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The 2013 Seminar on Environmental Management of New Chemical Substances was held by the Working Committee on Collaboration & Promotion of Industry, College and Institute supported by the Chinese Chemical Society on September 26th and 27th. In attendance were numerous renowned industry representatives, test agencies and interested stakeholders. Issues relating to new chemical notification and environmental management over the past 10 years were discussed. Participants also engaged in constructive dialogue with CRC-MEP staff that provided crucial information relating to compliance with toxicological requirements.
1. Toxicokinetic Test
Numerous attendees voiced concerns over issues relating to the costs associated with animal testing and the excessive duration required to conduct these tests. Industry stakeholders almost unilaterally advocated the implementation of alternatives to compulsory animal testing in favor of the use of in vitro alternative methods or other non-animal testing methods where sufficient information to substantiate minimal hazard was available. It was proposed that if a substance assessed under a battery of supporting toxicological tests proved relatively safe, then the toxicokinetic test shouldn’t be necessary. Additionally, reference data relating to exposure information or the notified use taken from EU REACH was also suggested as a viable alternative.
Attitude of Toxicological Experts from the Review Committee:
Use qualitative justification instead of toxicokinetic test?
Toxicological experts responded to the industry concerns but stuck firmly to the continued implementation of mandatory toxicokinetic testing. To elucidate the rationale behind these decisions, experts explained that it was not adequate to infer toxicokinetic properties from other toxicological endpoints. Toxicokinetic data provides the truest reflection of in vivo chemical dynamics and is an important tool to understand the absorption, distribution, metabolism, excretion (ADME) of chemicals.
Use QSAR models instead of toxicokinetic test?
QSAR models relating to ADME can be used as initial screening tools but are generally more suited to pharmacokinetic studies and drug discovery. The purpose of toxicokinetics in assessing new chemicals is to further explain the potential for adverse effects demonstrated in other toxicological tests, or provide a basis for more advanced testing or risk assessment. Hence, the existing QSAR models couldn’t completely substitute a full-scale toxicokinetic test.
Use in vitro alternative test instead of toxicokinetic test?
Currently the battery of approved in vitro tests is not adequate to fully assess toxicokinetics. At present only the skin absorption in vitro model is accepted by OECD. However, in vitro methods are applicable, reliable, and scientific, so if better alternative methods are validated, it is reasonable to expect them to be a viable alternative or adjunct to animal testing. From a regulatory perspective, toxicokinetic data is useful for the judgment and interpretation of other toxicological endpoints and also helpful for the application of risk assessment. Thus, the toxicokinetic test is needed when submitting the registration materials with the tonnage in excess of 10 t/a.
Reach24H Recommendations:
Toxicokinetics are comparable to other animal tests with long test cycles and high testing cost, i.e. chronic toxicity test, carcinogenicity test. It is our suggestion that the updated guidance would further consider the exposure information and notified uses of the test substance as qualifying condition of toxicokinetics. (Less than 10 uses are recommended, as too many uses would bring about extra management costs of the authority)
For second tier regular notification (10-100 t/a), only absorption data is required. We suggest to consider in vitro alternative method and (or) the qualitative justification of absorption properties derived from subacute or subchronic toxicity test.
2. Mutagenic Test and Classification
Several participants raised the same question as to why in vitro testing is still required if in vivo mutagenic test are already conducted. The toxicological experts indicated if only in vivo testing was implemented, it would be hard to comprehensively evaluate the mutagenic properties of the test substance as mutagenicity includes both gene mutation and chromosomal aberrations. To fully appreciate the mutagenic properties of a substance, it is necessary to conduct multiple tests, which is the standard operating protocols adopted by the US EPA, OECD etc.
Moreover, the registrants need to understand in vitro tests are not necessarily less time consuming than in vivo testing for mutagenicity testing, e.g. Ames test. If an Ames test gives a positive result, it indicates a mutagenicity probability of more than 50%. Crane Ji, Ph. D. from Huntsman made an excellent speech advocating genetic testing and germ cell mutagenic classification. He focused on how to further carry out subsequent testing after initial screening tests are complete and methodologies to ensure proper classification. He also emphasized a step by step test strategy to assess whether the substance has germ cell mutagenicity. He followed up by explaining that in cases where Ames test delivers positive results, it is sensible to carry out the further testing, in order to eliminate chances of false positives.
Ames tests which deliver positive results require further testing and increase both time and monetary costs for registrants. We suggest that in case of an Ames test with a positive result, in addition to conducting further testing, it is also necessary to assess the metabolic pathways involved and ensure it is not a species specific pathway with no significance for humans. In this instance, the weight of an Ames test with a positive result would be greatly decreased in significance and bearing on classification.
3. Qualifying Criteria for Regulatory Exemptions Need to be Clearly Defined
Attendees also voiced concerns over the lack of information relating to regulatory exemptions and asked for more detailed qualifying criteria instead of the current qualitative description of exemptions of toxicological endpoints, such as “difficult to penetrate the skin barrier” in the acute dermal toxicity, “the inhaled particle size distribution less than 1%” in the acute inhalation toxicity, “very low (No Observed Adverse Effect Level) value” in 28d repeated toxicity, “very high NOAEL value” in chronic toxicity.
Experts however responded with no definite answer that whilst these issues were currently under consideration, no such standard can be given in short time based on the current knowledge and experience accumulated.
Our suggestion is to present a rationale for any qualitative judgments made, citing as many supporting sources as possible, including but not limited to other countries’ registration guidance, research papers, journals, etc.
This workshop provided an important opportunity for dialogue between industry stakeholders and regulators. It provided policymakers insight into the practical problems encountered by industry and afforded industry an opportunity to challenge the decisions of policymakers.
