Trientine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data available

Additional information

No studies were located that could provide information on effects to fertility. An OECD 416 study is proposed

Short description of key information:
No data available

Effects on developmental toxicity

Description of key information

Two studies are available which were performed with TETA (CAS 112-24-3).  The key study is a gavage study according to OECD 414 (1983) , Klimisch 2 due to short exposure duration relative to today's guideline. The other study was a dermal study according to a protocol equivalent to OECD 414; Klimisch 2 due to short exposure duration relative to today's guideline, short exposure duration /days  as well as some other minor technical deviations  
Data from the stucturally related substances trientene.2HCl  (CASno. 38260-01-4) and Trientene.2HCl  (CASno. 38260-01-4) suggest that at very high dose levels these substances may have secondary  fetotoxic effects in the late stages of pregnancy , probably due to copper depletion..  However, there are considerable uncertainties with respect to toxicokinetecs, dose levels and relevance of  route of administration. 

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

750 mg/kg bw/day

Effect on developmental toxicity: via dermal route

Dose descriptor:

NOAEL

125 mg/kg bw/day

Additional information

In an oral (gavage) developmental toxicity study (Huntsman, 1984), no developmental effects were noted at dose levels of 75, 325 and 750 mg TETA per kg bw. No maternal toxicity was observed at any dose level barring a slightly reduced food intake. Dosing period was days 6-15 of pregnancy , i.e. shorter than required in today's guidelines.

The dermal developmental study in rabbits (Tyl, 1988) at levels of 5, 50 and 125 mg/kg bw did not show developmental effects a any dose level. maternal toxicity was seen at at 125.0 mg/kg/day, i.g. mortality (9.1%), transient reduced weight gain during exposure and clinical signs of toxicity. The treatment period was rather short, i.e. treatment on Days 6 -18 of pregnancy, which is comparable to Days 6 -15 for rats. In addition, although animals showed severe maternal toxicity (most probably because of local dermal toxicity), the dermal absorption rate was not established. The NOAEL, therefore, is at least 125 mg/kg bw/day.   

In summary, data from studies with TETA do not give any indication of developmental toxicity .

Studies with the structural analogues TETA-4HCl, CAS no 4961 -40 -4 and TETA.2HCl, CAS no 38260 -01 -4 suggest that these substances may cause copper depletion at higher dose levels, which in turn may lead to fetotoxicity at end of pregnancy in rats (Keen, 1983) and reduced body and brain weights at end of pregnancy in mice. (Tanaka et al, 1992 and 1993). However, there are considerable uncertainties for read-across to TETA with respect to toxicokinetics, dose levels and relevance of route of administration to humans.

Justification for classification or non-classification

Data from studies with TETA do not give any indication of developmental toxicity at a top dose of 750 mg/kg bw by gavage or 125 mg/kg bw by dermal exposure. However, as indicated in the discussion above and based on shortcomings in the available studies as well as data from structural analogues, no teratogenicity or early-to mid-of pregnancy developmental defects are to be expected, but embryotoxic effects at end of pregnancy, possibly due to copper depletion, cannot be excluded yet. Conclusion:

Inconclusive for classification.

A repeat developmental toxicity study is not deemed necessary.

It is likely that the effect of TETA.4HCl and TETA.2HCl upon post-implantation loss may be mediated by effects on the dam rather than direct embryotoxicity. These effects may be due to chelation and the subsequent decrease of plasma copper levels in the dam. Investigations should be considered to finally investigate the role of maternally-mediated toxicity. Therefore, it is proposed not to classify TETA at this time so that the additional research can be considered.