One-year time sequence inhalation toxicity study of vinyl chloride in rats. I. Growth, mortality, haematology, clinical chemistry and organ weights.

Wistar rats were exposed to atmospheres containing O (control) or 5000 ppm vinyl chloride monomer (VCM), 7 h/day, 5 days/week, for a period of 52 weeks. After 4, 13, 26 and 52 weeks each time 10 rats/sex/group were killed and subjected to extensive examinations. The present paper deals with growth, mortality, haematology, clinical chemistry and organ weights. Slight growth retardation throughout the experimental period and high mortality in the second half of the study were observed in VCM-exposed animals. Some of the haematological parameters and biochemical blood parameters were slightly influenced by VCM after an experimental period of 52 weeks only. Blood clotting time was generally slightly shorter in VCM-exposed rats than in controls. There were minor indications of increased potassium contents of the blood serum in VCM-exposed animals during the first half of the test period. The kidneys were adversely affected by VCM as appeared from increased blood urea nitrogen levels and relative kidney weights. After 52 weeks increased weights of heart and spleen, and slight signs of anaemia were noticed in VCM-exposed rats. The present study did not produce obviously suitable parameters for early diagnosing "VCM-disease" in man.

Repeated exposure to butenolide vapour: subacute study in Syrian golden hamsters.

The subacute inhalation toxicity of butenolide was examined in hamsters by repeated exposure of 4 groups of 10 males and 10 females to butenolide vapour at concentrations of 0, 5.4, 25 and 130 ppm respectively (6 h/day, 5 days/week) for a period of 13 weeks. The effects found at 130 ppm included eye irritation, salivation, nasal discharge, growth retardation, decreased number of eosinophils, increased liver weight, and hyper- and metaplastic epithelium in the nasal cavity. At the 5.4 and 25 ppm levels no changes were observed which could be attributed to butenolide; 25 ppm was, therefore, considered the highest no-toxic effect level observed. The actual no-adverse effect level was placed at 75 ppm.

Repeated exposure to acrolein vapour: subacute studies in hamsters, rats and rabbits.

The subacute inhalation toxicity of acrolein was examined in 4 groups of 20 hamsters, 12 rats and 4 rabbits each, exposed repeatedly to acrolein vapour at concentrations of 0, 0.4, 1.4 and 4.9 ppm (6 h/day, 5 days/week) for a 13-week period. The most important effects found at the highest level included mortality in rats, ocular and nasal irritation, growth depression and histopathological changes of the respiratory tract in each of the animal species exposed. The aberrations in the airways consisted of destruction and hyper- and metaplasia of the lining epithelium accompanied by inflammatory alterations. Rats appeared to be the most susceptible of the species examined and showed treatment-related abnormalities even at 0.4 ppm, whereas this exposure level was found to be a no-toxic effect level in both hamsters and rabbits.

Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment.

Aldehydes constitute a group of relatively reactive organic compounds. They occur as natural (flavoring) constituents in a wide variety of foods and food components, often in relatively small, but occasionally in very large concentrations, and are also widely used as food additives. Evidence of carcinogenic potential in experimental animals is convincing for formaldehyde and acetaldehyde, limited for crotonaldehyde, furfural and glycidaldehyde, doubtful for malondialdehyde, very weak for acrolein and absent for vanillin. Formaldehyde carcinogenesis is a high-dose phenomenon in which the cytotoxicity plays a crucial role. Cytotoxicity may also be of major importance in acetaldehyde carcinogenesis but further studies are needed to prove or disprove this assumption. For a large number of aldehydes (relevant) data on neither carcinogenicity nor genotoxicity are available. From epidemiological studies there is no convincing evidence of aldehyde exposure being related to cancer in humans. Overall assessment of the cancer risk of aldehydes in the diet leads to the conclusion that formaldehyde, acrolein, citral and vanillin are no dietary risk factors, and that the opposite may be true for acetaldehyde, crotonaldehyde and furfural. Malondialdehyde, glycidaldehyde, benzaldehyde, cinnamaldehyde and anisaldehyde cannot be evaluated on the basis of the available data. A series of aldehydes should be subjected to at least mutagenicity, cytogenicity and cytotoxicity tests. Priority setting for testing should be based on expected mechanism of action and degree of human exposure.

