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Frequently Asked Questions on the Health Risk Assessment of Glyphosate

BfR FAQs, 11 November 2011

Glyphosate (chemical name N-(Phosphonomethyl)glycine) is one of the most widely used active substances in pesticides worldwide. In the last few months a controversial discussion about the assessment of the health risks of the active herbicide substance glyphosate has emerged, largely as a result of a publication entitled "Roundup And Birth Defects: Is the Public Being Kept in the Dark?" released by the non-governmental organisation "Earth Open Source". This publication which came out in June 2011 accuses the German authorities involved in the EU assessment of glyphosate as well as the EU Commission itself of having known about the developmental toxicity properties of Glyphosate from as early as 1998 and 2002 respectively but of having kept these properties concealed from the public. Both risk assessment and authorisation of the active herbicide ingredient glyphosate have also been the subject of a brief enquiry to the German Government.

The BfR has now prepared questions and answers on the subject.

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Questions

• What is Glyphosate?
• How does Glyphosate work in plants?
• What properties did toxicological studies on Glyphosate reveal?
• What limit values to prevent health risks were inferred from these studies on glyphosate?
• Why is glyphosate deemed to be detrimental to reproduction and development by certain non-governmental agencies organisations?
• How are the glyphosate studies with clawed frogs and chickens to be interpreted from a regulatory viewpoint?
• Why is glyphosate not assessed as detrimental to reproduction and / or development by the authorities?
• How are other published glyphosate studies taken into account in regulatory decisions?

What is Glyphosate?

Glyphosate (chemical name: N-(Phosphonomethyl)glycine) is one of the most widely used active ingredients in herbicides worldwide to prevent unwanted plant growth in crop cultures or to kill plants or parts of plants. These substances are referred to as herbicides or, colloquially, as "weed control products".

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How does Glyphosate work in plants?

Glyphosate suppresses the enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase which in plants is essential for the biosynthesis of the amino acids phenylalanine, tyrosine and tryptophan. This enzyme neither exists in animals nor human beings.

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What properties did toxicological studies on Glyphosate reveal?

Following oral administration, about 30% of glyphosate was absorbed by the gastrointenstinal tract and eliminated almost completely within 7 days. In animal experiments, glyphosate showed low acute toxicity after single oral, dermal or inhalation administration. Glyphosate irritated the eyes but not the skin and did not show any sensitising properties.

Repeated administration of glyphosate in high doses led to changes in the liver and salivary glands. In addition, glyphosate produced irritation of the mucosa in the gastrointestinal tract and in the bladder.

In a number of standardised tests, glyphosate revealed no mutagenic properties. Long-term studies with rats and mice did not suggest any carcinogenic effect of glyphosate.

Studies in rats and rabbits indicated that glyphosate does not have any reproductive or developmental toxicity. Some deformities did occur following administration of high doses in pregnant rats and rabbits. However, since these effects were not reproducible and the females already showed significant symptoms of poisoning, no relevance for human beings was attached to these findings - in accordance with the common international assessment principles.

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What limit values to prevent health risks were inferred from these studies on glyphosate?

Internationally, the risks posed by active pesticide ingredients are generally assessed on the basis of the same scientifically recognised principles.

In the EU assessment procedure, the following limit values were inferred for glyphosate:

• ADI (acceptable daily intake): 0.3 mg/kg of bodyweight
• AOEL (acceptable operator exposure level), systemic: 0.2 mg/kg of bodyweight/day

The World Health Organisation (WHO) defined the following limit value in 2004:

• ADI (acceptable daily intake): 1.0 mg/kg of bodyweight

The American Environmental Protection Agency (EPA) has deduced the following limit values:

• Chronic RfD (chronic reference dose): 1.75 mg/kg of bodyweight/day (corresponds to the ADI)

 The inference of different ADI values is explained by the partially differing underlying data and the use of different studies as a basis for the limit value.

All three assessments agreed that it was not necessary to establish an acute reference dose (ARfD), since glyphosate showed low acute toxicity and no other effects such as developmental toxicity in rats and rabbits following single exposure were found.

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Why is glyphosate deemed to be detrimental to reproduction and development by certain non-governmental agencies organisations?

The non-governmental organisation (NGO) "Earth Open Source" published a report in June 2011 entitled "Roundup And Birth Defects: Is the Public Being Kept in the Dark?" This report accuses the German authorities involved in the EU assessment of glyphosate (notably the BfR and BVL) as well as the EU Commission itself of having known as early as 1998 and 2002 respectively about the developmental toxicity properties of glyphosate, but of having kept secret these findings from the public. "Earth Open Source" notably refers to some studies described in the EU assessment report on the development toxicity observed in rats and rabbits which, however, this NGO interprets and assesses differently from the authorities.

