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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
600 mg/kg bw/day
Additional information

According to Council Regulation 1907/2006/EC, column 1, Annex IX a two-generation reproduction toxicity study is the standard information required for a substance manufactured in quantities of 1000 tonnes or more. This study is not available. However, according to Council Regulation 1907/2006/EC, Annex XI, if there is sufficient weight of evidence for the absence of a particular dangerous property, further testing on vertebrate animals shall be omitted. Based on the combined repeated dose toxicity study with a reproduction/developmental toxicity screening test (according to OECD TG 422) for Glyoxylic Acid 50% and reproductive toxicity studies for metabolic precursors the endpoint fertility can be reliably assessed. Thus, a two-generation reproduction toxicity study with Glyoxylic Acid 50% is scientifically not justified.

Existing data for Glyoxylic Acid 50%

In a combined repeated dose toxicity study with a reproduction toxicity screening test according to OECD TG 422 and GLP, reproductive subgroups of 10 females and 5 male Crj:CD (SD) rats per dose were exposed to dietary concentrations of 0, 2000, 6000 or 18000 ppm Glyoxylic Acid 50% to screen for reproductive and developmental effects. The treatment of male and female rats started 2 weeks before cohabitation and was continued until week 6 of treatment for the males, and week 6 or 7 of treatment for the females (day 4 of lactation). The reproduction/developmental toxicity screening test found no evidence of impaired reproductive performance at these dietary concentrations. Mating performance and fertility were unaffected by treatment. Bodyweight gain and food intake of reproductive subgroup females during gestation and early lactation was unaffected. The duration of gestation was unaffected as well. Histopathological examination of the reproductive organs of males (testis, epididymides, seminal vesicles with coagulating gland, prostate) and females (ovaries, uterus with cervix and oviducts, vagina, pituitary, mammary tissue) did not reveal any treatment related effects. There was no effect on the survival, growth or development of the offspring up to day 4 of age. The NOAEL for reproductive/developmental toxicity was 18000 ppm (i.e. 600 mg/kg bw/d for males and 730 to 1257 (depending on study week) mg/kg bw/d for females).

Justification for the use of data on ethylene glycol or glyoxal

Ethylene glycol is metabolized by NADP-dependent alcohol dehydrogenase to glycolaldehyde, which is then metabolized to glycolic acid by aldehyde oxidase or to a lesser extent to glyoxal. Glyoxal is changed both to glycolic acid and to Glyoxylic Acid. Transformation to glycolic acid occurs in the presence of lactate dehydrogenase and/or aldehyde dehydrogenase or after reaction with glutathione via the glyoxalase I and II system. Glycolic acid is further oxidized to Glyoxylic Acid, mediated by lactic dehydrogenase or glycolic acid oxidase (Corley et al., 2005). Direct oxidation of glyoxal to Glyoxylic Acid is mediated by enzymes such as 2-ketoaldehyde dehydrogenase. Once Glyoxylic Acid is formed, it is enzymatically degraded very rapidly to a variety of products, mainly to glycine, to carbon dioxide and water via formic acid and to oxalic acid.

These data demonstrate the central role of Glyoxylic Acid in the metabolism of ethylene glycol and glyoxal. Thus, whenever ethylene glycol or glyoxal has been tested in animals, Glyoxylic Acid has been tested as well. Therefore, the data on reproductive toxicity of ethylene glycol or glyoxal can be used to support the evaluation of this endpoint for Glyoxylic Acid 50%. Studies examining effects on fertility are only available for ethylene glycol. They have been evaluated by the NTP-CERHR Expert Panel (2003). The outcome of the evaluation is reported below.

Reproductive toxicity of ethylene glycol

There were no data identified that permit the evaluation of reproductive toxicity in humans. Ethylene glycol was tested for reproductive toxicity in rats and mice. There are sufficient data to conclude that ethylene glycol is not a reproductive toxicant in rats exposed orally to 1,000 mg/kg bw/d via diet (DePass et al., 1986). The study in mice was essentially negative at doses up to 2,826 mg/kg bw/d via drinking water (Gulati et al., 1986). The studies available for review included a continuous breeding study in mice, a two-generation study in rats, and sub-chronic toxicity studies in rats.

The Expert Panel concluded that data in mice are sufficient to demonstrate no effect on fertility of male or female mice following oral exposure to up to 2,826 mg/kg bw/d ethylene glycol for approximately 22 weeks.

The Expert Panel concluded that the data are sufficient to demonstrate that ethylene glycol is not a reproductive toxicant in male and female rats following dietary exposure with up to 1,000 mg/kg bw/d for 7 weeks prior to mating in parental rats or from the time of conception through mating in their offspring.

