Natl Toxicol Program Tech Rep Ser. 1989 Mar;349:1-265.
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
五氯苯酚主要用作木材防腐剂，是一种杀生剂。通过向B6C3F1小鼠组喂食含有工业级混合物Dowicide EC - 7（一种工业级配方）、纯五氯苯酚或五氯苯酚原药的饲料30天，开展了其毒理学研究。在为期6个月的研究中使用了这三个等级以及另一种商业级五氯苯酚（DP - 2）。随后，对工业级五氯苯酚和Dowicide EC - 7进行了为期两年的饲料致癌性研究。还在鼠伤寒沙门氏菌和中国仓鼠卵巢（CHO）细胞中进行了遗传毒理学研究。
30天和16个月研究：将19只雄性小鼠和5 - 15只雌性小鼠分为若干组，连续30天喂食含有0、20、100、500、2500或12500 ppm工业级五氯苯酚、Dowicide EC - 7或纯五氯苯酚的饲料。对所有动物进行了尸检和组织病理学检查。对选定器官进行了称重。补充分析包括血液学、血清化学、尿液分析、免疫学和肝酶诱导。在所有三种物质的最高剂量（12500 ppm）组以及EC - 7和纯五氯苯酚（仅雄性）的2500 ppm组中均观察到与化合物相关的死亡。在出现死亡的组中还观察到体重增加减少。在接受500 ppm及以上纯五氯苯酚、工业级五氯苯酚或EC - 7的所有组中，均观察到与化合物相关的肝脏弥漫性小叶中心性细胞肿大、核肿大、核异型性、变性或坏死病变。与肝损伤相关的血清酶升高。
在为期6个月的研究中，将10只雄性和10只雌性小鼠分为若干组，喂食含有以下不同等级五氯苯酚且浓度各异的饲料：200、600或1800 ppm工业级五氯苯酚；200、600或1200 ppm DP - 2（30天研究中未使用）；200、600或1200 ppm EC - 7；或200、500或1500 ppm纯五氯苯酚，为期26 - 27周。10只雄性和10只雌性小鼠组成的共同对照组喂食对照饲料。另外还对雄性小鼠组进行了行为、组织病理学、临床病理学、生化和免疫效应检查。所有暴露于工业级五氯苯酚最高剂量的小鼠均死亡，暴露于DP - 2最高剂量的10只雄性小鼠中有2只死亡。暴露于EC - 7或纯五氯苯酚的小鼠未观察到死亡。仅在高剂量组（所有等级的五氯苯酚）中观察到最终体重明显降低。在亚致死剂量下未观察到与化学物质相关的临床症状。暴露5周后未观察到主要行为变化，但在暴露于所有四个等级五氯苯酚的雌性小鼠中，在研究结束时出现运动活动增加和惊吓反应增强。所有等级的五氯苯酚均导致与肝损伤相关的血清酶升高。所有等级的五氯苯酚还导致芳烃羟化酶的剂量相关诱导以及细胞色素P450增加。然而，工业级五氯苯酚比其他等级的五氯苯酚诱导作用更强。纯五氯苯酚对体液免疫或细胞介导免疫无影响。然而，DP - 2尤其是工业级五氯苯酚会抑制体液免疫功能。在暴露于所有等级五氯苯酚的小鼠中观察到肝脏重量的剂量相关增加。在暴露于所有等级五氯苯酚的雄性小鼠中观察到脾脏重量的剂量相关增加；在暴露于除纯五氯苯酚外所有等级五氯苯酚的雌性小鼠中观察到脾脏重量减少。暴露6个月后，组织病理学检查始终显示肝脏和膀胱有影响。所有四个等级五氯苯酚在所有剂量下均出现肝脏病变，但在暴露于纯五氯苯酚的小鼠中，在可比剂量下病变较轻；病变包括肝细胞核肿大、细胞肿大和变性。膀胱的变化包括表面上皮细胞中的棕色颗粒色素。未观察到与色素相关的炎症或增殖反应。主要基于在6个月研究中观察到的肝脏病变，在为期两年的研究中选择的饲料含有0、100或200 ppm工业级五氯苯酚或0、100、200或600 ppm EC - 7，喂食50只雄性和50只雌性小鼠组。由于经济考虑以及在6个月研究中观察到的临床病理综合征与EC - 7相似，因此未选择DP - 2和纯五氯苯酚进行为期两年的研究。
暴露于工业级五氯苯酚和EC - 7的小鼠平均体重在第36 - 82周之前与对照组相当。此后，在暴露于EC - 7的中、高剂量小鼠以及暴露于工业级五氯苯酚的高剂量小鼠中观察到4% - 22%的剂量相关体重下降。雌性比雄性受影响更大。暴露小鼠的饲料消耗量与对照组相似。工业级五氯苯酚的平均每日剂量约为17 - 18或,35 mg/kg，而EC - 7为17 - 18、34 - 37或114 - 118 mg/kg。在这些研究中使用的剂量下，暴露于工业级五氯苯酚或EC - 7似乎未影响小鼠的存活。
