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Neurotoxicity

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Description of key information

Data on neurotoxicity in rodents are available. Effects on the hypothalamus, pituitary gland and adrenals as well as neuroimmunological effects were detected in mice at low exposure levels of ≥ 0.1 ppm in inhalation studies. In young rats learning and memory were impaired after repeated inhalation exposure to 0.1 ppm formaldehyde. Since these effects might be related to olfactory stress, (unrelated to systemic toxicity) the relevance of these results for humans is questionable. Mice and rats are macrosmatics and human are microsmatics.
Neuropathological effects in the limbic system of rats were described after repeated inhalation exposure to dose levels >= 6 ppm. In none of these studies (published by the same working group) was the likely degeneration of the olfactory epithelium investigated. Since the olfactory system has direct connection to the limbic system these effects are considered not to be systemic effects but secondary to local effects in the nasal cavity (site of 1st contact).

Key value for chemical safety assessment

Additional information

The study reported by Sari et al. (2004) meets scientific standards with acceptable restrictions (no details about the test substance, generation of formaldehyde gas and no histopathological assessment of the nose). Study is limited to effects on the hypothalamus, pituitary gland and adrenals (HPA axis). Final evaluation/conclusion is not possible since described effects might be related to effects on the central nervous system induced by olfactory excitation in mice (macrosmatic animals; not discussed by the authors); the relevance for humans is questionable. Ten female C3H/He mice per group were exposed to 0, 0.08, 0.4, 2 ppm formaldehyde 16 h/day, 5 days per week for 12 weeks. Differentiation in allergy model groups (AG; i.p. 10 μg ovalbumin plus 2 mg alum 5-6 h before the 1st inhalation exposure; i.p. injections on day 21, 42, 63, and 77 of treatment period) and non-allergy group (NAG). A major finding in this study is that the number of CRH (corticotropin-releasing hormone) neurons in the periventricular nucleus of the hypothalamus, the number of ACTH (adrenocorticotropin hormone) producing cells in the pituitary and the expression of ACTH-mRNA in the pituitary gland was dose dependently increased in mice not made allergic to ovalbumin (NAG mice). These results might indicate an enhanced activation of the HPA axis (hypothalamus-pituitary-adrenals) by inhalation exposure to formaldehyde, a chemical stressor. The second main finding is the data from AG mice which were sensitized by ovalbumin; sensitization was confirmed by IgE production (data not shown). All measured parameters were higher in AG mice compared with NAG control mice. But with increasing exposure levels of formaldehyde different responses were found. At the low exposure level of formaldehyde, the allergic reaction and formaldehyde may act in synergistic manner as the HPA axis counteracts (see measured parameters) to both stresses (allergy and formaldehyde). At the high dose level of 2 ppm formaldehyde, the measured parameters were reduced compared to the low dose group or the high dose group of NAG mice. The authors suggested that CRH (corticotropin-releasing hormone) neurons in the hypothalamus of high dose AG mice have an impaired synthesis and secretion of corticotropin-releasing hormone which may inhibit the ACTH cells in the pituitary. The CRH neurons could not increase in the number to mitigate the effects of allergy and formaldehyde stress. The toxicological relevance and clinical implications of effects at the low dose level of 80 ppb in NAG mice and in AG mice is questionable. The effect levels are similar to the exposure levels of formaldehyde measured for housewives in indoor environments which varied between 9 and 259 ppb (OECD, 2004). However, in mice the low dose might result at least in stress due to olfactory excitation. In contrast to humans (microsmatics) rodents like mice are macrosmatics; the odor threshold for formaldehyde is expected to be much lower in macrosmatics. The olfactory excitation in humans at a concentration of 0.08 ppm is much lower since little or no excitation is expected (50-percentile detection threshold in humans is 0.145 ppm; WHO 1989, EHC 89, p. 78). Thus and in the absence of similar human responses/data, stress induced alterations of the HPA axis described in this study are considered to be of limited toxicological relevance for humans. Systemic effects of formaldehyde in the hypothalamus or the pituitary gland are not likely since toxicokinetic data in inhalation studies contradict such effects in the brain (no systemic availability; see Summary and discussion of Section Toxicokinetics). Furthermore, the data presented in this study should be confirmed by independent experiments; the NOEL should be determined.

Conclusion: Results suggest altered HPA axis functioning at very low dose levels after repeated inhalation exposure in mice. The effects might be related to stress induced by olfactory excitation. The relevance for humans is questionable.

In a further study of this working group (Sari et al., 2005) similar results were obtained. The outcome of this study suggested altered HPA axis functioning at very low exposure levels after repeated formaldehyde inhalation exposure in mice which was not triggered by prior toluene inhalation exposure. The effects might be related to stress induced by olfactory excitation (not discussed by the authors). The relevance for humans is again questionable.

In male and female rats learning and memory (water labyrinth task) were impaired after repeated inhalation exposure to 0.1 ppm formaldehyde (2 h/day for 10 consecutive days; analytical dose levels: 0, 0.1+-0.02, 0.5+-0.1, and 5.4+-0.65 ppm). However, a clear dose dependency was not reported (Malek et al., 2003). As with above mentioned studies on neurotoxicity, these effects might be related to olfactory stress and the relevance for humans is questionable.

In the study of Aslan et al. (2006) neonatal male Wistar rats were exposed post natal day 1 -30 to 0, 6, or 12 ppm (0, 7.2, 14.4 mg/m³) for 6 h/day and 5 days per week. Five animals from each group were sacrificed on postnatal day (PND) 30, and 5 males on PND 90. Brains were processed for neuropathology and the Cavalieri principle of stereological approaches was used to determine the volume of the dentate gyrus (DG) in the brain sections. The optical fractionator counting method was used to estimate the total number of granule cells in the DG. The appearance of granule cells in DG was normal in all PND 30 and PND 90 groups. Rats treated with 12 ppm were found to have significantly fewer granule cells than either the animals treated with 6 ppm or the control group at PND 90 but not at PND 30. Conclusion: Decreased neuron number of dentate gyrus granule cells occurred after sub-acute exposure during post natal development. This study meets scientific standards but final conclusion is not possible. Neuroanatomical effects in the dentate gyrus might be secondary to local effects in the upper respiratory tract including olfactory epithelium. Histopathology of the nasal cavity was not performed but effects are expected at these exposure levels especially in rats exposed during post natal development. No data were given about clinical signs or body weight or analytical concentrations.

Justification for classification or non-classification

Based on all available data, classification as a neurotoxic substance is not triggered according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.