Notat
Pesticider og Genteknologi
J.nr.
Ref.
January 2010
English translation
Annex 1
Cumulative health risk assessment of plant protection products (PPP) containing two or
more active substances
Limitation
A risk assessment of cumulative effects is conducted on the basis of a specific evaluation of the
toxicological profile of each active substance. A cumulative risk assessment is considered when
active substances cause severe adverse effects, such as congenital malformations, reproductiontoxicity, DNA-damage, cancer or other serious health problems (irreversible) due to a longer exposure. A cumulative risk assessment can be performed where active substances have an effect on
similar end-points (i.e. organ/tissue or equivalent effect seen in different organs/tissues). A cumulative risk assessment is not carried out if relevant data shows that the toxicity is due to toxicologically distinct mechanisms.
Risk assessment methods
A health risk assessment of PPP’s containing two or more active substances can be evaluated on
the basis of concentration-addition.
The risk assessment of PPP’s containing two or more active substances is being performed on
the basis of different paradigmas.

1. Paradigma
The individual health risk assessment of the substances should not show an
unacceptable risk, i.e. the Margin of Safety (MoS) between the critical toxicological effect,
NOAEL and the exposure, should for every active substance, have a minimum level of 100
and, in case of for substances with severe effects, higher. If so, the MoS should be added
and give a total of of 100 MoS, minimally. Furthermore, the AOEL (Acceptable Operator Exposure) for every active substance should not be exceeded.
MoS is added according to following formula:
1
1
1
-------+ ------- = -------MoS (A)
MoS(B) MoS (addition)
The terminology A and B specifies the active substances A and B.
1. Example
Substance A
NOAEL
Exposure
MoS:
5 mg/kg/day
0,02 mg/kg/day
250
Substance B
NOAEL
10 mg/kg/day
Exposure
0,06 mg/kg/day
MoS
167
1
1
1
------- + -------- = ---------- =>Total MoS is 101
250
167
0,0099
Since the total MoS is above 100, the product containing the substances A and B will not
constitute an unacceptable risk to health.
 2. Paradigma
If the productfor example contains two substances, classified as Rep 3; R63, and an extra safety factor of 3 is applied, then NOEAL (repro) is the lowest dose where reproductive toxicity effects are observed. The NOEAL (repro) should be divided with the extra safety factor, which
gives the established corrected NOAEL (repro-corr.), before the total MoS is calculated. The total MoS should then have a minimum value of 100 as the extra safety factor has already been
adjusted accordingly.
If another extra safety factor (5 or 10) is implemented for a different severe effect for example
cancer then NOAEL (cancer), should be divided by 5 or 10, and the total MoS calculated as in
2.
2. Example
A product contains two active substances. Both substances are classified as Rep 3; R63, and
NOAEL for repro-toxicity with en extra safety factor of 3 is the lowest NOAEL:
Substance A NOAEL (repro)
NOAEL (repro-corr.) 20/3 mg/kg/d. =
Exposure
MoS
20mg/kg/day
6,7mg/kg/day
0,035 mg/kg/day
191
Substance B NOAEL (repro)
24 mg/kg/day
NOAEL (repro-corr.) 24/3 mg/kg/d.=
8 mg/kg/d ay
Exposure
MoS
0,035 mg/kg/day
229
2
Since the total MoS is above100, the product containing substances A and B will not constitute
an unacceptable health risk.
Products containing more than two active substances can be calculated as follows
1
1
1
1
----------- + ---------- + ---------- + ……= -------------MoS(A)
MoS(B) MoS(C)
MoS (Total)
3