incidences of bone marrow hyperplasia in males and females and lymphoid hyperplasia of the axillary, inguinal, and mandibular lymph nodes; adrenal cortical hematopoietic cell proliferation; and mammary gland hyperplasia in females.

GENETIC TOXICOLOGY

Pyrogallol was tested in two independent bacterial mutation studies; both studies gave positive results in one or more strains of S. typhimurium or E. coli. In the first study, positive results were seen in S. typhimurium strain TA100 with and without S9 exogenous metabolic activation, and negative results were obtained in strain TA98. In the second study, which was conducted with the same lot of pyrogallol that was used in the 3-month and 2-year studies, positive results were obtained in S. typhimurium strains TA98, TA100, and in E. coli strain WP2 uvrA/pKM101 in the absence of S9. With S9, this sample of pyrogallol was mutagenic in the E. coli strain but gave equivocal responses in S. typhimurium strains TA98 and TA100.

In vivo, a micronucleus test that measured frequency of micronucleated polychromatic erythrocytes in bone marrow of male B6C3F1/N mice following three intraperitoneal injections of pyrogallol, gave negative results. In a second in vivo test, no increase in the frequency of micronucleated erythrocytes was observed in the peripheral blood of female B6C3F1/N mice treated with pyrogallol via dermal application for 3 months; in male mice, however, results were equivocal, based on a significant increase in micronucleated erythrocytes observed at a single dose level at the end of the 3-month study.

CONCLUSIONS

Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of pyrogallol in male or female F344/N rats administered 5, 20, or 75 mg/kg. There was equivocal evidence of carcinogenic activity of pyrogallol in male B6C3F1/N mice based on increased incidences of squamous cell papilloma of the skin at the site of application. There was some evidence of carcinogenic activity of pyrogallol in female B6C3F1/N mice based on increased incidences of squamous cell carcinoma of the skin at the site of application.

Dermal administration of pyrogallol caused increased incidences of nonneoplastic lesions of the skin at the site of application in male and female rats and mice, skin adjacent to the site of application in male and female mice, and mammary gland in female mice.

Synonyms: 1,2,3-Benzenetriol; 2,3-dihydroxyphenol; gallamine; pyrogallic acid; 1,2,3-trihydroxybenzene
Trade names: C.I. Oxidation Base 32, C.I. 76515, C.I. 76551, Fouramine Base AP, Fouramine Brown AP, Fourrine PG, Fourrine 85, Piral, Pyro


Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Pyrogallol
  Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1/N Mice
Female
B6C3F1/N Mice
Doses in ethanol by dermal application 0, 5, 20, or 75 mg/kg 0, 5, 20, or 75 mg/kg 0, 5, 20, or 75 mg/kg 0, 5, 20, or 75 mg/kg
Body weights Dosed groups similar to the vehicle control group Dosed groups similar to the vehicle control group Dosed groups similar to the vehicle control group 75 mg/kg group generally 10% less than the vehicle control group after week 52
Survival rates 23/50, 28/50, 28/50, 28/50 29/50, 33/50, 26/50, 31/50 37/50, 36/50, 34/50, 31/50 33/50, 30/50, 36/50, 17/50
Nonneoplastic effects Skin (site of application): hyperplasia (0/50, 6/50, 20/50, 50/50); hyperkeratosis (0/50, 2/50, 21/50, 48/50); inflammation (0/50, 0/50, 0/50, 46/50); sebaceous gland, hyperplasia (0/50, 0/50, 12/50, 48/50) Skin (site of application): hyperplasia (0/50, 9/50, 11/50, 49/50); hyperkeratosis (0/50, 6/50, 23/50, 49/50); inflammation (0/50, 3/50, 6/50, 49/50); sebaceous gland, hyperplasia (0/50, 0/50, 5/50, 41/50) Skin (site of application): hyperplasia (8/50, 24/50, 47/50, 50/50); hyperkeratosis (11/50, 43/50, 50/50, 50/50); inflammation (2/50, 6/50, 37/50, 44/50); fibrosis (3/50, 6/50, 28/50, 47/50); pigmentation (0/50, 0/50, 9/50, 39/50); sebaceous gland, hyperplasia (1/50, 6/50, 4/50, 24/50); ulcer (1/50, 1/50, 2/50, 23/50)
Skin: hyperplasia (1/50, 1/50, 3/50, 10/50); hyperkeratosis (1/50, 1/50, 3/50, 10/50); ulcer (0/50, 1/50, 3/50, 10/50); inflammation (1/50, 1/50, 3/50, 10/50); fibrosis (1/50, 1/50, 3/50, 10/50)
Skin (site of application): hyperplasia (20/50, 31/50, 49/50, 49/50); hyperkeratosis (24/50, 38/50, 49/50, 49/50); inflammation (12/50, 14/50, 42/50, 48/50); fibrosis (5/50, 6/50, 31/50, 49/50); pigmentation (0/50, 0/50, 35/50, 40/50); sebaceous gland, hyperplasia (1/50, 2/50, 6/50, 34/50); ulcer (2/50, 0/50, 3/50, 33/50)
Skin: hyperplasia (1/50, 2/50, 1/50, 9/50); hyperkeratosis (1/50, 2/50, 1/50, 9/50); ulcer (1/50, 1/50, 1/50, 9/50); inflammation (1/50, 0/50, 0/50, 9/50); fibrosis (1/50, 2/50, 1/50, 9/50); sebaceous gland, hyperplasia (1/50, 0/50, 1/50, 7/50)
Mammary gland: hyperplasia (5/50, 9/50, 3/50, 16/50)
Neoplastic effects None None None Skin (site of application): squamous cell carcinoma (0/50, 0/50, 0/50, 4/50)
Equivocal findings None None Skin (site of application): squamous cell papilloma (0/50, 0/50, 0/50, 2/50) None
Level of evidence of carcinogenic activity No evidence No evidence Equivocal evidence Some evidence
Genetic Toxicology of Pyrogallol
Assay Test System Results
Bacterial Mutagenicity Salmonella typhimurium Positive in one study in S. typhimurium strain TA100 with and without S9 and negative in TA98 under the same conditions; positive in a second study in TA98, TA100, and in E. coli WP2 uvrA/pKM101 without S9; equivocal in TA98 and TA100 and positive in E. coli with S9
Micronucleated erythrocytes Mouse bone marrow in vivo: Negative in males
 
Micronucleated erythrocytes Mouse peripheral blood in vivo: Equivocal in males and negative in females

 

Date: February 2013