d Study performed with either a single dose or multiple doses that had no adverse effect; the value is therefore the highest dose tested.

limited by their short duration; they are summarized briefly below. The results of. studies that were 90 days or longer in duration and in which NOELS were identified are described in greater detail and are shown in Table 3.

Mice

A study to determine the doses for a subsequent 2-year study was conducted, in which groups of 10 male and 10-female B6C3F₁ mice were provided with tap-water containing phenol (No. 690) at a concentration of 0, 100, 300, 1000, 3000,.or 10 000 mg/L for 13 weeks. The concentrations were calculated (Food & Drug Administration, 1993) to provide average intakes of 0, 25, 75, 250, 750, and 2500 mg/kg bw per day. All the mice survived to the end of the study: The mean body-weight gain of animals at the highest dose was depressed; animals in this group rejected the treated water. Microscopic examination revealed no treatment-related differences between treated and control mice. The NOELwas 750 mg/kg bw per day (National Toxicology Program, 1980).

Rats

A study to determine the doses for a subsequent 2-year study was conducted, in which groups of 10 male and 10 female Fischer 344 rats were provided with tapwater containing phenol (No. 690) at a concentration of 0, 100, 300, 1000, 3000, or 10 000 mg/L for 13 weeks. The concentrations were calculated (Food & Drug Administration, 1993) to provide average intakes of 0, 10, 30, 100, 300, or.1000 mg/ kg bw per day,. All the rats lived to the end of the study. Statistically significant decreases in mean body-weight gain were observed in animals of each sex at the highest dose; animals in this group rejected the treated water. No changes attributable to treatment were observed in tissues or organs. The NOEL was 300 mg/kg bw per day (National Toxicology Program, 1980).

Mice

In a 28-day study of toxicity, groups of five male and five female B6C3F₁ mice were fed diets containing ortho-cresol (No. 691), meta-cresol (No. 692), para-cresol (No. 693), or meta/para-cresol (60%/40%) at a concentration of 0, 300, 1000, 3000, 10 000, or 30 000 mg/kg, providing average intakes of 0, 62, 200, 580, 1700, or 4700 mg /kg bw per day. Nineteen animals died or were killed when moribund during the 28 days: two males and one female at the highest dose of ortho-cresol, one female at the second highest dose of meta-cresol, two males and two females at the highest dose of meta-cresol, one male at the second highest dose of para-cresol, and all animals at the highest dose of para-cresol; all animals treated with meta/para-cresol lived to the end of the study. Hunched posture, lethargy, and hypothermia were observed in the groups receiving the highest dose of any substance. At the end of the study, significantly decreased body-weight gains were reported for males or females receiving the two higher doses of any substance. A significantly increased relative liver weight over that of controls was reported in females given meta-cresol at the lowest dose, and this effect was observed consistently in animals at the three higher doses of any substance. Significantly increased relative weights of the brain and kidney were also found in groups receiving the two higher doses of any substance, but no microscopic changes were associated with these changes in organ weights. Uterine and ovarian atrophy were seen in several females mainly at the highest doses of ortho-, meta-, or meta/para-cresol. No gross lesions were seen in the organs of treated animals, but renal and hepatic necroses were prevalent in animals receiving the highest dose of para-cresol, all of which died early in the study. Bone-marrow hypocellularity was found in some mice at the highest doses of para- and meta/para-cresol, and mild nasal and respiratory epithelial hyperplasia was found in most of these animals-presumably due to irritation caused by the test substance. Minimal hyperplasia of the oesophagus, forestomach, and/or respiratory squamous-cell epithelium was also reported among animals in these groups (National Toxicology Program, 1992a).

