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Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, developed for use as a polymerization processing aid in the manufacture of fluoropolymers, was tested for its potential chronic toxicity and carcinogenicity in a 2-year oral dosing study in Sprague-Dawley rats. Male rats were given daily doses of either 0, 0.1, 1 or 50 mg/kg; females were given either 0, 1, 50 or 500 mg/kg. Body weights, food consumption and clinical signs were monitored daily; clinical pathology was conducted at designated intervals and animals were given a complete pathological evaluation after 12 months and 24 months of dosing. Normal survival was seen in all groups, no abnormal clinical signs were seen, and body weight gain was reduced only in female rats at 500 mg/kg. Both sexes at the high dose had mild decreases in red cell mass which were somewhat more pronounced in females. Clinical pathology indicative of liver injury was present in males that received 50 mg/kg and correlated with histomorphological liver changes that included both hypertrophic and degenerative/necrotic lesions. Similar histomorphological lesions were seen in the livers of females at 500 mg/kg. Previous shorter term toxicity studies have identified this chemical as a PPARα agonist and the finding of benign tumors of the liver, pancreas and/or testes in males at 50 mg/kg and females at 500 mg/kg is consistent with the rat response to peroxisome proliferators and is of questionable human relevance. Changes in the kidney, tongue, and stomach were observed only at the highest dose of 500 mg/kg in females. The no-observed-adverse-effect-level in this study lies between 1 and 50 mg/kg for males and between 50 and 500 mg/kg for females.

In epidemiology studies, the presence of perfluorooctanoate (PFOA) in human blood has been associated with higher serum cholesterol concentrations. A possible explanation for these results is that elevated serum cholesterol might reduce clearance of PFOA. In this study, female hamsters, which transport and regulate cholesterol in a manner similar to humans, were fed normal diet or diet supplemented with 0.05% cholesterol and 10% coconut oil (high-fat diet) resulting in hyperlipidemia throughout the study in supplemented animals. Hamsters on either a normal and high-fat diet were given oral doses of 0.1, 1.0, or 10 mg APFO/kg for 30 days. Serum PFOA concentrations evaluated 24 h after 1, 10, 20, and 30 doses of APFO were not altered in hyperlipidemic hamsters compared to those fed normal diet. For a given dose group, serum concentrations of PFOA were highest following the 10 doses (except for the 10 mg/kg group where concentrations were the highest after the first dose) and were lowest after 20 and 30 doses. Under the condition of this study, higher serum lipids did not affect the absorption and clearance of serum PFOA. Serum PFOA concentrations declined over the course of the study despite continued daily dosing with APFO. This does not support the hypothesis that higher serum lipids might increase the retention of PFOA in the body.

Previous studies suggested that perfluorooctanoate (PFOA) could activate the estrogen receptor (ER). The present study examined the hypothesis that PFOA can activate ER using an in vivo uterotrophic assay in CD-1 mice and an in vitro reporter assay. Pre-pubertal female CD-1 mice fed an estrogen-free diet from postnatal day (PND)14 through weaning on PND18 were administered 0, 0.005, 0.01, 0.02, 0.05, 0.1, or 1mg/kg PFOA or 17β-estradiol (E2, 0.5mg/kg) from PND18-20. In contrast to E2, PFOA caused no changes in the relative uterine weight, the expression of ER target genes, or the morphology of the uterus/cervix and/or vagina on PND21. Treatment of a stable human cell line containing an ER-dependent luciferase reporter construct with a broad concentration range of PFOA caused no change in ER-dependent luciferase activity; whereas E2 caused a marked increase of ER-dependent luciferase activity. These data indicate that PFOA does not activate mouse or human ER., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Perfluorooctanoate (PFOA) is a fully fluorinated eight-carbon fatty acid analog with exceptional stability toward degradation that has been used as an industrial surfactant and has been detected in environmental and biological matrices. Exposures to PFOA in the workplace and in the environment have continuously stimulated investigations into its potential human health hazards. In this article, the results of fifteen unpublished genotoxicity assays conducted with perfluorooctanoate (as either the linear or linear/branched ammonium salt (APFO) or the linear/branched sodium salt) are reported and include: seven mutation assays (three in vitro reverse mutation assays with histidine auxotrophic strains of Salmonella typhimurium , two in vitro reverse mutation assays with the tryptophan auxotrophic Escherichia coli WP2uvr strain, one in vitro mitotic recombination (gene conversion) assay with Saccharomyces cerevisiae D4, and an in vitro Chinese hamster ovary (CHO) HGPRT forward mutation assay); seven studies to assess potential for chromosomal damage (three in vitro CHO chromosomal aberration studies, an in vitro human whole blood lymphocyte chromosomal aberration study, and three in vivo mouse micronucleus assays); and an in vitro C3H 10T1/2 cell transformation assay. Although PFOA has not been demonstrated to be metabolized, all in vitro assays were conducted both in the presence and in the absence of a mammalian hepatic microsomal activation system. These assays were originally described in twelve contract laboratory reports which have been available via the United States Environmental Protection Agency public docket (Administrative Record 226) for over a decade; however, the details of these assays have not been published previously in the open scientific literature. With the exception of limited positive findings at high and cytotoxic concentrations in some assay trials which reflected the likely consequence of cytotoxic disruption of normal cellular processes and not a specific genotoxic effect, the results of the studies presented in this paper and other published results clearly demonstrate the absence of direct mutagenic or genotoxic risk associated with PFOA. This finding is consistent with the physical/chemical characteristics of PFOA and is supported by other published genotoxicity studies.

Two chronic dietary studies, conducted years apart, with ammonium perfluorooctanoate (APFO) in Sprague Dawley rats have been previously reported. Although both included male 300 ppm dietary dose groups, only the later study, conducted in 1990-1992 by Biegel et al., reported an increase in proliferative lesions (hyperplasia and adenoma) of the acinar pancreas. An assessment of the significance of the differences between both studies requires careful consideration of: the diagnostic criteria for proliferative acinar cell lesions of the rat pancreas (for example, the diagnosis of pancreatic acinar cell hyperplasia versus adenoma is based on the two-dimensional size of the lesion rather than distinct morphological differences); the basis for those criteria in light of their relevance to biological behavior; and the potential diagnostic variability between individual pathologists for difficult-to-classify lesions. A pathology peer review of male exocrine pancreatic tissues from the earlier study, conducted in 1981-1983 by Butenhoff et al., was undertaken. This review identified an increase in acinar cell hyperplasia but not adenoma or carcinoma in the earlier study. Both studies observed a proliferative response in the acinar pancreas which was more pronounced in the study by Biegel et al. Definitive reasons for the greater incidence of proliferative lesions in the later study were not identified, but some possible explanations are presented herein. The relevance of this finding to human risk assessment, in the face of differences in the biological behavior of human and rat pancreatic proliferative lesions and the proposed mechanism of formation of these lesions, are questionable.

This study examined the effect of prenatal perfluorooctanoic acid (PFOA) administration on pre- and postnatal development using peroxisome proliferator-activated receptor α (PPARα)-humanized mice to determine if species differences in receptor activity might influence the developmental effects induced by PFOA. Pregnant mice were treated daily with water or PFOA (3mg/kg) by po gavage from gestation day 1 (GD1) until GD17 and then either euthanized on GD18 or allowed to give birth and then euthanized on postnatal day 20 (PND20). No changes in average fetal weight, crown-to-rump length, or placental weight were observed on GD18. Expression of mRNA encoding the PPARα target genes acyl CoA oxidase (Acox1) and cytochrome P450 4a10 (Cyp4a10) in maternal and fetal liver was increased on GD18 in wild-type and PPARα-humanized mice but not in Pparα-null mice. On PND20, relative liver weight was higher in wild-type mice but not in Pparα-null mice or PPARα-humanized mice. Hepatic expression of Acox1 and Cyp4a10 mRNA was higher in wild-type mice but not in Pparα-null mice or PPARα-humanized mice on PND20. The percentage of mice surviving postnatally was lower in wild-type litters but not in litters from Pparα-null mice or PPARα-humanized mice. No changes in pup weight gain, onset of eye opening, or mammary gland development were found in any genotype. Results from these studies demonstrate that the developmental/postnatal effects resulting from prenatal PFOA exposure in mice are differentially mediated by mouse and human PPARα.