Human diets cooked by microwave or conventionally: comparative sub-chronic (13-wk) toxicity study in rats.

To compare the possible effects of microwave and conventional cooking on a range of common dietary components, mixed human diets containing beef, potatoes and vegetables were fed to groups of 10 male and 10 female Wistar rats for 13 wk. The diet ingredients were cooked by either of the methods in a normal and an abused manner, the latter consisting of the normal treatment followed by two cycles of reheating to approximately 85 degrees C and cooling. The cooked ingredients were freeze-dried, ground and mixed with supplements of vitamins and minerals to meet the rat requirements. An additional control group was fed a cereal-based rodent diet. Criteria to assess toxicity included clinical observations, ophthalmoscopy, growth, food and water intake, haematology, clinical chemistry, urinalysis, organ weights, micronucleated erythrocytes in bone marrow, gross examination at autopsy and microscopic examination of a wide range of organs. The results indicate no adverse effects of the diets cooked by microwave compared with those cooked conventionally.

Subchronic oral toxicity study with regular and enzymatically depolymerized sodium carboxymethylcellulose in rats.

Enzymatically depolymerized sodium carboxymethylcellulose (CMC-ENZ) is a new functional food ingredient which has a lower molecular weight and viscosity than regular sodium carboxymethylcellulose (CMC). Both compounds are known not to be absorbed to a significant extent, and the human safety of CMC as a thickening agent and stabilizer in food is well established. In the present study, the subchronic oral toxicity of CMC-ENZ was examined and compared with that of CMC in Wistar rats. Seven groups of 20 rats/sex were fed diets with 0 (controls), 2.5, 5 and 10% CMC and 2.5, 5 and 10% CMC-ENZ for a 3-month period. There was only one death that was unrelated to the treatment. Water intake, urine production and urinary sodium excretion increased with increasing doses of CMC and CMC-ENZ due to their sodium content of about 7-8%. The treatment-related occurrence of diarrhoea and caecal enlargement in the mid- and high-dose groups, a slight increase of plasma alkaline phosphatase, and increased urinary calcium and citrate excretions were considered to be generic effects that typically are observed in rodent studies with low digestible carbohydrates. The increased occurrence of nephrocalcinosis and hyperplasia of the urothelial epithelium in some of the treated groups was interpreted as an indirect consequence of a more alkaline urine coupled with an increased calcium excretion. As the frequency and severity of all these changes did not differ between corresponding CMC and CMC-ENZ dose groups, it is concluded that the two products have a similar toxicological profile.

Nitrite-induced adrenal effects in rats and the consequences for the no-observed-effect level.

In a previous subchronic oral toxicity study with potassium nitrite, hypertrophy of the adrenal zona glomerulosa was observed for all nitrite levels examined including the lowest level of 100 mg/litre. This present study was carried out, therefore, to establish a no-observed-effect level (NOEL) for nitrite. Groups of 10 male and 10 female 6-wk-old Wistar rats received KNO2 at levels of 12.5, 25, 50, 100 or 3000 mg/litre or NaNO2 at levels of 81 or 2432 mg/litre in the drinking water for 13 wk. The nitrite content of the drinking water in the latter two groups was equal to that of the 100 and 3000 mg KNO2/litre groups, respectively. Potassium and sodium concentrations were equalized in the corresponding test groups with KCl and NaCl, respectively. General health, behaviour and survival were not affected by the ingestion of nitrite. Body weight and food and liquid intake were slightly decreased in the 3000 mg KNO2/litre and 2432 mg NaNo2/litre groups for both sexes. Methaemoglobin concentration was significantly elevated in rats of both high-dose nitrite groups in wk 4 and 12, while slight increases in a number of red blood cell variables occurred with 3000 mg KNO2/litre in females in wk 12. Relative kidney weights were increased in both high-dose nitrite groups. In wk 4, plasma aldosterone and corticosterone levels were slightly decreased in males with 2432 mg NaNO2/litre and plasma corticosterone in females with 3000 mg KNO2/litre but not in wk 13. Systolic blood pressure was not affected by nitrite. Microscopic examination revealed slight hypertrophy of the adrenal zona glomerulosa in animals of the 100 and 3000 mg KNO2/litre and of the 81 and 2432 mg NaNO2/litre groups, the incidence and degree being dose related. The results obtained with 100 and 3000 mg KNO2/litre in the drinking water were comparable with those found at the same levels in the previous 90-day study. The effects with sodium nitrite were similar to those observed with potassium nitrite. The biological significance of the adrenal zona glomerulosa hypertrophy is discussed. It is concluded that the NOEL of KNO2 is 50 mg/litre in the drinking water, equivalent to about 5 mg/kg body weight/day.

