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Para-Nitrophenol Sodium Salt (PNSP) has relatively low acute inhalation toxicity; the 4-hr Approximate Lethal Concentration in rats is greater than 4.7 mg/l. One subacute study was conducted at 0, 0.34 and 2.47 mg PNSP/l for ten 6-hr exposures. Darker urine, proteinuria and elevated creatinine and SGOT were seen after exposure and were still evident after 14 days recovery. Methemoglobinemia also was seen and was reversible at 0.34 mg/l after 14 days. In addition, exposure to 2.47 mg/l caused elevated erythrocytes, hemoglobin and hematocrit. A second subacute study at 0.03 and 0.13 mg PNSP/l showed reversible methemoglobinemia only at 0.13 mg/l. The repeated dose no-observable effect level was 0.03 mg/l. No compound-related pathologic changes were noted in any of the studies.

Because of recent studies indicating possible embryolethality and teratogenicity of FD&C Red. No 2, and ad hoc committee was convened by the Food and Drug Administration to consider these questions. The committee suggested a collaborative study by three laboratories [Food and Drug Administration (FDA), Industrial Bio-Test Laboratories (IBT), and National Center for Toxicological Research (NCTR)] in which Red No. 2 was given at 200 mg/kg body weight, by gavage during days 0-19, 6-15, or 7-9 of gestation. FD*C Red No. 2 was also given at the same dose level via water bottle. Appropriate controls were utilized. FDA used Osborne-Mendel strain rats, IBT used Charles River strain also showed an increase in the same parameter for the same dose level and in addition showed a significant increase in the percentage of resorptions per litter. It was concluded that because of the inherent variation and the absence of an increase in abnormalities or other indications of embryotoxicity, there is reason to doubt that this effect is either biologically significant or reproducible.

Hexazinone [3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine 2,4(1H,3H)-dione; CAS 51235-04-2] was tested for oral toxicity in rats (both 90-day and 2-year feeding studies), mice (8-week and 2-year feeding studies), and dogs (90-day feeding study). The teratogenic potential was evaluated in rabbits and rats and functional reproductive capacity was studied in rats. Ninety-day feeding of up to 1000 ppm produced no signs of a toxic response in rats. Rats fed 5000 ppm had growth curves slightly inferior to those of the controls as the only detectable difference. Extending the feeding period to 2 years produced decreased body weights in males fed 2500 ppm (top level tested) and in females fed either 1000 or 2500 ppm. All other indices of response, including the type and distribution of tumors, were similar in the test and control rats with the no-effect level being 200 ppm. Eight-week feeding of up to 10,000 ppm in mice produced increased liver weight only at the highest level without any other changes. Two-year feeding of either 200, 2500, or 10,000 ppm resulted in sloughing of the distal tip of the tail and increased liver weights among mice fed 10,000 ppm. Hypertrophy of centrilobular hepatocytes and hyperplasic nodules were increased in mice fed either 2500 or 10,000 ppm. No evidence of a tumorigenic response was evident. The no-effect level was 200 ppm. Dogs fed 5000 ppm for 90 days had decreased rate of body weight gain with clinical enzyme changes suggestive of liver damage. Microscopic examination of the liver failed to reveal any alterations and dogs fed either 200 or 1000 ppm were indistinguishable from controls. The no-effect level in the dog was 1000 ppm. No evidence of a teratogenic response was seen in either rats or rabbits and reproduction capacity in rats fed up to 2500 ppm for three generations was unaffected.

Male albino mice in groups of eight were each given single doses, either by gavage or by intraperitoneal injection, of either technical chlordane (50 or 100 mg/kg), HCS-3260 (50 or 100 mg/kg), or heptachlor:heptachlor epoxide (25:75) (7.5 or 15 mg/kg). The males were subsequently mated with three untreated females for six consecutive weeks. No dominant lethal changes among females that had mated with the treated males were produced.

The volatile anesthetic, Isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether), was investigated at anesthetic concentrations to determine its effects on reproduction in rats treated prior to mating, on fetal development in rats and rabbits when administered during various stages of gestation, and on fetal survival in rats treated during late pregnancy. No adverse reproductive effects were observed, and no evidence of teratogenic activity was obtained. Fetal survival was low in rats exposed during late pregnancy but whether or not this finding is related to Isoflurane exposure requires confirmation.

