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Repeated dose toxicity: oral

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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

Constituent 1
Chemical structure
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

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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
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.

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