Lifetime (149-week) oral carcinogenicity study of vinyl chloride in rats.

A lifetime (149-wk) oral carcinogenicity study of vinyl chloride monomer (VCM) was carried out. Four groups of Wistar rats were used, each consisting of 100 males and 100 females, except for the high-dose group, which comprised 50 males and 50 females. VCM was administered by incorporating polyvinyl chloride powder with a high content of VCM into the diet. The actual exposure levels of VCM were 0 (control), 0.014, 0.13 and 1.3 mg VCM/kg body weight/day. Detailed histopathological examination was restricted to the liver. In the final stage of the study, the mortality in the high-dose group was slightly higher than in controls. A variety of VCM-related liver lesions was found in the high-dose group. The lesions included increased incidences of liver-cell polymorphism, hepatic cysts, foci of cellular alteration, neoplastic nodules, hepatocellular carcinomas and angiosarcomas. Compared with controls, there were increased incidences of hepatic foci of cellular alteration in females of the mid-dose group and of basophilic foci of hepatocellular alteration in females of both the low- and mid-dose groups. There was no evidence that feeding of VCM affected the incidence of tumours in organs other than the liver. Thus, the present study showed that the feeding of VCM at a level of 1.3 mg/kg body weight/day can induce neoplastic and non-neoplastic changes in the livers of male as well as female rats. The feeding of 0.014 or 0.13 mg VCM/kg body weight/day may result in an increased incidence of (basophilic) foci of cellular alteration in the liver of female rats. It was concluded that 0.13 mg VCM/kg body weight/day is the no-observed-adverse-effect level with respect to the induction of tumours in rats.

Subacute (4-wk) oral toxicity of a combination of four nephrotoxins in rats: comparison with the toxicity of the individual compounds.

In a 4-wk study, 10-wk-old Wistar rats were fed the nephrotoxins hexachloro-1,3-butadiene (HCBD), mercuric chloride, d-limonene and lysinoalanine either alone or in combination. These nephrotoxins damage epithelial cells of the proximal tubules, but by different mechanisms. Each chemical was given alone at a Minimum-Nephrotoxic-Effect Level (MNEL), and at a No-Nephrotoxic-Effect Level (NNEL). The combination was given at the MNEL, the NNEL and one-quarter of the NNEL of the individual chemicals. The individual nephrotoxins caused slight growth depression in males at the MNEL, but not at the NNEL, whereas the combination depressed growth slightly at the NNEL and severely at the MNEL. In females at the MNEL, only HCBD retarded growth; in contrast to the effect in males this was not aggravated by combined treatment. Nephrotoxicity was more severe in males fed the combination than in males given the nephrotoxins alone. The former showed decreased renal concentrating ability and moderate histopathological changes in the kidneys at the MNEL, and a dose-dependent increase in kidney weight and number of epithelial cells in the urine at the NNEL and the MNEL. The males treated with a single agent showed slightly increased kidney weights, and/or slight histopathological changes in the kidneys at the MNEL, and (with d-limonene only) epithelial cells in the urine at the NNEL and MNEL. In females, renal changes induced by the combination were not more severe than those observed with individual compounds. No adverse changes attributable to treatment were observed in rats fed the combination at one-quarter of the NNEL. In the present study, combined exposure to four nephrotoxins at their individual NNEL did not constitute an obviously increased hazard, indicating absence of synergistic interaction, whereas at the MNEL clearly enhanced (renal) toxicity occurred in males, although not in females.