In a 13-week study of toxicity, groups of 10 male and 10 female B6C3F₁.mice were fed diets containing ortho-cresol (No. 691) at a concentration of 0, 1250, 2500, 5000, 10 000, or 20 000 mg/kg or meta/para-cresol (60%/40%) at concentrations of 0, 625, 1250, 2500, 5000, or 10 000 mg/kg. The average intakes were reported to have been 0, 220, 450, 860, 2200, and 6000 mg/kg bw per day of ortho-cresol and 0, 110, 220, 440, 850, and 3200 mg/kg bw per day of meta/para-cresol. All mice lived to the end of the study, when the body weights of males and females receiving 20 000 mg/kg of diet of ortho-cresol were reduced by about 16% and 21%, respectively, and those of males and females receiving 10 000 mg/kg of diet of meta/para-cresol were reduced by about 9% and 7%, respectively, when compared with controls. Females receiving 10 000 mg/kg of diet of ortho-cresol also showed statistically significant decreases in weight gain (9% reduction compared with controls). Necropsy revealed significant increases in the relative weights of the liver in all groups of males given ortho-cresol and in males receiving 5000 or 10 000 mg/ kg of diet of meta/para-cresol. These responses are consistent with the known hepatocellular sensitivity of male B6C3F₁ mice (Maronpot & Boorman, 1982; Maronpot et al., 1987). The relative liver weights were also significantly increased in female mice receiving the three higher doses of ortho-cresol or the highest dose of meta/para-cresol. Males given the highest dose of ortho-cresol had significantly increased relative testicular weights and males and females at this dose had increased relative thymus weights. Haematology, clinical chemistry, and urinary analysis revealed normal values. Microscopic examination of liver tissue showed no remarkable changes. Minimal epithelial hyperplasia was seen in the forestomach in 4 of 10 males and 3 of 10 females receiving the highest dose of ortho-cresol. An increased incidence of hyperplasia of the nasal respiratory epithelium was found in males receiving the two higher doses of meta/para-cresol (4/10 at 5000 mg/kg of diet and 10/10 at 10 000 mg/kg of diet) and in females receiving the highest dose of this substance (7/10). Females given 20 000 mg/kg of diet of ortho-cresol had lengthened estrus cycles. No biologically significant changes in reproductive function were noted in animals given meta/para-cresol at any dose (National Toxicology Program, 1992a).

Rats

A 28-day range-finding study was conducted in which groups of five male and five female Fischer 344 rats were fed diets containing ortho-cresol (No. 691), meta-cresol (No: 692), para-cresol (No. 693), or meta/para-cresol (60%/40%) at a concentration of 0, 300, 1000, 3000, 10 000, or 30 000 mg/kg, providing average intakes of each substance of 0; 26, 87, 260, 860, and 2400 mg/kg bw per day. All rats lived to the end of the study. No clinical signs of toxicity were observed in rats given ortho- or meta-cresol, but male and female rats given the highest dose of para- or meta/para-cresol appeared thin, and animals at the highest dose of each cresol isomer had significantly reduced body-weight gain and decreased food consumption. Significantly increased relative liver weights were observed consistently in groups given the two highest doses of each isomer; a similar effect was seen in males given ortho- or meta/para-cresol at 3000 mg/kg of diet and in females given meta/para-cresol at 1000 or 3000 mg/kg of diet or para-cresol at 3000 mg/kg of diet. Significantly increased relative kidney weights were also observed generally at the two highest doses. The relative weights of the brain and testes were increased in animals at the highest doses; probably due to reduced body-weight gain. No gross or microscopic lesions were recorded in rats treated with ortho-cresol. Mild to moderate uterine atrophy was reported in females given the highest dose of meta- or para-cresol. para-Cresol induced bone-marrow hypocellularity in males at the three higher doses and in females at the two higher doses. This effect was also observed in rats given the highest dose of meta/para-cresol. Male and female rats at the three higher doses of this substance had mild epithelial hyperplasia of the nasal cavity, oesophagus, and forestomach. No gross lesions were seen in the organs of any treated animal (National Toxicology Program, 1992a).

A 13-week study was conducted in which ortho-cresol (No. 691) was given to groups of 30 male and 30 female Sprague-Dawley rats at a dose of 0, 50, 180, or 600 mg/kg bw per day by oral gavage in corn oil. Of the animals at the high dose, 19 females and nine males died during the study; no deaths occurred in the other groups. At the end of the study, males at the high dose showed a 10% reduction in body-weight gain when compared with controls. Clinical chemistry, haematology, urinary analyses, and measurements of organ weights revealed no significant changes in treated rats, No gross or histological lesions and no opthalmological changes were found. Congestion, oedema, and oil droplets were found in the lungs of the 28 animals at the high dose that died during the study, but the authors suggested that these findings were related to terminal stress and aspiration of the mixture of ortho-cresol and corn oil during convulsive seizures. The NOEL was 180 mg/kg bw per day (Environmental Protection Agency, 1988a).

