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NTP short-term reproductive and developmental toxicity studies on triphenyl phosphate (TPHP) and isopropylated phenyl phosphate (IPP)

Shannah Witchey, Brad Collins, Georgia Roberts, Keith Shockley, Molly Vallant, Eve Mylchreest, Barney Sparrow, Robert Moyer, Tomas Guilarte, Helen Cunny, Jeffrey Krause, Mamta Behl

DOI: https://doi.org/10.22427/NTP-DATA-002-00600-0003-000-1

SOT Poster: https://ntp.niehs.nih.gov/ntp/results/pubs/posters/witchey_sot20210312.pdf

The I03/I03C, I04/I04G, R19/R19G/R19C were updated on November 8, 2021 due to updates in the statistics.



As brominated flame retardants (FR) were phased out in the mid-2000s, use of alternative chemical FR, including aromatic phosphates (AP), steadily increased. Two APs, triphenyl phosphate (TPHP) and isopropylated phenol phosphate (IPP), are used in combination with other chemical FR as treatments to consumer products including foam-based furniture and infant products. TPHP and IPP are leaching into the environment with detectable levels found globally in indoor dust, indoor/outdoor air, aquatic biota and food. Human exposure is worldwide with the most common sources of exposure being contaminated food, drinking water, and house dust. This is concerning since there is little toxicity data available with which to evaluate potential risk from exposure of TPHP and IPP. To address this knowledge gap, we evaluated the toxicological effects of TPHP and IPP in a pre-and postnatal (perinatal) study in rats. TPHP and IPP were administered via dosed feed (in separate studies) at concentrations of 1000, 3000, 10,000, 15,000 and 30,000 ppm to time-mated Sprague Dawley (Hsd:SpragueDawley SD®) rats from gestation day (GD) 6 through postnatal day (PND) 56. At the time of weaning, pups continued exposure to the respective dam’s group until termination of study. Assessments of TPHP and IPP effects in this study included puberty, thyroid hormones, cholinesterase activity and brain inflammation using marker translocator protein 23 kDa (TSPO). F0 female survival was lower at ≥15,000 TPHP and ≥10,000 ppm IPP. A 15-38% decrease in litter survival PND 4-28 were observed at ≥10,000 ppm TPHP and ≥3000 ppm for IPP, respectively. Treatment-related effects were observed in both dams and pups for body weight,organ weight and cholinesterase activity. For both, TPHP and IPP a decrease in offspring body weight gain was observed at ≥1000 ppm ranging from 7-82% and6-20% decrease, respectively. A delay (≥2 days) in balanopreputial (BPS) at 1000, 3000 and 10,000 ppm TPHP and 1.6 day in 3000 ppm IPP was observed in males.In female offspring, vaginal opening (VO) was delayed ~2 days at 3000 ppm TPHP and IPP groups. No animals in the 15,000 ppm or 10,000 ppm (females only)TPHP treatment group achieved BPS or VO during time of examination. With TPHP exposure, acetylcholinesterase (AChE) activity was significantly decreased at≥10,000 ppm in dams and decreased activity was observed in offspring ≥10,000 ppm though it did not reach statistical significance. AChE activity in whole blood collected from dams and pups decreased (8-50%) in a dose-dependent manner across all IPP exposures. There was no significant increase in TSPO expression in dams; and some small increases were noted in pups exposed to 10,000 ppm TPHP and IPP. Additionally, preliminary data indicated that both TPHP and IPP crossed the placental barrier as well as the blood brain barrier as indicated by uptake in the brain. This work suggests the LOAEL for TPHP was 3000 ppm and for IPP was 1000 ppm. Studies are currently underway at the NTP to characterize longer-term effects on reproduction, development and developmental neurotoxicity following exposure to TPHP and IPP.

Triphenyl Phosphate (TPHP)

Study Tables

Isopropylated Phenyl Phosphate (IPP)

Study Tables