Effect of four‐week repeated inhalation exposure to unconjugated azodicarbonamide on specific and non‐specific airway sensitivity of the guinea pig

Gerlach, Robert F.; Medinsky, Michele A.; Hobbs, C.H.; Bice, David E.; Bechtold, William E.; Cheng, Yung‐Sung; Gillett, Nancy A.; Birnbaum, Linda S.; Mauderly, Joe L.

doi:10.1002/jat.2550090303

Cited by 13 publications

(6 citation statements)

References 25 publications

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“…tions used in the studies reported here (i.e., 100 and 200 mg/m3) suggests that the lung lesions in rats are not related to ADA exposure. In addition, two recent studies of acute and repeated inhalation exposure to ADA in guinea pigs did not report any evidence of airway irritation (Shopp, 1987) or a potential for sensitization to ADA (Gerlach et al, 1989). Pyelonephritis, renal tubular concretions, and intratubular renal crystals were noted after subchronic exposure of rats and mice to ADA by gavage, at levels of 2.5 g/kg body wt or greater per day.…”

Section: Discussionmentioning

confidence: 89%

“…No lesions were noted in respiratory tract tissue of animals euthanized immediately after exposure or 24 hr later. Repeated exposure of guinea pigs to 51 or 200 mg ADA/m3 for 4 weeks did not result in either specific or nonspecific airway sensitization on inhalation challenge with ADA or aerosolized histamine, respectively (Gerlach et al, 1989). The objective of the studies reported here was to describe the toxic effects in rats and mice of inhalation exposure for 2 or 13 weeks to airborne concentrations of ADA as high as 200 mg/m3.…”

mentioning

confidence: 96%

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Effect of inhaled azodicarbonamide on F344/N rats and B6C3F1 mice with 2-week and 13-week inhalation exposures*1

Medinsky

Bechtold

Birnbaum

et al. 1990

Fundamental and Applied Toxicology

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Azodicarbonamide (ADA), a compound used in the baking and plastics industries, has been reported to cause pulmonary sensitization and dermatitis in people. Two-week repeated and 13-week subchronic inhalation exposures of F344/N rats and B6C3F1 mice to ADA were conducted to determine the toxicity of inhaled ADA. The mean air concentrations of ADA in the 2-week studies were 207, 102, 52, 9.4, or 2.0 mg/m3. No exposure-related mortality nor abnormal clinical signs were observed in rats or mice during or after exposure. The terminal body weights were slightly depressed in the highest exposure group. Liver weights were lower in male rats exposed to 200 mg ADA/m3. No significant lesions were noted on either gross or histologic evaluation of rats or mice. In the 13-week subchronic study, the mean air concentrations of ADA were 204, 100, or 50 mg/m3. No mortality or clinical signs related to exposure were observed. The terminal body weights of exposed rats were not significantly different from those of control rats but were significantly depressed in mice exposed to 100 or 200 mg ADA/m3. No histopathological lesions were noted in mice. Lung weights were increased and enlarged mediastinal and/or tracheobronchial lymph nodes were noted in rats exposed to 50 mg ADA/m3. No exposure-related lesions were observed microscopically in rats exposed to 100 or 200 mg ADA/m3. All rats in the 50 mg ADA/m3 exposure group only had lung lesions that consisted of perivascular cuffing with lymphocytes and a multifocal type II cell hyperplasia, suggesting a possible immune reaction to an antigen in the lung. Viral titers for rats exposed to 50 mg ADA/m3 were negative for Sendai virus and pneumonia virus of mice, which produce similar lesions. The possibility of an unknown viral antigen causing this lesion cannot be eliminated. Lung tissue from male rats was analyzed for ADA and biurea, the major metabolite of ADA. No ADA was detected. The amount of biurea in the lungs increased nonlinearly with increasing exposure concentration, suggesting that clearance was somewhat impaired with repeated exposures. However, even at the highest exposure concentration, this amount of biurea was less than 1% of the estimated total ADA deposited over the exposure period. In summary, ADA is rapidly cleared from the lungs, even when inhaled at concentrations up to 200 mg/m3. Exposure to ADA for up to 13 weeks did not appear to be toxic to rodents.