Conclusion

The result of the OECD guideline 422 study with Glyoxylic Acid 50% supported by the data on ethylene glycol provide sufficient weight of evidence for the absence of reproduction toxicity of Glyoxylic Acid 50%. Based on this weight of evidence a two-generation reproductive toxicity study with Glyoxylic Acid 50% is scientifically not justified and can be omitted according to Council Regulation 1907/2006/EC, Annex XI.

References

Corley RA, Bartels MJ, Carney EW, Weitz KK, Soelberg JJ, Gies RA, Thrall KD (2005). Development of a physiologically based pharmacokinetic model for ethylene glycol and its major metabolite, glycolic acid, in rats and humans. Toxicological Sciences 85(1):476-490.

DePass LR et al. (1986). Three-generation reproduction and dominant lethal mutagenesis studies of ethylene glycol in the rat. Fund Appl Toxicol 7: 566-72.

Gulati DK et al. (1986). Ethylene glycol: reproduction and fertility assessment in CD-1 mice when administered in drinking water.(OH): Environmental Health Research and Testing.

National Toxicology Program (2003).Department of Health and Human Services; NTP-CERHR Expert Panel Report on the Reproductive and Developmental Toxicity of Ethylene Glycol.NTP-CERHR-EG-03.

 


Short description of key information:
There were no adverse effects on the fertility of male and female rats observed in a OECD guideline 422 study in rats. The result is supported by studies with the metabolic precursor ethylene glycol which showed no adverse effects on fertility.

Effects on developmental toxicity

Description of key information
There were no adverse effects on develpomental toxicity / teratogenicity observed in a OECD guideline 422 study in rats. The result is supported by the lack of developmental toxicity / teratogenicity of the metabolic precursor glyoxal when tested in rats according to OECD guideline 414.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
730 mg/kg bw/day
Additional information

According to Council Regulation 1907/2006/EC, column 1, Annex IX a teratogenicity study according to OECD guideline 414 is the standard information required for a substance manufactured in quantities of 1000 tonnes or more. This study is not available. However, according to Council Regulation 1907/2006/EC, Annex XI, if there is sufficient weight of evidence for the absence of a particular dangerous property, further testing on vertebrate animals shall be omitted. Based on the combined repeated dose toxicity study with a reproduction/developmental toxicity screening test (according to OECD TG 422) for Glyoxylic Acid 50% and a tertogenicity study for the metabolic precursor glyoxal, the endpoint developmental toxicity / fertility can be reliably assessed. Thus, a tertogenicity study with Glyoxylic Acid 50% is scientifically not justified.

Existing data for Glyoxylic Acid 50%

see "effects on fertility"

Existing data for glyoxal

The justification for the use of data on glyoxal is given above (see "effects on fertility").

Data on glyoxal and not on ethylene glycol are used because glyoxal is a direct metabolic precursor of Glyoxylic Acid and there is a tertogenicity study according to OECD guideline 414 availabe to the data submitter.

The developmental toxicity of Glyoxal 40% was studied according to OECD guideline 414 in rats at dose levels of 5, 25 and 125 mg/kg bw/d. Glyoxal 40% was administered to pregnant Wistar rats daily by stomach tube from implantation to one day prior to the expected day of parturition (days 6 -19 post coitum; p.c.) (Schilling et al., 2001).

Maternal toxicity was observed at 125 mg/kg bw/d i.e. transient and sporadically occurring salivation immediately after gavaging, significantly reduced food consumption, significantly lower corrected body weight gain. No substance related effects were observed on gestational parameters or fetuses. At 25 and 5 mg/kg bw/d, no substance related effects were observed on dams, gestational parameters or fetuses. Based on these results, the NOAEL for maternal toxicity is 25 mg/kg bw/d, while it is 125 mg/kg bw/d for prenatal developmental toxicity.

Thus, the oral administration of Glyoxal 40% to pregnant Wistar rats had no effects on fetal morphology at any dose levels tested.

Conclusion

These data taken together provide sufficient weight of evidence for the absence of teratogenicity of Glyoxylic Acid 50%. Therefore, a prenatal developmental toxicity study with Glyoxylic Acid is scientifically not justified and can be omitted according to Council Regulation 1907/2006/EC, Annex XI.

Justification for classification or non-classification

Based on the available data Glyoxylic Acid 50% has not to be classified and labelled for developmental or reproduction toxicity (sexual function, fertility and lactation) according to EU Regulation No. 1272/2008 and EU Directive 67/548/EEC.