Hexamethyidisiloxane: A 13-week subchronic whole-body vapor inhalation toxicity study in Fischer 344 rats.

Hexamethyldisiloxane (HMDS) is a volatile linear siloxane dimer used in many applications, including precision cleaning, active ingredient carrier, and as a manufacturing intermediate. The purpose of this study was to characterize the subchronic vapor inhalation toxicity of the material as part of a comprehensive toxicology program. Groups of 20 male and 20 female Fischer 344 (F344) rats were exposed to nominal (and mean actual) vapor concentrations of 0, 50 (50), 200 (194), 600 (593), 1,500 (1,509) and 5,000 (5,012) ppm of HMDS, 6 hours per day, 5 days per week, for 13 weeks. No treatment-related signs of clinical toxicity or mortality, statistically significant effects upon body weight gain or food consumption, ophthalmoscopic changes, gross macroscopic necropsy findings, or organ weight changes were noted. Minor hematological, clinical biochemical, and urinalysis changes were seen but were not considered to be of toxicological relevance. Histological lesions in the kidney apparently consistent with male rat-specific alpha-2-urinary globulin nephropathy were observed in male rats exposed to 593, 1,509, and 5,012 ppm of HMDS, accompanied by slightly increased plasma urea and creatinine concentrations. No other treatment-related histological changes were seen in HMDS-exposed rats.

HFA-134a (1,1,1,2-tetrafluoroethane); lack of oncogenicity in rodents after inhalation.

1. Groups of 60 male and 60 female B6C3F1 mice or HanIbm Wistar rats were exposed to HFA-134a using snout-only inhalation exposure techniques for periods of one hour daily for at least 104 weeks. HFA-134a was delivered directly from cylinders at vapour concentrations of 2500, 15,000 and 75,000ppm for mice and from metered-dose inhalers at vapour concentrations of 2500, 10,000 and 50,000ppm for rats. 2. Intended dosages were achieved. 3. Evidence of absorption was found at each dose level and was dose related. 4. Neither species suffered treatment related effects on survival, clinical signs, body weights, haematology nor on the type, incidence, site or severity of gross lesions. 5. There was no effect of treatment on the type, incidence, site or severity of neoplasms in mice or rats. 6. There were no non-neoplastic findings related to treatment in mice. 7. HFA-134a was considered not to be oncogenic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhalers.

[Experimental investigations on the tumorigenic activity of cigarette smoke condensate on mouse skin. VII. Comparative studies of condensates from different modified cigarettes (author's transl)]. / Experimentelle Untersuchungen über die tumorerzeugende Wirkung von Zigarettenrauch-Kondensaten an der Mäusehaut. VII. Einzelvergleiche von Kondensaten verschiedener modifizierter Zigaretten.

Condensate from different modified cigarettes were compared with condensate from a standard cigarette with regard to its tumorigenic activity on mouse skin. Significant lower effects were observed in test series with cigarettes from expanded tobacco. Different results were obtained in experiments with cigarettes from the new smoking materials. In one case the effect was higher, in two another cases the effect was lower in comparison to the effect of condensate from reference cigarettes. A certain influence may be referred to the diameter of the cigarette, i.e. a thinner cigarette shows a lower biological effect. The lowest tumoringenic effect was observed in tests with cigarettes with a high content of Burley-stems.

[Effect of nicotine in pigs (author's transl)]. / Die Wirkung von Nikotin beim Schwein

18 pigs in which venous catheters were positioned for long-term use were injected with nicotine in physiological saline: group 1: 1 mg without anaesthesia; group 2: 1 mg/animal, Hypnodil-anaesthesia; group 3: 0.0143 mg/kg body weight, Hypnodil-anaesthesia. The dose of 1 mg is corresponding to that amount of nicotine contained in the main smoke of a commercially used cigarette. The dose of 0.143 mg/kg body weight is calculated per 1 kg body weight assuming that a man of 70 kg body weight resorbes the total amount of nicotine (1 mg) after maximum inhalation. Application of 1 mg induced the following alterations: sino-auricular block, AV-block of first and second degree, asystolia up to 2 seconds, short decrease in blood pressure and bradycardia as well as flattening and/or inversion and biphasic reaction of T. A longer lasting increase in blood pressure was observed in non-anaesthesized animals. Animals treated with 0.0143 mg/kg body weight showed AV-block of first degree with subsequent extrasystoles. Blood pressure, heart rate and T-wave showed no alterations. Decisive for the induction and extent of acute disturbances seems to be the dose of nicotine. Therefore, a decrease of the nicotine content seems to be indicated toward a "less harmful cigarette".