Dimethylacetamide (DMAC) and dimethylformamide (DMF) continue to be important, widely used solvents involved in a wide variety of industrial applications. As liquids with relatively low vapor pressures, contact with both the integumentary and respiratory systems is the main source of human exposure. Although airborne control levels for the workplace have been established and industrial hygiene practices to limit dermal contact have been put in place, use of these chemicals has been associated with occupational illness, mainly in Asia where new and expanded uses have led to overexposures. Thus an update of the basic toxicology data including tables indicating the dose/exposure response characteristics of both DMAC and DMF is currently important. Both chemicals are similar from a toxicology perspective. Human experience has generally shown the materials to be without adverse effect except under conditions where airborne and dermal controls were not properly applied. The use of urinary metabolite monitoring has successfully been employed to measure integrated dermal and inhalation worker exposure. The chemicals are not particularly toxic following acute exposure but high doses can produce damage to the liver, the organ which is first affected by these two chemicals. Repeated dose/exposure studies have characterized both the targets of toxicity and the doses required to produce changes by various routes of exposure. Higher doses of these materials can produce changes in developing systems, infrequently in experiments at doses in which the maternal animal is unaffected, thus care needs to be taken when exposures are to women of child-bearing age. The chemicals appear to be low in genetic activity and inhalation exposures have not shown the materials to produce tumors in rodents except with DMF in a situation in which aerosol formation was encountered. This presentation extends the two previous reviews and, like those, includes updated information on acetamide and formamide and their monomethyl derivatives as well as the commercially important DMAC and DMF. Since a large portion of the newer information deals with effects in humans and biomonitoring, these sections are presented at the start of this review.

In order to assess the potential chronic toxicity and tumorigenicity of ammonium perfluorooctanoate (APFO), a 2-year dietary study was conducted with male and female rats fed 30 ppm or 300 ppm (approximately 1.5 and 15 mg/kg). In males fed 300 ppm, mean body weights were lower across most of the test period and survival in these rats was greater than that seen either in the 30 ppm or the control group. Non-neoplastic effects were observed in liver in rats fed 300 ppm and included elevated liver weight, an increase in the incidence of diffuse hepatocellular hypertrophy, portal mononuclear cell infiltration, and mild hepatocellular vacuolation without an increase in hepatocellular necrosis. Mean serum activities of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were elevated up to three times the control means, primarily at the 300 ppm dose. A significant increase in Leydig cell tumors of the testes was seen in the males fed 300 ppm, and tumors of the liver and acinar pancreas, which are often observed in rats from chronic exposure to peroxisome proliferating agents, were not observed in this study. All other tumor types were those seen spontaneously in rats of this stock and age and were not associated with feeding of APFO., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Sex-, species-, and chain length-dependent renal elimination is the hallmark of mammalian elimination of perfluorocarboxylates (PFCAs) and has been extensively studied for almost 30 years. In this review, toxicokinetic data of PFCAs (chain lengths ranging from 4 to 10) in different species are compared with an emphasis on their relevance to renal elimination. PFCAs vary in their affinities to bind to serum albumins in plasma, which is an important factor in determining the renal clearance of PFCAs. PFCA-albumin binding has been well characterized and is summarized in this review. The mechanism of the sex-, species-, and chain length-dependent renal PFCA elimination is a research area that has gained continuous interest since the beginning of toxicological studies of PFCAs. It is now recognized that organic anion transport proteins play a key role in PFCA renal tubular reabsorption, a process that is sex-, species-, and chain length-dependent. Recent studies on the identification of PFCA renal transport proteins and characterization of their transport kinetics have greatly improved our understanding of the PFCA renal transport mechanism at the molecular level. A mathematical representation of this renal tubular reabsorption mechanism has been incorporated in physiologically based pharmacokinetic (PBPK) modeling of perfluorooctanoate (PFOA). Improvement of PBPK models in the future will require more accurate and quantitative characterization of renal transport pathways of PFCAs. To that end, a basolateral membrane efflux pathway for the reabsorption of PFCAs in the kidney is discussed in this review, which could provide a future research direction toward a better understanding of the mechanisms of PFCA renal elimination.

Ammonium perfluorooctanoate (APFO), a processing aid used in the production of fluoropolymers, produces hepatomegaly and hepatocellular hypertrophy in rodents. In mice, APFO-induced hepatomegaly is associated with increased activation of the xenosensor nuclear receptors, PPARα and CAR/PXR. Although non-genotoxic, chronic dietary treatment of Sprague-Dawley (S-D) rats with APFO produced an increase in benign tumours of the liver, acinar pancreas, and testicular Leydig cells. Most of the criteria for establishing a PPARα-mediated mode of action for the observed hepatocellular tumours have been previously established with the exception of the demonstration of increased hepatocellular proliferation. The present study evaluates the potential roles for APFO-induced activation of PPARα and CAR/PXR with respect to liver tumour production in the S-D rat and when compared to the specific PPARα agonist, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy 14,643). Male S-D rats were fed APFO (300 ppm in diet) or Wy 14,643 (50 ppm in diet) for either 1, 7, or 28 days. Effects of treatment with APFO included: decreased body weight; hepatomegaly, hepatocellular hypertrophy, hepatocellular hyperplasia (microscopically and by BrdU labelling index), and hepatocellular glycogen loss; increased activation of PPARα (peroxisomal β-oxidation and microsomal CYP4A1 protein); decreased plasma triglycerides, cholesterol, and glucose; increased activation of CAR (CYP2B1/2 protein) and CAR/PXR (CYP3A1 protein). Responses to treatment with Wy 14,643 were consistent with increased activation of PPARα, specifically: increased CYP4A1 and peroxisomal β-oxidation; increased hepatocellular hypertrophy and cell proliferation; decreased apoptosis; and hypolipidaemia. With the exception of decreased apoptosis, the effects observed with Wy 14,643 were noted with APFO, and APFO was less potent. These data clearly demonstrate an early hepatocellular proliferative response to APFO treatment and suggest that the hepatomegaly and tumours observed after chronic dietary exposure of S-D rats to APFO likely are due to a proliferative response to combined activation of PPARα and CAR/PXR. This mode of action is unlikely to pose a human hepatocarcinogenic hazard.

Ammonium perfluorooctanoate (ammonium PFOA) is an industrial surfactant that has been used primarily as a processing aid in the manufacture of fluoropolymers. The environmental and metabolic stability of PFOA together with its presence in human blood and long elimination half-life have led to extensive toxicological studies in laboratory animals. Two recent publications based on observations from the Danish general population have reported: (1) a negative association between serum concentrations of PFOA in young adult males and their sperm counts and (2) a positive association among women with time to pregnancy. A two-generation reproduction study in rats was previously published (2004) in which no effects on functional reproduction were observed at doses up to 30mg ammonium PFOA/kg body weight. The article contained the simple statement: "In males, fertility was normal as were all sperm parameters". In order to place the recent human epidemiological data in perspective, herein we provide the detailed male reproductive parameters from that study, including sperm quality and testicular histopathology. Sperm parameters in rats from the two-generation study in all ammonium PFOA treatment groups were unaffected by treatment with ammonium PFOA. These observations reflected the normal fertility observations in these males. No evidence of altered testicular and sperm structure and function was observed in ammonium PFOA-treated rats whose mean group serum PFOA concentrations ranged up to approximately 50,000ng/mL. Given that median serum PFOA in the Danish cohorts was approximately 5ng/mL, it seems unlikely that concentrations observed in the general population, including those recently reported in Danish general population, could be associated causally with a real decrement in sperm number and quality.

Perfluorooctanoate (PFO) is a perfluorinated carboxylate that is widely distributed in the environment. A 2-year chronic study was conducted in rats fed either 30 or 300 ppm of ammonium perfluorooctanoate (APFO). To investigate the possible relationship of APFO exposure to proliferative mammary lesions, a Pathology Working Group (PWG) review of the original slides was performed. The consensus reached by the PWG was that the incidence of mammary-gland neoplasms was not affected by chronic dietary administration of APFO. Therefore, feeding female rats up to 300 ppm of APFO resulted in no increase in proliferative lesions of the mammary tissue.