Nine chemicals, with a range from extremely to slightly toxic, were used to measure the oral LD50 in both fasted (24-h) and non-fasted rats. Each chemical was tested as a solution or suspension in corn oil, responses within 14 days post-treatment were evaluated, and LD50S were calculated. Hexachlorophene was more toxic in non-fasted rats. The LD50 values for tetraethyl lead, methomyl and hexamethylenediamine were essentially the same in both fasted and non-fasted rats. Adiponitrile, bromobenzene, caffeine, carbon tetrachloride and N-butyl-1,6-hexamediamine yielded lower LD50 values in fasted rats. The use of non-fasted rats in acute oral toxicity determinations allows both the establishment of relative potency and the estimation of dosage levels for further repeated dose oral studies. The LD50 values obtained were generally (7 of 9) higher in non-fasted rats, but the magnitude of the differences was not great enough to suggest routine use of both fasted and non-fasted rats in oral toxicity studies.

A series of 7 compounds was evaluated for ocular irritancy potential in the rabbit eye when applied at volumes of 100 microliters (1 material) or 10 microliters (7 materials). All of the materials had been rated for ocular irritancy in previous tests and ranged in efficacy from mild to corrosive. Eyes were examined by two independent readers for up to 21 days post-dosing and evaluated by the Draize system. Only differences among rabbits were found to contribute to the observed variability of the scores obtained. Also, a dose-effect relationship was clearly discernable in terms of both duration of effect and maximal score. When these materials were tested at 10 microliters, the rank correlation of severity was not changed. Therefore, reducing the volume of test material instilled into the rabbit eye moderates the response without compromising test sensitivity.

The determination of urinary N-monomethylacetamide (MMAC) in the end-of-shift urine sample was used to monitor exposure to dimethylacetamide (DMAC). Five workers were observed followed for 4 consecutive weeks. Airborne DMAC appeared to account for the greatest amount of urinary MMAC detected and, at the exposure concentrations encountered (0.5 to 2 ppm), a relationship of 10 ppm urinary MMAC for each 1 ppm DMAC inhaled was observed. Interindividual variation was small and no evidence of build-up in MMAC urinary levels was seen in these subjects. Mean airborne DMAC concentrations were somewhat higher by the end of the week, but the magnitude was such that the differences were not statistically significant. It is concluded that changes in DMAC exposures can be quantitatively reflected by urinary MMAC.

Groups of male rats were exposed to specially prepared ultrafine Kevlar pulp fibers (du Pont's registered trademark for certain aramid fibers) at atmospheric concentrations of either 0.1, 0.5, 3.0, or 18 mg/m3 for 2 weeks. Rats were killed at 0 and 2 weeks and 3 and 6 months postexposure (PE) except the rats exposed to 18 mg/m3, which were killed 0, 4, and 14 days and 1, 3, and 6 months PE. Another group of male rats was exposed to 18 mg/m3 (respirable dust approximately 2.5 mg/m3) of commercial Kevlar fibers for 2 weeks and were killed at 0 and 2 weeks and 3 and 6 months PE. Inhaled ultrafine Kevlar fibers were mostly phagocytized by alveolar macrophages (dust cells) in the alveolar ducts and adjoining alveoli after exposure to either 0.1 or 0.5 micrograms/m3. Most dust cells had disappeared and lungs showed a normal appearance throughout 6 months PE. The pulmonary response almost satisfied the biological criteria for a nuisance dust. Rats exposed to 3 mg/m3 ultrafine Kevlar fibers revealed occasional patchy thickening of alveolar ducts with dust cells and inflammatory cells but with no collagen fibers deposited throughout 6 months PE. After exposure to 18 mg/m3 ultrafine Kevlar, the respiratory bronchioles, alveolar ducts, and adjoining alveoli showed granulomatous lesions with dust cells by 2 weeks PE. The granulomatous lesions converted to patchy fibrotic thickening with dust cells after 1 month PE. The fibrotic lesions were markedly reduced in cellularity, size, and numbers from 3 to 6 months PE but revealed networks of reticulum fibers with slight collagen fiber deposition.

The acute toxicity of oxamyl, an insecticide and nematicide, has been evaluated to establish proper handling guides. The material is highly toxic when given as a single oral dose; its LD50 is in fasted rats 2.5 to 3.1 mg/kg, 2.3 to 3.3 mg/kg in fasted mice, and 7 mg/kg in guinea pigs. A beagle dog given 30 mg/kg died, while 15 mg/kg was not lethal. In all species, clinical signs of cholinesterase inhibition (lacrimation, salivation, tremors) were observed. Cholinesterase activity was depressed in rats treated with a single oral dose. Atropine, when given immediately after oxamyl, was antidotal. When given by intraperitoneal injection, oxamyl was highly toxic to rats, mice, and guinea pigs. The material is a mild eye irritant with the reaction limited to the conjunctiva and iris, but systemic absorption via eye contact makes use of protective equipment essential. Oxamyl produces mild skin irritation and the dermal absorption toxicity in rats (LD50 is greater than 1,200 mg/kg) and rabbits (740 mg/kg) is relatively high suggesting limited absorption. No sensitization was produced when tested in guinea pigs. Oxamyl is highly toxic via inhalation with the 1-hr LC50 value in rats being 0.17 mg/liter (male) and 0.12 mg/liter (female). The corresponding 4-hr value is 0.064 mg/liter for male rats which indicates that concentration X time is a constant through the time periods tested. Repeated-dose studies, orally in rats and dermally in rabbits, showed oxamyl to be noncumulative, with the target system being the nervous system mediated through cholinesterase inhibition. No specific tissue or organ pathology was seen in either species tested.