Acute and subacute inhalation toxicity of germanium dioxide in rats.

Two acute (4 hr) and one subacute (4 wk) inhalation toxicity studies on germanium dioxide (purity > or = 99%, mean particle size 1.7-2.6 microns) were conducted in young adult Wistar rats. In the acute studies, exposure of two groups of five rats of each sex to maximum attainable concentrations of either 3.10 g amorphous or 1.42 g hexagonal germanium dioxide/m3 for 4 hr was not lethal. In the subacute study, four groups of five rats of each sex were exposed to 0, 16, 72 and 309 mg hexagonal germanium dioxide/m3 for 6 hr/day, 5 days/wk during 4 wk. Two additional groups of 5 rats per sex, exposed either to 0 or to 309 mg/m3, were kept for a 33-day post-exposure period. At the end of the treatment period, changes were observed only in rats of the high concentration group: these changes were decreased body weight gain (both sexes), decreases in haematocrit (females) and thrombocyte count (both sexes), and increases in neutrophil count (both sexes) and white blood cell count (females). On clinical chemistry evaluation, decreased fasting blood glucose (females), decreased total protein concentration (both sexes), increased plasma alanine aminotransferase and aspartate aminotransferase activities (females), increased plasma urea nitrogen (males) and increased plasma bilirubin level (females) were observed. In addition, urinary volume was elevated, and urine density and pH were lowered in both sexes. Relative weights of kidneys, spleen, heart and lungs were higher than in controls. Microscopic examination revealed effects on renal tubular epithelium. Effects on growth, kidneys, and liver were still present at the end of the 33-day recovery period. It was concluded that the 4-hr LC50 value of amorphous germanium dioxide was greater than 3.10 g/m3 and that of the hexagonal form greater than 1.42 g/m3. The no-adverse-effect-level in the 4-wk study using hexagonal germanium dioxide was 72 mg/m3.

Acute and subacute toxicity of tyramine, spermidine, spermine, putrescine and cadaverine in rats.

The acute and subacute toxicity of five biogenic amines-tyramine, spermidine, spermine, putrescine and cadaverine-were examined in Wistar rats. Tyramine and cadaverine had a low acute oral toxicity of more than 2000 mg/kg body weight. Putrescine had an acute oral toxicity of 2000 mg/kg body weight and spermidine and spermine each of 600 mg/kg body weight. All amines investigated caused a dose-related decrease in blood pressure after intravenous administration, except for tyramine, where an increase was found. In 6-wk studies the biogenic amines were administered in the diet to groups of 10 male and 10 female rats. Tyramine and cadaverine were given at levels of 0, 200, 2000 or 10,000 ppm, spermine and putrescine at levels of 0, 200, 2000 or 5000 ppm and spermidine at levels of 0, 20, 200 or 500/1000 ppm in the first study and at levels of 0 or 10,000 ppm in a second study. Spermine was the most toxic. The high dose level showed a great number of changes, such as emaciation, aggressiveness, convulsions and paralysis of the hind legs. Growth, food intake and water intake were considerably decreased. Slight anaemia (males) and changes in plasma clinical chemistry occurred. The relative weights of the thyroid, adrenals, spleen and heart were increased and that of the liver decreased. Impaired kidney function, together with renal histopathological changes and changes in plasma electrolytes and urea, occurred with spermine. Histopathological examinations also revealed decreased glycogen content in the liver, reduction of spermatogenesis, severe depletion of splenic white pulp, acute involution of the thymus and moderate myocardial degeneration in the heart. Myocardial degeneration was also seen in one mid-dose male. Adverse effects were also observed in the top dose groups of all other amines. Decreased body weights associated with diminished food intake were generally seen. Slight increases in packed cell volume, haemoglobin concentration and thrombocytes occurred with cadaverine. With spermidine, decreased plasma creatinine, calcium and inorganic phosphate were observed and decreased potassium levels with cadaverine. The no-observed-adverse-effect level was 2000 ppm (180 mg/kg body weight/day) for tyramine, cadaverine and putrescine, 1000 ppm (83 mg/kg body weight/day) for spermidine and 200 ppm (19 mg/kg body weight/day) for spermine.