8-2 fluorotelomer alcohol is a fluorinated chemical intermediate used to manufacture specialty polymers and surfactants. The potential subchronic toxicity and the reversibility of the effects of this chemical were evaluated following approximately 90 days of oral gavage dosing to Crl:CD(SD)IGS BR rats. A complete toxicological profile, including neurobehavioral assessments and hepatic beta-oxidation, were conducted at selected intervals and a group of rats was included for a 90-day postdosing recovery period. Dose levels tested were 0 (control), 1, 5, 25, and 125 mg/kg. No test-substance-related mortality occurred at any dose level. Rats at 125 mg/kg developed striated teeth, such that these animals were switched to ground chow at 77 days. No treatment-related alterations in body weight, food consumption, neurobehavioral parameters, or hematology/clinical chemistry were found. Hepatic beta-oxidation was increased in males at 125 mg/kg and in females at 25 and 125 mg/kg. In both males and females, plasma fluorine levels were increased at 125 mg/kg and urinary fluorine was elevated at > or =5 mg/kg. Degeneration/disorganization of enamel organ ameloblast cells was observed at 125 mg/kg in males, but not females. Liver weight increases accompanied by focal hepatic necrosis were observed at both 25 and 125 mg/kg, and chronic progressive nephrotoxicity occurred in female rats at 125 mg/kg. With the exception of hepatocellular necrosis in males at 125 mg/kg and the increased incidence and severity of chronic progressive nephropathy in females at 125 mg/kg, all other changes showed evidence of reversibility. The no-observed-adverse-effect level was 5 mg/kg.

Micronutrient malnutrition remains a problem of public health concern in most developing countries, partly due to monotonous, cereal-based diets that lack diversity. The study objective was to assess whether dietary diversity score (DDS) based on a simple count of food groups consumed and DDS using a 10-g minimum intake for each food group (DDS 10g) are good indicators of adequate micronutrient intake in 24-71-mo-old non-breast-feeding Filipino children. Pearson's correlation and linear regression were used to assess the utility of DDS and DDS 10g as indicators of micronutrient intake. Sensitivity and specificity analysis were used to determine the most appropriate cut-off point for using DDS to categorize children with high probability of adequate micronutrient intake. The average diet of the sample population consisted of 4-5 food groups. The mean probability of adequate nutrient intake (MPA) of 11 micronutrients was 33%. The Pearson's correlation coefficient between MPA and DDS was 0.36 (P<0.001) and for DDS 10g it increased to 0.44 (P<0.001). Intake of individual micronutrients was correlated to DDS for most nutrients. When maximizing sensitivity and specificity, the best cut-off points for achieving 50 and 75% probability of adequate micronutrient intake were 5 and 6 food groups, respectively. DDS and DDS 10g were both significant predictors of adequate micronutrient intake. This study demonstrates the utility of indicators of dietary diversity to predict adequate intake of micronutrients in the diets of young non-breast-feeding children.

Three alkyl diamines, which are by-products formed and separated during the production of hexamethylene diamine, have been tested, mostly for their acute toxicity. This paper reviews methodologies used and the results obtained from these three chemicals. All three tested [2-methyl-1,5-pentanediamine (2-MP), 1,3-diaminopentane (DAMP), and 1,2-cyclohexanediamine (DCH)] were 95% pure and were supplied by the DuPont Company. The acute toxicity of all three chemicals is relatively low with acute oral lethal levels in the rat ranging from 1000 to 2300 mg/kg. Single 4-h inhalation exposures show similarly low toxicity with lethality produced in the rat at concentrations ranging from 2.9 to 4.3 mg/L. These diamines are severe skin irritants in both the rabbit and the guinea pig and are also severe eye irritants (studied only in 2-MP). Dermal sensitization was seen in the guinea pig with DAMP and DCH but not with 2-MP. The irritant dose of these materials was shown in repeated exposure inhalation studies when 2-MP and DCH produced irritation in the upper respiratory tract (point of contact) with some lower lung involvement but no significant systemic effects. 2-MP when fed to rats produced a slight body weight effect at dose equivalents of 800 mg/kg with no other parameters affected. All three materials were inactive in Salmonella, and 2-MP did not produce chromosomal aberrations in cultured human lymphocytes. The main effects of this series of diamines appear related to their irritant properties, and attention needs to be paid to their delayed hypersensitivity potential.

The relationship between age and plasma concentration of perfluorooctanoate (PFOA) in young rats was investigated. The study was conducted in two phases in which male and female rats between 3 and 8 weeks of age were administered the ammonium salt of PFOA (APFO) by single oral gavage at either 10 or 30mg/kg. In Phase I, APFO was administered at a dose of 10mg/kg body weight to 27-, 34-, 38-, 48-, and 55-day-old male and female rats. Plasma was collected 24h after the dose. In Phase II, APFO doses of either 10 or 30mg/kg body weight were given to groups of 23-, 30-, and 32-day-old male and female rats, and plasma was collected at 2 and 24h after the dose (separate groups), and urine was collected for 24h. PFOA concentrations were measured by LC/MS/MS. In Phase I, plasma concentrations of PFOA were not dependent on age for rats 5 weeks of age and older; however, in 4-week-old rats, male plasma PFOA concentrations were 5-6 times lower than during weeks 5-8, and female plasma PFOA concentrations were 2.5-4 times higher than subsequent weeks. In Phase II, plasma samples collected 2h post-dosing indicated no significant difference in the PFOA uptake by age in females; although, in males, plasma PFOA concentrations were significantly less in 32-day-old rats, approximating one-half of the values observed at 23 and 30 days of age. Plasma samples collected 24h after dosing from 3- to 5-week-old rats indicated a slightly but significantly higher male plasma concentration at 30 and 32 days of age as compared to 23 days of age for the 30mg/kg dose group only. Significantly lower (approximately 10-fold) plasma PFOA concentrations occurred in 32-day-old females as compared with 23- and 30-day-old females at both 2 and 24h after the dose. Although statistically significant changes in urine PFOA concentrations did not occur between age and dose groups within sex, urine PFOA concentrations generally supported plasma elimination. At 23 days of age, the ratio of male to female plasma PFOA concentrations was approximately 2-3:1 compared to approximately 30:1 at 32 days of age. An unexplainable inconsistency in PFOA plasma concentrations for both sexes was noted when comparing Phase I values for 27-day-old rats to Phase II values for 23- and 30-day-old rats. The Phase I values for the 27-day-old rats of both sexes were five to six times lower than Phase II values for the 23- and 30-day-old rats. However, Phase I values for 34-day-old rats were comparable to Phase II values for 32-day-old rats. Despite this anomaly between the 23-, 27-, and 30-day-old rat values, there is strong evidence that age-dependent changes in the elimination of PFOA develop in female rats between 3 and 5 weeks of age, with a consistent marked difference occurring after 30 days of age.

The absorption, distribution, metabolism, and elimination of [3-14C] 8-2 fluorotelomer alcohol (8-2 FTOH, C7F1514CF2CH2CH2OH) following a single oral dose at 5 and 125 mg/kg in male and female rats have been determined. Following oral dosing, the maximum concentration of 8-2 FTOH in plasma occurred by 1 h postdose and cleared rapidly with a half-life of less than 5 h. The internal dose to 8-2 FTOH, as measured by area under the concentration-time curve to infinity, was similar for male and female rats and was observed to increase in a dose-dependent fashion. The majority of the 14C 8-2 FTOH (> 70%) was excreted in feces, and 37-55% was identified as parent. Less than 4% of the administered dose was excreted in urine, which contained low concentrations of perfluorooctanoate (approximately 1% of total 14C). Metabolites identified in bile were principally composed of glucuronide and glutathione conjugates, and perfluorohexanoate was identified in excreta and plasma, demonstrating the metabolism of the parent FTOH by sequential removal of multiple CF2 groups. At 7 days postdose, 4-7% of the administered radioactivity was present in tissues, and for the majority, 14C concentrations were greater than whole blood with the highest concentration in fat, liver, thyroid, and adrenals. Distribution and excretion of a single 125-mg/kg [3-14C] 8-2 FTOH dermal dose following a 6-h exposure in rats was also determined. The majority of the dermal dose either volatilized from the skin (37%) or was removed by washing (29%). Following a 6-h dermal exposure and a 7-day collection period, excretion of total radioactivity via urine (< 0.1%) and feces (< 0.2%) was minor, and radioactivity concentrations in most tissues were below the limit of detection. Systemic availability of 8-2 FTOH following dermal exposure was negligible.

