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NIEHS-05

NIEHS Report on the In Vivo Repeat Dose Biological Potency Study of Isopropylated Phenol Phosphate (CASRN 68937-417) in Male Sprague Dawley (Hsd:Sprague Dawley® SD®) Rats (Gavage Studies)

Abstract

Background: Isopropylated phenol phosphate (IPP) is an organophosphate flame retardant currently on the market that is used as a replacement for phased-out polybrominated diphenyl ethers. Commercially available IPP is a mixture of triphenyl phosphate and mono-, di-, and tri-isopropyl-substituted isomers. Toxicological information on this class of chemicals is sparse. A short-term, in vivo transcriptomic study was used to assess the biological potency of IPP.

Methods: Scientists at the Division of Translational Toxicology, National Institute of Environmental Health Sciences conducted this short-term in vivo biological potency study on IPP in young adult male Sprague Dawley (Hsd:Sprague Dawley® SD®) rats. IPP was formulated in corn oil and administered once daily for 4 consecutive days by gavage. IPP was tested at six doses (0, 77, 153, 306, 611, and 1,222 mg/kg body weight [mg/kg] corresponding to 0, 0.169, 0.338, 0.675, 1.35, and 2.7 mmol/kg). On study day 4, animals were euthanized, standard toxicological measures were assessed, and the liver was assayed in gene expression studies using Affymetrix microarrays. Modeling was conducted to identify the benchmark doses (BMDs) associated with apical toxicological endpoints and transcriptional changes in the liver. A benchmark response of one standard deviation was used to model all endpoints.

Results: Several clinical pathology and organ weight measurements showed dose-related changes from which BMD values could be obtained. The effects include decreased serum albumin/globulin ratio, increased relative liver weight, decreased serum albumin concentration, decreased creatinine level, decreased terminal body weight, and increased absolute liver weight. The BMDs and benchmark dose lower confidence limits (BMDLs) were 51.3 (27.0), 55.8 (33.7), 167.6 (63.2), 223.9 (158.9), 278.2 (187.3), and 400.0 (246.0) mg/kg, respectively. Although serum cholinesterase activity was significantly decreased and total cholesterol concentration was significantly increased in all dosed groups, beginning with 77 mg/kg (the lowest-observed-effect level), their BMD values were below the lower limit of extrapolation (<25.7 mg/kg). Highdensity lipoprotein (HDL) cholesterol concentration was also significantly decreased at all doses, beginning with 77 mg/kg, but a BMD (BMDL) was not determined because no viable model was available.

The top 10 most sensitive Gene Ontology biological processes had estimated BMD median values <25.7 mg/kg. The top 10 most sensitive individual genes also exhibited changes in expression at dose levels below which a reliable estimate of potency could be achieved (<25.7 mg/kg). Six of these genes were upregulated: Tbx3, Nr1d1, Nr1d2, Sik2, Oaf, and Dbp. Four genes, Gck, Syne1, Cdkn1a, and Cldn1, were downregulated.

Summary: Taken together, the most sensitive apical endpoint BMD (BMDL) value that could be reliably determined occurred at 51.3 (27.0) mg/kg. The BMDs (BMDLs) could not be determined for the top 10 most sensitive gene sets or the top 10 most sensitive individual genes and were estimated to be <25.7 mg/kg. Serum cholinesterase inhibition and increases in serum total cholesterol were also estimated to be <25.7 mg/kg. HDL cholesterol appeared to be a sensitive endpoint at all doses, but its BMD (BMDL) was not determined because no viable model was available. Future studies investigating lower doses would be helpful to obtain more accurate estimates of BMD values for the most sensitive gene sets, individual genes, and for serum cholinesterase inhibition and total cholesterol increases.

Citation: Auerbach SS, Behl MV, Collins BJ, Cora MC, Fostel JM, Ingle BL, Liu YF, Luh J, Roberts GK, Shipkowski KA, Waidyanatha S, Watson ATD. 2022. NIEHS report on the in vivo repeat dose biological potency study of isopropylated phenol phosphate (CASRN 68937-41-7) in male Sprague Dawley (Hsd:Sprague Dawley® SD®) rats (gavage studies). Research Triangle Park, NC: National Institute of Environmental Health Sciences. NIEHS Report 05. [https://doi.org/10.22427/NIEHS-05 Auerbach SS, Behl MV, Collins BJ, Cora MC, Fostel JM, Ingle BL, Liu YF, Luh J, Roberts GK, Shipkowski KA, Waidyanatha S, Watson ATD. 2022. NIEHS report on the in vivo repeat dose biological potency study of isopropylated phenol phosphate (CASRN 68937-41-7) in male Sprague Dawley (Hsd:Sprague Dawley® SD®) rats (gavage studies). Research Triangle Park, NC: National Institute of Environmental Health Sciences. NIEHS Report 05.]

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