Several important chemicals, including formaldehyde, 1,4-dichloro-2-butene, bis-chloromethyl ether, hexamethylphosphoramide, and epichlorohydrin have been shown to produce nasal tumours in rats following repeated or continuous inhalation exposures. Some of these compounds are respiratory irritants. To determine whether there is a correlation between the ability of a chemical to produce sensory irritation and to elicit nasal tumours, the atmospheric concentration causing a 50% decrease in the respiratory rate (RD50) of male rats was determined. Three other nasal tumorigens, dimethylcarbamoyl chloride, 2,3,4-trichloro-1-butene and 1,2-ethoxy-3-phenoxypropane, were also studied. No correlation between sensory irritation potency and nasal tumorigenic potential was observed. The most potent nasal tumorigen hexamethylphosphoramide, which produces tumours in rats following 12 months' continuous exposure to 50 ppb, failed to cause any decrease in respiratory rate when tested at 351 ppm (an aerosol exposure level which exceeds atmospheric saturation by approximately ten times).

Oxamyl (methylN',N'-dimethyl-N-[(methylcarbamoyl)oxy]-1-thiooxam imidate; CAS 23135-22-0) was tested for oral toxicity in the rat and dog (90-day and 2-year feeding studies) and in the mouse (2-year feeding study). Teratogenic potential was evaluated in the rat and rabbit and functional reproductive capacity was studied in the rat in a one- and a three-generation reproduction study. Rats fed a diet containing oxamyl at 500 ppm showed clinical signs of cholinesterase inhibition and body weight loss within 2 days. Feeding of either 100 or 150 ppm oxamyl for 90 days produced a reduced rate of weight gain without other signs of response, and no effects were detected at 50 ppm. An oxamyl feeding period of 2 years also showed depressed body weight gains in rats fed either 100 or 150 ppm. Cholinesterase activity was depressed only during the first week of feeding and only in the 150-ppm group. All other indices of response, including the type and distribution of tumors, were similar in the test and control rats and it was concluded that the no-observed-effect level was 50 ppm (equivalent to approximately 5 mg/kg). Mice fed oxamyl at 100 ppm for 6 weeks showed signs of cholinesterase inhibition and some mortalities, so the dietary concentration was reduced to 75 ppm in the 2-year study. Body weights of mice fed oxamyl at 50 or 75 ppm were lower than controls during the first 6 months of the study. No other signs of a toxic response to oxamyl were seen in mice and a no-observed-effect level of 25 ppm (approximately 2.5 mg/kg) was assigned to this compound. No evidence of a tumorigenic response was obtained. Dogs fed oxamyl at 150 ppm for 2 years showed marginal increases in serum alkaline phosphatase activity and cholesterol concentration but no tissue pathology was seen. No evidence of cholinesterase inhibition was seen. It was concluded that the no-observed-effect level for oxamyl in the dog was 100 ppm (approximately 2.5 mg/kg). In the one- and three-generation reproduction studies, litter sizes were somewhat lower in rats fed oxamyl at 100 or 150 ppm oxamyl with normal values seen at 50 ppm. Weanling body weights were normal in rats in the 50-ppm group for three generations but were reduced in the one-generation study. Pup body weights were lower in rats in both the 100- or 150-ppm groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Because of recent studies indicating possible embryolethality and teratogenicity of FD&C Red No.2, an ad hoc committee was convened by the Food and Drug Administration to consider these questions. The committee suggested a collaborative study by three laboratories [Food and Drug Administration (FDA), Industrial Bio- Test Laboratories (IBT), and National Center for Toxicological Research (NCTR)] in which Red No. 2 was given at 200 mg/kg body weight, by gavage during dose level via water bottle. Appropriate controls were utilized. FDA used Osborne-Mendel stran rats, IBT used Charles River, and NCTR used both strains. No significant increases in skeletal or visceral abnormalities were seen. No significant increase in resorptions was seen in the Osborne-Mendel strain, but the Charles River stain at IBT showed a significant increase in litters with two or more resorptions after dams had been given 200 mg/kg at 0-19 days of gestation. The NCTR study on the Charles River strain also showed an increase in the same parameter for the same dose level and in addition showed a significant increase in the percentage of resorptions per litter. It was concluded that because of the inherent variation and the absence of an increase in abnormalities or other indications of embryotoxicity, there is reason to doubt that this effect is either biologically significant or reproducible.

