Relative developmental toxicities of inhaled aliphatic mononitriles in rats.

The developmental toxicities of eight aliphatic mononitriles were studied in Sprague-Dawley rats after inhalation exposure for 6 hr/day, during Days 6 to 20 of gestation. The range of exposure concentrations for acetonitrile was 900 to 1800 ppm; for propionitrile and n-butyronitrile, 50 to 200 ppm; for isobutyronitrile, 50 to 300 ppm; for acrylonitrile and methacrylonitrile, 12 to 100 ppm; for allylnitrile 12 to 50 ppm; and for 2-chloroacrylonitrile, 1 to 12 ppm. Embryolethality was observed after exposure to 1800 ppm acetonitrile, 200 ppm propionitrile, 300 ppm isobutyronitrile; fetotoxicity was observed after exposure to 200 ppm propionitrile, n-butyronitrile, or isobutyronitrile, or to 25 ppm acrylonitrile in the presence of overt signs of maternal toxicity. In the absence of significant maternal toxicity, allylnitrile caused embryolethality, fetotoxicity, and clear teratogenicity at 50 ppm, and n-butyronitrile and methacrylonitrile caused fetotoxicity at 200 ppm and 100 ppm, respectively. While maternal toxicity was observed for 2-chloroacrylonitrile, it did not cause significant embryonal or fetal toxicity up to 12 ppm.

Adrenal-dependent leucopenia after short-term exposure to various airborne irritants in rats.

Leucopenia without any change in differential or red blood cell counts was observed in rats exposed for 4 h to increasing concentrations of the following airborne irritants: acetic acid, benzyl chloride, 1,2-dichlorobenzene, ethyl acetate, ethyl acrylate, formaldehyde, isophorone, mesityl oxide, phenol, styrene, toluene diisocyanate and vinyl toluene. This effect was abolished by adrenalectomy. Vinyl toluene and 1,2-dichlorobenzene induced leucopenia at levels as low as their current occupational standards of 50 ppm. With the exception of 1,2-dichlorobenzene, the tested compounds caused leucopenia only when exposure reached the irritant level. It is discussed that stress associated with the irritative effect of chemicals can confound specific haematological effects.

Nasal irritation and pulmonary toxicity of aliphatic amines in mice.

The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 15-min oronasal exposure to increasing concentrations of twenty aliphatic amines. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each test compound. Moreover, eight out of the twenty amines were tested for pulmonary toxicity in mice and for the effects of a 120-min exposure on the respiratory rates of non-anaesthetized, tracheally cannulated mice (RD50TC). Both allylamine and diallylamine showed RD50 values of 9 ppm and 4 ppm, respectively, while the RD50 values associated with exposure to saturated amines ranged from 50 to 200 ppm. Among the eight amines tested for both upper airway irritation and pulmonary toxicity, diisopropylamine and di-n-butylamine showed a RD50TC/RD50 ratio of less than 1, indicating that the respiratory toxicity induced by these two amines would be related primarily to pulmonary effects. On the basis of prior predictions proposed for upper airway irritants, tentative standards are given for ten amines. Moreover, it is suggested that the basis of standards for industrial exposure to diisopropylamine and di-n-butylamine should be specified.

Acetone compared to other ketones in modifying the hepatotoxicity of inhaled 1,2-dichlorobenzene in rats and mice.

The ability of acetone and 3 other ketone vapours to influence the hepatotoxicity of inhaled 1,2-dichlorobenzene (DCB) was examined in rats and mice. Methylethylketone, methylisobutylketone or cyclohexanone increased liver cytochrome P-450 content and glutathione-S-transferase (GST) activity, but did not affect serum glutamate dehydrogenase (GLDH) activity in rats. Pre-exposure to these ketones enhanced DCB-induced increase in serum GLDH activity (8-63-fold), while the increases in cytochrome P-450 content (33-86%) and GST activity (42-64%) were identical to those resulting from exposure to ketones alone. Each of the 3 levels of exposure to acetone elicited cytochrome P-450 and GST responses comparable with those caused by the other ketones. In spite of that, acetone pre-exposure potentiated (4785 ppm), reduced (10670 ppm) or suppressed (14790 ppm) DCB-induced liver toxicity. In mice, the 3 ketones mentioned above interacted with DCB on centrolobular liver glucose-6-phosphatase (G-6-Pase) while acetone pre-exposure elicited an interactive G-6-Pase response in the mediolobular area alone, suggesting topographic change.

Inhalation teratology study on hexachloro-1,3-butadiene in rats.

Pregnant rats were exposed to 0, 2, 5, 10 or 15 ppm hexachloro-1,3-butadiene (HCBD) 6 h/d during days 6-20 of gestation. Maternal reproduction and fetal parameters were evaluated on gestational day 21. A significant reduction in maternal weight gain and in fetal body weight occurred at 15 ppm. The incidences of external, visceral and skeletal alterations were not significantly increased in any of the HCBD-exposed groups. It is concluded that exposure of pregnant rats to HCBD by inhalation of concentrations high enough to cause maternal and slight fetal toxicity is neither embryotoxic nor teratogenic.

