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Mode of Action Analysis / Human Relevance Framework

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Subchronic toxicity feeding studies for mineral paraffin oils conducted with Fischer-344 (F-344) rats reported toxicity effects occured in the liver and mesenteric lymph nodes and characterised by increased organ weights, microscopic inflammatory changes (microgranulomas) and presence of saturated mineral hydrocarbons in affected tissues. In general, the type of toxicity effects seen in F344 rats is associated with strain-specific essentially reactions to a foreign body (i.e. presense of unchanged mineral hydrocarbons in the tissues).

 

Repeated dose toxicity studies in animals exposed to Mineral Paraffin Oil via inhalation report similar results being concentration-related accumulation of alveolar macrophages with oil droplets in the lung. Exposure to high aerosol concentrations result in inflammatory responces (lipid pneumonia) to the presence of deposited aerosols.

 

Mineral oil-based products did not cause any mortality or clinical signs of toxicity when tested in rats via skin exposure at concentration of 2000 mg/kg bw. From the data on toxicokinetics, long carbon chain aliphatic hydrocarbons of petroleum origin have only limited absorption, including dermal exposure. Thus, molecules with carbon chain of 30 (and greater) cannot be absorbed through the skin.

 

The only toxicity effect that can be associated with long-term skin exposure to mineral oil is carcinogenicity, which is mostly attributed to the presence of PAH. This will be discussed in section 5.8 for carcinogenicity.

 

The lipogranulomas associated with exposure to mineral hydrocarbons (Mineral Paraffin Oils) have also been observed in human tissues. However, these findings are generally considered as clinically unimportant and described as benign lesions that contain mineral oil droplets, without evidence of inflammation, fibrosis or clinically significant organ dysfunction. 

 

The following systemic toxicity values were observed in animal studies:

 

Short-term Toxicity (up to 28 days/4 weeks exposure):

 

·       LOAEL (subacute, inhalation, Wistar rats) =500 mg/m3 (pulmonary effects, including slight accumulation of macrophages in the alveolar lumen and increase in total cells in lavage fluid.

 

Subchronic Exposure (up to 90 days/ 13 weeks):

 

·       LOAEL (subchronic, oral, F-344 female rats:) =2000 ppm (161 mg/kg bw/day) –changes in absolute and relative organ weights (liver and mesenteric lymph node); microscopic changes in liver and mesenteric lymph nodes (increased incidence of microgranuloma formation).

·       LOAEL (subchronic, oral, CRL:CD female rats) = 20000 ppm (1624 mg/kg bw/day) –slightly increased incidence of minimal multifocal chronic inflammation in liver.

·       LOAEL (subchronic, inhalation, Sprague-Dawley rats) = 150 mg/m3 (pulmonary effects).

 

Chronic Exposure (up to 24 months/2 years):

 

·       LOAEL (chronic, oral, F-344 rats) =25000 ppm (962 mg/kg bw/day –males; 1135 mg/kg bw/day –females) –microscopic changes (granulomatous inflammation in mesenteric lymph nodes).

·       LOAEL(chronic, inhalation, dogs) = 100 mg/m3 – histopathological changes in lungs (oil microgranulomas).

·       LOAEL (chronic, inhalation, rats)=100 mg/m3 - histopathological changes in lungs (oil microgranulomas).

·       NOEL (chronic, inhalation, rabbits) =100 mg/m3.

·       NOEL (chronic, inhalation, hamsters) =100 mg/m3.

·       NOEL (chronic, inhalation, mice) =100 mg/m3.

 

 

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