Triphenyl phosphate

Endocrine disrupter mammalian screening – in vivo (level 3)

Administrative data

Endpoint:

endocrine disrupter mammalian screening – in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Neonatal triphenyl phosphate and its metabolite diphenyl phosphate exposure induce sex- and dose-dependent metabolic disruptions in adult mice

Author:

Wang D et al

Year:

2018

Bibliographic source:

Environmental Pollution 237 (2018) 10-17

Materials and methods

Principles of method if other than guideline:

no guideline followed but uterotrophic assay according to general standard

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Triphenyl phosphate

EC Number:

204-112-2

EC Name:

Triphenyl phosphate

Cas Number:

115-86-6

Molecular formula:

C18H15O4P

IUPAC Name:

triphenyl phosphate

Test animals

Species:

mouse

Strain:

ICR

Sex:

female

State:

immature female

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

corn oil

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

subcutaneous injection once daily for three consecutive days

Frequency of treatment:

subcutaneously injected once daily for three consecutive days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

200 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

600 mg/kg bw/day

No. of animals per sex per dose:

7-8 females

Control animals:

yes, concurrent vehicle

Details on study design:

Animals were terminated 24 h after the last treatment and the uteri were dissected and weighed.

Positive control:

100 µg/kg bw/day ethinylestradiol

Results and discussion

Endocrine disrupting potential:

negative

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

Any other information on results incl. tables

Impact of neonatal TPP exposure on endocrine systems

At 12 weeks, there were no differences in estradiol levels between the control and treatment groups. At 19 days, the presence of MOFs in the ovaries of immature mice was detected in one of six ovaries in the TPP-L group, while none were present in the remaining treatment groups. The uterotrophic bioassay was not shown to increase uterine weight for any of the TPP or DPP doses in either mice or rats. The positive control ethinylestradiol led to a stron increase in uterine weight.

Impact of neonatal TPP exposure on body weight, body composition, and OGTT In males, there were no significant differences in body weight prior to 6 weeks; however, after this time, there was a significant increase in body weight gain in the TPP-L group compared to the controls, extending to 12 weeks. No significant effects on body weight were observed for the remaining treatment groups during the experimental period. In females, none of the treatments had any effect on body weight.

Considering the changes in body weight observed in male mice compared to female mice, body composition and glucose tolerance were evaluated only in males. OGTT performed at 10 weeks did not show any glucose intolerance in any of the dosage groups. The exact conditions of the glucose test are not clearly described, but the result is described with no intolerance in any of the dosage groups. At 12 weeks, no differences were observed in abdominal adipose weight in all treatment groups compared to the controls.

Impact of neonatal TPP exposure on the metabolic profiles of adult male mice

Metabolomics analyses revealed a dose- and sex-specific response of adult mice to TPP and DPP exposures. Although the findings showed perturbations of metabolic profiles induced by neonatal TPP or DPP exposure, the underlying mechanisms of action for these changes remain unknown.

Applicant's summary and conclusion

Executive summary:

A traditional uterotrophic bioassay was performed by Wang D et al. (2018) in 17-days old female ICR mice. The immature animals were subcutaneously injected once daily for three consecutive days with solutions of corn oil (control), 200 or 600 mg/kg TPP, 200 or 600 mg/kg DPP, or 100 µg/kg ethinyloestradiol as a positive control. Animals were terminated 24 h after the last treatment and the uteri were dissected and weighed. The uterotrophic bioassay was not shown to increase uterine weight for any of the TPP or DPP doses in either mice or rats.

Wang D et al. also investigated the effects of triphenyl phosphate (TPP) and one of its main metabolite diphenyl phosphate (DPP) on the endocrine systems and metabolic profiles in 8 newborn ICR mice per group after neonatal subcutaneous exposure from postnatal days 1-10 at two dosages (2 and 200 µg per day). Both TPP and DPP had no negative effect on uterine weight, glucose tolerance, and estradiol levels. Histopathological investigation of ovaries showed no consistent effects. Multi-oocyte follicles were recorded only in the low TPP dose group, while none were present in the remaining treatment groups. Metabolomics analyses revealed a dose- and sex-specific response of adult mice to TPP and DPP exposures. Although the findings showed perturbations of metabolic profiles induced by neonatal TPP or DPP exposure, the underlying mechanisms of action for these changes remain unknown.