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2.8. Reproductive toxicity 2.8.1. Human data February 2010 European Commission Employment, Social Affairs and Inclusion <strong>Recommendation</strong> <strong>from</strong> <strong>the</strong> <strong>Scientific</strong> <strong>Committee</strong> on Occupational Exposure Limits for diacetyl No human data are available on <strong>the</strong> reproductive or developmental toxicity of diacetyl. 2.8.2. Animal data Fertility No specific investigations of effects on fertility in animals are available in <strong>the</strong> open literature Developmental toxicity Groups of 25-27 Syrian golden hamsters, 21-24 CD-1 mice, and 21-23 albino Wistar rats were given a solution containing 90% diacetyl by gavage on days 6-10 of gestation for hamsters and days 6-15 of gestation for mice and rats. The doses for all species were 16, 74, 345, or 1600 mg/kg bw per day. No effects were seen on maternal survival, weight, or reproductive parameters or on fetal survival or macroscopic appearance of external, skeletal, or soft tissues (WHO, 1999). <strong>Recommendation</strong>s The OEL is recommended to protect <strong>the</strong> health of workers in manufacturing industry who may potentially be exposed to this chemical, implicated as an etiological agent in <strong>the</strong> development of bronchiolitis obliterans syndrome. SCOEL recognises that diacetyl may not be <strong>the</strong> only factor contributing to bronchiolitis obliterans syndrome, and that more data are needed on <strong>the</strong> exposures in manufacturing industry leading to this serious health condition and on animal models of <strong>the</strong> disease. It is evident <strong>from</strong> human data and <strong>from</strong> animal experiments that <strong>the</strong> critical target of diacetyl toxicity is <strong>the</strong> respiratory tract. Exposure to butter flavouring fumes during food manufacture has been associated with <strong>the</strong> development of respiratory disease, characterised by irreversible, fixed airways obstruction often accompanied by persistent dry cough and shortness of breath upon exertion. Several employees have been diagnosed with a serious condition known as bronchiolitis obliterans. Bronchiolitis obliterans is a condition characterised by <strong>the</strong> irreversible fixed airways obstruction caused by <strong>the</strong> narrowing of <strong>the</strong> bronchiolar lumen by submucosal fibrosis or fibrous tissue in <strong>the</strong> adventia or adjacent alveolar septa. The exact diagnosis of bronchiolitis obliterans is made histologically. When fixed airways obstruction occurs toge<strong>the</strong>r with demonstrated radiological changes, <strong>the</strong> diagnosis of bronchiolitis obliterans syndrome has recently come into use; in <strong>the</strong> absence of radiological changes, fixed airways obstruction is used. It has been argued that <strong>the</strong> association of diacetyl with bronchiolitis obliterans may not be causal. There are multiple chemical exposures in <strong>the</strong> food and flavourings industry, and few, if any, of <strong>the</strong> cases have been exposed only to diacetyl. In one popcorn plant (plant A in Appendix Table 2), a high frequency (5 of 13 workers, approximately 40%) of bronchiolitis obliterans syndrome was seen in <strong>the</strong> area with <strong>the</strong> highest exposure, <strong>the</strong> mixing room, where mean concentrations were about 30-40 ppm with peaks up to 1230 ppm (Kreiss et al.2000; Kullman et al. 2005; Kanwal et al. 2006). In o<strong>the</strong>r areas of <strong>the</strong> plant including <strong>the</strong> packing area, in o<strong>the</strong>r popcorn plants and in a factory producing diacetyl, with reported exposure levels of below 1 ppm to a few ppm diacetyl, 3-4 percent of <strong>the</strong> workers were identified to have <strong>the</strong> bronchiolitis obliterans syndrome. As <strong>the</strong> exposure concentration measured in <strong>the</strong> packing area of plant E (Appendix, Table 2) was considered more uniform and three cases of bronchiolitis obliterans were observed at 0.3 ppm (area sampling) and 0.6 ppm (personal sampling), this range can be considered as a reference point for <strong>the</strong> establishment of an OEL. O<strong>the</strong>r workers have developed obstructive and restrictive lung diseases at <strong>the</strong>se levels although <strong>the</strong> reliability of <strong>the</strong> reported exposure 12 12
February 2010 European Commission Employment, Social Affairs and Inclusion <strong>Recommendation</strong> <strong>from</strong> <strong>the</strong> <strong>Scientific</strong> <strong>Committee</strong> on Occupational Exposure Limits for diacetyl levels cannot be assessed, as <strong>the</strong> values could be 4 times higher or even an order of magnitude greater. Also, peak exposures in <strong>the</strong> past may have been higher. Exposure of mice to 100 ppm diacetyl (6 h/day, 12 weeks) caused moderate nasal injury, and peribronchial lymphocytic inflammation accompanied by epi<strong>the</strong>lial atrophy, denudation, and regeneration, while exposure to 50 ppm caused similar but less marked changes and exposure to 25 ppm produced minimal to mild inflammation in <strong>the</strong> nasal epi<strong>the</strong>lium. Since <strong>the</strong>se effects have been observed at much higher levels than in humans, <strong>the</strong> animals are considered to be much less sensitive to diacetyl than humans. Fur<strong>the</strong>rmore, SCOEL considered <strong>the</strong> available animal studies to be inappropriate to derive an OEL, since <strong>the</strong>re is no likely explanation for <strong>the</strong> differences observed among species. However, <strong>the</strong>y are supportive of <strong>the</strong> OEL based on human data recommended by <strong>the</strong> <strong>Committee</strong>. Diacetyl showed some genotoxic and mutagenic potential in vitro, and evidence of initiation/promotion activity was reported in rat stomach mucosa in vivo. A negative result was however obtained in an in vivo mouse micronucleus test at levels of up to 500 mg/kg bw. A single relatively short-term carcinogenicity study of limited validity provided equivocal evidence of carcinogenicity. SCOEL considers that, although more information on <strong>the</strong>se aspects would be useful and is recommended, <strong>the</strong> available data on genotoxicity and carcinogenicity of diacetyl are not sufficiently convincing to preclude establishment of an Occupational Exposure Limit for diacetyl. Considering <strong>the</strong> uncertainties in <strong>the</strong> available database on diacetyl and on exposure to butter flavourings, in particular regarding duration and extent of exposure and its correlation with <strong>the</strong> onset of respiratory disease, SCOEL recommends an OEL of 0.1 ppm for diacetyl. This OEL has been derived <strong>from</strong> <strong>the</strong> concentration range of 0.3 ppm (area sampling) and 0.6 ppm (personal sampling). Measurements difficulties are not foreseen at <strong>the</strong> proposed limit. 13 13
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