Ministry of Agriculture and Rural Affairs of the People's Republic of China

Date: 25-08-2012

Issued by MOA

In order to set technical basis for MRL establishment and risk assessment to human health, Ministry of Agriculture formulatedthe Guidelines for Developing ADIs on Pesticide. With approval of the Committee of National Pesticide Residue Standards Evaluation, it is hereby officially released.

　　

Annex: Guidelines for Developing ADIs on Pesticide

Annex:

Guidelines for Developing ADIs on Pesticide

I. Purpose and scope

In order to set technical basis for MRL establishment and risk assessment to human health, and guarantee agri-product quality & safety and the people’s health, Ministry of Agriculture formulatedthe Guidelines for Developing ADIs on Pesticide( the Guidelines).

The Guidelines apply to develop acceptable daily intake (ADI) for pesticide with threshold effect.

II. Terminology and Definitions

1.Acceptable daily intake (ADI)
An estimate of the amount of a substance that can be ingested on a daily basis over a lifetime without appreciable risk to health.It is usually expressed in mg/kg bw, milligrams (of the substance) per kilograms of body weight per day.

2. No-observed-adverse- effect level (NOAEL)
The highest concentration or amount of a substance, found by experiment or observation, which causes no detectable adverse alteration of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions.

3. Lowest-observed- adverse-effect level (LOAEL)
The lowest concentration or amount of a substance, found by experiment or observation, which causes an adverse alteration of morphology, functional capacity, growth, development, or life span of a target organism distinguishable from normal (control) organisms of the same species and strain under defined conditions of exposure.

4. Benchmark dose (BMD)
Derived from the dose-response curve, BMD is a dose that produces a predetermined change in response rate of an adverse effect (1%-10% in general) compared to background. In general, a 95% lower confidence limit on the dose at the BMD is applied and called benchmark dose lower confidence limit, BMDL.

5. Uncertainty factor (UF)
When establishing ADI for pesticide, there are uncertainties in extrapolating animal data to humans and uncertainties of database deficiencies. In order to address these uncertainties, a numeral value (equal to or greater than one) is used to divide NOAEL or LOAEL values derived from animal toxicity experimental data to estimate an ADI value for the whole human population, and thenumeral value is called uncertainty factor.

III. Procedures of establishing ADI for pesticide

1. Determining NOAEL or BMDL
Based on toxicological analysis and assessment that detect the most sensitive endpoint of the most sensitive animal, data evaluation and statistical analysis shall be conducted to give a NOAEL.

1.1 Comprehensive toxicological evaluation. Based on submitted registration information, comprehensive toxicological analysis and assessment shall be conducted to complete toxicological database. Attention shall be paid to special toxic effects like mutagenicity, reproductive and developmental toxicity, carcinogenicity, and neurotoxicity, etc. Besides registration information, reference data of other reliable sources shall be used, such as evaluation reports of developed countries and international organizations, and published documents and literatures, etc.

1.2 Determining sensitive endpoint. Usually, test data of chronic toxicity, carcinogenicity and two-generation reproductive toxicity, etc. shall be used for establishing ADI. Analysis and evaluation approaches shall be applied to generate the most sensitive endpoint of the most sensitive animal.

1.3 Setting NOAEL. An appropriate test approach shall be selected according to the sensitive endpoint for setting NOAEL of ADI. Test data and sensitive endpoint shall be included in NOAEL instruction.

1.4 BMDL as an alternative of NOAEL. When there is a well-established dose-response model, or the NOAEL is unavailable, or the chronic exposure dose of a pesticide is close to ADI, BMDL is recommended as an alternative of NOAEL.

2. Selecting UF
When establishing ADI, there are uncertainties in extrapolating animal data to humans and uncertainties of database deficiencies. In order to reduce these uncertainties, UF shall be applied.

A 100-fold UF is usually applied in extrapolating animal data to humans (i.e., interspecies difference) and extrapolating average humans data to sensitive sub-groups (i.e., intraspecies variability), with a 10-fold factor to allow for interspecies difference, and another 10-fold factor to allow for intraspecies variability.

Besides interspecies difference and intraspecies variability, the efficiency and validity of toxicological database and the nature of adverse effects shall also be taken into consideration to determine the UF. Based on the specificity of the case and available data, UF could be modified or reduced, as appropriate. For example, when a dose has no maternal toxicitybut teratogenicity on test animal, usually a 10-fold UF is added; and when valid data (i.e. human data in particular) is available, the UF of intraspecies variability could be adjusted appropriately.

To determine an UF, analysis and assessment approaches shall be applied for each pesticide in association with experience of experts. Although there may be various uncertainties, or even incomplete data, the maximum of UF is 10000 in general. See Table 1 for uncertaintycircumstance & UF adopted in ADI deduction.

Table 1 Uncertainty circumstance & UF adopted in ADI deduction

Uncertainty circumstance	Factor
Extrapolation from experimental animal to average humans, including: Toxicokinetics difference Toxicodynamic difference	10(total) 4 2.5
Extrapolation from average humans to sensitive sub-groups, including: Toxicokinetics difference Toxicodynamic difference	10(total) 3.16 3.16
Extrapolation from LOAEL to NOAEL	10
Deduction from sub-chronic experiment data to chronic data	10
Severe toxicity detected	10
Incomplete data collections	10

3. Calculating ADI
NOAEL or BMDL is divided by proper UF to give the ADI. The formula of calculating ADI is as the following:
ADI=NOAEL/UF or ADI=BMDL/UF

IV.Special circumstances for developing ADI

1. Establishing provisional ADI
Provisional ADI for pesticide shall be established upon any of the following conditions:

1.1 Limited toxicological data.

1.2 The updated data call in question an established pesticide ADI and show the necessity for revising it, and a provisional ADI is required during data collection period.

Generally, larger UFs shall be used in establishing provisional ADI.

2. Establishing category ADI
One ADI can be set for the whole category upon any of the following conditions:

2.1 Pesticides are identical in toxic mechanism, target and effect;

2.2 Pesticides are similar in chemical structure;

3. Exemption of establishing ADI
When there is adequate evidence that the pesticide is risk-free of chronic exposure, ADI formation can be exempted.

Relevant Annexes：

Announcement No.1825 of the Ministry of Agriculture