Inhalation Toxicity Study In Rats Research Articles

Acute and two-week inhalation toxicity studies in rats for Polyalphaolefin (PAO) fluid

ABSTRACT Formal occupational exposure limits (OELs) for polyalphaolefin (PAO) fluids have not been proposed. Specific PAO fluids are utilized as aircraft hydraulics or heat sink coolants for electronics and aircraft service air. Toxicity was compared for a PAO fluid in male and female Fischer 344 rats using acute inhalation (0, 100, 500, or 1000 mg/m3 aerosol for 6 hr) and two-week inhalation (0, 20, 100, or 300 mg/m3 aerosol for 6 hr/day, 5 days/week) studies. Neurobehavioral tests following acute exposure showed that both genders were less responsive after exposure to 1000 mg/m3 PAO, and to a lesser extent following 500 mg/m3 PAO. Body weight, food, and water consumption were also affected with recovery after 24 hr. Histopathology for the acute group demonstrated an exposure response increase in severity (minimal to mild) of lesions in the posterior nasal cavities and lungs. Severity of lesions was reduced in the recovery groups (normal to minimal). Acute effects were short-lived and recoverable. Following the two-week exposure, effects were limited to lesions only in the posterior nasal cavities and lungs of the high exposure group, with less severity than in the acute exposure high concentration group. Short-term repeated exposure did not result in any cumulative effects except for minimal respiratory tract changes in the 300 mg/m3 exposure group. Data-driven operational exposure limits (OpELs) were proposed based upon Acute Exposure Guideline Levels process resulting in values of 28, 28, 14, 3.5, and 1.7 mg/m3 for 10 and 30 min, 1, 4, and 8 hr, respectively.

Trifluoroiodomethane (CF3I) (2019).

Trifluoroiodomethane (CF3I) is a colorless and odorless gas used primarily as a fire suppressant. CF3I has low acute inhalation toxicity. The no-observed adverse effect level (NOAEL) of CF3I for cardiac sensitization in dogs was 2000 ppm. The potential effects of 4-week inhalation exposure in both rats and mice have been examined. In rats, the NOAEL was 10,000 ppm, and in mice, the NOAEL was 10,000 ppm. In a subchronic inhalation study in rats, the lowest observed adverse effect level (LOAEL) was 20,000 ppm for thyroid-related effects; the study NOAEL (for non-thyroid-related effects) was 20,000 ppm. In a reproductive/developmental inhalation toxicity study in rats, 20,000 ppm CF3I produced minimal general toxicity and no indication of reproductive or developmental toxicity. The LOAEL for parental toxicity (based on thyroid hormone effects) was 2000 ppm; excluding thyroid effects, the parental NOAEL was 7000 ppm CF3I. The observed effects on the thyroid in rats were considered of less relevance to human risk assessment than the other observed systemic effects because of known species-specific differences in sensitivity to thyroid hormone perturbations. There are no chronic toxicity or carcinogenicity studies available. CF3I had mixed results in various in vitro and in vivo genotoxicity assays. The NOAEL of 7000 ppm from the reproductive/developmental inhalation study was used as the point of departure (POD) for workplace environmental exposure level (WEEL) value development. This POD was adjusted to account for interindividual variability, duration of exposure, and database limitations. The resulting 8-h time-weighted average WEEL value of 500 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to CF3I. A 15-min short-term exposure limit of 1500 ppm was also established to protect workers from potential cardiac effects produced by acute, high-dose inhalation of CF3I.

1,1,2,2-Tetrafluoroethane (HFC-134) (2018).