Chronic (89-week) feeding study with hydroxypropyl distarch phosphate, starch acetate, lactose and sodium alginate in mice.

A chronic feeding study was carried out in mice with two chemically modified potato starches, hydroxypropyl distarch phosphate (HP-starch) and starch acetate (AC-starch), and with lactose and sodium alginate. Each of the materials was fed to a group of 75 male and 75 female mice for 89 wk. The dietary level of the test products was gradually increased until the diets contained (by weight) 55% HP-starch, 55% AC-starch, 55% lactose or 25% alginate. The control diet contained 55% pregelatinized potato starch. Each of the four test materials caused increased water consumption, distinct caecal and colonic enlargement, a slightly increased incidence of intratubular nephrosis and, with the exception of AC-starch, also slightly lower body weights. An increased incidence of gastric trichobezoars was observed in mice fed either the modified starches or lactose. The occurrence of concrements in the renal pelvis along with slight urinary changes, such as increased amounts of amorphous material in the urine and increased urinary Ca content, in mice fed HP-starch, AC-starch or lactose was regarded as an effect of little, if any, toxicological significance. Alginate fed at 25% (w/w) of the diet was nephrotoxic to mice, as shown by extremely high water consumption, high urine production, urinary incontinence, high pH and low specific gravity of the urine, increased level of blood urea nitrogen, increased kidney weights, distension of the renal calyx and the high incidence of dilated distal tubules. Caecal and colonic enlargement and changes in urinalysis were found to be reversible and had completely or largely disappeared within 2-5 wk of the cessation of the treatment in wk 87. The incidence of intratubular calcinosis or of concrements in the pelvic space was not reduced during the recovery period. The study did not provide any evidence of carcinogenicity of the products tested.

Evaluation of the oral toxicity of potassium nitrite in a 13-week drinking-water study in rats.

A subchronic oral toxicity study with potassium nitrite (KNO2) was carried out in rats. Groups of ten male and ten female 6-wk-old rats received KNO2 in the drinking-water (tap-water) at levels of 0, 100, 300, 1000 and 3000 mg/litre for a period of 13 wk. The potassium concentration in the nitrite solutions was equalized by adding potassium chloride (KCl) up to the potassium level of the 3000-mg KNO2/litre solution. An additional group of ten males and ten females received drinking-water supplemented with KCl only, at an amount resulting in a potassium concentration equivalent to that of the 3000-mg KNO2/litre solution. Body weight, food intake and food efficiency were decreased at 3000-mg/litre level in males, while liquid intake was decreased in males given 1000 and 3000 mg/litre and in females given 3000 mg/litre. There was significant increase in the methaemoglobin concentration in animals given 3000 mg/litre, while slight decreases in red blood cell variables occurred at the 1000- and 3000-mg/litre dose. No impaired renal function was observed in any of the test groups, although the relative weight of the kidneys and the plasma urea nitrogen level was increased at 3000 mg/litre. There was a slight decrease in plasma alkaline phosphatase activity at 3000 mg/litre. A small amount of nitrite was present in the saliva of the rats receiving 3000 mg/litre but there was no evidence of increased mutagenic activity in the urine of these rats. Interestingly, hypertrophy of the adrenal zone glomerulosa was observed in all test groups, the incidence and degree being dose related. It was concluded that in the study reported here the no-effect level is lower than 100 mg KNO2/litre in the drinking-water, which is equivalent to a level lower than 10 mg KNO2/kg body weight/day.

4-week oral toxicity study of a combination of eight chemicals in rats: comparison with the toxicity of the individual compounds.

