Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
1998
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetraphenylphosphonium phenolate
EC Number:
239-480-3
EC Name:
Tetraphenylphosphonium phenolate
Cas Number:
15464-47-8
Molecular formula:
C24H20P.C6H5O
IUPAC Name:
tetraphenylphosphanium benzenolate
Constituent 2
Chemical structure
Reference substance name:
Phenol
EC Number:
203-632-7
EC Name:
Phenol
Cas Number:
108-95-2
Molecular formula:
C6H6O
IUPAC Name:
phenol
Test material form:
solid: crystalline
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: analytically confirmed
- Homogeneity and stability of the test substance in the solvent/vehicle: analytically confirmed
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: none

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Hsd Cpb:WU (SPF-bred)
- Source: Harlan-Winkelmann GmbH, 33178 Borchen, Germany
- Acclimation period: at least 7 days prior to mating
- Body weight of animals at the time of mating: 386-438 g for males, 216-254 g for females
- Age at the day of mating: 15-17 weeks
- Housing: individually in Makrolon cages (MIII type)
- Diet and water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): approximately 50
- Air changes (per hr): > 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 2002-01-21 to experimental completion date (fetal visceral evaluation) on 2003-10-21

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
400
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Fresh adminstration fromulations for each concentration were prepared daily.

VEHICLE
- vehicle: Polyethylene glycol 400
- Justification for use and choice of vehicle (if other than water): Based on trial formulations.
- Amount of vehicle (if gavage): 5 mL/kg bw

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity and stability for at least 4 hours at room temperature was confirmed over the concentration range 0.2 to 270 mg/mL.
Accuracy of formulations was proven at two days during inlife phase.
Details on mating procedure:
Animals were mated by placing two females overnight together with one male rat. If sperm count was detected in the vaginal smear taken on the morning following mating, this day was regarded as day 0 of gestation.
Duration of treatment / exposure:
Days 6 - 19 post-coitum, inclusive; fetuses were delivered by cesarean section on day 20 p.c.
Frequency of treatment:
Once daily
Duration of test:
from day 0 to necropsy at day 20 p.c.
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
160 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
27 pregnant females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In order to set the dose levels for the main teratology study, a dose range finding study was performed. Four groups of 8 pregnant females were exposed to 0, 10, 40 and 160 mg/kg bw/day for Days 6 to 19 post-coitum inclusive by oral gavage.

Based on the results of the dose range finding study, selected dose levels for the main study were 10, 40 and 160 mg/kg bw/day.

Examinations

Maternal examinations:
CLINICAL EXAMINATIONS: Yes
- Time schedule: in general twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: on day 0 pc and daily from day 6 to 20 pc

FOOD CONSUMPTION: Yes
- Days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-20 post-coitum.

WATER CONSUMPTION: Yes
- Once daily. Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.

POST-MORTEM EXAMINATIONS: Yes
- All animals surviving to the end of the observation period and the animal showing premature delivery were sacrificed using cardiotomy under deep carbon dioxide anestesia.
Ovaries and uterine content:
Each ovary and uterine horn of animals surviving to planned necropsy was dissected and examined as quickly as possible to determine:
- The number of corpora lutea.
- The weight of the (gravid) uterus.
- The number and distribution of live and dead fetuses.
- The number and distribution of embryo-fetal deaths (early and late resorptions).
- The weight of each fetus.
- The sex of each fetus from the ano-genital distance (during necropsy) and also from gonadal
inspections (during further fetal examination).
- Externally visible macroscopic fetal abnormalities.
Fetal examinations:
External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).
Statistics:
yes
Historical control data:
yes, historical data on fetal morphology are part of the report

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
treatment resulted in increased incidences of salivation after administration at al dose levels, possibly a result of a bad taste or olfactory component of the test substance. For the reddish discolored salivation that was observed at 40 mg/kg bw and above a treatment related effect could not be excluded.
Mortality:
no mortality observed
Description (incidence):
two females in the control group and one female in the 160 mg group died/were sacrificed due to misapplication.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 160 mg/kg bw body weight gain from days 6-19 pc was distinctly reduced compared to control animals (54.8 g versus 76.4 g).
Also the corrected body weight gain from days 0-20 was lower in 160 mg/kg bw animals than in control animals (19.2 g versus 46.7 g).
Description (incidence and severity):
Food intake was reduced from start of treatment to the end of gestation at the 160 mg/kg bw dose level.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
necropsy revealed no treatment related findings.
Neuropathological findings:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
At 60 mg/kg bw/day, a significant increase in pre-implantation loss was observed (12.2 % compared to 6.0 % in the control group). Treatment was started on Day 6 post-coitum, after implantation has occurred, therefore this finding is considered not to be related to treatment. Moreover, no dose response relationship was noted.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: reddish discolored salivation after administration at >= 40 mg/kg bw and distinctly reduced body weight and food consumption at 160 mg/kg bw

Maternal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
other: general maternal toxicity
Description (incidence and severity):
very slight severity at 40 and 160 mg/kg bw

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
160 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects at this dose

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Executive summary:

In a prenatal developmental toxicity study performed according to OECD TG 414 mated female Wistar rats were assigned to four dose groups, each containing twenty-seven animals. The test item was administered once daily by gavage from Day 6 to 19 post-coitum at doses of 10, 40 and 160 mg/kg bw/day. The animals were sacrificed on day 20 pc. The rats of the control group received the vehicle, Polyethylene glycol 400, alone.

With regard to maternal toxicity salivation occured in all treated animals. At 40 mg/kg bw and above reddish discolored salivation was observed that was considered as treatment related and adverse. At 160 mg/kg bw body weight development was distinctly impaired and food intake was reduced.

No further maternal toxicity or any developmental findings became obvious.

In conclusion and based on the results in this prenatal developmental toxicity study the maternal No Observed Adverse Effect Level (NOAEL) was established as being 10 mg/kg bw/day and the NOAEL for developmental toxicity was determined with 160 mg/kg bw.