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 96%

Effect of inhaled azodicarbonamide on F344/N rats and B6C3F1 mice with 2-week and 13-week inhalation exposures*1

Medinsky

Bechtold

Birnbaum

et al. 1990

Fundamental and Applied Toxicology

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“…It has been previously demonstrated that the values of SRaw, as measured by our system, are reasonably ac curate and reliable when compared with those mea sured by a pleural catheter technique [14,15]. There fore, it is proposed that our method mainly measures the changes in the lower airways, although the upper airways component may contribute in part.…”

Section: Discussionmentioning

confidence: 97%

“…Pulmonary function in unanesthetized guinea pigs was mea sured using a two-chambered, whole-body plethysmograph, which was described by Gcrlach et al [14] ( fig. 2).…”

Section: In Vivo Bronchoconstriction Experimentsmentioning

confidence: 99%

Attenuation of Antigen-Induced Bronchoconstriction in Guinea Pigs by a New Xanthine Derivative (HW A448)

Sugiyama¹,

Gang²,

Bergren³

et al. 1991

Int Arch Allergy Immunol

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We examined the effect of a new xanthine derivative, HWA448, on antigen-induced bronchoconstriction in actively sensitized guinea pigs. Guinea pigs were sensitized by intraperitoneal injection of bovine serum albumin (BSA) on two occasions, separated by 10 days. Two weeks after the second injection, the animal was placed in a two-chambered whole body plethysmograph and specific airway resistance (SRaw) was monitored for 10 min after an aerosol inhalation of BSA. HWA448 prevented the increase in SRaw after challenge (at 5 and 20 mg/kg i.p.). Aminophylline also prevented the increase in SRaw at 20 mg/kg, but not at a 5-mg/kg dose. The concentration of HWA448, which produced 50% relaxation of the tracheal rings constricted with 0.1 mM of histamine, was 49.9 μM as compared with 18.2 μM in aminophylline. HWA448 has a protective effect on antigen-induced bronchoconstriction in guinea pigs and may be a useful agent in the therapy of bronchial asthma.

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“…According to the authors, the observed erythematous reactions resulted from a foreign body reaction caused by azodicarbonamide. The exposure to azodicarbonamide by inhalation did not influence body weights or cause histopathological changes (Gerlach et al 1989). …”

Section: Sensitizing Effects On the Airwaysmentioning

confidence: 97%

Azodicarbonamide [MAK Value Documentation, 2017]

Hartwig

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated azodicarbonamide [123‐77‐3] to derive a maximum concentration at the workplace (MAK value), considering all toxicological endpoints. Available publications and unpublished study reports are described in detail. The critical effect is the occurrence of reactions in the airways in exposed workers. In the view of the Commission, the present inhalation studies in animals are not appropriate for the derivation of a MAK value as human airways are probably more sensitive than rodent airways. The workplace investigations show no clear correlation of exposure and frequency of respiratory symptoms. Nevertheless, from the NOAEC of 36 µg/m 3 for lung function measurements in a small group of injection‐molding workers in the plastics industry, a MAK value of 20 µg/m 3 I is established. Due to the incomplete information on the relevant exposure scenario and the uncertainty regarding first occurrence of workplace related symptoms, this value should be considered as preliminary. As local effects are critical, azodicarbonamide is assigned to Peak Limitation Category I and the default excursion factor of 1 is designated. Since developmental toxicity studies are not available, Pregnancy Risk Group D is assigned. There are no carcinogenicity studies and azodicarbonamide is not regarded as germ cell mutagen. Skin contact is not expected to contribute significantly to systemic toxicity. The metabolism of azodicarbonamide and its reactivity do not point to stable protein binding in vivo and therefore, skin or respiratory sensitization is unlikely. Clear‐cut clinical findings or positive results from animal studies on skin sensitization are not available, but the negative results in experimental animals are difficult to evaluate due to the low solubility of the compound. Although azodicarbonamide affects the respiratory tract in several case reports with positive bronchial provocation tests, sensitization by a known mechanism is not adequately verified. Additionally, it appears questionable whether a mono‐causal relationship of respiratory symptoms and azodicarbonamide exposure can really be assumed. In conclusion, a sensitizing effect of azodicarbonamide is not sufficiently proven. Completed: March 22, 2017

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Effect of four‐week repeated inhalation exposure to unconjugated azodicarbonamide on specific and non‐specific airway sensitivity of the guinea pig

Cited by 13 publications

References 25 publications

Effect of inhaled azodicarbonamide on F344/N rats and B6C3F1 mice with 2-week and 13-week inhalation exposures*1

Effect of inhaled azodicarbonamide on F344/N rats and B6C3F1 mice with 2-week and 13-week inhalation exposures*1

Attenuation of Antigen-Induced Bronchoconstriction in Guinea Pigs by a New Xanthine Derivative (HW A448)

Azodicarbonamide [MAK Value Documentation, 2017]

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