In a 4-wk oral toxicity study, 4-wk-old male and female Wistar rats were exposed to a combination of arbitrarily chosen chemicals comprising sodium metabisulphite, Mirex, Loperamide, metaldehyde, di-n-octyltin dichloride, stannous chloride, lysinoalanine and potassium nitrite. The dose levels used were based on the "no-observed-adverse-effect level" (NOAEL) and the "minimum-observed-adverse-effect level" (MOAEL) of the individual compounds obtained in similar studies with Wistar rats previously performed at TNO-CIVO, and comprised 0 (controls), 1/10 and 1/3 of the NOAEL, the NOAEL and the MOAEL. In comparison with the adverse effects of the individual compounds, both more severe and less severe adverse effects were observed at the MOAEL of the combined compounds, indicating interaction of effects at this exposure level. Slightly decreased haemoglobin content and slightly increased relative kidney weight were the only treatment-related adverse effects seen in the NOAEL group. In the 1/10 and 1/3 NOAEL groups no untoward effects were found that could be related to treatment. The present study clearly demonstrates absence of a simple additive effect, and provides some, but no convincing, evidence for an increased risk from exposure to a combination of chemicals when each chemical is administered at its own individual NOAEL. At lower dose levels no increased risk appears to exist. These generalizations may not be fully justifiable from a purely scientific point of view but are the most important practical lesson learnt from the present study.

Evaluation of the oral toxicity of acetaldehyde and formaldehyde in a 4-week drinking-water study in rats.

A subacute oral toxicity study of acetaldehyde and formaldehyde was carried out in rats. Groups of ten male and ten female 5-wk-old rats received one of the aldehydes in the drinking-water for a period of 4 wk, acetaldehyde being given at dose levels of 25, 125 and 675 mg/kg body weight/day and formaldehyde at dose levels of 5, 25 and 125 mg/kg body weight/day. A group of 20 males and 20 females served as controls and received unsupplemented drinking-water ad lib. An additional group of ten males and ten females was given unsupplemented drinking-water in an amount equal to the amount of liquid consumed by the group given the top dose of formaldehyde. Food and liquid intake were decreased in the groups on the top dose of both acetaldehyde and formaldehyde. Hyperkeratosis of the forestomach, observed only in the top-dose rats, was the only adverse effect of acetaldehyde detected. Effects of formaldehyde, also observed only in the top-dose group, were yellow discoloration of the fur, decreased protein and albumin levels in the blood plasma, thickening of the limiting ridge and hyperkeratosis in the forestomach, and focal gastritis in the glandular stomach. It was concluded that in this study the no-observed-adverse-effect levels of acetaldehyde and formaldehyde were 125 and 25 mg/kg body weight/day, respectively.

Two-year drinking-water study of formaldehyde in rats.

Formaldehyde was administered in the drinking-water to groups of 70 male and 70 female Wistar rats for up to 24 months. Survivors of subgroups of ten rats/sex/group each were killed after 12 or 18 months. The mean formaldehyde doses administered were 0, 1.2, 15 or 82 mg/kg body weight/day for males, and 0, 1.8, 21 or 109 mg/kg/day for females. There were no adverse effects on general health, survival or haematological or clinical chemistry parameters. Body weight and food intake were decreased in the high-dose group. Liquid intake was decreased by 40% in the high-dose group in both sexes in comparison with the controls. There was a slight temporary increase in the density of urine, whereas there was a tendency towards lower urine production in the high-dose group. The relative kidney weights were increased in the high-dose females. Gross examination at autopsy revealed a raised and thickened limiting ridge of the forestomach in most high-dose rats. In addition, several rats in the high-dose group showed irregular mucosal thickenings in the fore- and/or glandular stomach. Treatment-related histopathological gastric changes seen in most of the animals of the high-dose group included papillary epithelial hyperplasia frequently accompanied by hyperkeratosis and focal ulceration in the forestomach and focal chronic atrophic gastritis, occasionally accompanied by ulceration and/or glandular hyperplasia, in the glandular stomach. A higher incidence and/or degree of renal papillary necrosis occurred in the high-dose rats. From this study it appeared that the 'no-observed-adverse-effect level' of formaldehyde was 15 and 21 mg/kg body weight/day for male and female rats, respectively. Oral administration of formaldehyde at doses of 82 and 109 mg/kg/day to male and female rats, respectively, caused severe damage to the gastric mucosa but did not result in gastric tumours or tumours at other sites. The study did not provide any evidence of carcinogenicity of formaldehyde after oral administration.

