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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 6 1993 - July 4 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD-Guidline study conducted in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
2-benzyloxy-naphthalene
IUPAC Name:
2-benzyloxy-naphthalene
Constituent 2
Chemical structure
Reference substance name:
2-(phenylmethoxy)naphthalene
EC Number:
405-490-3
EC Name:
2-(phenylmethoxy)naphthalene
Cas Number:
613-62-7
Molecular formula:
C17H14O
IUPAC Name:
2-(benzyloxy)naphthalene
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): BNE
- Substance type: organic
- Physical state: solid
- Analytical purity: 99.8%
- Lot/batch No.: 20979
- Expiration date of the lot/batch: August 31, 1994
- Stability under test conditions: stable for 7 days at 60 mg/ml in corn oil
- Storage condition of test material: at room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL-Biological Research Laboratories Ltd., Wölferstrasse 4, CH 4414 Füllinsdorf / Switzerland
- Age at study initiation: 11 weeks
- Weight at study initiation: 185 - 228 g
- Fasting period before study: no
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days minimum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3 °C
- Humidity (%): 40 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12 h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

The mixtures of the test article and vehicle were prepared daily before administration.
BNE was weighed into a glass beaker on a tared precision balance and the vehicle added (w/v). The mixtures were prepared using a mortar and pestle. During the daily administration period, homogeneity was maintained using a magnetic stirrer.

VEHICLE
- Amount of vehicle (if gavage): 2 ml / kg bw
- Source: Corn oil of specific quality, Siegfried AG, CH 4800 Zofingen / Switzerland.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability of the test article/vehicle mixtures were determined on one occasion before starting the study. Samples were taken immediately after preparation and again 2 hours later. During the dosing period of this study, samples were taken for confirmation of concentration, hommogeneity and stability on one occasion. analyses were performed by the RCC Analytical Chemistry Laboratory using a method supplied by the sponsor.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1.0
- Length of cohabitation: overnight
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 through to day 15 post coitum.
Frequency of treatment:
once daily
Duration of test:
On day 21 post coitum, the females were killed by CO2 asphyxiation and the fetuses were removed by Caesarean section.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300 1000 mg / kg bw / day
Basis:
actual ingested
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dosages were based on the results of the dose range-finding study.
- Animal assignment: Mated rats were assigned to the different groups on the day of mating using a random algorithm.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on day 21 post coitum
- Organs examined: all internal organs with emphasis upon the uterus, uterine content, position of fetuses in the uterus and number of corpora lutea
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Soft tissue examinations / Head examinations: Yes: half per litter
Statistics:
The following statistical methods were used to analyze body weights, food consumption, reproduction and skeletal examination data:
Means and standard deviation of various data were calculated. Univeriate one-way analysis of variance was used to assess the significance of intergroup differences. If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-one t-test), based on a pooled variance estimate, was applied for intergroup comparisons (i.e. single treatment groups against the control group).
The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.
Individual values, means, standard deviations and t-statistics were rounded off before printing.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
2-(phenylmethoxy)naphthalene was adiminstered orally by gavage once daily to mated female Wistar rats at dosages of 100, 300, and 1000 mg/kg body weight/day from day 6 ghrough to day 15 post coitum to assess the effects on embyonic and fetal development.
No test article-related effect on the maternal or fetal organism was noted up to and including the highest dose level of 1000 mg/kg bw/day, which was considered to be the no-observable adverse effect level (NOAEL).
Under the conditions described for this study, 2-(phenylmethoxy)naphthalene did not reveal any teratogenic potential up to and including the highest dose level of 1000 mg/kg bw/day.
Executive summary:
The purpose of this study was to assess the effects of 2-(phenylmethoxy)naphthalene on embryonic and fetal development in pregnant Wistar rats.

Each group consisted of 25 mated female rats. 2-(phenylmethoxy)naphthalene was administered orally by gavage once daily from day 6 through to day 15 post coitum, at dose levels of:

Group 1: 0 mg/kg bodyweight/day (vehicle conrol)

Group 2: 100 mg/kg bodyweight/day

Group 3: 300 mg/kg bodyweight/day

Group 4: 1000 mg/kg bodyweight/day

The dosages were based on the results of the dose range-finding study. The dose volume was 2 ml/kg body weight with a daily adjustment to the acutal body weight. Control animals were dosed with the vehicle alone (corn oil).

Females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section. the examination of the dams and fetuses was performed in accordance with international recommendations.

Results

Maternal Data

General Tolerability

No animal died before scheduled necropsy. No test article-related clinical symptoms or postmortem findings were noted. Mean daily food consumption, body weight gain and corrected body weight gain (corrected for uteris weight) were unaffected by the treatment with the test article.

Reproduction Parameters

The reproduction parameters of dams showed no test article-related differences to those of the vehicle control dams.

Fetal Data

Evaluation of external examinations (for abnormal findings), visceral examination (Wilson's technique), and skeletal examinations (for abnormal findings and stage of development) showed no test article-related effects.

Sex ratios of all groups compared favorably. Differences noted in mean fetal body weights were considered to be incidental.

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