Hexachlorophene (HCP) was studied for mutagenic effects in the dominant lethal test on mice. Groups of male mice were treated with either 2.5 or 5.0 mg hexachlorophene per kg body weight as a single intraperitoneal injection. Control animals were treated with the propylene glycol vehicle. Each male was mated with 3 untreated females for each of 8 consecutive weeks with the uterus of the females examined at mid-pregnancy for signs of early embryonic death. Treatment did not alter mating capacity and fertility of the males. The administration of hexachlorophene had no influence on pre- or post-implantation losses. An increase in early resorptions among female mice bred to males treated with the reference compound, methyl methanesulfonate (MMS) given a single i.p. injection of 100 mg/kg, indicated the susceptibility of the mouse strain used to a known mutagen. It is concluded that hexachlorophene at maximally tolerated doses is not mutagenic in the dominant lethal test in mice.

Too much of the information required for rigorous assessment of the diagnostic value of a positive HL-A 27 test is not available. Certainly there would seem to be no case for population screening, not least because effective prophylaxis is not possible. At present sacroiliac radiographs have greater value in the clinical situation, and it seems unlikely that the contribution they make to diagnosis will be challenged. The absence of the HL-A 27 antigen may have some value as an exclusion test, but careful prospective studies are required, as well as a more detailed cost-benefit appraisal of this test.

Substances that cause liver damage in humans were identified through a literature search conducted on Toxline and Medline. Using the same search strategy, species other than man were selected, in whom hepatic injury could be attributed to exposure to the identified substances. A total of 38 substances were identified as producing liver damage, manifested by either clinical chemistry or histopathology. The substances included 24 drugs, 9 industrial chemicals, 3 environmental agents, 1 pesticide, and ethanol. Twelve of the 36 compounds have been toxicologically evaluated in man, rodent, and non-rodent. Histopathologic liver damage was reported in all three species for 11 of these compounds. Only carbencillin produced histopathologic damage in man but not in either the rodent or non-rodent. Where clinical chemistry changes were reported for all three species categories, only eight substances induced similar reactions in all three species. Only with two substances did man and rodent react similarly (both positive), while the non-rodent was negative. The two substances were polychlorinated biphenyl (PCB) and tetrachlorethane. In the majority of the cases in which either or both histopathologic or clinical chemistry changes were reported for man or for the rodent or non-rodent, the changes that occurred were qualitatively similar. The rodent was as sensitive a predictor for hepatic effects as the non-rodent. Although it is impossible to predict how liver damage observed in a laboratory animal is correlated with human liver damage, hepatotoxicity in the rodent must be considered as indicative of potential hepatic damage in man.

Thirty and 60 mg/kg captan, administered in the diet during the entire gestation period or during gestation and an 8-week lactation period, caused no adverse effects in either mothers or progeny, and captan is thus judged to be nonteratogenic in beagles.

Crl:CD rats were exposed (whole body) to mancozeb by inhalation at 0, 1, 17, 55, 110, 890, or 1890/500 mg/m3 for 6 hr/day from Day 6 through 15 of gestation (sperm-positive vaginal smear considered Day 1). Dams were killed 1 day prior to natural delivery and fetuses were examined externally, viscerally, and skeletally for any alterations. Maternal toxicity, as evidenced by significantly decreased body weight gain, hindlimb paralysis, general debilitation, and death or termination in extremis, was noted among rats exposed to mancozeb at concentrations of 500 to 1890 mg/m3. Dams from the 55 and 110 mg/m3 groups exhibited decreased body weight gain and hindlimb weakness. There was no maternal toxicity for dams exposed at a concentration of 17 mg/m3. Embryofetal toxicity, as evidenced by a significantly increased incidence of totally resorbed litters, external hemorrhage, and wavy ribs, was noted at concentrations of 55 mg/m3 and above. The embryofetal toxicity occurred only at concentrations toxic to the dam. Among the groups exposed to mancozeb, the incidence of major malformations was not dose related. Hence, under the test conditions of this study, mancozeb was not found to be teratogenic and produced no toxicity unique to the conceptus.