1,1,2,2-Tetrafluoroethane (HFC-134) is a colorless gas used as a foam expansion agent and heat transfer fluid. HFC-134 has a low acute inhalation toxicity with an LC50 of >244,000 ppm. The no-observed adverse effect level (NOAEL) and lowest-observed adverse effect level for cardiac sensitization (in epinephrine-challenged beagle dogs) were 75,000 and 100,000 ppm, respectively. A subacute 4-week GLP inhalation toxicity study exposed male and female Crl: CD®BR rats (10/sex) to 0, 2000, 10,000, or 50,000 ppm via whole-body inhalation. Transient and non-dose-response-related body weight changes were observed throughout the exposure period, but no statistically significant, test substance-related adverse effects were observed in any clinical observations, chemistry, hematology, or pathology. This study identified a NOAEL for HFC-134 of 50,000 ppm, the highest exposure level tested. HFC-134 is not genotoxic in in vitro studies; however, no in vivo studies are available. No developmental or maternal toxicity was found in female rats exposed to HFC-134 up to 50,000 ppm via whole-body inhalation in two different studies. Based on data for a similar material (HFC-134a), HFC-134 is not expected to be extensively metabolized or to cause genetic toxicity or carcinogenicity. The HFC-134 workplace environmental exposure level (WEEL) is based primarily on the subacute 4-week inhalation toxicity study in rats with the NOAEL of 50,000 ppm selected as the point of departure for the derivation of the 8-h TWA, health-based WEEL value. The developmental toxicity study also had a NOAEL of 50,000 ppm and was the highest exposure level tested. The subacute inhalation NOAEL was adjusted to account for interindividual variability, subacute to chronic duration, animal to human extrapolation, daily duration of exposure, and residual uncertainty. In addition, the lack of adverse effects noted in the toxicology studies for HFC-134a was considered. The resulting 8-h TWA WEEL value of 1000 ppm is expected to provide a significant margin of safety against the production of any potential adverse health effects in workers following long-term inhalation exposure to HFC-134.

Differentiating between Testicular Toxicity and Sexual Immaturity in Ortho-phthalaldehyde Inhalation Toxicity Studies in Rats and Mice

Early deaths of young or juvenile animals (before sexual maturation is achieved) in routine regulatory safety studies present pathologists and toxicologists with the challenge of interpreting findings in the male reproductive tract. Additionally, the advent of toxicity testing regulations has resulted in a growing need for the use of juvenile animals in toxicology studies. Here, we present the reproductive toxicity findings from a 13-week inhalation toxicity study with ortho-phthalaldehyde (OPA) in male rats and mice as a case example for working through this challenging task. In this study with OPA, survival was significantly reduced in the two highest exposure concentrations of OPA tested. Early deaths and histopathological lesions in the testes and epididymides were generally also limited to these two highest exposure groups. Therefore, there was concern that peripubertal morphological features could be a confounding factor for the histopathological evaluation of exposure-related testicular and epididymal findings. Although it can be difficult to differentiate exposure-related effects from the normal morphological features defining peripubertal changes in the testes and epididymides in animals that die early in a toxicity study, the use of age-matched controls in this case study with OPA provided a reference and aided in the differentiation of these effects.

Aerosols of synthetic amorphous silica do not induce fibrosis in lungs after inhalation: Pathology working group review of histopathological specimens from a subchronic 13-week inhalation toxicity study in rats

In a subchronic (13-week) inhalation toxicity study with a terminal sacrifice (after 13 weeks inhalation) and several recovery period sacrifices (13, 26, 39, and 52 weeks), the effects of AEROSIL® 200 (pyrogenic synthetic amorphous silica (SAS)), AEROSIL® R 974 (surface-treated pyrogenic SAS), and SIPERNAT® 22 S (precipitated SAS) were tested in rats at multiple dose levels. The aforementioned materials are all SAS products. A comparative group of animals was exposed to quartz dust. This study attempts to reexamine the lung tissues originally evaluated in a study published by Reuzel et al. using the current standards. To reach a high level of credibility, the results of the reevaluation were subsequently examined by a pathology working group (PWG). In particular, the reevaluating pathologist and the PWG concluded that, even though quartz (crystalline silica) persisted, induced alterations in the lungs following 13 weeks of exposure to amorphous silicas were reversible following 52 weeks of recovery. A long-term adversity has not been established with SAS products. However, quartz dust damages lungs significantly by causing pulmonary fibrosis.

3-Nitro-1,2,4-triazol-5-one (2014).

