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Key value for chemical safety assessment

Effects on fertility

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

TNPP exposure over four generations did not reveal any significant effect on reproduction up to 500 mg/kg/d, the highest dose tested, except for a possible reduction of litter size, born from F1 and F2 generations at the highest dose. This slight tendency seems to be confirmed by the OECD 421 study in which a slight but significant litter size reduction was observed at the highest dose (1000 mg/kg/day). In this same study, maternal toxicity was observed at the dose of 1000 mg/kg/day. At the dose of 1000 mg/kg/day, a decrease of the ovary weight of F0 females and the decrease of epididymides weight in F1 males suggest an oestrogen-like activity of the test substance. No other significant effects on reproductive toxicity were observed in this study.

Phenomenon of dystocia observed in dams at the highest dose in the study of Tyl (2002) is viewed as maternal toxicity, due from the adjustments of dosing volume on gd 14 and especially on gd 20, resulting in over dosing the dams in late gestation. Actually, the dosing volume of the test chemical was adjusted for each dam based on each new body weight. This means that the dosing volumes for the F0 dams during gestation were adjusted on gd 0, 7, 14, and 20. The pregnant rat CD (SD) females gain approximately 150 g or more during gestation but with the body weight gain from gd 14 to parturition (the “last trimester”) of at least 100 g, due almost entirely to the rapid growth of the uterine contents. For gavage studies, test chemical intake (in mg/day) during this period is increased by as much as 30% because of the adjustment for maternal body weight, especially from gd 20 to parturition (gd 22 ± 1). Thus, the dose in mg/kg/day, based on the actual maternal body weight minus the uterine contents, is similarly increased by ~30%. This can result in overdosing the dam (and conceptuses) and is likely the cause of the excessive peri-parturitional maternal toxicity observed.

The risk of increased maternal toxicity in late pregnancy from bolus gavage dosing is due to: (a) the maternal liver (although it is enlarged in late pregnancy in response to the pregnancy and the increased test chemical load) is not enlarged commensurate with the increased test chemical dose; (b) test chemical is likely not equally distributed between maternal and fetal compartments, so the relative maternal burden may be even greater; and (c) gastrointestinal tract motility is reduced in late pregnancy, so there is likely increased absorption of the test chemical from the gut due to longer transit times. 

 

Based on these observations, the NOAELs for reproductive toxicity and for maternal toxicity were 200 mg/kg/day, derived from the OECD 421 study (considered as a key study for risk characterisation as a recent study, following OECD guideline).


Short description of key information:
Some limited effects were seen at highest doses of 500 and 1000 mg/kg/day in two separate studies. NOAEL is 200 mg/kg/day is based on Tyl 2002 study.

Effects on developmental toxicity

Description of key information
No developmental effects were observed.  NOAEL of 1000 mg/kg/day based on Tyl 2002 study.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

No indication of any developmental effect was observed in studies. NOAEL for developmental effects is1000 mg/kg/day, although based on a reduced number of animals.

Justification for classification or non-classification

This chemical is not classified as toxic to reproduction (fertility and development) according to the criteria of the European Union.