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Neurotoxicity

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Description of key information

The potential neurotoxicity of ethylbenzene has been thoroughly assessed in studies conducted in adult and developing animals. No adverse effects on neurodevelopment were observed in F1 parental or F2 offspring were observed.

Key value for chemical safety assessment

Additional information

The potential neurotoxicity of ethylbenzene has been thoroughly assessed in studies conducted in adult and developing animals.

 

In the section for repeated dose toxicity, studies specifically related to ototoxicity are described in detail. Furthermore, a 90-day oral gavage study on male and female rats specifically designed to detect neurotoxic effects (according to the EPA OPPTS 877.6200 guideline, similar to OECD 424) has already briefly been mentioned in this section (Li et al., 2010). In this study young adult animals received gavage doses twice daily at 0, 25, 125 and 250 mg/kg per dose (total daily dosages of 0, 50, 250 and 500 mg/kg bw/d) and a post-exposure recovery group was added to the control and high dose animals. Apart from general and detailed clinical observations, parameters specifically related to neurotoxicity included ophthalmology, neurobehavioural assessments (functional observational battery – FOB, motor activity) and a detailed histopathology of the eye, brain, spinal cord, hindlimb peripheral nerves, and muscle. No adverse findings indicative for neurotoxicity were observed up to the highest dose of 500 mg/kg bw/d.

 

The negative findings in this study specifically designed for neurotoxicity testing are corroborated by the results of standard repeated dose studies: no adverse effects were observed in brain, spinal cord, and sciatic nerve in the 2-year bioassay in rats and mice by inhalation up to 750 ppm (NTP, 1999), in the 13-week inhalation study in rats and mice up to 1000 ppm (NTP, 1992), or in the 13-week oral gavage study in rats at doses up to 750 mg/kg bw/d including organs such as liver, kideneys, adrenals, testes, epididymes, ovaries, uterus, spleen, brain, heart, thymus,

ophthalmology, FOB, and motor activity (Mellert et al., 2007).

 

In a developmental neurotoxicity study (DNT) possible neurotoxic effects on the developing organism were investigated (WIL Research Laboratories Inc., 2005; Faber et al., 2007. F1 females and F2 pups (male and female) from the 2-generation study (Faber et al., 2006) were used. The F1 animals were treated by gavage from lactation days 1-4 at dose levels up to 342 mg/kg bw/d and subsequently by direct inhalation at 0, 25, 100, and 500 ppm. F2 animals were indirectly exposed via their mothers in utero and during lactation. Parameters investigated corresponded to those of OECD guideline 426.

In F1 animals: FOB.

In F2 animals: developmental landmarks, neurobehavioral evaluations (with FOB, locomotor activity, acoustic startle response, learning and memory in the water maze), and detailed investigations of the brain (weight, neurohistopathology, morphometry).

No adverse effects on neurodevelopment were observed in F1 parental or F2 offspring were observed.

The following information is taken into account for any hazard/risk assessment:

The potential neurotoxicity of ethylbenzene has been thoroughly assessed in studies conducted in adult and developing animals. No adverse effects on neurodevelopment were observed in F1 parental and F2 offspring were observed.

Justification for classification or non-classification

Based on the absence of behavioral or morphological changes indicative of specific, persistant, or progressive action on the nervous system in standard neurotoxicity studies of adult and developing animals, no classification of ethylbenzene for nervous system effects is warranted. (See repeated exposure toxicity section for recommended classification for auditory effects).

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