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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Rationale: GLP Guideline study
Cross-reference
Reason / purpose:
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:
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.
Principles of method if other than guideline:
Method: Modified
GLP compliance:
yes
Limit test:
no
Justification for study design:
Expanded exposure duration and endpoint evaluations. See full report for details.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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
Details on mating procedure:
Mating period lasted for 2 weeks; gestation and lactation lasted 3 weeks
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
16 weeks
Frequency of treatment:
1/day 7d/wk
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
5 mg/kg bw/day (actual dose received)
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
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
Details on study design:
The study design greatly exceed typical exposure durations and included additional endpoint of the F0 and F1 generations.

Examinations

Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of (5/sex/litter as nearly as possible)

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: On the day of birth (postnatal day [pnd] 0), anogenital distance was measured and body weights recorded for all live F1 pups in all litters.

GROSS EXAMINATION OF DEAD PUPS:
The culled F1 pups were weighed, euthanized, and necropsied with complete external and visceral examinations.
Postmortem examinations (offspring):
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.
Reproductive indices:
For the remaining F1 pups after standardization performed, survival indices were calculated at least weekly through weaning (pnd 21).

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 40 mg/kg bw/day
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F1 generation

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
15 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: This value is for F1 toxicity during lacation.

Overall reproductive toxicity

Reproductive 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:

Used for data submission.