3-Nitro-1,2,4-triazol-5-one (NTO) is a potential replacement for energetics in military munitions. It is a component of IMX-101, a munition designed to prevent unintentional detonation. This report summarizes the dermal, oral, and inhalation animal toxicity data, including the results of genotoxicity and limited reproductive and developmental studies. NTO has an acute LD50 in rats and mice of >5000 mg/kg, is a potential eye and skin irritant, but does not induce skin sensitization. Acute inhalation toxicity studies in rats were negative, but testicular hypoplasia was observed in a 14-day oral study in rats administered NTO at >500 mg/kg/day. Similar findings were noted in an oral 90-day study at dosages >315 mg/kg/day and in reproductive toxicity studies at >125 mg/kg/day. NTO did not cause any developmental defects. All genotoxicity studies were negative. ADME and pharmacokinetics data showed rapid uptake and elimination of NTO from both inhalation and oral intakes. Biotransformation by liver microsomes demonstrated two separate pathways, one aerobic and the other anaerobic. NTO is not considered an endocrine disruptor. There is very little human data regarding NTO or the IMX-101 mixtures. Using testicular changes in rats as the point of departure for deriving a Workplace Environmental Exposure Level (WEEL) for NTO, the resulting BMDL10 was 40 mg/kg/day, and the 8-hour time-weighted average was 2 mg/m2.

Graphistrength© C100 MultiWalled Carbon Nanotubes (MWCNT): thirteen-week inhalation toxicity study in rats with 13- and 52-week recovery periods combined with comet and micronucleus assays

Graphistrength© C100 provides superior electrical and mechanical properties for various applications and is one of the industrial MWCNT referenced in the OECD sponsorship program for the safety testing of nanomaterials. Graphistrength© C100 is formed of MWCNT (ca. 12 walls, outer mean diameter ca. 12 nm, length ca. 1 µm) agglomerated in particles with a granulometry centered on 400 µm. A general feature of MWCNT after inhalation or intratracheal exposures is the induction of an inflammatory reaction in the lungs sometimes associated with local genotoxic effects. Most of the in vitro and in vivo genotoxicity data available on Graphistrength© C100 are negative. However, a weak DNA damage activity in the in vitro and in vivo FPG-modified Comet assays and a weak clastogenic effect in the in vitro micronucleus test were reported. After investigating different parameters for the aerosol generation, male and female Wistar rats were exposed by nose-only inhalation (6h/day, 5d/week) to target concentrations of 0.05, 0.25 and 5.0 mg/m3 air of a respirable aerosol (MMAD < 3 µm) and sacrificed immediately after 4 and 13 weeks of exposure and 13 and 52 weeks of recovery after the 13-week exposure. Clinical, biological and histological evaluations were performed according to the OECD TG 413. Broncho-alveolar lavage fluid (BALF) was collected and analysed for cytokines and inflammatory parameters. Immediately after 13 weeks of exposure, chromosomal aberrations in the bone marrow cells of males and females were evaluated by the micronucleus test (OECD TG 474) and DNA damage in the lung, kidney and liver cells of males were assessed by both the standard and the human 8-oxoguanine DNA N-glycosylase 1 (hOGG1)-modified comet assay (OECD TG 489). Concentration-related deposition of black particles (MWCNT) was observed in lungs. At all sacrifice periods, an inflammatory lung reaction was observed in rats exposed to 5.0 mg/m3 associated with changes in the differential white blood cells counts. The lung inflammation was characterized by changes in the cytological, biochemical and cytokine parameters of the BALF, an increase of the lung weight, an interstitial inflammation mainly around the alveolar ducts at the bronchiole-alveolar junction and a cell hypertrophy/hyperplasia in the terminal and respiratory bronchioles. The slight changes in BALF parameters observed at 0.25 mg/m3 recovered after the 13-week treatment-free period and were not associated with any of the histological changes observed in lungs at 5.0 mg/m3. Signs of lung clearance of the MWCNT were observed at 0.05 and 0.25 mg/m3. After a one year treatment-free period, the inflammatory lung reaction was slight and of similar intensity that at the earlier sacrifice periods. Additional findings were minimal/slight bronchiolar/alveolar cell hypertrophy/hyperplasia and focally extensive alveolar septal fibrosis. No other pathological change was observed, nor was there any brain translocation via the olfactory bulb. The microscopic observations of the pleura were unremarkable. Neither increase in the number of micronucleated polychromatic erythrocytes nor increase in percent DNA damage were observed at any concentration. In conclusion, a lung inflammation characteristic of an overload with insoluble particles was observed after a 13-week inhalation exposure to 5.0 mg/m3 of Graphistrength© C100. A No-Observed Adverse Effect Concentration (NOAEC) of 0.25 mg/m3 was established for the repeated-dose toxicity and Graphistrength© C100 appears of low concern in term of local and systemic genotoxicity.