Concentration-related changes in blood and tissue parameters of hepatotoxicity and their interdependence in rats exposed to bromobenzene and 1,2-dichlorobenzene.

Liver damage resulting from 4 h exposure to bromobenzene (BB) (146-957 ppm) and 1,2-dichlorobenzene (DCB) (245-739 ppm) as model toxicants was evaluated in rats. The modifications considered were the increases in serum glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities and the decreases in centrolobular liver-cell glucose-6-phosphatase (G6-Pase) staining intensity. A linear inverse relationship was established between the logarithmic values of blood enzyme activities and liver G6-Pase staining intensity. In addition, the levels of exposure to each test chemical were found to be linearly related to liver G6-Pase staining intensity and to the logarithmic values of blood enzyme activities.

Quantitative evaluation of sensory irritating and neurobehavioural properties of aliphatic ketones in mice.

A decrease in respiratory rate resulting from irritation of upper airways and a decrease in duration of immobility in a 'behavioural despair' swimming test occurred in mice during and following short-term inhalation exposures to some commonly used aliphatic ketones. Linear concentration-effect relationships were obtained that allowed two different median active levels (MALs) to be calculated. MALs that produced a 50% decrease in respiratory rate (RD50) were calculated as indicators of the sensory irritation potency of diisobutyl ketone, mesityl oxide, methyl amyl ketone, methyl isoamyl ketone and methyl propyl ketone. MALs that produced a 50% decrease in immobility (ID50) were determined for acetone, isophorone, mesityl oxide, methyl amyl ketone, methyl isoamyl ketone, methyl isobutyl ketone and methyl propyl ketone. The systematic determination of MALs permits classification of ketones in terms of their relative potencies for eliciting a given effect. The lowest MAL indicates the primary manifestation of toxicity, against which protection should be taken. MALs associated with such critical responses may be useful in the establishment of safe levels of occupational exposure to ketones, a conclusion supported by the linear relationship that was found to exist between MALs and occupational standards.

Short-term inhalation test for evaluating industrial hepatotoxicants in rats.

Liver damage was investigated in rat using serum enzyme activities measurements. Responses were recorded 24 h after whole body inhalation exposure to vapors of bromobenzene, carbon tetrachloride, chloroform, o-dichlorobenzene, 1,2-dichloroethane and dimethylformamide as model toxicants. First, rats were exposed during a single 4 h period to different concentrations of each solvent and the minimally active concentration was determined. Second, repeated exposures to chemicals at this concentration level (6 h daily, 2 or 4 days) were used in order to examine whether hepatotoxicity was enhanced. GLDH and SDH are more sensitive and more constant indices than GOT and GPT. It appears that a single exposure period induced more marked serum activities enhancement than repeated exposures.

Concentration-dependent behavioral changes in mice following short-term inhalation exposure to various industrial solvents.

Mice were exposed during a 4-hr period to various concentrations of 13 aliphatic or aromatic solvents which affect primarily the central nervous system (CNS). The test compounds were benzyl chloride, butyl alcohol, chlorobenzene, cyclohexanone, 1,2-dichloroethylene, diisobutyl ketone, isopropyl acetate, methyl ethyl ketone, styrene, tetrachloroethylene, 1,1,1-trichloroethane, toluene, and ortho-xylene. After exposure, measurements were made to see whether these neurotoxicants would decrease the immobility developed in a "behavioral despair" swimming test. Each chemical was shown to reduce the total duration of immobility measured over a 3-min period in a concentration-related manner. The systematic determination of the atmospheric concentrations responsible for a 50% decrease in immobility (ID50) permitted classification of the solvents in terms of their relative potencies. The possibility of using such experimental data as tentative guidelines for setting safe levels of work exposure to the neurotoxicants was suggested, considering the existence of quantitative relationships between the ID50 values and the current occupational standards.

Sensory irritation caused by various industrial airborne chemicals.

A short inhalation experiment was performed on mice using 22 industrial airborne irritants. The parameter chosen as an index of sensory irritation was the reflex decrease in respiratory rate. For each compound, systematic determination of the concentration associated with a 50% decrease in the respiratory rate (RD50) permitted, on the basis of the same end point, a comparison of their relative potencies. The possibility of using the obtained data as initial guidelines to establish acceptable Threshold Limit Values (TLVs) in the workplace was examined.

[Interaction between benzene and toluene in long term inhalation exposure in rats (author's transl)]. / Etude toxicologique chronique par inhalation chez le rat de l'association benzène - toluène.

Industrial chemicals are seldom used as pure substances; hazards resulting from exposure to mixtures have, however not been solved. Our study deals with chronic inhalation toxicity of a mixture of benzene and toluene; few studies have been completed on this subject. Our results show: - leucopenia with benzene alone, at a concentration of 50 p.p.m., that is not detectable in the presence of toluene; - metabolic variations consisting in: a decrease in the phenol urinary rate versus time with benzene alone; a sharp decrease of this rate from the third month of exposure on, in presence of toluene.