Groups of 20 Fischer 344 rats of each sex were fed diets containing ortho-cresol or meta/para-cresol (60%/40%) at a concentration of 0, 1900, 3800, 7500, 15 000, or 30 000 mg/kg for 13 weeks, providing average intakes of 0, 130, 250, 500, 1000, and 2000 mg/kg bw per day. All rats lived to the end of the study except for one female receiving the highest dose of ortho-cresol. At the end of the study, the body weights of males and females at the two higher doses of both substances were significantly lower than those of. controls, except for males given 15 000 mg/kg of diet of ortho-cresol. The relative weights of the liver were increased in males and females at the three higher doses of both isomers. The relative weights of the kidney were increased in animals at the two higher doses of ortho-cresol and in males at the three higher doses and females at the highest dose of meta/para-cresol. The relative weights of the testes were increased in males at the highest dose of ortho-cresol and at the two higherdoses of meta/para-cresol. Substantially increased concentrations of serum bile salts were reported in male and female rats given either isomer, particularly at the two highest doses, throughout the study. Consistent decreases in the activity of 5'-nucleotidase in serum were seen in rats given meta/para-cresol. Mild uterine atrophy was observed at the two higher doses of meta/para-cresol. Minimal to mild hypocellularity of the bone marrow was reported in males. and females at the two higher doses of both isomers, except in males at 15 000 mg/kg of diet of ortho-cresol. All animals receiving meta/para-cresol showed hyperplasia of the olfactory and respiratory epithelium. Both isomers lengthened the estrus cycle of females treated at 7500 or 30 000 mg/kg of diet. The NOEL for both ortho-cresol and meta/para-cresol was 250 mg/kg bw per day (National Toxicology Program, 1992a).

A 13-week study was conducted in which groups of 30 male and 30 female Sprague-Dawley rats were given para-cresol at a dose of 0, 50, 175, or 600 mg/kg bw per day by oral gavage. At the end of the study, the mean body weights of males and females at the highest dose were significantly lower than those of controls. Females at the intermediate and high doses showed statistically significant reductions in erythrocyte count, haemoglobin, and haematocrit, but compensatory responses to the anaemic state were not observed. Females at the highest dose also had elevated liver transaminase activity, but this finding was attributed to large increases in 4/10 animals, including two with chronic hepatic inflammation. Statistically significant increases in serum cholesterol were reported in females at the highest dose and in total protein in males at the two higher doses. Necropsy revealed significantly increased relative kidney weights in males at the intermediate dose and in males and females at the highest dose. Significantly increased relative weights of the liver, heart, testis, and brain were noted in males at the highest dose, while females at the lowest dose showed significantly increased relative spleen weights. Gross examination showed no treatment-related lesions. Histological evaluation revealed a significantly increased incidence of chronic nephropathy in males at the lowest and highest doses. A significantly increased incidence of epithelial metaplasia of the trachea was observed in animals at the highest dose than in controls, but no other treatment-related histological findings were reported. The NOEL was 50 mg/kg bw per day (Environmental Protection Agency, 1988b).

Groups of 20-32 male and female Charles River CD rats were fed a basal diet supplemented with para-ethylphenol (No. 694) for 90 days, giving average intakes of 0.20 mg/kg bw per day for males and 0.22 mg/kg bw per day for females. A control group was fed the basal diet alone. Weekly measurements of body weight, food consumption, and the calculated efficiency of food use showed no significant differences from controls. Haematological examinations and clinical chemistry performed at weeks 7 and 13 showed no effects. At necropsy, there were no significant changes in liver or kidney weights. Gross and histological examination of a wide range of organs (unspecified in the report) revealed no lesions related to treatment with either substance. The NOEL was 0.20 mg/kg bw per day (Posternak & Linder, 1969).

Groups of 13 white rats (sex not specified) were given 2,6-xylenol (No. 707) at a dose of 0.06 or 6.0 mg/kg bw per day by stomach tube for 8 months. No effects on weight gain, haemoglobin concentration, or erythrocyte count were seen, but the higher dose had adverse effects on the cells of the liver, spleen, kidneys, and heart. No pathological or histological changes were seen at the lower dose. The NOEL was 0.06 mg/kg bw per day (Maasik, 1970).

In the study described above, groups of 13 white rats were given 3,4-xylenol (No. 1708) at a dose of 0.14 or 14 mg/kg bw per day by stomach tube for 8 months. Animals given the higher dose showed delayed weight gain and significantly decreased haemoglobin concentration and erythrocyte count. Adrenaline injections were used to study the effects of 3,4-xylenol on the capacity to regulate blood pressure. This capacity was impaired at the higher dose, but it is unclear whether the effect was statistically significant. The high dose had adverse effects on the cells of the liver, spleen, kidneys, and heart, but no pathological or histological changes were seen at the lower dose. The NOEL was 0.14 mg/kg bw per day (Maasik, 1970).

