Review of the earth open source (eos) report " roundup and birth defects: is the public being kept in the dark?"



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APPENDIX 3: ASSESSMENTS OF REPRODUCTIVE TOXICITY STUDIES

A3.1 Rats

The German BVL has evaluated eight reproduction studies on glyphosate in rats, of which six were included only in the EU (1998) review, one appeared in the JMPR (2004b) review, and the remaining study was assessed in both reviews. The toxicological end-points examined included oestrus cycling, mating performance, pregnancy rate, gestation length, numbers, sexes, growth, post-natal developmental landmarks and onset of puberty in pups, bodyweights, histology of the reproductive organs and analysis of sperm and oocytes.



Moxon (2000) [Reviewing Agency: BVL] The study was performed over two generations at dietary glyphosate concentrations of 1000, 3000 and 10 000 ppm. In the JMPR review, the BVL found no effects on sexual development or fertility at up to the highest dietary concentration of 10 000 ppm (985 mg/kg bw/d). A NOAEL for parent and offspring toxicity was set at 3000 ppm (293 mg/kg bw/d) based on a reduction in bodyweight of F1A pups and a subsequent reduction in bodyweight of F1 parent males at 10 000 ppm.

Brooker et al (1992) [Reviewing Agency: BVL] This was a two-generation study performed at dietary glyphosate concentrations of 1000, 3000 and 10 000 ppm in the diet. For the EU review, the BVL based a NOEL for parental toxicity of 1000 ppm (79 and 87 mg/kg bw/d in males and females) on histological abnormalities in the parotid and submaxillary salivary glands at glyphosate dietary levels of 3000 and 10 000 ppm. A NOEL of 10 000 ppm (ca 797 and 881 mg/kg bw/d in males and females) was set for effects on reproduction and pups.

In the JMPR review, the BVL concluded that there had been no effects on sexual development or fertility at up to the highest dietary concentration of 10 000 ppm. A NOAEL of 3000 ppm (197 mg/kg bw/d) for parent and offspring toxicity was assigned based on increased food and water consumption in F1 females, depressed bodyweight in F1 males, and an increased incidence of cellular alteration of the salivary glands in F0 and F1 adults at 10 000 ppm13.



Brooker et al (1991c) [Reviewing Agency: BVL] Prior to the main study (above), a one generation range finding experiment was performed on small numbers of rats at dietary glyphosate concentrations of 0, 3000, 10 000 and 30 000 ppm. The parental generation received treatment from GD 3 to PND 21, after which their offspring were treated until termination a six weeks of age. Fecundity and pup survival were unaffected, but [unquantified] reductions in pup bodyweight occurred at all doses. Hence, a NOEL was not established. The BVL discounted this finding because none of the fully comprehensive reproduction studies reviewed for the EU had found treatment-related effects on pups at up to and including 10 000 ppm.

Reyna (1990) [Reviewing Agencies: BVL and US EPA] A two-generation study was performed at dietary levels of 0, 2000, 10 000 and 30 000 ppm. In-life and post mortem examinations conformed with OECD TG 416 and included histological examination of reproductive organs from all control and high dose F0 and F1 adults and one F2B weanling/sex/litter. A NOEL of 10 000 ppm (722 and 757 mg/kg bw/d for males and females, respectively) was assigned for parental and offspring toxicity. This was based on reduced bodyweight gain and soft faeces in adults receiving 30 000 ppm, and reductions in litter size and pup bodyweight gain during lactation at this same dietary level.

The US EPA (1993) evaluation of Reyna (1990) differed slightly from the EU / BVL assessment insofar as there was no mention of decreased litter size, but was otherwise closely similar. The EPA assigned a systemic NOEL of 10 000 ppm (500 mg/kg bw/d), a reproductive NOEL of 30 000 ppm (1500 mg/kg bw/d) and a developmental NOEL of 10 000 ppm (500 mg/kg bw/d). The doses appear to have been estimated, rather than having been calculated from parental food intake.



Suresh (1993b) [Reviewing Agency: BVL], In this two-generation study compliant with OECD TG 416, there were no treatment-related effects on the parents or offspring at the highest administered dietary level of 10 000 ppm, equivalent to ca 700 – 800 mg/kg bw/d. The BVL therefore set a NOEL of 10 000 ppm.

Antal (1985) [Reviewing Agency: BVL] Similarly, the BVL assessed this three-generation study as having demonstrated no effects of treatment at the highest dietary concentration of 5000 ppm in the diet, or 462 and 502 mg/kg bw/d in males and females. A NOEL of 5000 ppm was therefore assigned for parental and reproductive toxicity.

Bhide (1988b and 1988c) & Schroeder and Hogan (1981) [Reviewing Agencies: BVL, US EPA and Australian DoHA] These three studies were performed at very low doses, and the BVL / EU regarded them as providing supplementary information only. No treatment-related effects occurred in the parental generations or offspring in a three-generation study at dietary feeding levels of 0, 75, 150 and 300 ppm, equivalent to ca 15 mg/kg bw/d at the high dose (Bhide, 1988b); during a single-generation study by oral gavage at 0, 5 and 10 mg/kg bw/d prior to mating, through pregnancy and up to PND 21 (Bhide, 1988c); or in a three-generation dietary study at 0, 3, 10 and 30 mg/kg bw/d (Schroeder and Hogan, 1981).

The DoHA (1985) and the US EPA (1993) also assessed Schroeder and Hogan (1981) as having demonstrated no treatment-related effects on the parental or filial generations, and set a NOEL of 30 mg/kg bw/d. This NOEL forms the basis for the current Australian ADI for glyphosate, of 0.30 mg/kg bw/d. A DoHA (1992) evaluation reached the same conclusions as the BVL with regard to the studies by Bhide (1988b and 1988c).



Stauffer Chemical Company (1983a) [Reviewing Agency: Australian DoHA] In a two-generation study with glyphosate trimesium in rats at dietary concentrations of 0, 150, 800 and 2000 ppm (equivalent to ca 7.5, 40 and 100 mg/kg bw/d), the only adverse effect on reproductive indices was a reduction in litter size at 2000 ppm. A NOEL of 150 ppm was assigned for the parental animals and offspring based on reduced bodyweight gain, food consumption and plasma protein and albumin levels in adults and depressed pup bodyweight and relative spleen weight at and above 800 ppm (DoHA, 1991).
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