A large database exists describing the pharmacokinetic behavior of perfluorooctanoic acid (PFOA) following oral exposure. The objective of this study was to examine the concentration- and time-dependence of the pharmacokinetics of inhaled PFOA in rat plasma to determine equivalent inhalation and oral (from literature values) exposure levels. The study was comprised of two separate experiments: a single 6-h inhalation exposure and repeated inhalation exposures for 3 weeks (6h per day, 5 days per week). In both experiments, male and female rats were exposed nose-only to aerosol atmospheres of either 0, 1, 10, or 25mg/m(3) PFOA. In the single exposure experiment, blood was drawn via the tail vein pre-exposure, four times concurrent to exposure, and six times post-exposure up to 24h. In the repeated exposure experiment, blood was collected immediately before and after exposure 3 days per week. Plasma PFOA concentrations were quantitated by liquid chromatography-mass spectrometry (LC-MS). Following the single exposures, plasma PFOA concentrations were directly proportional to airborne concentrations in both male and female rats. Elimination of PFOA from the plasma was sex-dependent, with female rats eliminating PFOA much more rapidly than male rats. Following repeated PFOA exposure, there was little daily PFOA carryover observed in plasma samples from female rats, while males demonstrated an accumulative pattern over the 3-week period. Peak post-exposure PFOA plasma concentrations in female rats averaged 1, 2, and 4 microg/mL when exposed to 1, 10, and 25mg/m(3) PFOA, respectively, and returned to baseline levels by the time of the next pre-exposure sample collection. Male rats reached steady state plasma concentrations of 8, 21, and 36 microg/mL (ppm) after 3 weeks of exposure to 1, 10, and 25mg/m(3) PFOA, respectively. These results demonstrate that the pharmacokinetic properties of inhaled PFOA in male and female rats are similar to those observed in male and female rats following oral dosing with PFOA. It is thus possible to use this internal dose metric (plasma PFOA) for route-to-route dose extrapolation, with inhalation exposures of 1, 10, and 25mg/m(3) PFOA corresponding to oral doses of approximately 0.3, 1.0, and 2.0mg/kg in rats.

The purpose of this study was to compare the toxicity of linear/branched ammonium perfluorooctanoate (APFO) with that of linear and branched APFO. Linear/branched APFO (approximately 80% linear and 20% branched isomers) was formerly used in the production of commercial products. The extensive toxicologic database for APFO has been developed essentially using this mixture of isomers. The trend now is to use APFO containing only the linear isomer. The current study was performed to determine if the toxicological database developed for the linear/branched isomer is applicable to the linear isomer. To determine the contribution of branched APFO to the toxicity of linear/branched APFO, a form of APFO that was 100% branched was synthesized. Rats and mice were given doses by oral gavage ranging from 0.3 to 30 mg/kg of either the linear/branched, linear, or branched APFO for 14 days. Clinical signs, body weights, food consumption, selected hematology and serum lipid parameters, liver and kidney weights, hepatic peroxisomal beta-oxidation, and serum PFOA concentrations were evaluated. Mean body weights were about 20% lower in rats and mice dosed with 30 mg/kg of linear/branched or linear APFO compared to controls, and 3-5% lower in animals dosed with 30 mg/kg of branched APFO. In rats, all three forms reduced lipids. In mice, all three forms reduced total and HDL cholesterol similarly but triglycerides were increased at lower doses. Increased peroxisomal beta-oxidation activity and serum PFOA concentrations were seen in both species but these effects were least pronounced in rats dosed with the branched material. In rats, serum PFOA levels were 20-51 ppm at Lowest Observed Effect Levels (LOEL) of 0.3-1 mg/kg, based primarily upon lipid parameters. In mice, serum PFOA levels were 10-14 ppm at the LOEL of 0.3 mg/kg, based primarily upon relative liver weight. In both rats and mice, the overall responses to the linear/branched and the linear forms of PFOA were similar, but the branched form appears to be less potent. Based on these results, and for the endpoints evaluated in this study, the toxicological database developed primarily from testing linear/branched APFO is applicable to linear APFO.

A combined repeated-dose toxicity study with reproduction was conducted with 2-pentenenitrile (2-PN). Rats (10/sex per dose level) were dosed with 2-PN once daily by gavage at dose levels of either 0, 1, 3, or 10 mg kg(-1) day(-1) for 28 days, prior to and during cohabitation, and through day 3 of lactation. General clinical observations were recorded daily; body weights were recorded weekly. A neurobehavioral evaluation consisting of a functional observational battery and motor activity was conducted in all parental rats (10/sex per group). Clinical pathology parameters (hematology, clinical chemistry, coagulation) were measured in parental rats. Pup weights and clinical signs were recorded at birth and on lactation day 4. Parental rats were given a gross pathological examination, organ weights were obtained, and histological examination was conducted for the control and 10 mg kg(-1) day(-1) groups. No effects were seen with regard to mortality, clinical signs, functional observational battery and motor activity, hematology, or organ weights. Females receiving 10 mg/kg and males from all dose groups showed lower body weight gains and feed efficiency. Increased albumin concentrations were seen in both sexes given 10 mg/kg. Females in the 10 mg/kg group showed degeneration of the olfactory mucosa. No effects on the numbers of pups born, number surviving to lactation day 4, pup weight, and no gross anatomical development changes were observed. Under the conditions of this study, the no-observed-effect level (NOEL) for systemic toxicity in rats was 3 mg kg(-1) day(-1), based on degeneration of olfactory mucosa in females at 10 mg kg(-1) day(-1). The NOEL for reproductive and neurobehavioral toxicity in rats and for toxicity to offspring was 10 mg kg(-1) day(-1), the highest dose level tested.

Male and female mice, rats, hamsters, and rabbits were treated with a single oral dose of 14C-ammonium perfluorooctanoate (APFO), and the excretion and tissue distributions were followed for 120 h (168 h in the rabbit). Substantial sex and species differences in the excretion and disposition of 14C-radioactivity derived from 14C-labeled APFO were observed in this study. The female rat and the male hamster excreted more than 99% of the original 14C activity by 120 h after dosing; conversely, the male rat and the female hamster excreted only 39% and 60% of the original 14C activity, respectively, by 120 h postdosing. The male and female rabbits excreted the 14C activity as rapidly and completely as the female rat and the male hamster, whereas male and female mice excreted only 21% of the original 14C activity by 120 h postdosing. The rapid excretors (female rat, male hamster, and male and female rabbits) contained negligible amounts of 14C in organs and tissues at sacrifice. The slow excretors exhibited the highest 14C concentrations in the blood and liver followed by the kidneys, lungs, and skin.

1,3-Propanediol (504-63-2) was studied to determine the potential effects following repeated inhalation exposures to rats. Rats were exposed 6 hr/day, 5 days/wk for 2 wk (9 exposures) to vapor or vapor/aerosol mixtures of either 0, 41, 650, or 1800 mg 1,3-propanediol/m(3). In vivo responses were observed or measured daily. Clinical pathology and tissue pathology analyses were conducted after the 9th exposure and on half of each group following an 18-day recovery (nonexposure) period. All rats showed normal body weights. No unusual external signs of response were seen, and no deaths were encountered. Clinical pathology (blood counts, serum chemical parameters) and tissue pathology (gross pathology, organ weights, and histopathology) examinations in the 1,3-propanediol exposed rats were similar to those in the unexposed controls. The highest concentration tested, 1800 mg/m(3), which was the highest concentration that could practically be generated, was the no-observed-effect level (NOEL) for this study. 1,3-Propanediol does not appear to pose a significant hazard via inhalation of either the vapor or a vapor/aerosol mixture.

This study was conducted to develop a quantitative understanding of the potential for gestational and lactational transfer of perfluorooctanoate (PFOA) in the rat. Time-mated female rats were dosed by oral gavage once daily at concentrations of 3, 10, or 30 mg/kg/day of the ammonium salt of PFOA (APFO) starting on gestation (G) day 4 and continuing until sacrifice. On days 10, 15, and 21G, five rats per dose level were sacrificed and blood samples were collected 2h post-dose. Embryos were collected on day 10G, amniotic fluid, placentas, and embryos/fetuses were collected on days 15 and 21G, and fetal blood samples were collected on day 21G. Five rats per dose level were allowed to deliver and nurse their litters, and on days 3, 7, 14, and 21 post-partum (PP) milk and blood samples of maternal and pup were collected 2h post-dose. All samples were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) for PFOA concentration. Concentrations of PFOA in maternal plasma and milk attained steady state during the sampling interval. The steady-state concentrations in maternal plasma were 10-15, 25-30, and 60-75 microg/mL in rats receiving 3, 10, and 30 mg/kg, respectively. Steady-state concentrations in milk were approximately 10 times less than those in maternal plasma. The concentration of PFOA in fetal plasma on day 21G was approximately half the steady-state concentration in maternal plasma. The milk concentrations appeared to be generally comparable to the concentrations in pup plasma. Pup plasma concentrations decreased from day 3PP to day 7PP, and were similar on days 7, 14, and 21PP at all dose levels. PFOA was detected in placenta (days 15 and 21G), amniotic fluid (days 15 and 21G), embryo (days 10 and 15G), and fetus (day 21G). These pharmacokinetics allow estimation of the dose to developing and nursing rat offspring following maternal exposure.

