Toxicology studies of
pentachlorophenol, a
biocide used primarily as a wood preservative, were conducted by feeding diets containing a technical-grade composite,
Dowicide EC-7 (a technical grade formulation), or pure
pentachlorophenol to groups of B6C3F1 mice for 30 days. These three grades plus another commercial grade of
pentachlorophenol (DP-2) were used in 6-month studies. These studies were followed by 2-year carcinogenicity studies of technical-grade
pentachlorophenol and of
Dowicide EC-7 in feed. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary (CHO) cells. Thirty-Day and Sixteen-Month Studies: Groups of 19 male mice and 5-15 female mice were fed diets containing 0, 20, 100, 500, 2,500, or 12,500 ppm technical-grade
pentachlorophenol,
Dowicide EC-7, or pure
pentachlorophenol for 30 consecutive days. Necropsies and histopathologic examinations were performed on all animals. Selected organs were weighed. Supplemental analyses included hematology, serum chemistry, urinalysis, immunology, and hepatic enzyme induction. Compound-related deaths were observed at the highest dose (12,500 ppm) with all three materials and at 2,500 ppm with EC-7 and pure
pentachlorophenol (males only). Decreases in
body weight gain were also observed in the groups in which deaths occurred. Diffuse centrilobular cytomegaly, karyomegaly, nuclear atypia, degeneration, or
necrosis of the liver were compound-related lesions observed in all groups that received pure
pentachlorophenol, technical-grade
pentachlorophenol, or EC-7 at 500 ppm and above. Serum
enzymes associated with liver injury were increased. In the 6-month studies, groups of 10 male and 10 female mice were given diets containing the various grades of
pentachlorophenol at the following dietary concentrations: 200, 600, or 1,800 ppm technical-grade
pentachlorophenol; 200, 600, or 1,200 ppm DP-2 (not used in the 30-day studies); 200, 600, or 1,200 ppm EC-7; or 200, 500, or 1,500 ppm pure
pentachlorophenol for 26-27 weeks. Common control groups of 10 male and 10 female mice were fed control diets. Additional groups of male mice were examined for behavioral, histopathologic, clinical pathology, biochemical, and immunologic effects. All mice exposed at the highest dose of technical-grade
pentachlorophenol died, as did 2/10 male mice exposed at the highest dose of DP-2. No deaths were observed in mice exposed to EC-7 or pure
pentachlorophenol. Markedly lower final
body weights were observed in the high dose groups only (all grades of
pentachlorophenol). No chemical-relatedclinical signs were observed at sublethal doses. No major behavioral changes were observed after 5 weeks' exposure, but increased motor activity and heightened startle responses were present at the end of the study in female mice exposed to all four grades of
pentachlorophenol. All grades of
pentachlorophenol caused increases in serum
enzymes associated with liver injury. All grades of
pentachlorophenol also resulted in a dose-related induction of aryl
hydrocarbon hydroxylase and an increase in
cytochrome P450. However, the technical grade was a more powerful inducer than the other grades of
pentachlorophenol. Pure
pentachlorophenol had no effect on humoral or cell-mediated immunity. However, DP-2 and particularly technical-grade
pentachlorophenol depressed humoral immune function. A dose-related increase in liver weight was observed in mice exposed to all grades of
pentachlorophenol. A dose-related increase in spleen weight was observed in male mice exposed to all grades of
pentachlorophenol; a decrease in spleen weight was observed in female mice exposed to all grades of
pentachlorophenol except pure. After 6 months' exposure, histopathologic examination consistently revealed effects in the liver and urinary bladder. The liver lesions were present at all doses with all four grades of
pentachlorophenol but were less severe at comparable doses in the mice exposed to pure
pentachlorophenol; they consisted of hepatocellular karyomegaly, cytomegaly, and degeneration. The changes in the urinary bladder consisted of a brown granular pigment in the cells of the surface epithelium. No
inflammation or proliferative response was associated with the pigment. Based primarily on the liver lesions observed in the 6-month studies, diets chosen for the 2-year studies contained 0, 100, or 200 ppm technical-grade
pentachlorophenol or 0, 100, 200, or 600 ppm EC-7, fed to groups of 50 male and 50 female mice. DP-2 and pure
pentachlorophenol were not chosen for the 2-year studies because of economic considerations and because the clinicopathologic syndrome observed in the 6-month studies was similar to that observed with EC-7.