This concerns, for example, a study on rabbits which a German manufacturer requested from an Indian test laboratory in 1993. In this study, some foetuses in the treated groups showed a finding called "dilated heart". For "Earth Open Source" this is a clear indication that Glyphosate can cause deformities. In the EU, this study was assessed in the context of all existing studies on developmental toxicity. The mentioned finding was not confirmed in several newer and qualitatively superior studies, nor was it clearly dose-related. Moreover, heart dilation was observed most frequently in the highest dosage which was already deadly for 50% of the females. This last fact alone led to great doubt about the quality and validity of the study. Taking into consideration all these aspects, the dilation of the heart was not taken to be an indication of possible deformities in human beings.

The same applies to further studies with rats and rabbits which "Earth Open Source" claimed to indicate developmental toxicity of glyphosate without - contrary to international standard scientific practice - taking into account the dose / effect relationship, the reproducibility of the effects nor historical control data (i.e. data obtained from control groups in comparable studies from the same laboratory).

Additionally, "Earth Open Source" holds that the developmental toxicity of glyphosate in mammals is supported by corresponding effects in frog and chicken embryos.

Not only the EU but also the WHO and the US-EPA have come to the conclusion that glyphosate is detrimental neither to the reproduction nor the development of mammals including humans.

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How are the glyphosate studies with clawed frogs and chickens to be interpreted from a regulatory viewpoint?

Even if it is possible in principle to detect certain development toxicity effects of chemical substances in experiments on frogs or chicken embryos, these are nevertheless not validated as test systems in human toxicological tests of active ingredients in plant protection products and other chemicals. This means that they have not been verified with regard to the informational value, practicability and repeatability of the results, nor have they been recognised by the EU and other international organisations (such as the OECD). For this reason, the findings of such studies are of limited use in terms of health risk assessment.

As regards the studies conducted by Professor Carrasco (University of Buenos Aires) with frog and chicken embryos - which according to "Earth Open Source" are of great relevance for the health assessment of glyphosate - it must further be taken into account that the test substances were administered directly to the offspring, i.e. by mixing them into the culture medium and / or through injection into the chicken eggs. The guidelines for the toxicity test of chemicals prescribe, however, that the test substance must be administered to the females via oral / dermal or inhalation routes, i.e., the offspring is exposed in dependence of the test substance passing through the placenta. Since the above-mentioned experiments on frog and chicken embryos do not adequately take into account the exposure conditions that apply to human beings, nor the toxicokinetics or the metabolism in the mammal organism and given the fact that a sufficient number of other significant studies are available, these experiments only play a subordinate role in the health risk assessment of glyphosate.

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Why is glyphosate not assessed as detrimental to reproduction and / or development by the authorities?

According to the legal specifications, testing for development toxicity properties of PSM substances must be carried out on two mammalian species (rats and rabbits); for these species, a large database exists to prove applicability of the results to humans. The test substance is normally administered to the females orally, though in case of corresponding exposure of humans, it can alternatively be administered through the skin or by inhalation. The internationally binding testing guidelines lay down that the highest dosage must only cause slight toxic effects in the pregnant females, since an embryonic or foetal toxic effect can also occur as a result of maternal toxicity, reduced water or feed intake, stress, specific nutritional deficiencies or other unspecified influences. A possible impact of these factors on the development of the progeny must therefore be given special attention. After all, it is critical for the assessment of the findings and the legal classification of the substance into hazardous substances whether the toxic effect on the embryo or foetus occurs at a dose with or without pronounced maternal toxicity.

If the studies on rats and rabbits conducted in accordance with the guidelines are given precedence over other studies in the health risk assessment, there are no convincing indications that glyphosate has developmental toxicological properties.

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How are other published glyphosate studies taken into account in regulatory decisions?

University laboratories usually conduct toxicological studies with active herbicide ingredients for research purposes. Such studies too are taken into consideration in the assessment. For regulatory decisions as part of the risk assessment of pesticides, they are in most cases of only limited use, however, since the testing methodology usually does not conform to international guidelines, because they do not meet the requirements of "good laboratory practice" (GLP) and because usually only a summary of the findings of such studies is published. Moreover, such studies typically use the weed control product as a whole rather than just the active substances which makes it difficult or altogether impossible to compare them with the existing regulatory studies from the approval procedure.

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