Commission Regulation (EU) 2018/782Show full title

II.6.4.2.2. Neurotoxicity, developmental neurotoxicity and delayed neurotoxicity U.K.

II.6.4.2.2.1. Neurotoxicity testing shall be required where repeated dose studies indicate that there may be a relevant concern. U.K.

II.6.4.2.2.2. Substances that have been shown in other toxicological assays to cause histological, biophysical or biochemical changes to the nervous system, or to cause neuro-behavioural changes, shall also be tested for neurotoxicity. Physicochemical properties, structure-activity information and recorded adverse effects in humans may give further indication on the need for neurotoxicity tests. U.K.

II.6.4.2.2.3. Neurotoxicity testing shall be performed using the oral route and shall follow the advice given in the Organisation for Economic Cooperation and Development (‘OECD’) Guidelines for the Testing of Chemicals — Test Guideline 424(1) on the methodology to be used in neurotoxicity studies in rodents. This study may be performed as a stand-alone study or may be incorporated in other repeated dose toxicity studies. U.K.

II.6.4.2.2.4. Although OECD Test Guideline 424 does not specifically address effects on the activity of acetylcholinesterase, this end point shall be included in all repeated dose toxicity studies for specific substances known or suspected to have such activity (for example, organophosphates or carbamates). Testing for cholinesterase inhibition shall at least include measurements in brain and erythrocytes. U.K.

II.6.4.2.2.5. If a substance has been shown to cause neuropathology or neurotoxicity in adults, or cause other types of toxicity indicative of nervous system involvement at a developmental stage, developmental neurotoxicity testing may be considered necessary. In such a case, OECD Test Guideline 426(2) which advises on the methodology to be used in developmental neurotoxicity studies shall be followed. The extended one generation reproductive toxicity study (OECD Test Guideline 443(3)) also provides for developmental neurotoxicity testing. U.K.

II.6.4.2.2.6. Organophosphates shall be tested for delayed neurotoxicity in a hen assay that incorporates measurement of neuropathy target esterase (‘NTE’) in brain tissue. Both single exposure (OECD Test Guideline 418(4)) and repeated exposure (OECD Test Guideline 419(5)) shall be considered. While single dose studies performed according to OECD Test Guideline 418 may only allow identification of a delayed neurotoxicity effect, repeated dose studies (OECD Test Guideline 419) may allow identification of a NO(A)EL or BMDL. U.K.

II.6.4.2.2.7. The neurotoxicity studies shall allow the establishment of NO(A)ELs or LO(A)ELs or BMDL which shall be taken into account when determining the toxicological ADI or alternative limit. U.K.

(1)

OECD Test No 424: Neurotoxicity Study in Rodents (http://www.oecd-ilibrary.org/environment/test-no-424-neurotoxicity-study-in-rodents_9789264071025-en).

(2)

OECD Test No 426: Developmental Neurotoxicity Study (http://www.oecd-ilibrary.org/environment/test-no-426-developmental-neurotoxicity-study_9789264067394-en)

(3)

OECD Test No 443: Extended One-Generation Reproductive Toxicity Study (http://www.oecd-ilibrary.org/environment/test-no-443-extended-one-generation-reproductive-toxicity-study_9789264185371-en).

(4)

OECD Test No 418: Delayed Neurotoxicity of Organophosphorus Substances Following Acute Exposure (http://www.oecd-ilibrary.org/environment/test-no-418-delayed-neurotoxicity-of-organophosphorus-substances-following-acute-exposure_9789264070905-en).

(5)

OECD Test No 419: Delayed Neurotoxicity of Organophosphorus Substances: 28-day Repeated Dose Study (http://www.oecd-ilibrary.org/environment/test-no-419-delayed-neurotoxicity-of-organophosphorus-substances-28-day-repeated-dose-study_9789264070929-en).