[Experimental studies on tumorigenic activity of cigarette smoke condensate on mouse skin. V. Comparative studies of condensates from different modified cigarettes (author's transl)]. / Experimentelle Untersuchungen über die tumorerzeugende Wirkung von Zigarettenrauch-Kondensaten an der Mäusehaut. V. Mitteilung: Einzelvergleiche von Kondensaten verschiedener modifizierter Zigaretten

The tumorigenic effect of smoke condensates from reference cigarettes and different modified cigarettes has been investigated on the mouse skin. The following results have been obtained: 1. Reconstituted tobacco sheets made from the blend of the reference cigarette T as well as different other tobacco mixtures showed a reduced tumorigenic effect. 50% or 20% of reconstituted tobacco sheets as additive to the tobacco T showed reduced tumorigenic effect too. 2. A dark tobacco mixture (cigar type) as well as the Virginia tobacco of the mixture T showed no significant differences in biological activity compared to the reference tobacco. Condensate of the Burley tobacco of the blend T showed a reduced tumorigenic effect. 3. A small amount of nitrate as additive (1.8% total nitrate) only showed a limited reduction of the tumorigenic effect. 4. Condensate of a cigarette with commercially used filters, 20% reconstituted tobacco sheets and a total nitrate content of 1.8% showed a distinctly reduced tumorigenic effect. 5. Statistical evaluations of this experiment indicated that each of the applied dose should not be too high. Application of high doses did not lead to a further increase of tumor incidence. Cytotoxicity and viscosity of higher concentrated solutions may be responsible for this fact.

[Experimental studies on the rumorigenic activity of cigarette smoke condensate on mouse skin. VI. Fractionation of cigarette smoke condensate (author's transl)]. / Experimentelle Untersuchungen über die tumorerzeugende Wirkung von Zigarettenrauch-Kondensaten an der Mäusehaut. VI. Mitteilung: Untersuchungen zur Fraktionierung von Zigarettenrauch-Kondensat

This experiment has been performed to clarify the question to which extent fractions containing polycyclic aromatic hydrocarbons (PAH) or other carcinogenic compounds are responsible for the biological activity of cigarette smoke condensate. With chromatographic procedures using organic gels it was possible to separate quantitatively polar compounds from the PAH-fraction and to obtain fraction IX representing 0.4% of the whole condensate. In this fraction the PAH were enriched 250fold. Significant losses of tumorigenic effects by this fractionation method could not be observed. This PAH-containing fraction showed 50% of activity compared with the overall activity of whole smoke condensate of a reference cigarette. A so-called PAH-free fraction showed with 7% of the overall activity of the whole smoke condensate a weak carcinogenic effect. The importance of PAH for the tumorigenic effect of cigarette smoke is emphasized by these results.

Effect of high doses of nicotine in pigs. I. Changes of the electrocardiogram.

Pigs in which venous catheters were positioned for long-term use were injected i.v. with high doses of nicotine in physiol. saline. The LD50 was 2.656 mg/kg body weight. Clinical symptoms were mainly: forced respiration, muscular tremor to tetanoid spasms, cyanosis of the skin, salivation and sometimes vomiting. The degree and duration of symptoms were dose-dependent. Ecg changes in anaesthesized pigs following intravenous nicotine injections of 0.126 mg/kg and 0.378 mg/kg at 15 minutes' interval were immediately commencing disturbances of the heart rate in form of bradycardia and asystolia. After 5 sec we observed extrasystoles, tachycardia, sino-auricular block and AV-block of first and second degree as well as a number of T- and P-changes. Changes of the ecg were observed generally for 10 to 15 min, however, the T-wave remained sometimes negative or biphasic-preterminal negative for some hours.

Uptake of carbon monoxide in blood of miniture pigs and other mammals.

Different affinities of blood for CO were observed in in vivo and in vitro experiments. Hamsters showed the greatest relative affinity (1.0), the corresponding value for rats was 0.8, for pigs 0.74 and for rabbits 0.58. The upward shift of the saturation curves was dependent on the rate of respiratory exchange per unit of body weight, e.g. the curves were less steep for pigs than for rabbits. After increased motor activity the equilibrium saturation of CO in blood is reached more rapidly. From the results of in vitro experiments the following affinity constants for the blood of different species could be calculated: pig K = 130, hamster K = 181, rat I = 141, rabbit K = 109. For equal atmospheric CO concentrations the saturation values were lower (37-40%) in experiments in vitro than in vivo. Similar saturation values were obtained with light excluded, when O2 concentration was decreased to the level of alveolar oxygen concentration. With regard to the affinity of blood for CO, the blood of domestic pigs did not differ from that of minature pigs in in vitro experiments.