Hexamethylendiamine (HMDA; CAS No. 124-09-4; 6055-52-3 for the dihydrochloride salt) is moderately toxic following acute doses/exposures with oral lethal doses in rats ranging from 750 to 1500 mg/kg. HMDA is extremely irritating to the skin and eyes and is not a sensitizer in guinea pigs. Repeated exposure inhalation studies have defined the upper respiratory tract to be the first target of HMDA. The irritation seen is proportional to the exposure concentration. Systemic damage is limited. Genetic testing is not extensive, but there is no indication of activity. HMDA is neither a developmental nor a reproductive toxin, but in one developmental study, the fetal No-observed-adverse-effect-level (NOAEL) was lower than that of the maternal animal. No carcinogenicity studies have been conducted. Documented human experience is limited, but indications of HMDA's irritative properties are found in the literature. HMDA does not persist or bioaccumulate in the environment. The chemical is not particularly toxic to fish and aquatic invertebrates but is quite toxic to algae. HMDA is rapidly absorbed and metabolized by the rat with little tissue storage.

Rat and human epidermal membranes were mounted onto in vitro diffusion cells with an exposure area of 0.64 cm2, and skin integrity was confirmed using electrical impedance. Following membrane selection, Fluorad FC-118, a 20% aqueous solution of ammonium perfluorooctanoate (AFPO), was applied to the epidermal surface of each skin replicate at approximately 150 microL/cm2 and the donor chamber opening occluded with Parafilm. Serial receptor fluid samples were collected hourly from 1 to 6 h and at 12, 24, 30, and 48 h and analyzed by liquid chromatography-mass spectrometry (LC-MS) for APFO anion (PFO-). For rat skin, the time to steady-state penetration (6500+/-3000 ng APFO x cm(-2) x h(-1)) occurred in less than 12 h, which was sustained until termination (48 h). Based on the concentration of the applied test material, the permeability coefficient (Kp) for APFO in rat skin was calculated to be 3.25+/-1.51 x 10(-5) cm/h. By end of the 48-h exposure period, only a small portion of the total APFO applied (1.44+/-1.13%) had penetrated through rat skin. For human skin, steady-state penetration of APFO (190+/-57 ng APFO x cm(-2) x h(-1)) was reached by 12 h. Based on the concentration of the applied test material, the permeability coefficient for APFO in human skin was calculated to be 9.49+/-2.86 x 10(-7) cm/h. By the end of the 48-h exposure period, only a negligible amount of the total APFO applied (0.048+/-0.01%) had penetrated through human skin. Thus, under infinite dose and occlusive conditions, the steady-state penetration of APFO from a 20% solution was approximately 34-fold faster through rat skin than human skin.

The potential maternal and developmental toxicity of 8-2 Telomer B Alcohol was assessed in rats. Groups of 22 time-mated female Crl:CD (SD)IGS BR rats were administered oral gavage doses as suspensions of 8-2 Telomer B Alcohol in aqueous 0.5% methylcellulose from day 6 through 20 of gestation (G) at daily doses of either 0, 50, 200, or 500 mg/kg. Under the conditions of this study, adverse maternal toxicity was produced at 500 mg kg(- 1) day(- 1) and consisted of maternal mortality, decreased body weights and body weight gains, and increased clinical observations of toxicity. One litter at 500 mg kg(- 1) day(- 1) consisted of one early resorption and was believed to be secondary to overt maternal toxicity, although single conceptus litters occur historically in this strain of rats. Developmental toxicity at 500 mg kg(- 1) day(- 1) consisted of increased fetal skeletal variations (delayed pelvic bone ossification and wavy ribs). At 200 and 500 mg kg(- 1) day(- 1), there were transient reductions in maternal feed consumption. In addition, there were slight increases in the incidence of delayed fetal skull bone ossification at 200 and 500 mg kg(- 1) day(- 1). The no-observed-adverse-effect level (NOAEL), defined as the highest dose at which adverse effects attributable to the test substance were not detected, for both maternal and developmental toxicity, is considered to be 200 mg kg(- 1) day(- 1). Thus, 8-2 Telomer B Alcohol is not considered to be a selective developmental toxicant in rats. The transient and quantitative nature of the observations in the 200 mg/kg group supports the conclusion that these findings were not adverse.

The pharmacokinetics of perfluorooctanoate (PFOA) in cynomolgus monkeys were studied in a six-month oral capsule dosing study of ammonium perfluorooctanoate (APFO) and in a single-dose iv study. In the oral study, samples of serum, urine, and feces were collected every two weeks from monkeys given daily doses of either 0, 3, 10, or 20 mg APFO/kg. Steady-state was reached within four weeks in serum, urine, and feces. Serum PFOA followed first-order elimination kinetics after the last dose, with a half-life of approximately 20 days. Urine was the primary elimination route. Mean serum PFOA concentrations at steady state in the 3, 10, and 20 mg/kg-day dose groups, respectively, were 81, 99, and 156 microg/ml in serum; 53, 166, and 181 microg/ml in urine; and, 7, 28, and 50 microg/g in feces. Mean liver concentrations reached 16, 14, and 50 microg/g in the 3, 10, and 20 mg/kg groups, respectively. In the iv study, three monkeys per sex were given a single dose of 10 mg/kg potassium PFOA. Samples were collected through 123 days. The terminal half-life of PFOA in serum was 13.6, 13.7, and 35.3 days in the three male monkeys and 26.8, 29.3, and 41.7 days in the three females. Volume of distribution at steady state was 181 +/- 12 and 198 +/- 69 ml/kg for males and females, respectively. Based on the result of both the oral and iv studies, the elimination half-life is approximately 14-42 days, and urine is the primary route of excretion.

Ammonium perfluorooctanoate is a perfluorinated carboxylate that is used commercially as a processing aid in the production of fluorinated polymers. Perfluorooctanoate (PFOA) has been found in human blood of the general population from exogenous sources. This report presents the results of a 13-week dietary toxicity study in male rats and was designed to identify potential target organ(s), dose response, and to explore possible relationships of PPARalpha activation to potential liver effects and hormonal changes. Rats were fed dietary levels of 0, 1, 10, 30, and 100 ppm (equivalent to 0, 0.06, 0.64, 1.94, and 6.5 mg/kg/day) for 13 weeks. A control group pair-fed adjusted to the 100 ppm level and groups allowed to recover for 8 weeks were included. Sacrifices were conducted after 4, 7, and 13 weeks of feeding and after 8 weeks of recovery. At each sacrifice, gross and histopathology was conducted on selected tissues and measurements of hepatic palmitoyl CoA oxidase (PCoAO), as well as serum estradiol, luteinizing hormone, testosterone, and PFOA were determined. There were no clinical signs or mortality. Body weight gains were reduced in the 100 ppm dose group. Liver weights (absolute and relative), PCoAO activity, and hepatocyte hypertrophy (minimal to mild) were increased in the 10 ppm dose group and above and were reversible in recovery. Under the study conditions, hormone levels appeared unchanged. PFOA serum concentrations increased in a dose-related fashion, appeared to reach steady-state by test week 5, and declined rapidly through the recovery period. Serum PFOA concentrations at the end of the treatment period were 7.1, 41, 70, and 138 microg/mL in the 1, 10, 30 and 100 ppm dose groups. The study no effect level was 1 ppm (0.06 microg/mg) with doses of 10 ppm (0.64 microg/mg) and higher producing adaptive and reversible liver changes.

PFOA is a peroxisome proliferator (PPAR agonist) and exerts morphological and biochemical effects characteristic of PPAR agonists. These effects include increased beta-oxidation of fatty acids, increases in several cytochrome P-450 (CYP450)-mediated reactions, and inhibition of the secretion of very low-density lipoproteins and cholesterol from the liver. These effects on lipid metabolism and transport result in a reduction of cholesterol and triglycerides in serum and an accumulation of lipids in the liver. The triad of tumors observed (liver, Leydig cell, and pancreatic acinar-cell) is typical of many PPAR agonists and is believed to involve nongenotoxic mechanisms. The hepatocellular tumors observed in rats are likely to have been the result of the activation of the peroxisome proliferator activated receptor alpha (PPARalpha). The tumors observed in the testis (Leydig-cell) have been hypothesized to be associated with an increased level of serum estradiol in concert with testicular growth factors. The mechanism responsible for the acinar-cell tumors of the pancreas in rats remains the subject of active investigation. The mechanism resulting in the hepatocellular tumors in rats (PPARalpha activation) is not likely to be relevant to humans. Similarly, the proposed mechanism for Leydig-cell tumor formation is of questionable relevance to humans. Acinar tumors of the pancreas are rare in humans, and the relevance of the these tumors, as found in rats, to humans is uncertain. Epidemiological investigations and medical surveillance of occupationally exposed workers have not found consistent associations between PFOA exposure and adverse health effects.