Two groups of five male and five female weanling Osborne-Mendel rats received a diet containing thymol (2-isopropyl-5-methylphenol, No. 709) at a concentration of 1000 or 10 000 mg/kg for 19 weeks, calculated (Food & Drug Administration, 1993) to provide average intakes of 50 or 500 mg/kg bw per day. Body weights, food intake, and the general condition of each animal were recorded weekly. At the end of the study, haematological parameters were measured in both groups and animals at the higher dose were necropsied. No effects on growth or haematological parameters were reported, and no macroscopic or microscopic changes were observed in tissues from rats at the higher dose. The NOEL was 1000 mg/kg bw per day (Hagan et al., 1967).

Mice

Groups of five male and five female B6C3F₁ mice were given resorcinol (No. 712) at a dose of 0, 37.5, 75, 150, 300, or 600 mg/kg bw per day by oral gavage on 5 days/week for 17 days. The clinical findings at the three higher doses included prostration and tremors lasting up to 2 h. One male at 300 mg/kg bw per day and five females and four males at 600 mg/kg bw per day died during the study. At necropsy, the organ weights were found to be similar to those of control animals. Microscopic examination of tissues revealed no abnormalities attributable to treatment (National Toxicology Program, 1992b).

Groups of 10 male and 10 female B6C3F₁ mice were given resorcinol (No. 712) at a dose 0, 28, 56, 112, 220, or 420 mg/kg bw per day by oral gavage for 13 weeks. Deaths during the study occurred only among animals at the highest dose (seven males and seven females during the first week, one male at week 4, and one female at week 12). Dypnoea, prostration, and tremors were observed in males at the highest dose-within 30 min after treatment. At the end of the study, the two surviving male; at this dose showed a statistically significant decrease in mean body weight. No other significant changes in body weight were observed. Significant decreases in the absolute and relative weights of the adrenal gland were observed in all groups of treated males. Haematology and clinical chemistry showed no effects, and gross and microscopic examinations revealed no lesions related to treatment. The NOEL was 220 mg/kg, bw per day (National Toxicology Program, 1992b).

Rats

Groups of five male and five female Fischer 344/N rats were given resorcinol (No. 712) at a dose of 0, 27.5, 55, 110, 220, or 450 mg/kg bw per day by oral gavage on 5 days/week for 17 days. Males at the two higher doses and females at the four higher doses showed clinical signs including hyperexcitability and tachypnoea lasting up to 2 h. None of the rats died. The final mean body weights of the treated animals were comparable to those of controls. Females at the highest dose had significantly decreased absolute and relative thymus weights, but no other significant changes in organ weights were reported. Microscopic examination of the tissues revealed no abnormalities attributable to treatment (National Toxicology Program, 1992b).

Groups of 10 male and 10 female Fischer 344/N rats were given resorcinol (No 712) at a dose 0, 32, 65, 130, 260, or 520 mg/kg bw per day by oral gavage for 13 weeks. Eight males and 10 females at the highest dose died within the first 4 weeks; the deaths of two males and four females in the group at 260 mg/kg by per day dose during the first week were attributed to accidental administration o 520 mg/kg bw per day. The final mean body weights of the treated animals were comparable to those of controls. At necropsy, statistically significant increases it the absolute and relative weights of the liver were reported for males receiving 130 or 260 mg/kg bw per day and females receiving 65, 130, or 260 mg/kg bw per day of resorcinol. Significantly increased absolute and relative adrenal gland weights were also reported in all surviving treated males. Haematology, clinical chemistry, and gross and microscopic examination revealed no findings related to treatment (National Toxicology Program, 1992b).

Groups of 20-32 male and female Charles River CD rats were fed a basal diet supplemented with 2,6-dimethoxyphenol (No. 721) for 90 days, providing average intakes of 6.0 mg/kg bw per day for males and 6.8 mg/kg bw per day for females. A control group was fed the basal diet alone. Weekly measurements of body weight, food consumption, and calculated efficiency of food use showed no significant differences from controls. Haematological and clinical chemical examinations at weeks 7 and 13 showed no effects. At necropsy, there were no significant changes in liver or kidney weights. Gross and histological examination of a wide range of organs (unspecified in the report) revealed no lesions related to treatment with either substance. The NOEL was 6.0 mg/kg bw per day (Posternak & Linder, 1969).

