2-(phenylmethoxy)naphthalene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19 November 1993 - 4 May 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD-Guideline Study conducted under GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

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: (P) males 6 wks, females 9 wks
- Weight at study initiation: (P) Males: 132.8 - 159.8 g; Females: 160.4 - 189.4 g
- Housing: individually

- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3 °C
- Humidity (%): 40 - 70 %
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12 h

Route of administration:

oral: feed

Vehicle:

acetone

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test article was dissolved in acetone, mixed with granulated feed in a Buehler Mixer, type DDMA-0.5 and pelleted in a Buehler pelleting machine type DFPL. Water was added to each feed preparation at an approximate 1:10 volume/weight ratio to ensure pelleting, after which the pellets were dried with warm air for approximately 48 hours before storage.

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): Kliba 343 (batches 86/93 and 70/94 rat/mouse maintenance diet, Klingentalmuehle AG, CH 4303 Kaiseraugst, Switzerland)
- Storage temperature of food: room temperature

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility reasons
- Concentration in vehicle: no data

Details on mating procedure:

- M/F ratio per cage: 1.0
- Length of cohabitation: up to 16 days
- Proof of pregnancy: sperm in vaginal smear / vaginal plug referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis of the test article, its content, homogeneity and stability in the feed pellets were determined before starting the test. In this study, feed samples for conten and homogeneity were taken before the start of the prepairing period and at the end of gestation/start of lactation period. The analyses were performed in the analytical laboratories of RCC Umweltchemie AG according to an analytical method supplied by the sponsor.

Duration of treatment / exposure:

the P generation animals of both sexes received the test article in the diet prior to pairing (males for 70 days, females for 14 days). The animals continued to receive the diets during pairing until sacrifice. The dams were sacrificed on day 21 post partum, the males were sacrificed on days 29 or 30 of the after pairing period.

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 600, 3000, 15000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: dose levels were proposed by the sponsor based upon the results of a previous study.
- Rationale for animal assignment (if not random): random
- Other:

Positive control:

no

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once or twice per day

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

Oestrous cyclicity (parental animals):

During the treatment period prior to pairing, vaginal smears were taken from all females to determine estrous cycles. The various stages of the estrous cycle (proestrus, estrus, metestrus, diestrus) were recorded.

Sperm parameters (parental animals):

Parameters examined in P male parental generations:
prostate, seminal vesicales with coagulating gland, testes with epididymides and pituitary were examined histopathological

Litter observations:

Pups were weighed individually on days 0 (if possible) and/or 1, 4, 7, 14, 21 of the lactation period. To prevent cannibalism immediately after birth the pups were weighed individually on day 0 post partum but not tattooed. The dams and pups were observed daily for survival and behavioral abnormalities in nesting and nursing.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals were sacrificed on days 29 or 30 of the after peiring period.
- Maternal animals: All surviving animals were sacrificed on day 21 post partum.

GROSS NECROPSY
- Gross necropsy consisted of macroscopical examination for any structural abnormalities or pathological changes.

HISTOPATHOLOGY / ORGAN WEIGHTS
Any gross lesions, the ovaries, pituitary, prostate, seminal vesicles with coagulating gland, testes with epididymides, uterus and cervix and vagina were prepared for microscopic examination.

Postmortem examinations (offspring):

external and internal examination for abnormalities.

Statistics:

The following statistical methods were used to analyse body weights, food consumption and reproduction data:
- Means and standard deviation of various data were calculated.
- Univariate one-way analysis of variance was used to assess significance of intergroup differences.
- If the variables could be assumed to follow a normal distribution the Dunnett many-one t-test, based on a pooled variance estimate, was used 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.

Reproductive indices:

Birth Index

Offspring viability indices:

Viability index, weaning index

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

In the high dose female group, the mean daily food consumption and mean body weight were reduced during the prepairing, gestation and lactation periods. this finding was considered to be test article- related.
In the mid-dose female group, very slight toxic effects were characterized by minimal reductions of mean daily food consumption during gestation and lactation, and slightly reduced body weight gain during prepairing, gestation and lactation.
The mean daily food consumption and mean body weights of low-dose gemale group were similar to those of control females throughout the prepairing gestation and lactation periods.

No test article-related effects upon mean daily food consumption and mean body weights of parent males were evident.

In the high-dose female group, the following test article-related findings were noted:
- reduced mean number of implantations per dam,
- increased post-implantation loss
- reduced birth index
- reduced mean litter size.

These parameters were unaffected in groups 2 and 3.

