p-nonylphenol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Mass spectrometric determination of p-nonylphenol metabolism and disposition following oral administration to Sprague-Dawley rats

Author:

Daniel R. Doergea,*, Nathan C. Twaddlea, Mona I. Churchwella, Hebron C. Changa, Retha R. Newboldb, K. Barry Delclosa

Year:

2002

Bibliographic source:

Reproductive Toxicology 16 (2002) 45–56

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

In Vivo metabolism and disposition study of p-nonylphenol in rat

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

p-nonylphenol

EC Number:

203-199-4

EC Name:

p-nonylphenol

Cas Number:

104-40-5

Molecular formula:

C15H24O

IUPAC Name:

4-nonylphenol

Details on test material:

- Name of test material (as cited in study report): p-nonylphenol (NP)
- Molecular formula (if other than submission substance): C15-H24-O
- Molecular weight (if other than submission substance): 220.354 g/mole
- Substance type: Organic
- Physical state: No data available
- Impurities (identity and concentrations): 5% of branched side chain isomers of 2-NP

Radiolabelling:

not specified

Test animals

Species:

rat

Strain:

other: CD (Sprague-Dawley)

Sex:

male/female

Administration / exposure

Route of administration:

other: Oral gavage and feed

Vehicle:

other: sesame oil and NP-fortified diets

Details on exposure:

The low serum NP levels measured in rats receiving the 750 ppm diet precluded a detailed study of NP toxicokinetics in these animals. The rats were removed from the control diet and within 4 h were administered NP by gavage at 50 mg/kg using a 50 mg/mL solution of NP in sesame oil.

Duration and frequency of treatment / exposure:

141 days daily for feed and 4 h for gavage

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 200 and 750 ppm (0, 0, 1.25, 10 and 50 mg/kgbw/day)and 50 mg/kg

No. of animals per sex per dose / concentration:

6 male, 6 female

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

No data available

Details on study design:

The low serum NP levels measured in rats receiving the 750 ppm diet precluded a detailed study of NP toxicokinetics in these animals. Animals receiving 25 ppm diet would not contain detectable serum levels of NP. Therefore, the six male and six female littermates that had been maintained on the 25 ppm NP-fortified diet until PND 115 were placed on the control diet for one month prior to use in a toxicokinetic gavage exposure study on PND 145.No overt toxicity was observed in the 50-day NP dose range-finding study below 500 ppm and the one month period on control diet was predicted to reverse any enzyme induction that might have occurred. The rats were removed from the control diet and within 4 h was administered NP by gavage at 50 mg/kg using a 50 mg/mL solution of NP in sesame oil. Blood was collected from the tail vein of each rat at 0.25–12 h, allowed to clot at 0°C for 30 min, then centrifuged to produce serum, and aliquots were frozen at 70°C until analysis.

Results and discussion

Preliminary studies:

Yes, no overt toxicity was observed in the 50-day NP dose range-finding study below 500 ppm.

Main ADME results

Main ADME results 1

Type:

absorption

Results:

NP was rapidly absorped

Main ADME results 2

Type:

distribution

Results:

Distributed in serum,kidney, livers, brain and Placental transfer

Main ADME results 3

Type:

metabolism

Results:

Rapied first-pass metabolism

Main ADME results 4

Type:

excretion

Results:

Rapidly eliminated by glucuronidation

Toxicokinetic / pharmacokinetic studies

Details on absorption:

NP was rapidly absorped

Details on distribution in tissues:

No significant sex difference in the distribution was observed at any time point or overall in treated rats. The largest difference between females and males was observed in the livers with more similar levels observed in kidney and brain. Reproductive tissues generally contained low levels of total NP with the exception of prostate. The aglycone content was measured in livers from rats on the 50 mg/kg diet. Female livers contained an average of 44% aglycone and male livers contained an average of 13% aglycone. Female brains were found to contain NP aglycone levels that averaged 57% of total NP. Placental transfer into serum and brain in pregnant female rats.