Adiponitrile (ADN) has moderate acute toxicity with an oral LD50 in rats of 100 to 500 mg/kg and a 4-hr LC50 in rats of 1.71 mg/L (vapor plus aerosol). ADN produced slight eye but no skin irritation in rabbits. Repeated exposures by inhalation produced changes in the hematologic profile with effects seen at 100 or 300 mg/m3. The hematologic changes were reversible upon cessation of further inhalation exposures. Dogs fed up to 500 ppm (equivalent to 12-15 mg/kg) showed no effects but 1,000 ppm produced vomiting and nausea which limited further testing at that concentration. ADN was not a genetic toxin, developmental toxin, reproductive toxin nor did it produce an increase in tumors in a 2-yr drinking water study in rats. Human experience reports are limited to one accidental poisoning case and a few skin exposures resulting in transient irritation and inflammation. ADN is rapidly absorbed and excreted by mammals, and is metabolized to some extent although unchanged ADN is readily detected in urine, and does not bioaccumulate.

Ammonium perfluorooctanoate (APFO) is a surfactant used primarily as an aid in processing various fluoropolymers. Many toxicology and epidemiological studies have been conducted with APFO; however, no specific information regarding functional reproduction was previously available. Therefore, the potential reproductive toxicity of APFO across two generations of offspring was studied using current EPA OPPTS 870.3800 guidelines. Male and female Sprague-Dawley rats were dosed orally with 0, 1, 3, 10, or 30 mg/kg APFO. Parental (P) generation rats ( approximately 6 weeks old) were dosed at least 70 days prior to mating and until sacrificed (after mating for male rats; after weaning for female rats). F(1)-generation rats were dosed similarly, beginning at weaning. The F(2)-generation pups were maintained through 22 days of lactation. Reproductive parameters evaluated in P- and F(1)-generation rats included estrous cycling, sperm number and quality, mating, fertility, natural delivery, and litter viability and growth. Age at sexual maturation in F(1), anogenital distance in F(2), and presence of nipples (males) in F(2)-generation pups were also determined. Feed consumption, body-weight gain, selected organ-weights, gross pathology and appropriate histopathology were evaluated. Reproductive endpoints including mating, fertility, and natural delivery were not affected in either generation. P- and F(1)-generation male rats showed decreased body weight, and liver and kidney weight increases at all doses. The 30 mg/kg F(1)-generation pups had decreased birth weight. Viability was reduced in the 30 mg/kg F(1)-generation pups in apparent relationship to reduced body weight at birth and weaning; however, F(2)-generation pups at 30 mg/kg, although somewhat lighter, did not show a loss in viability. Preputial separation and vaginal opening were somewhat delayed at 30 mg/kg, but these rats went on to show normal reproductive performance. No-observed-adverse-effect-levels were >30 mg/kg for reproductive function of P- and F(1)-generation rats, 10 mg/kg for F(1)-generation pup mortality, birth weight, and sexual maturation, and less than 1mg/kg for male body-weight and organ-weight changes.

The potential maternal and developmental toxicity of dimethylpiperidone (DMPD) was assessed in rats. Groups of 25 mated female Crl:CD (SD)IGS BR rats were exposed by inhalation (whole-body exposures) for approximately six hours per day over days 7-21 of gestation (G); day 1G was the day of copulation plug detection. The exposure levels were 0, 52, 260, or 340 (vapor plus aerosol) mg/m3 DMPD. During the in-life portion, body weights, food consumption, and clinical observation data were collected. On day 22G, the dams were euthanized and examined for gross external and internal alterations. The uterine contents were described and the fetuses were weighed and examined for external, visceral, and skeletal alterations. Maternal toxicity was seen at both 260 and 340 mg/m3. At 340 mg/m3, evidence of maternal toxicity included mortality, increased clinical observations, and decreased body weight and food consumption. At 260 mg/m3, maternal toxicity was limited to increased clinical observations and decreased food consumption. Developmental toxicity was also produced at 260 and 340 mg/m3. At 340 mg/m3, evidence of developmental toxicity included decreased fetal weight, increased embryofetal lethality with concomitant reductions in litter size, and increased fetal malformations and variations. At 260 mg/m3, effects in fetuses were limited to slightly decreased fetal weight and increased fetal variations; additionally, one litter from this level consisted entirely of resorptions. There were no compound-related effects in either dams or fetuses at 52 mg/m3. It was, therefore, concluded that DMPD was not selectively toxic to the rat conceptus.

This inhalation toxicity study in rats was conducted to assess the hazard potential for workers inhaling Nylon respirable fibers. Groups of 48 male rats each were exposed, nose-only, 6h per day, 5 days per week, for 4 weeks to aerosols of uncoated, finish-free Nylon respirable-sized, fiber-shaped particulates (RFP) at concentrations of 0, 4, 15 and 57 fibers (f)/cm3. Nylon RFPs were prepared using flock rotary cutters followed by vigorous opening procedures. After exposures, the lungs of sham and Nylon-exposed rats were assessed at 1 and 8 days, and 1, 3, 6 and 12 months postexposure. The results showed that the retained mean lung burdens at 1 day postexposure were 1.75E+07 RFP/lung (high level). Mean lengths and diameters of the Nylon aerosol were 9.8 and 1.6 microm, respectively. Lung clearance of Nylon RFPs was rapid over the 12-month period. There were no significant increases in lung weights, indications of pulmonary inflammation, or alveolar macrophage functional deficits in Nylon-exposed animals versus controls based on cell differentials, bronchoalveolar lavage (BAL) fluid analyses, and macrophage phagocytosis or chemotaxis activity. Histopathology revealed no adverse lower pulmonary or upper respiratory effects. In summary, the no-observed-effect level (NOEL) for inhaled Nylon RFP was 57f/cm3 (20mg/m3), the highest concentration tested.

The potential maternal and developmental toxicity of cyclododecatriene (CDDT) was assessed in rats. Groups of 22 time-mated female Crl:CD (SD) BR rats were exposed by inhalation (whole-body, 6 h/day) to either 0 (control), 10, 25, or 67 ppm CDDT over days 6-20 of gestation (days 6-20 G); the day of copulation plug detection was designated day 0 G. The dams were euthanized on day 21 G, and their abdominal and thoracic viscera were examined grossly. The fetuses were weighed, sexed, and examined for external, visceral, and skeletal alterations. Evidence of maternal toxicity was seen at 25 and 67 ppm. There were compound-related reductions in maternal body weight and food consumption parameters as well as increased occurrences of wet and stained fur at these exposure levels. Developmental toxicity evident as reduced mean fetal weight and delayed skeletal ossification was seen only at 67 ppm. There was no evidence of either maternal or developmental toxicity at 10 ppm. Thus, the no-observed-effect level (NOEL) for maternal toxicity was 10 ppm, and the NOEL for developmental toxicity was 25 ppm. Because developmental toxicity was observed only after exposures that also produced signs of maternal toxicity, CDDT was not considered to be a selective developmental toxicant in the rat.

Methylglutaronitrile (MGN) is a high-boiling (263 degrees C) solvent/intermediate used in the fiber industry. Twenty male rats per group were exposed nose-only to condensation aerosol/vapor concentrations of approximately either 5, 25, or 200 mg/m3 of MGN for 6 h/day, 5 days/week over a 4-week period. Ten rats/group were sacrificed one day after the final exposure and the remaining rats after a four-week recovery period. No effects were observed in clinical observations during the exposure period, but body-weight depression was observed in the 200 mg/m3 group. The 200 mg/m3 group showed minimal decreases in red blood cell count, hemoglobin, and hematocrit values accompanied by increases in reticulocytes. There were no other effects observed in clinical or pathologic evaluations in the study. A neurobehavioral battery of tests (including grip strength, functional observational battery, and motor activity tests) given at the end of the exposure and recovery periods showed no MGN effects. During the 4-week recovery, body weights in the 200 mg/m3 group returned to normal and the hematologic findings in all groups were normal. Based on the above findings of body weight depression at 200 mg/m3, the no-observed-adverse-effect level (NOAEL) for this study was considered to be 25 mg/m3.

