Reaction products of triphenyl phosphite and isodecanol (1:1)

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Remarks:

70-day repeat dose exposure in an expanded OECD 422 study

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

yes

Remarks:

This protocol exceeded the OECD 422 study design by following the F1 offspring to adulthood, with continued exposure and assessments of neurologic, immunologic and reproductive structures and functions. The protocol also assessed F0 recovery males, 28-day

Principles of method if other than guideline:

Method: Expanded OECD 422 study with extended dosing (up to 70-days) and dosing in the second generation.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triphenyl phosphite

EC Number:

202-908-4

EC Name:

Triphenyl phosphite

Cas Number:

101-02-0

Molecular formula:

C18H15O3P

IUPAC Name:

triphenyl phosphite

Details on test material:

- Name of test material (as cited in study report): TPPi
- Analytical purity: 99.7%
- Lot/batch No.: 237T03101

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Premating exposure period for males (P and F1) as appropriate: 2 weeks
Premating exposure period for females (P and F1) as appropriate: 2 weeks

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

16 weeks

Frequency of treatment:

1/day 7d/wk

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, 15 and 40 mg/kg/day
Basis:

No. of animals per sex per dose:

10 animals/sex/dose for 2 weeks of prebreed exposure (males and females); Five additional F0 males per group from the control and 40 mg/kg/day groups were designated as recovery animals and held without dosing for 2 weeks after the F0 male dosing period was completed, to evaluate recovery from any possible treatment-related effects identified in the high-dose group. Additional 28-day females (5/group at 0 and 40 mg/kg/day) and 28-day recovery females (5/group at 0 and 40 mg/kg/day) were also similarly assessed.

Control animals:

yes

Examinations

Sacrifice and pathology:

- All F0 parental animals, non-selected F1 weanlings and retained F1 adults were necropsied with complete histologic evaluation of 5 selected F0 males and females in the 0 and 40 mg/kg/day groups. Because of extreme toxicity in the F1 offspring at 40 mg/kg/day, no F1 offspring were retained after weaning. Therefore, tissues from 5 F1 males and females per group at 0 and 15 mg/kg/day were examined histopathologically.

- Hematology, clinical biochemistry and urinalysis (males only) were performed at necropsy for 5 randomly selected parental F0 males and females and for F1 adult males and females per dose group.

Other examinations:

Histopathology was performed on F1 males and females (5/sex/group) at 0 and 15 mg/kg/day.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Haematological findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

2

Key result

Dose descriptor:

LOAEL

Effect level:

40 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

neuropathology

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The F0 male and female systemic no observable adverse effect (NOAEL) was 15 mg/kg/day. The NOAELs for F0 reproductive toxicity were at or above 40 mg/kg/day for males and females. The NOAELs for F1 offspring toxicity during lactation were 15 mg/kg/day for males and females. The F1 male and female systemic NOAEL was also 15 mg/kg/day.

Executive summary:

The F0 male and female systemic no observable adverse effect (NOAEL) was 15 mg/kg/day. The NOAELs for F0 reproductive toxicity were at or above 40 mg/kg/day for males and females. The NOAELs for F1 offspring toxicity during lactation were 15 mg/kg/day for males and females. The F1 male and female systemic NOAEL was also 15 mg/kg/day.