On 30 Sep 2017, the Chinese Ministry of Agricultures issued Announcement 2586, “Guideline for the Establishment of Acute Reference Dose (ARfd)”. The guideline will serve as the technical basis for MRL establishment and dietary risk assessment of pesticides in China.
The guideline provides the precondition, procedure and parameter selection for the calculation of pesticide acute reference dose, which goes through three stages:
1. Determination of NOAEL (no-observed-adverse- effect level) or BMDL (benchmark dose). The researcher should take comprehensive evaluation of all toxicological characteristics and then identify the most sensitive acute toxicological endpoints on the most susceptible test animals. Specifically, an experiment based on these endpoints and animals will be performed for the determination of NOAEL. If there is suitable dose-response model or the NOAEL is indeterminable, or the long-term exposure value is fairly close to ADI (acceptable daily intake), BMDL can be utilized to replace the NOAEL for ARfD determination.
2. Selection of UF (uncertainty factor). UF can be multiplied or reduced from the starting value of 100, depending on the inter and intra species differences when extrapolating NOAEL from test animal to human and that from general population to susceptible population, the differences between toxicokinetics to toxico-dynamics characteristics, the quality and reliability of toxicological data and specificity of different adverse effects. The maximum uptake value of UF is 10000 and the condition and ratio for the multiplication are also specified.
3. The ARfD can be obtained by dividing the NOAEL by the UF: ARfD =NOAEL/UF or ARfD =BMDL/UF
The guideline also outlines particular features for ARfD establishment:
A pesticide active ingredient can be established with more than one ARfD if the risk to specific population was taken into account;
If a pesticide metabolite was designated as a residue ( defined as toxicologically significant derivatives present in food, agricultural produce and feed due to the uses of pesticide, including, but not limited to, pesticide active ingredient, by-product, metabolite, resultant and impurity ) or the metabolite was detected in human but not yet detected in animal metabolic study and the toxicological character was inconsistent with the parent compound(active ingredient), the establishment of ARfD should be based on the metabolite rather than the pesticide active ingredient .
If the ARfD obtained in accordance with the guideline was lower than the established ADI, it should be consider whether to revise the existing ADI. If the deduced ARfD is very conservative and the short term dietary risk assessment still suggests risky, specific toxicity study should be additional conducted to refine the ARfD;
ARfD, ADI, Pesticide Dietary Risk Assessment and Pesticide Registration
In 2012, China developed a guideline for ADI establishment, which follows similar concept and procedures. The utilization scenario and differences between ARfD and ADI were further explained the Announcement 2308-the “Guideline for the Risk Assessment of Pesticide in Food” and the” Guideline for the MRL Establishment of Pesticide in Food”. Both the ARfD and ADI are utilized for pesticide risk assessment and MRL establishment, but the ARfD is applicable to pesticide with acute effect, resulting different areas of concern during NOAEL determination and their final outcomes:
| Toxicological Endpoints Concerned for NOAEL Determination |
ADI | Mutagenicity, reproduction and developmental toxicity, carcinogenicity and neurotoxicity, etc. |
ARfD | Clinical signs, body weight change, changes of body weight, food and water intake, mortality, methemoglobinemia (caused by oxidative compounds converting heme iron to fe3+ instead of fe2+), neurotoxicity, teratogenicity and developmental toxicity |
To facilitate the long term dietary risk assessment and MRL establishment, China released a voluntary agricultrial standard, the “NY/T-28/4-2015 Pesticide Acceptable Daily Intake” at the end of 2015. A totally of 554 ADIs are suggested, of which 24 are temporary ones. However, the ADI and dietary/residue risk issues have continuously hindered the registration of novel active ingredients in recent years. In 2015, two full registration submitted by Nissan Chemical, Amisulbrom fungicide and Metazosulfuron herbicide were disapproved by the 20th and 21st National Expert Committee of Pesticide Registration. As an important part of China’s pesticide risk assessment system, dietary risk assessment report will be mandatorily required for registration of new active ingredient after the promulgation of new data requirement.
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