Phenylphosphinic acid was fed in graded concentrations of either 0 (control), 100, 1,000, or 10,000 ppm to rats for 28 days. These concentrations provided average daily doses of 8, 76, and 779 mg/kg (males) and 9, 83, and 859 mg/kg (females). No signs of adverse response were detected at any concentration up to the highest levels tested, 10,000 ppm or 779 (male) or 859 (female) mg/kg. Parameters measured were clinical signs, growth, neurobehavior, ophthalmology, and clinical and anatomical pathology. Phenylphosphinic acid is very low in toxicity following 31 days of feeding to the rat.

A mixture of 1,3-dimethyl-2-piperidinone and 1,5-dimethyl-2-piperidinone (DMPD) (approximately 63-37 parts by weight) was tested for its inhalation toxicity in rats following 90-day repeated exposures. Male and female rats were exposed whole-body to either 0, 51, 230, or 310 mg/m(3) DMPD for 6 h/day, 5 days/weak for 90 days. Clinical signs, growth, clinical pathology, tissue pathology, neurobehavior, neuropathology, and semen quality were evaluated. No compound-related adverse effects were noted in clinical signs, body weights, food consumption, clinical laboratory evaluations, neurobehavioral evaluations, neuropathology, or sperm counts. Laryngeal changes consisting of minimal squamous epithelial hyperplasia and degeneration/necrosis of the cartilage were present in male and female rats exposed to 310 mg/m(3) both immediately following exposure and after the 1-month recovery period Male rats exposed to DMPD had increased relative kidney weights, increased formation of hyaline droplets and granular casts, and increased incidence of chronic progressive nephropathy. These kidney effects are consistent with increased accumulation of the urinary protein alpha(2 mu)-globulin, which has been well essential for several xenobiotics. The subsequent increased incidence of progressive nephropathy was specific to male rats with the alpha(2 mu) syndrome. Male and female rats exposed to 230 or 310 mg/m(3) had centrilobular hepatocellular hypertrophy, and male rats exposed to 310 mg/m(3) had increased relative liver weights. These liver changes were reversible following the recovery period and were considered not to represent adverse toxicological effects of treatment. Since the male rat-specific renal findings do not connote adversity for man and are net considered relevant to human hazard assessment, the no-observed-effect level in male and female rats was 230 mg/m(3), based on the microscopic changes in the larynx exposed to 310 mg/m(3).

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was administered daily by oral gavage to groups of Crl:CD (SD)IGS BR rats at dose levels of 0 (control), 30, 100, or 300 mg/kg/day. Female rats were dosed for four weeks premating, through mating, gestation, and lactation (a total of 55 to 63 days of treatment). Male rats were treated for 55 days (four weeks premating and through mating). Premating, body weights, food consumption, and clinical signs were recorded. Hematology, clinical chemistry, and urine analyses were conducted at the end of the premating period. A neurobehavioral test battery was conducted prior to and after four weeks of treatment. After the premating period, females were paired with males from the same groups for 1-2 weeks. Litters were delivered, pups were evaluated for structural integrity, and pup body weights were recorded on days 0 and 4 postpartum. Lactating females and their offspring were sacrificed on postpartum day 4. Selected organs were weighed and the tissues were examined microscopically from the lactating females. Offspring were examined for clinical abnormalities. A test substance-related reduction in body weight gain occurred in male rats administered 300 mg/kg/day. Decreased body weight gain in the 300 mg/kg/day males was accompanied by increased food consumption and decreased food efficiency. Females administered 100 or 300 mg/kg/day had test substance-related, significantly decreased body weight and body weight gain during gestation, that was accompanied by a significant increase in food consumption (300 mg/kg/day group only), and significantly decreased food efficiency. There were no test-substance related effects on clinical observations in males or females during the premating phase, or in females during gestation or lactation. Neurobehavioral parameters and motor activity were unaffected by CDDT-treatment. During this study, statistically significant treatment-related changes were observed in several clinical pathology parameters. The decreases in red cell mass (RBC, HGB, HCT) were minimal and, due to the magnitude, were not expected to result in biological effects. Similarly, minimally increased potassium and mildly decreased triglycerides were not of a magnitude to be biologically significant. Finally, changes in serum enzymes (AST, ALT, ALP), urea nitrogen, and serum protein occurred in directions that are not associated with toxicity. The changes in urine volume, urine concentration, and urea nitrogen may be the result of elevated glomerular filtration rate and altered tubular fluid flow, in the absence of any histopathological change. No effects on reproduction in parental males or females were produced by CDDT. Body weights of pups in the 300 mg/kg group were significantly decreased on postpartum days 0 and 4. There were no test-substance related effects on clinical observations, number of pups born, and the number of pups born alive, or the number of pups surviving through lactation day 4. The no-observed-adverse-effect level (NOAEL) for CDDT was 30 mg/kg/day based on decreased body weight and body weight gain, increased food consumption, and decreased food efficiency in females administered 100 or 300 mg/kg/day. The NOEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during lactation.

Adipic acid has very low acute toxicity in rats with an LD50 > 5000 mg/kg. Adipic acid produced mild to no skin irritation on intact guinea pig skin as a 50% concentration in propylene glycol; it was not a skin sensitizer. Adipic acid caused mild conjunctival irritation in washed rabbit eyes; in unwashed rabbit eyes, there was mild conjunctival irritation, minimal iritis, but no corneal effects. Adipic acid dust may irritate the mucous membranes of the lungs and nose. In a 2-year feeding study, rats fed adipic acid at concentrations up to 5% in the diet exhibited only weight loss. Adipic acid is not genetically active in a wide variety of assay systems. Adipic acid caused no developmental toxicity in mice, rats, rabbits, or hamsters when administered orally. Adipic acid is partially metabolized in humans; the balance is eliminated unchanged in the urine. Adipic acid is slightly to moderately toxic to fish, daphnia, and algae in acute tests.

Rats were exposed by inhalation to either 0.5 ppm 1,4-dichlorobutene-2 (DCB) for two years or to 5.0 ppm for seven months, 2.5 ppm for five months, and no further exposure for 12 months prior to sacrifice. Malignant and non-malignant tumors of the nasal tissues were seen in both test groups with the incidence and proportion of malignant tumors being much higher in the 5.0/2.5 ppm rats. Under the conditions of this study, DCB is carcinogenic in rats of both sexes.

Kapton Film is a polymer with high strength and thermal resistance finding use in a wide variety of applications. In the preparation of this film, the uncured material could contain up to 30% dimethylacetamide (DMAC). Note that the final product Kapton Film has been thermally cured with the DMAC removed. During processing, dermal contact with the film is anticipated, and the possibility exists of DMAC transfer from the uncured film, to and through the skin. In this study, 2 x 2-inch pieces of film were applied to the skin of a group of rabbits and secured in place for a single 4-hour contact time. An amount of liquid DMAC corresponding to the amount contained in the 2-inch square was applied to the skin of a separate group of rabbits for 4 hours. Urine samples were collected over the intervals of application to 4 hours post application (8 hours total) or 4 to 20 hours post application (16 hours). The amount of the urinary metabolite monomethylacetamide (MMAC) was determined analytically in these samples. Urine from 2 untreated rabbits was collected at the same time to serve as controls. The amount of urinary MMAC found in the rabbit rine from animals exposed to uncured Kapton Film at both ollection intervals was similar to the amount seen in the controls (background). Rabbits treated with DMAC liquid had measurable urinary MMAC levels that were approximately 100 times background. It is concluded that, under the conditions of this study, very little, if any, DMAC from the uncured Kapton Film was absorbed through the skin (and excreted in the urine as MMAC).

Tetramethylurea (TMU, CAS No. 632-22-4) was tested for its inhalation toxicity in rats following repeated exposures. Male rats were exposed whole-body to TMU for 6 hours/day, 5 days/week for a total of 9 exposures over 2 weeks. Concentrations of 0 (control), 2, 20, and 100 ppm were studied. Four groups of 10 rats each were used to measure clinical signs and growth, clinical pathology (including hematology, biochemistries, and urine analysis), and tissue pathology. One-half of the rats were sacrificed 1 day following the 9th exposure; the other half underwent an 18-day recovery period prior to being sacrificed (recovery group). Body weight gains in rats exposed to 100 ppm were reduced as compared to the controls; no body weight effects were seen in either 2 or 20 ppm rats and no clinical signs of toxicity were observed in rats at any of the levels throughout the study. No compound-related clinical pathology changes were seen in any of the test groups and tissue pathology effects only occurred in the nasal tissue. In rats exposed to 100 ppm, microscopic observations of degeneration, necrosis, and ulceration of olfactory mucosa was seen. These lesions were still present but seen as recovering and healing after the 18-day recovery. Under the conditions of this test, the no-observed-adverse-effect level (NOAEL) was determined to be 20 ppm based upon both body weight changes and upper respiratory tract pathologic changes in 100 ppm rats.