Because of recent studies indicating possible embryolethality and teratogenicity of FD&C Red No. 2, anad hoc committee was convened by the Food and Drug Administration to consider these questions. The committee suggested a collaborative study by three laboratories [Food and Drug Administration (FDA), Industrail Bio- Test Laboratories (IBT), and National Center for Toxicological Research (NCTR)] in which Red No. 2 was given at 200 mg/kg body weight, by gavage during days 0-19, 6-15, or 7-9 of gestation. FD&C Red No. 2 was also given at the same dose level via water bottle. Appropriate controls were utilized. FDA used Osborne-Mendel strain rats, IBT used Charles River, and NCTR used both strains. No significant increases in skeletal or visceral abnormalities were seen. No significant increase in resorptions was seen in the Osborne-Mendel strain, but the Charles River strain at IBT showed a significant increase in litters with two or more resorptions after dams had been given 200 mg/kg at 0-19 days of gestation. The NCTR study on the Charles River strain also showed an increase in the same parameter for the same dose level and in addition showed a significant increase in the percentage of resorptions per litter. It was concluded that because of the inherent variation and the absence of an increase in abnormalities of other indications of embryotoxicity, there is reason to doubt that this effect is either biologically significant or reproducible.

The purpose of these studies was to evaluate the effects of selected polydimethylsiloxanes on reproduction and fetal development in rats and rabbits and to determine the mutagenic potential of one such material in mice. In two separate three-phase studies in rats and rabbits with a 350 centistoke medical grade fluid, the only significant effect noted was an apparent dose-related incidence of in utero mortality at dose levels of 200 and 1,000 mg/kg sc in rats in one study. No evidence of fetotoxicity was obtained in the second study at the same dose levels. The incidence of talipes varus at a sc dose level of 200 mg/kg in rabbits (8.8%) is at or above that expected for control populations. The nonoccurrence of talipes varus at the higher level of 1,000 mg/kg and the absence of this defect in the companion study casts doubt on the significance of this finding. A 7-cs pump fluid was nonteratogenic in rats at oral doses as high as 1,000 mg/kg and was nonmutagenic in ma1e mice at ip doses of 5 and 10 g/kg. A 10-cs fluid was nonteratogenic in rabbits at a dermal dose level of 200 mg/kg.

The acute toxicity of hexazinone, a herbicide intended for general noncropland areas and selected crop uses (alfalfa and sugarcane), has been evaluated to establish proper handling guidelines and to measure its potential impact on the environment. The material is slightly to moderately toxic when given as a single oral dose; its LD50 in male rats is 1690 mg/kg, in male guinea pigs 860 mg/kg, and in male dogs greater than 3400 mg/kg although in the dog emesis prevented accurate quantitation. When the material is administered intraperitoneally, the LD50 in rats is 530 mg/kg. Repeated doses (five oral doses per week for 2 weeks) of 300 mg/kg to rats produced slight weight loss in one of two replicate experiments. In both studies, no gross or histologic alterations were apparent. Hexazinone is a moderate to severe eye irritant in the rabbit and produced only mild erythema in rabbit skin at 5278 mg/kg, a dose which did not produce lethality or other clinical signs. Subchronic dermal exposures (10 consecutive doses) to rabbits produced increases in serum alkaline phosphatase and glutamic-pyruvic transaminase at the highest levels tested (680 and 770 mg/kg in two separate experiments) with no effects seen at 150 mg/kg. There were no alterations in livers from treated rabbits examined by light microscopy. No dermal sensitization was produced when concentrations of up to 50% were tested in guinea pigs. One-hour inhalation exposure of up to 7.48 mg/liter did not produce mortality in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonium perfluorooctanoate (CAS Registry No. 3825-26-2) is used commercially in the aqueous polymerization of fluorinated monomers. Because the chemical exists as a fine white powder which can come in contact with skin, its dermal toxicology was studied in rabbits and rats. Dermal applications of 0.5 g for 24 hr produced mild irritation to rabbit skin. The dermal LD50 was 4300 mg/kg for rabbits, 7000 mg/kg for male rats, and greater than 7500 mg/kg for female rats. Rat skin showed less irritation than rabbit skin and the general effects were more pronounced for the male (compared to the female) rat. Subchronic dermal treatment (10 applications, 5 doses, 2 rest days, 5 doses) with either 0, 20, 200, or 2000 mg/kg resulted in no, no, mild, or marked decreases in body weights, respectively. Increases in serum enzyme activities indicating hepatic effects occurred in treated rats. Liver weights were increased and necrosis and enlargement of hepatocytes were microscopically observed. Rats in the 2000 mg/kg-dose group also had epidermal necrosis at the application site. Blood organofluorine amounts were increased in a dose-related manner. All of the treatment-related toxicity findings resolved during a 42-day recovery period although prior exposure was evident by the presence of organofluorine in the blood.