Groups of 15 male and 15 female SPF-derived CFE rats were given diet; containing 4-(para-hydroxyphenyl)-2-butanone (No. 728) at a concentration of 0, 0.1, 0.2, 0.4, or 1.0% for 13 weeks. The average intakes, calculated on the basis of data on body weights and food consumption, were 0, 70, 140, 280, and 700 mg/kg bw per day. No changes in appearance, behaviour, or food intake were noted at any time during the study. A slight but statistically significant (p < 0.05) reduction in weight gain was observed in male rats at the highest dose from week 5 onwards, but the decrease in weight was not associated with decreased food consumption. No significant differences were found in absolute organ weights. In males, the relative weights of the liver and kidney were increased at the two higher doses and those of the adrenal gland at the highest dose. The increases in relative organ weights may have been due to the decrease in body weight. Urinary analyses showed ketones in the urine of all treated animals at 7 and 13 weeks. The authors reported that this effect appeared within 12 h in rats fed a diet containing 1% 4-(para-hydroxyphenyl)-2-butanone for-7 days, and disappeared within 9 h when the rats were returned to normal diet. The ketonuria, which was possibly due to metabolites present in the urine, was considered not to be a toxic effect. Histopathological examination of rats at the highest dose showed no effect of treatment on organs of the digestive, reproductive, circulatory, or central nervous systems (Gaunt et al.,1970). The NOEL of 280 mg/kg bw per day is 10 000 times greater than the estimated daily per capita intake of 4-(para-hydroxyphenyl)-2-butanone in Europe (46 µg/kg bw per day) and the USA (63 µg/kg bw per day) from use as a flavouring substance.

A study in which three beagle dogs (sex not specified) were given phenyl salicylate (No. 736) at a dose of 250 or 500 mg/kg bw per day in a capsule for 51 days was reported as an abstract. All the treated animals showed decreased appetite, body weight, and activity and dark urine and faeces. The serum activities of alanine and aspartate aminotransferases were elevated. In a subsequent study, three beagle dogs were given phenyl salicylate at a dose of 125 mg/kg bw per day in a capsule for 51 days. At this dose, phenol excretion was markedly elevated. Haematology and tests for liver and kidney function, performed regularly, showed no effects. At necropsy, no gross or microscopic abnormalities were observed, but the usefulness of this study is limited by deficiencies in reporting (Kociba et al., 1976).

2.3.2.4 Long-term studies of toxicity and carcinogenicity

Mice

Groups of 50 male and 50 female B6C3F₁ mice were given tap-water containing phenol (No. 690) at a concentration of 0, 2500, or 5000 mg/L for 103 weeks, calculated (Food & Drug Administration, 1993) to provide average intakes of 0, 620, or 1200 mg/kg bw per day. The animals were observed twice daily and weighed every 2 weeks during the first 12 weeks, monthly thereafter, and at the end of the study. Water consumption was recorded weekly. Gross and histological examinations were performed on all major organs and tissues, including those of animals found dead or killed moribund during the study. No clinical signs of toxicity were seen. Although the mean body weights were significantly reduced at most times in all treated groups, the food consumption did not differ significantly from that of controls. Water consumption was depressed by 25% in the low-dose group and 40-50% in the high-dose group compared with controls. Neoplasms were observed in both control and treated animals but were of similar number and type to those observed in ageing control B6C3F₁ mice in previous studies. Phenol was considered not to be carcinogenic, and there was no histological evidence of toxicity (National Toxicology Program; 1980).

Rats

Groups of 50 male and 50 female Fischer 344 rats were given tap-water containing phenol (No. 690) at a concentration of 0; 2500; or 5000 mg/L for 103 weeks calculated (Food & Drug Administration, 1993) to provide average intakes of 0, 250, or 500 mg/kg bw per day. The same protocol of observations and necropsy as used in the study in mice described above was followed. There was no significant difference in the rate of survival between treated and control rats. Animals at the high dose had lower mean body weights than controls, although the food consumption was comparable. The water consumption of rats at the low and high doses was depressed by 20% and 10% of that of controls, respectively. No clinical signs of toxicity were observed. Significantly increased incidences of leukaemias, lymphomas, and phaeochromocytomas of the adrenal medulla were observed only in males at the low dose. However, none of the tumours were clearly associated with exposure to phenol. The NOEL was 250 mg/kg bw per day (National Toxicology Program, 1980).