A two-year feeding study in rats and an 18-month feeding study in mice were conducted to evaluate the potential chronic toxicity and oncogenicity of NMP in Crl:CD (SD)BR rats and B6C3F1/CrlBR mice. Groups of 62 male and female rats were administered diets containing 0, 1600, 5000, or 15,000 ppm of NMP for approximately 2 years. Groups of 50 male and female mice were administered diets containing 0, 600, 1200, or 7200 ppm NMP for approximately 18 months. In vivo parameters were evaluated weekly during the first 3 months of the study, and every other week or monthly during the remainder of the study. For rats, an ophthalmoscopic examination was conducted prior to study start and near the end of the study. Periodically, blood samples were collected from rats and mice for determination of leukocyte differential counts, and from mice for red blood cell morphology. After approximately 2 years of dietary administration in rats and 18 months in mice, all surviving animals were sacrificed. Selected tissues were processed for morphological evaluation. Over the course of the two-year study in rats, test substance-related decrements in body weight and weight gain occurred in 15,000 ppm males and females, which correlated with decreased food consumption and food efficiency. A toxicologically significant, test substance-related increase in the incidence of severe chronic progressive nephropathy occurred in 15,000 ppm males. Several morphological changes noted grossly and/or microscopically were secondary to the increased severity of chronic progressive nephropathy. NMP was not oncogenic in male or female rats at dietary concentrations of 15,000 ppm and below. A test substance-related decrease in the percentage of 15,000 ppm males surviving to the end of the two-year study compared to the control group resulted from the higher incidence of severe chronic progressive nephropathy. However, a sufficient population of 15,000 ppm rats were at risk for potential oncogenicity, so the lower survival did not impair the ability to detect an oncogenic response in this study. There were no adverse, test substance-related effects on the incidences of clinical observations, ophthalmic observations, or differential leukocyte counts in males or females, or on survival of females at any dietary concentration. Male and female mice administered dietary concentrations of 7200 ppm had significantly increased liver weight, significantly increased incidence of hepatocellular adenoma, and significantly increased foci of cellular alteration in the liver. At 7200 ppm, male mice also had an increased incidence of hepatocellular carcinoma while the increased incidence of hepatocellular carcinoma in female mice fell within the historical control range. In addition, the incidence of hepatocellular hypertrophy was increased in 7200 ppm males. Liver weight and hepatocellular hypertrophy were also increased in 1200 ppm males. There were no adverse, test substance-related effects on the incidences of clinical observations, food consumption, body weight, differential leukocyte counts, red blood cell morphology, or survival in either males or females at any dietary concentration. Under the conditions of the study, the no-observed-effect level for NMP was 5000 ppm for male and female rats, 600 ppm for male mice, and 1200 ppm for female mice.

In the first half of the twentieth century epidemiologic evidence linked elevated incidences of pulmonary fibrosis and cancer with inhalation of chrysotile and crocidolite asbestos, a family of naturally occurring inorganic fibrous materials. As the serpentine and amphibole forms of asbestos were phased out, synthetic vitreous fibers (SVFs; fiber glass, mineral wool, and refractory fiber) became increasingly utilized, and concerns were raised that they too might cause adverse health effects. Extensive toxicological research on SVFs has demonstrated that their pulmonary effects are directly related to fiber dose in the lung over time. This is the result of deposition (thin fibers deposit in the lower lung more efficiently than thick fibers) and lung-persistence ("biopersistence" is directly related to fiber length and inversely related to dissolution and fragmentation rates). In rat inhalation studies, asbestos was determined to be 7- to 10-fold more biopersistent in the lung than SVFs. Other than its effect on biopersistence, fiber composition did not appear to play a direct role in the biological activity of SVFs. Recently, the utilization of man-made organic fibers (MMOFs) (also referred to by some as synthetic organic fibers) has increased rapidly for a variety of applications. In contrast to SVFs, research on the potential pulmonary effects of MMOFs is relatively limited, because traditionally MMOFs were manufactured in diameters too thick to be respirable (inhalable into the lower lung). However, new developments in the MMOF industry have resulted in the production of increasingly fine-diameter fibers for special applications, and certain post-manufacturing processes (e.g., chopping) generate respirable-sized MMOF dust. Until the mid-1990s, there was no consistent evidence of human health affects attributed to occupational exposure to MMOFs. Very recently, however, a unique form of interstitial lung disease has been reported in nylon flock workers in three different plants, and respirable-sized nylon shreds (including fibers) were identified in workplace air samples. Whether nylon dust or other occupational exposures are responsible for the development of lung disease in these workers remains to be determined. It is also unknown whether the biological mechanisms that determine the respirability and toxicity of SVFs apply to MMOFs. Thus, it is appropriate and timely to review the current data regarding MMOF workplace exposure and pulmonary health effects, including the database on epidemiological, exposure assessment, and toxicology studies.

Groups of 20 male Crl:CDBR rats each were exposed, whole-body, for six hours/day, for a total of nine exposures over a two-week period to concentrations of 52, 150, or 500 ppm of 1,5-cyclooctadiene vapor. A control group of 20 male rats was exposed simultaneously to houseline air. Ten rats per group were used for standard toxicological evaluations and ten rats per group for neurotoxicity testing. In the standard toxicology group, at the end of the exposure period, blood and urine samples were collected for clinical analyses, and five rats per group were sacrificed for pathologic examination. After a two-week recovery period, the surviving rats in the standard groups were also given clinical and pathological examinations. The neurotoxicity group was given a functional observational battery (FOB) test and motor activity evaluations after the fourth and ninth exposures. In addition, six of ten neurotoxicity rats per exposure group were given neuropathology evaluations at the end of the exposure period. In rats exposed to 500 ppm of 1,5-cyclooctadiene there was an absence of alerting response toward the end of the daily six-hour exposures. These rats appeared to recover within 1/2 hour after exposure. This effect was not observed in the other test groups. The FOB evaluation showed an increase in the number of rats found sleeping in the 500 and 150 ppm groups compared to controls after the last exposure, but there were no treatment-related effects in the motor activity evaluation. Since there were no other neurobehavioral findings and no toxicity findings in the 150 ppm group, the sleeping behavior in the 150 ppm group was considered insufficient evidence of an adverse effect. Clinical laboratory evaluation of the 500 ppm group showed urinary pH decreases at the end of the exposure period but not after the two-week recovery period. There were no other toxicologically important changes in urine analysis, hematologic, or blood chemistry evaluations attributable to the test compound. Histologic effects were found in the nose and kidneys of rats in the 500 ppm group. There was a mild degeneration/necrosis of nasal olfactory epithelium observed immediately after the exposure period and a mild degeneration/regeneration in this area observed after the two-week recovery. In addition, there were increased kidney weights in the 500 ppm group immediately after exposure along with increased hyaline droplets in the kidneys. These effects were reversible after the two-week recovery period. There were no significant nasal or kidney effects observed in the 150 and 52 ppm test groups, and no other organ weight or histological effects attributable to the test compound observed in the standard toxicology groups at either evaluation time. The neuropathologic evaluation showed only one minor lesion in one 500 ppm-group rat and this was not considered to be attributable to exposure to 1,5-cyclooctadiene. Based on the decreased alerting response observed in rats during exposure at 500 ppm, and on the effects observed in the nose, kidney, and urine in rats at this concentration, the no-observed-adverse-effect (NOAEL) level in this study was considered to be 150 ppm.

The developmental toxicity of tetramethylurea (TMU) was assessed in rats by inhalation exposure of the test material over days 6-20 of gestation. Groups of 25 mated female Crl:CD BR rats were exposed whole-body for 6 hours/day to concentrations of either 0, 2, 20 or 100 ppm TMU. The dams were euthanized on day 21 and the offspring were weighted, sexed, and examined for external, visceral, and skeletal alterations. Maternal toxicity was demonstrated at both 20 and 100 ppm. Maternal body weights, weight changes, and food consumption were statistically significantly reduced at these concentrations; effects were more pronounced at 100 ppm. There was evidence of developmental toxicity only at 100 ppm. The only finding was a decrease in mean fetal weight. No fetal malformations or variations occurred in fetuses derived from rats exposed to all 3 test concentrations (up to 100 ppm). The maternal no-observed-effect-level (NOEL) was 2 ppm, the fetal NOEL was 20 ppm. Thus, TMU was not considered to be uniquely toxic to the rat conceptus.