Criteria for the selection of aerosol concentrations to be used in inhalation studies assessing the toxicity and carcinogenicity of chemical substances were discussed by the authors in a meeting sponsored by the National Toxicology Program. Concepts in the design of aerosol inhalation studies emerged from that meeting and are being communicated through this publication. Inhalation studies assessing the toxicity and carcinogenicity of aerosols have often used maximum exposure levels on the basis of technological feasibility. Evidence has now accumulated that the amount of pulmonary burden of deposited particles impacts on particle clearance above some as yet not well-defined exposure concentration. The sequelae are such that lung clearance decreases with increased particulate burden to the point of approaching complete cessation. This paper focuses on the major determinants in establishing maximal aerosol concentrations for use in inhalation toxicity studies with special emphasis on experimental design features to assess lung retention. The subject matter of this paper is a rapidly developing area in terms of knowledge. Accordingly, the contents of this article are intended as guidelines and not as absolute rules for the conduct and interpretation of inhalation exposure studies.

The teratogenic potential of 1,1,3,3-tetrabutylurea (TBU) was evaluated in the Crl:CD(SD)BR rat. Doses of 25, 50 or 100 mg TBU/rat/day in 0.5 ml dimethyl phthalate were applied to the shaven dorsal skin on days 6-15 of gestation, the day on which a sperm-positive vaginal smear was present being designated day 1. The rats were killed 1 day before natural delivery and the foetuses were examined for external development, structure and integrity of internal tissues and organs, and skeletal development. No maternal effects were seen in rats exposed to 25 mg TBU, but skin irritation and a reduction in maternal body-weight gains were seen in rats treated with either 50 or 100 mg/day, the effects being more pronounced in the 100-mg/day group. In the latter group, the number of pregnancies maintained was reduced and the number of resorptions per litter, calculated only on the litters with resorptions, was increased. Foetuses derived from the females treated with 100 mg/day were slightly smaller than the controls but were structurally normal. The outcome of pregnancy was unaltered in rats given either 25 or 50 mg TBU/day. No increase in malformed foetuses was observed in any of the test groups. Under the conditions of this study, TBU was not teratogenic when applied dermally to rats at doses up to 100 mg/day.

Four groups of 100 male and 100 female rats were exposed to ultrafine Kevlar fibrils at concentrations of 0, 2.5, 25, and 100 fibrils/cc for 6 hr/day, 5 days/week for 2 years. One group was exposed to 400 fibrils/cc for 1 year and allowed to recover for 1 year. At 2.5 fibrils/cc, the lungs had normal alveolar architecture with a few dust-laden macrophages (dust cell response) in the alveolar airspaces. At 25 fibrils/cc, the lungs showed a dust cell response, slight Type II pneumocyte hyperplasia, alveolar bronchiolarization, and a negligible amount of collagenized fibrosis in the alveolar duct region. At 100 fibrils/cc, the same pulmonary responses were seen as at 25 fibrils/cc. In addition, cystic keratinizing squamous cell carcinoma (CKSCC) was found in 4 female rats, but not in male rats. Female rats had more prominent foamy alveolar macrophages, cholesterol granulomas, and alveolar bronchiolarization. These pulmonary lesions were related to the development of CKSCC. The lung tumors were derived from metaplastic squamous cells in areas of alveolar bronchiolarization. At 400 fibrils/cc following 1 year of recovery, the lung dust content, average fiber length, and the pulmonary lesions were markedly reduced, but slight centriacinar emphysema and minimal collagenized fibrosis were found in the alveolar duct region. One male and 6 female rats developed CKSCC. The lung tumors were a unique type of experimentally induced tumors in the rats and have not been seen as spontaneous tumors in man or animals. Therefore, the relevance of this type of lung tumor to the human situation is minimal.

Dibutylhexamethylenediamine (DBHMD), a polymer intermediate, is strongly alkaline and is corrosive to eyes and skin. Its inhalation toxicity was defined in rats in both acute and subchronic studies. A 4-hr LC50 of 0.22 mg/litre was obtained for DBHMD of either 80.6 or 98.25% purity. Clinical signs of irritation were apparent during and immediately following exposure and no delayed deaths occurred. The mortality dose-response line was relatively steep. Reduction of exposure times to 5 min produced an LC50 of 51 mg/litre, with similar clinical signs and a steep dose-response line. These data suggest that the product of concentration and time (Ct) is constant for exposure times ranging from 5 min to 4 hr. Repeated (ten) exposures to 0.0125 mg/litre caused no signs of adverse response in rats. A concentration of 0.0234 mg/litre caused some mortality, mucous-membrane irritation, changes in haematological parameters (including erythrocyte counts, haemoglobin, concentration and total and differential leucocyte counts) and an increased acidity and decreased volume of urine. Death at this exposure level was attributed to cardiac failure secondary to pulmonary oedema and congestion, with evidence of hepatic congestion, diffuse cardiac myocytolysis and oedema, and thymic atrophy and congestion. Changes in the heart and thymus were seen in one of two rats killed after the tenth exposure. Clinical and pathological changes observed after the ten exposures were absent after a 14-day recovery period. DBHMD is highly toxic following acute inhalation and produces a steep dose-response following either single or multiple exposures.