Comparative hazard identification of nano- and micro-sized cerium oxide particles based on 28-day inhalation studies in rats

There are many uncertainties regarding the hazard of nanosized particles compared to the bulk material of the parent chemical. Here, the authors assess the comparative hazard of two nanoscale (NM-211 and NM-212) and one microscale (NM-213) cerium oxide materials in 28-day inhalation toxicity studies in rats (according to Organisation for Economic Co-operation and Development technical guidelines). All three materials gave rise to a dose-dependent pulmonary inflammation and lung cell damage but without gross pathological changes immediately after exposure. Following NM-211 and NM-212 exposure, epithelial cell injury was observed in the recovery groups. There was no evidence of systemic inflammation or other haematological changes following exposure of any of the three particle types. The comparative hazard was quantified by application of the benchmark concentration approach. The relative toxicity was explored in terms of three exposure metrics. When exposure levels were expressed as mass concentration, nanosized NM-211 was the most potent material, whereas when expression levels were based on surface area concentration, micro-sized NM-213 material induced the greatest extent of pulmonary inflammation/damage. Particles were equipotent based on particle number concentrations. In conclusion, similar pulmonary toxicity profiles including inflammation are observed for all three materials with little quantitative differences. Systemic effects were virtually absent. There is little evidence for a dominant predicting exposure metric for the observed effects.

Collection, Validation and Generation of Bitumen Fumes for Inhalation Studies in RatsPart 3: Regeneration of Bitumen Fumes, Inhalation Setup, Validation

Undertaking a chronic inhalation study on bitumen fume presents a challenge in terms of generating sufficient amounts of representative fume. The objective of the study described in this and in previous publications was to collect sufficient fume and use this to develop a laboratory-generated exposure atmosphere, for use in chronic inhalation toxicity studies in rats that resembles, as closely as possible, personal exposures seen in workers during road paving operation. To achieve this goal, atmospheric workplace samples were collected at road paving work sites and compared with bitumen fume condensate samples collected from the headspace of hot bitumen storage tanks. In Parts 1 and 2, we described the collection and analysis of workplace samples, the strategy for in-line extraction of a suitable fraction of bitumen fume collected from the headspace of a bitumen storage tank and the comparison of the collected condensate to the workplace samples. This paper (Part 3) describes the regeneration of bitumen fume for inhalation and the exposure setup used for inhalation studies.

Collection, Validation and Generation of Bitumen Fumes for Inhalation Studies in Rats Part 2: Collection of Bitumen Fumes from Storage Tanks

The objective of the study described in this and an accompanying series of papers was to develop a laboratory generated exposure atmosphere to be used for chronic inhalation toxicity studies in rats that resembles, as closely as possible, personal exposures seen by workers during road paving operations. To achieve this objective, atmospheric workplace samples were collected at road paving worksites and compared analytically with bitumen fume samples collected from the headspace of hot bitumen storage tanks. In Preiss et al. (2006) the collection and analysis of workplaces samples is described. This contribution describes the strategy for the in-line extraction of a suitable fraction of bitumen fume collected from the headspace of a bitumen storage tank and the comparison of the collected condensate to workplace samples. Results show that is possible to develop a collecting procedure that allows sampling from hot bitumen storage tanks in an operational asphalt mixing plant. The sampling procedure has been optimized to collect material that matches the workplace samples as closely as possible. The comparison to workplace samples has been performed using parameters that can be analyzed in both the workplace samples and the bitumen fume condensate collected from the tanks. Boiling point distribution (BPD), UV fluorescence (UV-Fl) and content of individual polycyclic aromatic hydrocarbons (PAH) were selected as parameters. The BPD of the final collected bitumen fume condensate did not differ by more than 17 degrees C from any point on the average BPD curve of the workplace samples, in the range from 5 to 95%. UV-Fl of the bitumen fume condensate nearly exactly matched the average UV-Fl of the workplace samples. However, the sum of the 17 PAHs analyzed in the test samples, compared to the mass of the condensate, is lower by a factor of approximately 3 than the sum of the 17 PAHs in some personal samples compared to the mass of Total Organic Matter (TOM). It has to be recognised that during the collection of the workplace samples, despite all efforts a number of the workers who carried a personal sampler could not be prevented from smoking.