The following parental reproduction data were considered to be unaffected by the treatment with the test article at all dose levels:
- mating performance and fertility
- mean precoital time
- mean duration of estrous cycle
- mean duration of gestation
- mean post-natal loss
- mean breeding loss.

Dose descriptor:

NOAEL

Effect level:

ca. 600 mg/kg diet

Based on:

test mat.

Sex:

female

Basis for effect level:

other: overall effects body weight; food consumption and compound intake

Dose descriptor:

NOAEL

Effect level:

ca. 3 000 mg/kg diet

Based on:

test mat.

Sex:

female

Basis for effect level:

other: number of implantation sites; birth index; litter size;

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

In male and female offspring of the mid- and high-dose group, the mean bith weight (day 0 post partum) and body weight development (days 14-21 post partum) was generally reduced when compared with that of the control offspring.
These findings were considered to be related to the treatment with the test article.

Reproductive effects observed:

not specified

Conclusions:

On the basis of this one-generation reproduction study with 2-(phenylmethoxy)naphthalene in Wistar rats, the no-observable adverse effect level was 600 ppm (mg/kg diet) for the maternal organism, 3000 ppm for maternal reproduction parameters and neonatal organism.
There was no evidence for any teratogenic activity of the test article.

Executive summary:

The purpose of this one-generation reproduction toxicity study was to provide general information concerning the effects of the test article on reproductive functions as assessed by gonadal function, estrous cycle, mating behaviour, conception, parturition, lactation, weaning and the growth and development of the offspring. The study also provided information about the effects of the test article on neonatal morbidity, mortality, behavior and preliminary data on teratogenesis.

The control group received untreated diet. Each group of the P generation consisted of 25 male and 25 female rats. The animals received the following nominal dietary concentrations:

Group 1: 0 ppm (mg/kg diet, control)

Group 1: 600 ppm (mg/kg diet)

Group 1: 3000 ppm (mg/kg diet)

Group 1: 15000 ppm (mg/kg diet)

The following results were obtained:

Parental Data: P Generation

General Tolerability

All parent animals survived to scheduled necropsy and no test article-related clinical symptoms were evident.

The food consumption and body weight gain of parent males was unaffected by treatment.

Reductions of food consumption were noted throughout the study in females treated at 15000 ppm, and during gestation and lactation in females treated at 3000 ppm. Body weight gain was reduced throughout the stury in females treated at dose levels of 300 and 15000 ppm. these findings were considered to be test article related.

The food consumption and body weight gain of females treated at 600 ppm showed no test article-induced differences.

Reproduction data

Parent females treated with 15000 ppm showed reduced mean number of implantations per dam, increased post-implantation loss, reduced birth index and reduced mean litter size. No test article-related effects were evident in females treated with 3000 and 600 ppm.

The remaining reproduction parameters (mating performance and fertility, duration of estrous cycles, mean precoital time, duration of gestation, postnatal and breeding losses) were unaffected at all dose levels.

Pathology

All abnormal macroscopical findings were considered to be incidental. There was no histopathological evidence of toxicity.

Litter Data: F1 Pups

At 15000 and 3000 ppm, reduced mean birth weight were noted in pups on day 0 post partum. Although generally similar in these groups on days 4 and 7 post partum, reduced body weight gain was ascertained in these pups from days 14 -21 post partum.

No evidence of test article-related effects on birth weights or body weight gain were seen in pups at 600 ppm.

The sex ratios of all groups compared favorably and no test article-related abnormal findings were ascertained during first litter check, during lactation or during necropsy.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

351.4 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

One study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

An One-Generation study is available and effects on fertility are observed. As toxic effects on the maternal organism occure at lower doses, it can be concluded that the fertility effects result from the condition of the maternal organism rather than from the substance itself.

Short description of key information:
An One-Generation study is available and effects on fertility are observed. A NOAEL of 351.4 mg/kg bw/day for toxicity to reproduction can be established. Furtheron toxic effects to the maternal organism were reported and a NOAEL of 71.1 mg/kg bw/day is derived.

Justification for selection of Effect on fertility via oral route:
One study available

Effects on developmental toxicity

Description of key information

A prenatal developmental study is available showing no toxic effects either on the maternal organism nor on the unborn. Under the conditions described for the study, 2-(phenylmethoxy)naphthalene did not reveal any teratogenic potential.

Link to relevant study records

Reference

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.

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

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

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.

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.

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.

Details on maternal toxic effects:

Maternal toxic effects:no effects

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

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Abnormalities:

not specified

Developmental effects observed:

not specified

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

One study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for selection of Effect on developmental toxicity: via oral route:
One study available

Justification for classification or non-classification

The study results are conclusive but not sufficient for classification.