Triphenyl phosphite

Neurotoxicity

Description of key information

TPP produced evidence of neurotoxicity in the presence of other signs of systemic toxicity at an oral dose of 40 mg/kg/day in a well conducted OECD 422 study which was extended and studied effects in F1 offspring treated to postpartum Day 70.  The NOAEL for systemic toxicity (including neurotoxicity) in both the parental animals and the F1 offspring was 15 mg/kg/day.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

15 mg/kg bw/day

Species:

rat

Additional information

TPPi was administered by gavage once daily at 0, 5, 15, and 40 mg/kg/day to parental F0 CD® (SD) rats, 10/sex/group, through prebreed, mating, gestation, and lactation and direct dosing to Fl offspring (10/sex/group) from weaning to postpartum day 70 (Tyl, 2004). Treatment with TPPi resulted in adult F0 parental toxicity at 40 mg/kg/day, increasing over time (reduced body weights, ataxia, and foot splay).

 

F1 offspring in the 40 mg/kg/day group were terminated at pnd 22 due to mortality and reduced body weight gain during lactation. F1 offspring from the other groups were weaned at Day 22 and then treated with TPPi for 7 weeks (until postpartum day 70). For these retained Fl males and females, in-life systemic parameters (including FOB) were unaffected.

 

Based on these results, the F0 male and female systemic no observable adverse effect level (NOAEL) was 15 mg/kg/day. The Fl adult male and female systemic NOAEL was also 15 mg/kg/day.

 

In addition, TPP has been also been identified as a neurotoxicant, at high doses, in a number of acute studies published in the literature, and in a review published by Abou-Donia (1992). All of these studies appear to have been run at concentrations one to two orders of magnitude higher than the recent, GLP, multi-generational study conducted on TPP (Tyl 2004), which included behavioral and neurotoxicity endpoints. As such, the NOAEL from the Tyl study for repeat dose toxicity is also considered to be appropriate for the neurotoxicity endpoint.

 

Reference: Abou-Donia MB. (1992) Triphenyl Phosphite: A Type II Organophosphorus Compound-Induced Delayed Neurotoxic Agent. In J. Chambers and P. Levi (Eds), Organophosphates: Chemistry, Fate and Effects (pp 327 – 351). San Diego, CA: Academic Press.