Nonylphenol, branched, ethoxylated

Endpoint summary

Key value for chemical safety assessment

Absorption rate - oral (%):

20

Absorption rate - dermal (%):

1

Additional information

Oral

 

The metabolism of nonyl phenol ethoxylates takes place by shortening the ethylene oxide chain, carboxylation of the alkyl chain by omega oxidation and subsequent glucoronide and sulphate conjugation (CIR, 1983).

 

Knaak et al. (1966) fed 67 mg/kg of NP-¹⁴C TP-9 (a commercial product containing on average 9 moles of EO per mole of NP, i.e. NPE-9) or ¹⁴C-NP to rats and followed urinary, faecal over a period of 7 days and CO₂ excretion over a period of 4 days. Within the observed time period, 20% of the NP-¹⁴C TP-9 was excreted in urine, 78% in faeces and none as¹⁴CO₂ ¹⁴C-NP per se was found to be excreted in a similar manner. In the same study, Knaak et al. also exposed rats to 7, 10, 12 and 15 mole adducts of NP isolated from ethylene oxide-labelled TP-9. The 12 and 15 mole adducts were excreted to a greater extent in the feces than the 7 and 10 mole adducts, while the reverse situation occurred in urine.

 

Modelling the metabolism of NPE-2 and NPE-4 in liver using the using prediction tools such as the OECD toolbox, SMARTCyp and Meta2DPrint suggests that both ethoxylates follow similar metabolic pathways with oxidation and subsequent shortening of the ethoxy chain and oxidation/hydroxylation of the branched nonyl chain being the main Phase I transformation reactions. Glucorinidation and sulphation follow in Phase II. The observed and simulated liver metabolism data for NP indicates that it is likely to undergo predominantly oxidation in Phase I and subsequent glucouronation and sulphation in Phase II. Thus, based on their similar metabolic pathways, read-across from NPEO to NPE-4 is justified and considered more appropriate than reading across to data from NP.

Oral absorption of the nonyl phenol ethoxylates constituting NPEO will be favoured by their low molecular weights (ca. 264 – 485) but may be limited by water solubility and high log Pow values (> 4). For the purpose of DNEL derivation and risk assessment, a conservative oral absorption value of 20% was selected.

Dermal

A study was conducted to evaluate the absorption of NP in isolated perfused skin (IPPSF) and to compare the percutaneous absorption to a previous published in vitro porcine study in a flow-through diffusion cell system (PSFT). The isolated perfused porcine skin flap used for the study was created on the ventral abdomen. Two single-pedicle axial pattern skin flaps, each lateral to the ventral midline on the pig abdomen, were created during stage 1 and harvested during stage 2 surgery. The flaps were cannulated, flushed to clear the vasculature of blood and transferred to a perfusion chamber. The flaps were perfused for 1 h prior to dosing, during which arterial and venous samples were collected to determine glucose utilization and zero-time perfusate samples for flux determinations. A stomahesive template was secured to the flap with skin-bond. The skin flap was returned to the chamber and dosed with¹⁴C radiolabeled test substance and after the perfusion was resumed. Perfusate samples were later collected and analyzed for glucose and radioactivity.The remaining venous efflux was collected for ¹⁴C determination. The flap and cradle were removed from the flap chamber and rinsed for recovery and the dose area was washed. The tape strips were placed in vials containing ethyl acetate for estimation of stratum corneum penetration.

Flow-through diffusion cell system: Pig skin was dermatomed and circular sections were mounted epidermal side up in diffusion cell blocks. Skin was equilibrated in the diffusion cell chambers prior to dosing. A constant perfusate flow rate was maintained during the study. Treatments were dosed with test substance to a nonoccluded areal and perfusate was collected during the study. At the completion of the study tape strips were collected for estimation of stratum corneum penetration. The upper half of the chamber was rinsed and the wash collected for mass balance determination. The remaining skin section was divided into dosing site and peripheral tissue. Perfusate and all tissue samples were then analyzed for total¹⁴C determination.

The amount of applied chemical that penetrates the stratum corneum and skin in the skin flap is considered to be the maximum estimate in humans that ultimately could be absorbed since it assumes no loss due to exfoliation of the stratum corneum. Comparison of the skin flap results with those from previous studies indicates that the amounts absorbed into the perfusate are remarkably similar, although a smaller percentage of the applied dose penetrated into the skin flap.

Under the study conditions, the test substance was considered to be minimally absorbed in the isolated perfused skin flap model and the potential systematic exposure from skin contact in humans is considerably less than 1%. The authors found similar results with NPE-4 and NPE-9 (Monteiro-Riviere et al., 2003).