The subacute toxicity of sodium saccharin and 2 hydrolytic derivatives, o-sulfamoylbenzoic acid (Compound I) and ammonium o-carboxybenzene sulfonate (Compound II) was evaluated by feeding each of the compounds alone at a dietary level of 20 000 ppm to both beagle dogs and albino rats. Additionally, groups of dogs and rats were fed combinations of the 3 materials at levels up to 20 000 ppm (2000 ppm sodium saccharin, 9000 ppm of both Compound I and II). Dogs were maintained on the test diets for 16 weeks, rats for 13 weeks. No signs of a pharmacotoxic response to the test materials were observed. Parameters determined for treated animals, including growth, food consumption, hematologic profiles, clinical blood chemistry studies, urinalyses, organ weight and ratio data, and both gross and microscopic pathologic evaluation, were not significantly different from control values. From these findings, it is suggested that there is little toxicologic hazard associated with ingestion of the 2 hydrolytic derivatives of sodium saccharin.

Tetraethylene Glycol-Di-N-Heptanoate (TEGDH), a chemical added to polymers to improve flexibility, has a very low acute toxicity following both oral administration and inhalation in rats. The oral LD50 is 25 g/kg in females and greater than 25 g/kg in males. Its approximate lethal concentration for a 4-hr. inhalation exposure is 14.2 mg/L with no mortalities occurring at 13.7 mg/L. The chemical produces mild to moderate irritation on rabbit skin, is not an eye irritant in the rabbit, and is not a sensitizer in the guinea pig. Repeated exposures by the oral route (28 consecutive doses of 1 g/kg) or by inhalation (6 hr/day, 5 days/week for 4 weeks at 1 mg/L) failed to produce any significant adverse response in rats. The material appears to have very low toxicity both when given orally or by inhalation and when the treatment is either acute (single dose) or subchronic (4 weeks).

Dimethylformamide (DMF, CAS No. 68-12-2) and dimethylacetamide (DMAC, CAS No. 127-19-5) are widely used for their superior solvent properties. A series of single and multiple dose experiments in rodents were conducted to determine the target organs, and to establish doses which, under various routes of administration, produced those changes. DMF produced moderate irritation in the rabbit eye, with the corneal response clearing in 2 to 4 weeks. DMAC produced only mild, quickly reversible conjunctival irritation. Oral doses of DMF to the rat of 2,250 mg/kg or greater produced lethality which was associated with liver damage. Lethality occurred following oral doses of 4,500 mg/kg DMAC with LD50's for male and female rats of 5,809 and 4,930 mg/kg, respectively. The 1 hour LC50 by inhalation for DMAC in the rat was 2,475 ppm or greater. Sensory irritation was produced in the mouse at concentrations of 1,658 ppm or greater for DMF. Repeated oral doses of 450 mg DMF/kg to rats produced reduced body weight gain and liver injury with both changes being reversible. DMAC tested similarly produced body weight effects, liver injury, and testicular changes in the rat with all changes again being readily reversible. Dermal doses of 2,000 mg/kg of either DMF or DMAC were poorly tolerated by rabbits. DMAC was slightly more toxic with all treated rabbits dying of acute hepatic necrosis. Repeated inhalation of 2,000-2,500 ppm produced mortality in rats exposed to DMF but not DMAC. Liver injury was seen with DMF, testicular changes with DMAC. DMF and DMAC both produced slight anemia and leukocytosis in rats during 90 days of feeding. Liver weights were elevated in rats fed DMF, but not DMAC, at a level of 1,000 ppm. The "no-observed effect level" in rats fed DMF for 90 days was 200 ppm. The overall toxicologic profiles of both DMAC and DMF are similar with the target organ being the liver.

Ammonium perfluorooctanoate (CAS Registry No. 3825-26-1) is a fine white powder which can become airborne; hence its inhalation toxicity was studied in the male rat. The compound was found to be moderately toxic following single 4-hr exposures, with an LC50 of 980 mg/m3. This concentration produced both an increase in liver size and corneal opacity. Both findings diminished with increasing time after exposure. Subchronic head-only inhalation exposures (6 hr/day on 5 days/wk for 2 wk to 0, 1, 8 or 84 mg/m3) suppressed body-weight gain at 84 mg/m3. Reversible liver-weight increases, reversible increases in serum enzyme activities, and microscopic liver pathology, including necrosis, occurred at exposure of 8 and 84 mg/m3. No ocular changes were produced. Concentrations of organofluoride in the blood showed a dose relationship with initial levels of 108 ppm in rats treated at 84 mg/m3 falling to 0.84 ppm after 84 days with a blood half-life of 5-7 days. The no-observed-effect level was 1 mg/m3 and a mean organofluoride blood level of 13 ppm was detected in rats immediately after the tenth exposure to an atmospheric level of 1 mg ammonium perfluorooctanoate/m3.