Details on excretion:

Rapied first-pass metabolism were observed and Two major glucuronides were observed in rat serum and liver by LC-ES/MS analysis. Substantial amounts of NP-catechol glucuronides were also observed in serum and liver.

Toxicokinetic parameters

Toxicokinetic parameters:

AUC: Male - 240 61, Female -350 77

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Yes , NP-glucuronides and putative nonylcatechol-glucuronides

Any other information on results incl. tables

Levels of total NP in female rat tissue. NP was determined in the indicated tissues in nmol/g using LC-APCI/MS as described in the Methods section.

The values shown have been adjusted for the responses observed in the respective control tissue and represent means ± SD for n = 6. The limit of quantification (LOQ) in serum was approximately 0.23 μM. Samples not analyzed are designated NA.

Dietary Dose	Serum	Liver	Kidney	Uterus	Brain	Mammary	Ovary
750 ppm-female	0.93 ± 0.28	8.1 ± 8.6	2.4 ± 2.4	0.080 ± 0.11	1.4 ± 1.2	< LOQ	< LOQ
200 ppm	< LOQ	3.5 ± 1.7	NA	NA	NA	NA	NA

 

Levels of total NP in male rat tissue. NP was determined in the indicated tissues in nmol/g using LC-APCI/MS as described in the Methods section.

The values shown have been adjusted for the responses observed in the respective control tissue and represent means  ± SD for n = 6. Samples not analyzed are designated NA

Dietary Dose	Serum	Liver	Kidney	Prostate	Brain	Testes
750 ppm	0.35 ± 0.20	2.6 ± 3.2	2.1 ± 2.0	0.82 ± 0.11	0.42 ± 0.70	< LOQ
200 ppm	< LOQ	1.6 ± 1.7	NA	NA	NA	NA

 

Toxicokinetics of NP following gavage administration of 50 mg/kg to male and female rats. Area under the concentration-time curves, elimination and absorption half-times were determined graphically for individual rats as described in the Methods section and values shown represent means ± SD (n = 6)

Sex	t1/2Elim (h)	t1/2Abs (h)	AUC (μ Mh)
Male	3.1 ±  0.52	0.37 ± 0.14	240 ± 61
Female	4.0 ± 1.5	0.90 ± 0.70	350 ± 77^a

^aStatistically different from male AUC data (P < 0.02).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
On the basis of observed result it is concluded the p-nonylphenol have rapide absorption and elimination. Metabolisum is gender-specific and distribution is aglycone estrogen-responsive. Hance, expected to have Low bio-accumulation potential based on study results.

Executive summary:

In a in vivometabolism and disposition study,CD (Sprague-Dawley) male and female rats were treated with p-nonylphenol orally by gavage at 0, 0, 1.25, 10 and 50 mg/kgbw/day and by feed 50 mg/kg. It was observed that p-nonylphenol were rapidly absorbed in serum. The largest difference between females and males was observed in the livers with more similar levels observed in kidney and brain. Reproductive tissues generally contained low levels of total NP with the exception of prostate. The aglycone content was measured in livers from rats on the 50 mg/kg diet. Female livers contained an average of 44% aglycone and male livers contained an average of 13% aglycone. Female brains were found to contain NP aglycone levels that averaged 57% of total NP. Placental transfer into serum and brain were observed in pregnant female rats. NP was rapidly eliminated by glucuronidation from serum. The higher tissue concentrations of total NP in females as compared to males in relative serum concentrations were observed. However, the much higher levels of total NP in female livers, coupled with the higher levels of aglycone, suggest that gender-specific metabolic factors affecting clearance. The active aglycone form can still accumulate in estrogen-responsive tissues of rats. Therefore, On the basis of observed result it is concluded the p-nonylphenol have rapide absorption and elimination. Metabolisum is gender-specific and distribution is aglycone estrogen-responsive. Hance, expected to have Low bio-accumulation potential based on study results.