N,N'-ethylenebis[N-acetylacetamide]

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

A two-generation reproductive toxicity study has not been performed with TAED. However, there is sufficient information available to allow the scientifically solid evaluation of this toxicity endpoint (Roth, 2009):

TAED was examined for 90 -day repeated dose toxicity in the rat following oral, inhalation and dermal administration. In all studies the liver was identified as the main target organ and no substance related adverse effects were noted on reproductive organs or hormonally active tissues which might influence reproduction.

Kinetic data demonstrate that TAED is extensively metabolized in the liver via deacetylation to triacetyl ethylenediamine (TriAED) and diacetyl ethylenediamine (DAED), which are rapidly excreted in the urine. Thus, an accumulation of TAED or its metabolites in tissues relevant for reproduction can be excluded.

TAED consists of acetic acid and ethylenediamine (ED). Both substances are of no concern regarding reproductive toxicity. As ED is metabolised to monoacetyl ethylenediamine (MAED) and to a minor extent to DAED, both compounds were present when ED was tested for reproductive toxicity. Therefore, it can be concluded that MAED and DAED are of no concern regarding reproductive toxicity. These data clearly demonstrate that TAED and its metabolites TriAED and DAED do not have a structural alert regarding reproductive toxicity.

Overall, the existing toxicity and kinetic data on TAED and the data on reproductive toxicity and metabolism of the TAED constituents acetic acid and ethylenediamine demonstrate that TAED has no reproductive toxicity potential. Based on this weight of evidence, it is concluded that a two-generation study with TAED is scientifically not justified and thus not needed.

Short description of key information:
There is no two-generation reproductive toxicity study available for TAED. However, using a weight of evidence approach TAED is considered to have no reproductive toxicity potential.

Effects on developmental toxicity

Description of key information

The NOEL for maternal toxicity was 40 mg/kg bw/d, the NOAEL between 40 and 200 mg/kg bw/d (based on reduced body weight gain and food consumption observed at 200 and 1000 mg/kg bw/d). For fetuses the NOEL/NOAEL was 200 mg/kg bw/d for developmental toxicity (based on reduced fetal weight at 1000 mg/kg bw/d) and the NOAEL for teratogenicity was 1000 mg/kg bw/d (based on the absence of visceral and skeletal malformations or anomalies at all dose levels).

Additional information

Teratogenicity was evaluated in groups of 25 pregnant Sprague-Dawley rats treated with TAED by gavage at dose levels of 0, 40, 200 and 1000 mg/kg bw/d from day 6 to 15 of pregnancy. The dams were caesarean-sectioned on day 20 of gestation and subjected to post-mortem examination. No clinical signs, behavioral changes, death or abortion were noted in any group. A significantly lower mean daily food consumption was seen in the 200 and 1000 mg/kg bw/d groups during the treatment period day 6 -15 in comparison with the control group. This was accompanied by a significantly lower body weight gain during the treatment period day 6 -10 in the 200 mg/kg bw/d group and day 6 -10 and 10 -15 in the 1000 mg/kg bw/d group and lead to significantly lower mean body weights from day 10 until the end of pregnancy in the 1000 mg/kg bw/d group. Visceral and skeletal malformations or anomalies were not significantly increased at all dose levels in comparison to the controls. Mean fetal and mean placental weight were significantly decreased and the percentage of skeletal variants was significantly increased at the high dose. The NOEL for maternal toxicity was 40 mg/kg bw/d (based on a dose dependent reduction in body weight development and food consumption at 200 and 1000 mg/kg bw/d. The study authors did not deduce a NOAEL for maternal toxicity. However, as the effect on food consumption and body weight gain observed at 200 mg/kg bw/d was transient and did not influence fetal development, a NOAEL for maternal toxicity above 40 mg/kg bw/d can be assumed. A comparison of this NOAEL with the NOAEL of 90 mg/kg bw/d derived for the non-pregnant rat in the 90 -d repeated dose toxicity study demonstrates that the pregnant rat and non-pregnant rat have a similar susceptibility. For fetuses the NOEL/NOAEL for developmental toxicity was 200 mg/kg bw/d (based on reduced fetal weight at 1000 mg/kg bw/d) and the NOAEL for teratogenicity was 1000 mg/kg bw/d (based on the absence of visceral and skeletal malformations or anomalies at all dose levels).

Justification for classification or non-classification

The devepomental toxitiy of TAED was evaluated in rats according to OECD guideline 414 study and GLP. No adverse effects on the development of the offspring was found in the absence of maternal toxicity or the presence of slight maternal toxicity.

The reproductive toxicity with respect to sexual function, fertility and lactation has been assessed in a weight of evidence approach. Based on the existing toxicity and kinetic data on TAED and the data on reproductive toxicity and metabolism of the TAED constituents acetic acid and ethylenediamine it is demonstrated that TAED has no reproductive toxicity potential.

It is concluded that TAED is not subject to classification and labelling according to Directive 67/548/EEC and Regulation 1272/2008/EC regarding reproductive toxicity.