Methyl 2,2-difluoromalonyl fluoride (MMF) is highly toxic by inhalation producing mortality in rats exposed for 4 hours to 0.55 mg/L. Repeated inhalation exposures of rats to 0.009 mg/L produced irritation but no other signs of a toxic response. Mortality was encountered following repeated exposures to 0.066 mg/L.

Ammonium perfluorononanoate (CAS Registry No. 4149-60-4) is a white powder that can become airborne. Its acute inhalation toxicity in male rats was studied. Male rats were exposed for single 4-hr periods to dust concentrations ranging from 67 to 4600 mg/m3. The LC50 was determined to be 820 mg/m3, with the lowest concentration causing death being 590 mg/m3. Ammonium perfluorononanoate was classified as moderately toxic by the acute inhalation route. Exposure to ammonium perfluorononanoate caused a pronounced increase in liver size. The acute toxicity of ammonium perfluorononanoate appears to be similar to that of its 8-carbon homologue, ammonium perfluorooctanoate, but considerably less than that of the 10-carbon homologue, perfluoro-n-decanoic acid.

The approximate lethal dose (ALD) to rats following oral administration of nine chemicals was determined. The ALD (lowest dose at which death was produced) for each chemical was used to define the general order of toxicity as being either extremely, highly, moderately, slightly, or practically non-toxic. For each of the nine chemicals tested, the category indicated by the ALD was identical with the category determined in the more extensive LD50 studies. In this study, an average of 6.8 rats was needed to determine the ALD while an average of 56.3 rats was needed to determine the LD50.

The industrial use of certain acetamides and formamides (particularly DMAC and DMF) for their solvent properties has resulted in rather extensive examination of their biological properties. Both DMAC and DMF are rapidly absorbed through biological membranes and are metabolized by demethylation first to monomethyl derivatives and then to the parent acetamide or formamide. Relatively high single doses to various species following oral, dermal, i.p., i.v., or inhalation exposures generally are required to produce mortality. The liver is the primary target following acute high level exposure, but massive doses can also produce damage to other organs and tissues. Repeated sublethal treatment by various routes also shows the liver to be the target organ with the degree of damage being proportional to the amount absorbed. With MMF, the potential usefulness as a cancer chemotherapeutic agent needs to be measured against the hepatotoxic effects produced in man. Acetamides and formamides are generally inactive in mutagenicity tests. Mammalian test systems do not appear to be genetically sensitive and DMF has been recommended for use as the vehicle in microbial assays designed to test for genetic activity of hard-to-dissolve chemicals. Embryotoxicity can be demonstrated at high doses; doses which generally show toxicity to the maternal animals. Structural abnormalities in sensitive species such as the rabbit are produced following exposure at near-lethal levels. The spectrum of abnormalities seen is broad and fails to show any time or site specificity in terms of developing organs/organ systems. Inhalation exposures to DMAC and DMF at levels producing some maternal toxicity in rats have produced no teratogenic response and only slight evidence of embryotoxicity. Long-term feeding of relatively high levels of acetamide produces liver cancer in rats. DMAC and DMF appear to be noncarcinogenic. The environmental toxicity of these chemicals is low. Liver damage can be produced by overexposure to these chemicals in man. Airborne concentrations need to be controlled and care should be taken to avoid excessive liquid contact as the chemicals are absorbed through the skin. A relationship exists between the amount of DMAC or DMF absorbed and the amount of MMAC or MMF excreted in the urine so that biomonitoring of the urinary metabolites can indicate situations in which total exposures, both dermal and inhalation, are excessive. An interaction between DMF and ethanol occurs such that signs, including severe facial flushing, appear when DMF-exposed individuals consume alcoholic beverages.

The weight of the mouse liver following feeding of ammonium perfluorooctanoate, ammonium perfluorononanoate, Telomer B ammonium sulfate, and WG-III was increased in a dose-dependent manner. Dietary levels of 3 ppm or greater ammonium perfluorooctanoate for either 14 or 21 days produced a significant elevation in liver weight both on an absolute and on an organ/body weight ratio basis. Similarly, ammonium perfluorononanoate produced significant increases at the lowest level tested, 3 ppm. Telomer B ammonium sulfate and WG-III also produced liver weight increases but at higher feeding levels. The striking increase in liver weight following relatively short-term exposures in mice makes this a useful screening test for comparing the liver-enlarging capacity of ammonium perfluorooctanoate and related fluorochemicals.