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Key value for chemical safety assessment

Effects on fertility

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

There are no data available from a screening reproduction toxicity study or a two-generation reproduction toxicity study.

2-phosphonobutane-1,2,4-tricarboxylic acid is of very low systemic toxicity after sub-chronic exposure with NOEL levels at or above 424 mg/kg/day (males) and 633 mg/kg/day (females)(Löser and Kaliner, 1976). Toxicologically relevant information concerning reproduction can be deduced from this sub-chronic study because gravimetric and histopathologic investigation of the reproductive organs was reported. Testes and ovaries were weighted for all animals (15/sex/group). No compound related difference in organ weight was observed in any dose group. In addition histopathologic evaluation was performed in all dose groups (5/sex/dose). No compound related effect war observed in any reproductive organ investigated; seminal vesicle, prostate, testes and adrenals in males; uterus and ovaries in females.

Taken together, the toxicological profile of 2-phosphonobutane-1,2,4-tricarboxylic acid is very consistent over a variety if different endpoints and parameters examined and the substance is shown to be of very low toxicity for any endpoint. Especially no effects are reported at any dose group in any parameter investigated, including gravimetric and histopathologic evaluation of reproductive organs, in a sub-chronic repeated dose toxicity study even at high doses 424 mg/kg/day (male rats) and 633 mg/kg/day (female rats), a dose very close to the limit dose for guideline studies. As outlined above repeated dose toxicity studies are considered to provide sufficient and sensitive information for fertility if histological examination of the reproductive organs is covered.


Short description of key information:
Taken together, based on the overall very low toxicity and the available data covering reproduction parameters, there is sufficient data available to conclude that 2-phosphonobutane-1,2,4-tricarboxylic acid is not a reproduction toxicant.

Effects on developmental toxicity

Description of key information
Data on developmental toxicity are available in a prenatal developmental toxicity study similar to OECD TG 414 (Renhof, 1984).  Under the experimental conditions, the test item is considered to have no maternal or embryonic toxic effects and no teratogenicity effects in rats, even at the highest dose tested 1000 mg/kg/day (limit dose).
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

Data on developmental toxicity are available in a prenatal developmental toxicity study similar to OECD TG 414 (Renhof, 1984). The test compound, 2-phosphonobutane-1,2,4-tricarboxylic acid, was administered by gavage to 25 female Wistar rats per group from gestation day 6 to 15 at dose levels of 0, 100, 300, and 1000 mg/kg bw/day. No signs of maternal toxicity were observed (incl. death, weight loss, changes in appearance and behaviour). No compound related effect was observed on fertility, embryo and foetus development (incl. resorptions, placenta weight, skeletal and internal malformation). Under the experimental conditions, the test item is considered to have no maternal or embryonic toxic effects and no teratogenicity effects in rats.

Justification for classification or non-classification

Based on the low toxicity profile and the available data on reproduction, there is sufficient data available to conclude 2-phosphonobutane-1,2,4-tricarboxylic acid is not a reproduction toxicant. Thus, according to EU Directive 67/548/EC and according to EU regulation No. 1272/2008 (GHS; amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006) 2-phosphonobutane-1,2,4-tricarboxylic acid should not be classified.

Additional information