Mosquito coil smoke inhalation toxicity. Part I: Validation of test approach and acute inhalation toxicity

Burning mosquito coils indoors to repel mosquitoes is a common practice in many households in tropical countries. The evaluation and assessment of the inhalation toxicity of smoke emitted from mosquito coils appear to be particularly challenging due to the complex nature of this type of exposure atmosphere. The potential health implications of the gases, volatile agents and particulate matter emitted from burning coils or incense have frequently been addressed; however, state-of-the-art inhalation toxicity studies are scarce. The focus of this paper was comparatively to evaluate and assess the appropriateness and practical constraints of the whole-body versus the nose-only mode of exposure for inhalation toxicity studies with burning mosquito coils. With regard to the controlled exposure of laboratory animals to complex smoke atmospheres the nose-only mode of exposure had distinct advantages over the whole-body exposure, which included a rapid attainment of the inhalation chamber steady state, minimization of particle coagulation and uncontrolled adsorption of condensate onto the chamber surfaces. While in whole-body chambers a different kinetic behaviour of volatile and particulate constituents was found which caused inhomogeneous, i.e. artificially enriched atmospheres with volatile components at the expense of aerosols, the nose-only mode of exposure provided maximum exposure intensities without losses of the particulate phase of the exposure atmosphere. Collectively, the results obtained support the conclusion that the dynamic nose-only mode of exposure is experimentally superior to the quasistatic whole-body exposure mode which provides the least control over exposure atmospheres and the outcome highly contingent on selected experimental factors. Acute inhalation toxicity studies in rats suggest that the most critical metrics of exposure are apparently related to (semi)volatile upper respiratory tract sensory irritants, whilst the asphyxic component, carbon monoxide, plays a role only at overtly irritant exposure levels. However, this study was conducted at exposure concentrations much higher than encountered by people in residential settings and the effects observed under these conditions may not be relevant to hazards from exposures at common use levels. Neither an acute 8 h exposure of rats nor the 1 h sensory irritation study in mice and rats provided experimental evidence that irritant particle-related effects had occurred in the lower respiratory tract. In summary, the protocols devised evaluate and assess the acute inhalation toxicity of mosquito coil smoke demonstrating that the nose-only mode of exposure of rats to the smoke of mosquito coils is suitable to assess the toxic potency of different coils. The nose-only mode has clear advantages over the whole-body exposure mode. The inhalation studies conducted show unequivocally that acute toxic effects are difficult to produce with this type of product even under rigorous testing conditions.

Four-week inhalation toxicity study in rats with nylon respirable fibers: rapid lung clearance.

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.

Final report on the safety assessment of aluminum starch octenylsuccinate.

Aluminum Starch Octenylsuccinate is the aluminum salt of the reaction product of octenylsuccinic anhydride with starch. It is used in cosmetics at concentrations as high as 30% as an anticaking agent and a nonaqueous viscosity increasing agent. No information was available on the presence of impurities in the cosmetic-grade ingredient. When used in foods, Aluminum Starch Octenylsuccinate is identified as a modified food starch, and is subject to limitations on heavy metal residues. Oral studies using Aluminum Starch Octenylsuccinate or its related sodium salt produced no adverse systemic, reproductive, or developmental effects. Dermal injections produced no abnormal skin or systemic reactions in guinea pigs. Ocular toxicity was assessed in rabbits and using an in vitro test (chorioallantoic membrane vascular assay). In both cases no toxicity was seen. An acute inhalation toxicity study in rats was negative. Clinical tests indicated little irritation potential and no sensitization. Absent data on impurities in cosmetic-grade material, it was determined that such material should meet the same impurities requirements established for modified food starches. Based on these available data the Cosmetic Ingredient Review Expert Panel concluded that Aluminum Starch Octenylsuccinate is safe as used in cosmetic formulations provided that established limitations imposed on heavy metal concentrations are not exceeded.

International Profiles in Toxicology: Biography of Vincenzo Cuomo, MD, Ph.D.