Mice

Groups of 60 male and 60 female B6C3F₁ mice were given resorcinol (No. 712) at a dose of 0, 110, or 220 mg/kg bw per day in deionized water by oral gavage on 5 days/week for 104 weeks. All animals were observed twice daily, and clinical signs were noted every 4 weeks. Body weights were measured weekly through week 13 and every 4 weeks thereafter until the last 3 months, when they were recorded every 2 weeks. Ten mice of each sex per dose were selected for interim evaluations of organ weights, haematological and clinical chemical parameters, and histology. Necropsies were performed on all remaining animals at the end of the study. Complete histological examinations were conducted on all control and high-dose mice. For animals at the low dose, only tissues containing gross lesions were examined microscopically at both the interim and terminal evaluations.

The mean body weights of all treated males and females at the low dose were comparable to those of controls throughout the study; however, the mean body weights of females at the high dose were 10-15% lower than those of controls from week 85 through week 104. Recumbence and tremors were common among all treated mice for a short period after dosing. No treatment-related effects were reported at the 15-month interim evaluation. The survival rate of treated mice at termination was similar to that of controls. Some animals examined at 6, 12, 18, and 24 months had mouse hepatitis virus, but no clinical or histological evidence of disease was detected. The incidences of neoplastic and non-neoplastic lesions were not statistically or biologically increased in any group of mice. The clinical signs (ataxia, recumbency and tremors) observed in all treated mice suggest an effect on the central nervous system; however, there were no associated morphological findings. Similar clinical signs were observed in rats in the bioassay described below (National Toxicology Program, 1992a).

Rats

Groups of 60 male and 60 female Fischer 344/N rats were given resorcinol (No. 712) at a dose of 0, 110, or 220 mg/kg bw per day in deionized water by oral gavage on 5 days/week for 103 weeks. Some rats were given one or two extra doses during week 104. As 16 females at the high dose died after 22 weeks of treatment, four further groups of 60 females were given doses of 0, 50, 100, or 150 mg/kg bw per day. The same protocol of observations and evaluations as used in the study in mice described above was followed. Ten rats of each sex per dose were used for interim evaluations of organ weights, haematology, clinical chemistry, and histology at 15 months. As several males at the high dose died prematurely, the remaining animals in the interim group of males at this dose were not killed as originally planned. Instead, 10 males at the high dose in the 2-year study group that either died or were killed when moribund during weeks 62 and 67 were used for the interim histological evaluation. Organ weighings, haematology, and clinical chemistry were not performed in this group of male rats.

At the 15-month interim evaluation, significantly reduced terminal body weights were found for high-dose males (220 mg/kg bw per day) and females (150 mg/kg bw per day). Significantly increased relative weights of the brain were found in males at the low dose and of the liver in females at the high dose, which were associated with decreased body weights. Haematology and clinical chemistry revealed no treatment-related effects (assessed in female rats only). No treatment-related neoplastic or non-neoplastic lesions were found in any group.

The mean body weights of males given 220 mg/kg bw per day and females given 150 mg/kg bw per day were significantly lower than those of controls throughout the 2-year study, whereas the mean body weights of animals at the low dose were comparable to those of controls. Haematology and clinical chemistry revealed normal values. Ataxia, prostration, salivation, and tremors were observed shortly after treatment in all groups of treated males and in females receiving 100 or 150 mg/kg bw per day. These effects lasted for 0.5-1 h and became more pronounced at the end of each 5-day dosing period. The rate of survival of males and females at the high dose was significantly lower than that of controls. At the end of the study, 57% of control males, 15% of high-dose males, 68% of control females, and 50% of high-dose females were still alive. Some animals examined at 6,12, 18, and 24 months were found to be infected with Sendai virus and rat sialodacryoadenitis virus (which is a type of rat coronavirus); however, no clinical or histological evidence of disease was found. Complete histological examination on all remaining animals at the end of the study revealed no pathological lesions. The incidence of neoplastic or non-neoplastic lesions was not statistically or biologically significantly increased in any treated group. A statistically significant decrease in the incidence of mammary gland fibroadenomas was observed in all three groups of treated females, the lesions occurring in 18% of high-dose females, 24% of mid-dose females, 28% of low-dose females, and 50% of control females. In all groups, the incidences were within the range of historical controls (16-53%). Although clinical signs (ataxia, prostration, salivation, and tremors) suggesting an effect of resorcinol on the central nervous system were observed in male rats at both doses and females at the two higher doses, there were no related morphological findings. Similar clinical signs were observed in mice in the bioassay described above (National Toxicology Program, 1992b).

