Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Two repeated dose toxicity studies for the oral route are available. The study period is 28 days and 90 days, respectively.
The lowest identified NOAEL of 82 mg/kg bw/day was found for males in the sub-chronic study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 April 1993 - 29 March 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD-Guideline study conducted under GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
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 Ltd., Wölferstrasse 4, CH-4144, Füllinsdorf, Switzerland
- Age at study initiation: 6 weeks
- Weight at study initiation: Males: 136-170 g, Females 117-143 g
- Housing: 5 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +- 3 °C
- Humidity (%): 40 - 70 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12 h
Route of administration:
oral: feed
Vehicle:
acetone
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): every 2 weeks
- Mixing appropriate amounts with (Type of food):
The appropriate amount of BNE was dissolved in 400 ml of acetone and this was added to approx. 1 kg of diet and mixed thoroughly. Control diet was treated in the same manner, but without the addition of BNE. This pre-mix was then triturated with the appropriate amount of diet. Water (1:11 volume /weight) was added to aid pelleting. The pellets were dried for approximately 24 hours before storage. The control animals received similarly prepared pellets, but without the test substance.
- Stability: Stability of at least 21 days has been confirmed during an earlier study
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of diets of all concentrations prepared during weeks 1, 6 and 12 were analysed to chekc the accuracy and homogeneity of preparation.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 200, 1000, 5000, 20000 ppm / day BNE
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for selecting satellite groups: some animals were allowed a 4-week recovery period to assess the reversibility of any effects seen.
- Post-exposure recovery period in satellite groups:
Positive control:
no positive control
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly and at termination

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

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to commencement of study and during the last week of treatment
- Dose groups that were examined: prior to commencement: all animals, during last week: control and high dose animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to post mortem examination
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to post mortem examination
- Animals fasted: Yes
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: during week 13 (test and control groups) or week 17 (recovery group)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
The following statistical methods were used to analyse the body weight, food consumption, organ weights and clinical laboratory data:
Univariate 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-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups.
Tht Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
All tests were two-sided and in all cases p<0.05 was accepted as the lowest level of significance.
Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.
Individual values, means, standard deviations and statistics were rounded off before printing. For example, test statistics were calculated on the basis of exact values for means and pooled variances and then rounded off to two decimal places. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
The exact Fisher-test was applied to the ophthalmoscopic examination data.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
The only changes seen in this study were a reduced body weight or body weight gain of males and females exposed to 20000 ppm 2-(phenylmethoxy)naphthalene in the diet and only in females exposed to 5000 ppm 2-(phenylmethoxy)naphthalene in the diet and increased organ:body weight ratios as noted for the brain, liver, kidneys, testes and spleen from animals of the same groups.
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: body weight; organ weights;
Dose descriptor:
NOAEL
Effect level:
ca. 98 mg/kg bw/day (nominal)
Based on:
other: calculated from food consumption
Sex:
female
Basis for effect level:
other: recalculation from mg/kg diet
Dose descriptor:
NOAEL
Effect level:
ca. 82 mg/kg bw/day (nominal)
Based on:
other: calculated from food consumption
Sex:
male
Basis for effect level:
other: recalculation from mg/kg diet
Critical effects observed:
not specified

Increases in organ :body weight ratios were not accompanied by histopathological changes in these organs. In addition, the increased organ: body weight ratios may have resulted from the decrease in body weights noted from these animals.

There were no changes detected in clinical appearance, food consumption, ophthalmoscopic observations, clinical laboratory investigations, macroscopic observations and microscopic observations that were considered to be the result of treatment with 2-(phenylmethoxy)naphthalene.

Conclusions:
From the results presented in the report a definitive No Observed Adverse Effect Level (NOAEL) of 1000 ppm 2-(phenylmethoxy)naphthalene in the diet (82 mg/kg bw/day for males and 98 mg/kg bw/day for females) was established.
Executive summary:

In this 90 day dietary toxicity study, 2-(phenylmethoxy)naphthalene was included in the diet at exposure levels of 0, 200, 1000, 5000 and 20000 ppm and fed ad libitum to SPF-bred Wistar rats. the study consisted of five groups, each group comprising 10 males and 10 females. Groups 1 (Control), 4 (5000 ppm) and 5 (20000 ppm) contained 10 additional males and females, which served as a recovery group.

All animals were subjected to daily clinical observation. Body weight and food consumption were measuered weekly and, for body weights, also on the day of necropsy. Ophthalmoscopic examinations were performed prior to commencement of treatment on all animals and at week 13 on all animals of the control and high dose groups. During the last week of treatment (week 13) and the last week of recovery (week 17) blood as well as urine were collected from each animal for clinical laboratory investigations. At the end of week 13 all animals of the main group and at the end of week 17 all animals of the reovery groups were necropsied and macroscopic observations and organ weights recorded. Samples of all tissues were taken and fixed. A selection of organs form animals of the control and hgh dose groups and samples of the lunds, liver, kidneys and all gross lesions of all groups were histologically processed and subsequently subjected to pathological examination.

At 200 ppm in the diet: No treatment-related changes detected.

At 1000 ppm in the diet: No treatment-related changes detected.

At 5000 ppm in the diet: 1) Body weight and body weight gain of females were lower than controlsduring the treatment period.

2) Brain, liver and spleen weights of females were noted as increased after correction for body weight at week 13.

At 20000 ppm in the diet: 1) Body weight and body weight gain of males and females were lower than controls during the treatment period and particularly for males also during the recovery period.

2) liver weights of males and females kidney and testis weights of males and spleen weights of females were noted as increased after correction for body weight at week 13.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
82 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two studies available with conclusive results.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Two studies are available, the Effect levels are comparable. The sub-chronic study was selected due to the longer exposure period.

Justification for classification or non-classification