Aluminum Starch Octenylsuccinate is the aluminum salt of the reaction product of octenylsuccinic anhydride with starch. It is used in cosmetics at concentrations as high as 30% as an anticaking agent and a nonaqueous viscosity increasing agent. No information was available on the presence of impurities in the cosmetic-grade ingredient. When used in foods, Aluminum Starch Octenylsuccinate is identified as a modified food starch, and is subject to limitations on heavy metal residues. Oral studies using Aluminum Starch Octenylsuccinate or its related sodium salt produced no adverse systemic, reproductive, or developmental effects. Dermal injections produced no abnormal skin or systemic reactions in guinea pigs. Ocular toxicity was assessed in rabbits and using an in vitro test (chorioallantoic membrane vascular assay). In both cases no toxicity was seen. An acute inhalation toxicity study in rats was negative. Clinical tests indicated little irritation potential and no sensitization. Absent data on impurities in cosmetic-grade material, it was determined that such material should meet the same impurities requirements established for modified food starches. Based on these available data the Cosmetic Ingredient Review Expert Panel concluded that Aluminum Starch Octenylsuccinate is safe as used in cosmetic formulations provided that established limitations imposed on heavy metal concentrations are not exceeded.

Two-Year Inhalation Toxicity Study in Rats with Hydrochlorofluorocarbon 123

Two-Year Inhalation Toxicity Study in Rats with Hydrochlorofluorocarbon 123. Malley, L. A., Carakostas, M., Hansen, J. F., Rusch, G. M., Kelly, D. P., and Trochimowicz, H. J. (1995). Fundam. Appl. Toxicol. 25, 101-114. The potential chronic toxicity and oncogenicity of hydrochlorofluorocarbon 123 (HCFC-123) was evaluated by exposing male and female rats to 0, 300, 1000, or 5000 ppm HCFC-123 for 6 hr/day, 5 days/week, for 2 years. Clinical pathology was evaluated at 6, 12, 18, and 24 months. An interim termination and measurements of hepatic cell proliferation and beta-oxidation activity were conducted at 12 months. The terminal euthanization occurred at 24 months. Males and females exposed to 5000 ppm and females exposed to 300 or 1000 ppm had lower body weights and body weight gains. Serum triglyceride and glucose concentrations were significantly decreased at all exposure concentrations in both sexes. Serum cholesterol was also lower in 300, 1000, and 5000 ppm females and in 5000 ppm males. Alterations in serum protein concentrations occurred at 300, 1000, and 5000 ppm. Survival was higher in 1000 and 5000 ppm males and females. At 24 months, increased relative liver weight occurred in 5000 ppm males, and decreased absolute kidney weight occurred in 5000 ppm males and in 1000 and 5000 ppm females. Benign hepatocellular adenomas were increased in 5000 ppm males and in all test groups of females. Hepatic cholangiofibromas were also increased in 5000 ppm females. Pancreatic acinar cell adenomas were increased in all test groups of males, and acinar cell hyperplasia was increased in the 1000 and 5000 ppm males and females. Benign testicular interstitial adenomas and focal interstitial cell hyperplasia were also increased in all male test groups compared to controls. Diffuse retinal atrophy was increased in all male and female test groups, but it was considered to be an indirect compound-related effect. Hepatic beta-oxidation activity (peroxisome proliferation) was higher in 300, 1000 and 5000 ppm males and 1000 and 5000 ppm females. Compound-related differences in the rate of hepatic cell proliferation were not observed at any exposure concentration. Decreased incidences of a variety of age-related lesions occurred at 1000 and 5000 ppm.

Acute Inhalation Toxicity Studies in Rats with a Respirable-Sized Experimental Carbon Fibre: Pulmonary Biochemical and Cellular Effects

Acute Inhalation Toxicity Studies in Rats with a Respirable-Sized Experimental Carbon Fibre: Pulmonary Biochemical and Cellular Effects

A subchronic inhalation toxicity study in rats exposed to silicon carbide whiskers

To determine whether inhaled silicon carbide whiskers (SiC) cause lung damage in rats, four groups (50 males/50 females each) of rats were exposed to air only or to one of three concentrations of SiC 6 hr/day, 5 days/week for 13 weeks. Half (25 males/25 females/group) were euthanized at the end of exposure, the remainder 26 weeks later. Mean concentrations were 0, 630, 1746, and 7276 SiC whiskers/ml (0.09, 3.93, 10.7, and 60.5 mg/m 3). Although there were no concentration-related changes in body weight, clinical chemistry, or hematological data attributable to SiC, lung weights were increased in the high concentration exposure group at both euthanization times. In all whisker-exposed groups, after 13 weeks of exposure, the incidence of the following lung and lymph node lesions was higher than in controls: inflammatory lesions; bronchiolar, alveolar, and pleural wall thickening; focal pleural fibrosis in lung; and reactive lymphoid hyperplasia in bronchial and mediastinal lymph nodes. After 26 weeks of recovery, lung inflammatory lesions had decreased and fewer rats had enlarged lymph nodes, but the incidence of alveolar wall thickening, focal pleural wall thickening, and adenomatous hyperplasia of lung had increased further. Incidence and severity appeared to be dose-related. Therefore, until longer term studies are undertaken and it is established whether the above observed lesions will progress to more severe pathological entities, it is prudent to adopt stringent handling procedures for silicon carbide whiskers.