2.3.2.5 Genotoxicity

Negative results were reported in the standard assay for reverse mutation in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 incubated with phenol at concentrations up to 9400 µg/plate (Florin et al., 1980; Gocke et al., 1981; Pool & Lin, 1982; Haworth et-al., 1983; Aeschbacher et al.; 1989; Massey et al., 1994); ortho-cresol at up to 5000 µg/plate (Douglas et a1., 1980; Florin et al., 1980 Nestmann et al., 1980; Pool & Lin, 1982; Haworth et al., 1983; Massey et al., 1994); meta-cresol and para-cresol at up to 5000 µg/plate (Douglas et a1., 1980; Florin et al., 1980; Nestmann et al., 1980; Pool & Lin,.1982;Haworth et al., 1983); para-ethylphenol, 2,5-xylenol, 2,6-xylenol, and 3,4-xylenol at 367 µg/plate (Florin et al., 1980); 4-(1,1-dimethyl)ethyl phenol at up to 2000 µg/plate (Dean et al., 1985); thymol at up to 1000 µg/plate (Florin et al., 1980; Azizan & Blevins, 1995); 2-phenylphenol at up to 200 µg/plate (National Toxicology Program, 1986); resorcinol at up to 7700 µg/plate (Gocke et al., 1981; Haworth et al., 1983); guaiacol at up to 111 726 µg/plate (Douglas et al., 1980; Nestmann et al., 1980; Pool & Lin, 1982; Haworth et al., 1983; Aeschbacher et al., 1989); 2,6-dimethoxyphenol at up to 16 000 µg/plate (McMahon et al., 1979; Douglas et al., 1980; Florin et al., 1980; Pool & Lin, 1982); 2-hydroxyacetophenone at 408 µg/plate (Florin et al., 1980); and phenyl salicylate at up to 333 µg (Zeiger et al., 1987), with and without metabolic activation (see Table 4). However, in an assay with a modified minimal ZLM medium for Escherichia coli, the results varied by bacterial strain (Gocke et al., 1981). At concentrations of 470-9400 µg/plate, phenol caused reverse mutation only in strain TA98 in the presence of metabolic activation. Resorcinol was mutagenic at doses of 550-7700 µg/plate only in TA1535 without metabolic activation and in TA100 with metabolic activation. The same authors reported negative results in all five S. typhimurium strains with and without metabolic activation in the standard Vogel-Bonner medium, which contains a concentration of citrate and other ions that is two to four times higher (Gocke et al., 1981). Negative results with phenol and resorcinol at doses up to 3333 µg/plate were reported in another study when Vogel-Bonner medium was used (Haworth et al., 1983). No mutagenicity was found in E. coli exposed to 2,6-dimethoxyphenol at concentrations up to 1000 µg/ml (McMahon et al., 1979).

Forward mutation was not induced in mouse lymphoma L5178YTk^+/- cells by phenol at concentrations of 100-3200 µg/ml or resorcinol at 125-2000 µg/ml without metabolic activation (McGregor et al., 1988). However, positive results were reported with phenol at concentrations of 5-42 µg/ml with activation and 178-887 µg/ml without activation (Wangenheim & Bolcsfoldi, 1988). Positive results in this assay were also reported with 2-phenylphenol at doses of 0.32-60 µg/ml without metabolic activation and 0.32-5 µg/ml with activation, but these doses were cytotoxic (National Toxicology Program, 1986).

Sister chromatid exchange was not induced in human lymphocytes by phenol at concentrations up to 188 µg/ml, ortho-cresol at up to 54 µg/ml, meta-cresol at up to 108.µg/ml, para-cresol at up to 54 µg/ml, para-ethyl phenol at up to 27 µg/ml, 2,6-xylenol at up to 31 µg/ml, resorcinol at up to 28 µg/ml, 2,6-dimethoxyphenol at up to 77 µg/ml (Jansson et al., 1986, 1988) or para-vinylphenol at up to 12 µg/ml (Jansson et al., 1988) (see Table 4). Phenol at 19 µg/ml also did not induce sister chromatid exchange in human lymphocytes, but positive results were reported when the