暴露于工业级五氯苯酚或EC - 7的雄性和雌性小鼠中，肝细胞腺瘤和癌的发生率增加（与剂量相关），尽管暴露于工业级五氯苯酚的雌性小鼠中增加不太明显（腺瘤或癌合并：工业级：雄性 - 对照组，7/32，22%；低剂量组，26/47，55%；高剂量组，37/48，77%；雌性 - 3/33，9%；9/,49，18%；9/50，18%；EC - 7：雄性 - 对照组，6/35，17%；低剂量组，19/48，40%；中剂量组，21/48，44%；高剂量组，34/49，69%；雌性 - 1/34，3%；4/50，8%；6/49，12%；31/48，65%）。雄性小鼠中嗜铬细胞瘤的发生率在工业级五氯苯酚（0/31；10/45，22%；23/45,，51%）和EC - 7（1/34，3%；4/48，8%；21/48，44%；45/49，92%）组中均显著高于对照组。在暴露于最高剂量EC - 7的雌性小鼠中这些肿瘤也增加（0/35；2/49，4%；2/46，4%；38/49，78%），但在暴露于工业级五氯苯酚 的雌性小鼠中未增加（2/33，6%；2/48，4%；1/49，2%）。在接受工业级五氯苯酚（雄性：1/31；10/45；雌性：0/33；4/48；2/49）或EC - 7（雄性：1/34；19/48；13/48；1/49；雌性：2/35；1/49；5/46；17/49）的小鼠中，肾上腺髓质增生的发生率增加。在接受工业级五氯苯酚（0/35；3/50，6%；6/50，12%）或EC - 7（0/35；1/50，2%；3/50，6%；8/49，16%）的高剂量雌性小鼠中，脾脏和/或肝脏血管肉瘤的发生率显著高于对照组。暴露于工业级五氯苯酚或EC - 7的小鼠在肝脏、脾脏和鼻子中出现与化合物相关的非肿瘤病变。肝脏病变包括透明细胞灶、慢性活动性炎症、色素沉着、坏死、细胞肿大、造血细胞增殖和胆管增生的发生率与剂量相关增加。在接受工业级五氯苯酚的给药雄性和高剂量雌性小鼠中，脾红髓髓外造血增加的发生率增加（雄性：5/30；15/23；18/46；雌性：2/33；4/13；11/47）。在接受EC - 7的高剂量小鼠中，鼻粘膜急性灶性炎症和嗅上皮灶性化生的发生率增加（炎症 - 雄性：4/35；1/13；3/16；47/49；雌性：0/35；0/14；2/5；46/48；灶性化生 - 雄性：2/35；1/13；2/16；46/49；雌性：1/35；0/14；2/5；45/48），但在暴露于工业级五氯苯酚的小鼠中未出现。
五氯苯酚（纯度91.6%；纯度与毒理学研究中使用的工业级五氯苯酚相当）在有无外源性代谢激活剂（S9）的情况下对鼠伤寒沙门氏菌TA98、TA100、TA1535或TA1537菌株均无致突变性。在培养的CHO细胞的细胞遗传学研究中，五氯苯酚在有S9代谢激活剂存在时会导致染色体畸变增加，但在无S9时不会；相反，姐妹染色单体交换（SCE）仅在无S9时诱导产生。
对五氯苯酚两年研究的数据、文件和病理材料进行了审核。审核结果表明，研究的开展有充分记录，支持本技术报告中的数据和结果。
在这些为期两年的饲料研究条件下，有明确证据表明，喂食含有工业级五氯苯酚饲料的雄性B6C3F1小鼠具有致癌活性，表现为肾上腺髓质和肝细胞肿瘤发生率增加。有一些证据表明，暴露于工业级五氯苯酚的雌性B6C3F1小鼠具有致癌活性，表现为血管肉瘤和肝细胞肿瘤发生率增加。有明确证据表明，暴露于五氯苯酚、EC - 7的雄性B6C3F1小鼠具有致癌活性，表现为肾上腺髓质和肝细胞肿瘤发生率增加。有明确证据表明，暴露于五氯苯酚、EC - 7的雌性B6C3F1小鼠具有致癌活性，表现为肾上腺髓质和肝细胞肿瘤以及血管肉瘤发生率增加。各性别小鼠中与化学物质相关的非肿瘤病变发生率增加包括肝细胞肿大、坏死、炎症、色素沉着、透明细胞灶和肝内胆管增生。
氯酚；PCP；五氯酚；五氯；五氯苯酚；五氯酚（西班牙语）；五氯酚（葡萄牙语）；2,3,4,5,6 - 五氯苯酚
Acutox；Chem - Penta；Chem - Tol；Cryptogil ol；Dowicide 7；Dowicide EC - 7；Dow Pentachlorophenol DP - 2抗菌剂；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