Body Weights and Survival in the Two-Year Studies: Mean
body weights of mice exposed to technical-grade
pentachlorophenol and EC-7 were comparable to those of controls until weeks 36-82. Thereafter, a 4%-22% dose-related decrease was observed in the mid and high dose mice exposed to EC-7 and in high dose mice exposed totechnical-grade
pentachlorophenol. Females were more affected than males. Feed consumption by exposed mice was similar to that by controls. The average daily doses of technical-grade
pentachlorophenol were approximately 17-18 or 35 mg/kg compared with 17-18, 34-37, or 114-118 mg/kg of EC-7. Survival of mice did not appear to be affected by exposure to either technical-grade
pentachlorophenol or EC-7 at the doses used in these studies. Neoplastic and Nonneoplastic Effects in the Two-Year Studies: The incidences of
hepatocellular adenomas and
carcinomas were increased (dose related) in male and female mice exposed to either technical-grade
pentachlorophenol or EC-7, although the increase was less marked in females exposed to technical-grade
pentachlorophenol (
adenomas or
carcinomas, combined: technical-grade: male-- control, 7/32, 22%; low dose, 26/47, 55%; high dose, 37/48, 77%; female--3/33, 9%; 9/49, 18%; 9/50, 18%; EC-7: male--control, 6/35, 17%; low dose, 19/48, 40%; mid dose, 21/48, 44%; high dose, 34/49, 69%; female-- 1/34, 3%; 4/50, 8%; 6/49, 12%; 31/48, 65%). The incidences of
pheochromocytomas in male mice were significantly greater than those in controls for both technical-grade
pentachlorophenol (0/31; 10/45, 22%; 23/45, 51%) and EC-7 (1/34, 3%; 4/48, 8%; 21/48, 44%; 45/49, 92%). These
neoplasms were also increased in female mice exposed to EC-7 at the highest dose (0/35; 2/49, 4%; 2/46, 4%; 38/49, 78%) but not in those exposed to technical-grade
pentachlorophenol (2/33, 6%; 2/48, 4%; 1/49, 2%).
Hyperplasia of the adrenal medulla was observed at increased incidences in mice that received either technical-grade
pentachlorophenol (male: 1/31; 10/45; female: 0/33; 4/48; 2/49) or EC-7 (male: 1/34; 19/48; 13/48; 1/49; female: 2/35; 1/49; 5/46; 17/49). The incidences of
hemangiosarcomas in the spleen and/or liver were significantly greater than those in controls for high dose female mice that received technical-grade
pentachlorophenol (0/35; 3/50, 6%; 6/50, 12%) or EC-7 (0/35; 1/50, 2%; 3/50, 6%; 8/49, 16%). Compound-related nonneoplastic lesions occurred in the liver, spleen, and nose in mice exposed to either technical-grade
pentachlorophenol or EC-7. The lesions in the liver included dose-related increased incidences of clear cell foci, chronic active
inflammation, pigmentation,
necrosis, cytomegaly, proliferation of hematopoietic cells, and bile duct
hyperplasia. Increased amounts of extramedullary hematopoiesis of the splenic red pulp were observed at increased incidences in dosed male and high dose female mice that received technical-grade
pentachlorophenol (male: 5/30; 15/23; 18/46; female: 2/33; 4/13; 11/47). Acutefocal
inflammation of the nasal mucosa and focal
metaplasia of the olfactory epithelium were observed at increased incidences in high dose mice that received EC-7 (
inflammation--male: 4/35; 1/13; 3/16; 47/49; female: 0/35; 0/14; 2/5; 46/48; focal
metaplasia-- male: 2/35; 1/13; 2/16; 46/49; female: 1/35; 0/14; 2/5; 45/48) but not in mice exposed to technical-grade
pentachlorophenol. Genetic Toxicology:
Pentachlorophenol (91.6% pure; equivalent in purity to the technical-grade
pentachlorophenol used in the toxicology studies) was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation (S9). In cytogenetic studies with cultured CHO cells,
pentachlorophenol produced an increase in
chromosomal aberrations in the presence but not the absence of S9 metabolic activation; conversely, sister chromatid exchanges (SCEs) were induced only in the absence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of
pentachlorophenol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity for male B6C3F1 mice fed diets containing technical-grade
pentachlorophenol, as shown by increased incidences of adrenal medullary and hepatocellular
neoplasms. There was some evidence of carcinogenic activity for female B6C3F1 mice exposed to technical-grade
pentachlorophenol, as shown by increased incidences of
hemangiosarcomas and hepatocellular
neoplasms. There was clear evidence of carcinogenic activity for male B6C3F1 mice exposed to
pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular
neoplasms. There was clear evidence of carcinogenic activity for female B6C3F1 mice exposed to
pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular
neoplasms and
hemangiosarcomas. Chemically related increased incidences of nonneoplastic lesions in mice of each sex included hepatocellular cytomegaly,
necrosis,
inflammation, pigmentation, and clear cell foci and intrahepatic bile duct
hyperplasia. Synonyms or Common Names: chlorophen; PCP; penchlorol;
penta; pentachlorofenol; pentachlorofenolo; pentachlorphenol; 2,3,4,5,6-pentachlorophenol Trade Names: Acutox; Chem-
Penta; Chem-Tol; Cryptogil ol;
Dowicide 7;
Dowicide EC-7; Dow
Pentachlorophenol DP-2 Antimicrobial; Durotox; EP 30; Fungifen; Fungol; Glazd
Penta; Grundier Arbezol; Lauxtol; Lauxtol A; Liroprem; Moosuran; Pentacon;
Penta-Kil; Pentasol; Penwar; Peratox; Permacide; Permagard; Permasan;Permatox; Priltox; Permite; Santophen; Santophen 20; Sinituho; Term-i-Trol; Thompson's Wood Fix; Weedone; Witophen P