Acute (24 hr) toxicity of a combination of four nephrotoxicants in rats compared with the toxicity of the individual compounds.

To identify possible hazards of combined exposure to chemicals with the same target organ, a 24-hr single dose experiment was carried out in which the renal toxicity of mercuric chloride, potassium dichromate, d-limonene and hexachloro-1:3-butadiene administered simultaneously was compared with the nephrotoxicity of the individual compounds, using a total of 11 groups each consisting of five 12-wk-old male Wistar rats. The dose levels used were based on the results of a range-finding study with the individual compounds in the same strain of rats kept under similar experimental conditions, and comprised the 'Minimum-Nephrotoxic-Effect Level' (MNEL) and the 'No-Nephrotoxic-Effect Level' (NNEL) of each of the four compounds alone and in combination. A group of vehicle-treated rats served as controls. At the MNEL of the combination, antagonism of effects was encountered, seen for example as less severely increased activity of gamma-glutamyl transferase in the urine. Synergism of effects was also observed, for example increased severity of renal tubular necrosis, and more markedly increased activity of urinary lysozyme, lactate dehydrogenase, alkaline phosphatase and N-acetyl-beta-glucosaminidase. More importantly, however, at the NNEL of the combination no signs of impaired renal function or renal damage were observed, suggesting absence of both dose additivity and potentiating interaction at the tested subeffective levels of the individual nephrotoxicants.

Repeated exposure to acetaldehyde vapor. Studies in Syrian golden hamsters.

The subacute inhalation toxicity of acetaldehyde was examined with four groups of 20 hamsters each, exposed repeatedly to acetaldehyde vapor at concentrations of 0, 390, 1,340, and 4,560 ppm (six hr day, five days/week) for a 90-day period. The highest level induced growth retardation, ocular and nasal irritation, increased numbers of erythrocytes, increased weights of heart and kidneys, and severe histopathological changes in the respiratory tract that mainly consisted of necrosis, inflammatory changes, and hyper- and metaplasia of the epithelium. The upper segments of the respiratory tract were much more severely injured than the lower parts. At 1,340 ppm treatment-releated changes included increased kidney weights in males and slight hyper- and metaplastic changes of the tracheal epithelium; 390 ppm was considered a no toxic effect level.

Four-week oral toxicity study with erythritol in rats.

Erythritol was orally administered to Wistar rats at dietary levels of 0, 5, and 10% for 4 weeks. Soft stools and diarrhea were observed in male and female animals of the 10% group and in female animals of the 5% group. These symptoms disappeared during the course of the study. Mean body weights of male rats in the high-dose group were significantly lower than those of controls during the course of the study. No such differences were observed in females. Small statistically significant changes in certain hematological, clinical chemistry, and urine parameters were noted in the high-dose group but were judged not to be biologically important. Weights of the cecum were increased relative to those of the controls. No treatment-related histological changes were observed. No ill effects, other than early diarrhea, were observed from erythritol levels at 5 or 10% in the diet. Based on these results, it was concluded that the feeding of erythritol at a dietary level of 10% did not result in toxicologically significant effects.

Toxicology of sulphiting agents. I: Animal studies.

Oral toxicity studies of sulphite in animals are briefly reviewed. On the basis of a chronic toxicity/carcinogenicity study of sodium metabisulphite in rats JECFA established an ADI of 0.7 mg SO2/kg using a safety factor of 100. The effects of sodium metabisulphite (1% Na2S2O5) on the composition of semi-purified rat diets during storage for at least three months have been studied. Under these conditions sulphite induced rancid off-flavours in diets containing unsaturated fats. The feeding of such stored sulphited-diets to rats resulted in growth retardation and diminished food efficiency. The extractability of the lipids from these diets was markedly reduced. Extraction with hexane, followed by ethanol extraction did not remove the toxic factor(s). It was suggested that sulphite in stored semi-purified diets may react with unsaturated fats leading to the formation of polymers of unsaturated fatty acids and/or other toxic substances. It is recommended that special attention is paid to the fatty acid composition of sulphited foods to be stored.