Dimethylethanolamine: Acute, 2-week, and 13-week inhalation toxicity studies in rats

Dimethylethanolamine (DMEA) is a volatile, water-soluble amine that has applications in the chemical and pharmaceutical industries. These studies evaluated the acute and subchronic inhalation toxicity of DMEA. Acute (4-hr) exposures of Wistar rats to DMEA vapor resulted in an LC50 value (95% confidence limits) of 1641 (862–3125) ppm. Clinical signs of nasal and ocular irritation, respiratory distress, and body weight loss were observed in rats exposed to 1668 ppm DMEA and higher. In the 2-week study, F-344 rats exposed to 98, 288, or 586 ppm DMEA for 9 days (6 hr/day) during an 11-day period also exhibited signs of respiratory and ocular irritation (except the 98 ppm group). All animals of the 586 ppm group and 4 of 15 male rats of the 288 ppm group died. Body weight values for the 288 ppm group were reduced to about 75% of preexposure values, while the 98 ppm group gained 35% less weight than controls. Statistically significant differences in clinical pathology parameters (288 ppm group) and in organ weight values (288 and 98 ppm groups) probably resulted from the decreased food consumption and not from specific target organ toxicity. In the groups evaluated histologically (the 98 and 288 ppm groups) the eye and nasal mucosa were the primary target organs. In the 13-week subchronic study, F-344 rats were exposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/week for 13 weeks. The principal exposure-related changes were transient corneal opacity in the 24 and 76 ppm groups; decreased body weight gain for the 76 ppm group; and histopathologic lesions of the respiratory and olfactory epithelium of the anterior nasal cavity of the 76 ppm group and of the eye of several 76 ppm group females. Rats maintained for a 5-week recovery period only exhibited histological lesions of the nasal tissue, with the lesions being decreased in incidence and severity. DMEA acts primarily as an ocular and upper respiratory tract irritant and toxicant at vapor concentrations of 76 ppm, while 24 ppm or less produced no biologically significant toxicity in rats. Thus, 24 ppm was considered to be the no-observable-effect level.

Diethylene glycol monomethyl ether 13-week vapor inhalation toxicity study in rats

Male and female Fischer 344 rats were exposed to 0, 30, 100, or 216 ppm diethylene glycol monomethyl ether (DEGME) vapors (0, 0.15, 0.49, or 1.06 mg/liter) 6 hr/day, 5 days/week, for 13 weeks. The 216-ppm exposure level was the maximum practically attainable concentration, and it was more than 60% of the theoretical maximum vapor concentration for DEGME at 25°C and 1 atm pressure. Body weights, organ weights, hematological analyses, clinical chemistry analyses, urinalyses, and gross and histopathological examinations revealed no indication of a treatment effect in either male or female rats. Based on the absence of treatment-related effects in this study and the low vapor pressure of the material, DEGME should not present the same degree of inhalation hazard as its structural homolog, ethylene glycol monomethyl ether.

Dipropylene glycol monomethyl ether: A 13-week inhalation toxicity study in rats and rabbits

Fischer 344 rats (10/sex/exposure concentration) and New Zealand White rabbits (7/sex/exposure concentration) were exposed to 0, 15, 50, or 200 ppm (0, 91, 303, or 1212 mg/m 3) of dipropylene glycol monomethyl ether (DPGME) for 6 hr/day, 5 days/week for 13 weeks. Criteria of response included general observations, body weights, clinical chemistry, hematology, urinalyses (rats only), necropsy, organ weights, and histopathology. There were no effects attributed to exposure to DPGME at any exposure concentration in either male or female rats or rabbits. The highest concentration tested (200 ppm) was approximately 40% of a saturated DPGME atmosphere, Based on the low vapor pressure of DPGME, and results in this 13-week study, DPGME appears to have a low subchronic vapor inhalation toxicity hazard.