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Description of key information

Repeated dose subchronic toxicity study was performed by Oser (1965) to determine the toxic nature of test chemical. The chemical was dosed to FDRL strain rats at dose levels of 5.1 mg/Kg in males and 5.7 mg/Kg in females for 90 days. Concurrent solvent control was also incorporated in the study. The animals were noted for usual observations (i.e. body weight and food consumption), haematological and blood chemical determinations, gross pathology and histopathology respectively. Administration of test substance for 90 days at a level in excess of at least 100 times the maximum estimated daily dietary intake in man evoked no adverse effect on growth, food consumption, haematology, blood chemistry, liver and kidney weights or on gross and microscopic appearance of major organs at autopsy. Hence, the No Observed Adverse Effect Level (NOAEL) for test substance is considered to be 5.1 mg/Kg in males and 5.7 mg/Kg in females. The present study is single dose study.The study does not conclude conclude higher dose value. Henceforth it is acceptable to take such low NOAEL .

Repeated inhalation

 

According to column 2 of REACH Annex VIII, the acute toxicity inhalation study need not be conducted because exposure of humans via inhalation route is not likely taking into account the low vapour pressure of the substance2-Ethoxynaphthalene,which is reported as 0.5182 Pa. Also considering the particle size distribution of the substance the majority of the particle size was determined to be in the range of 150-53 micron which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical2-Ethoxynaphthaleneis highly unlikely. Therefore this study is considered for waiver.

 

Repeated dermal

 

The acute toxicity value for 2-Ethoxynaphthalene (as provided in section 7.2.3) is >5000 mg/kg body weight.The substance was also found to be not irrtating to skin. Also, given the use of the chemical as dye compound; repeated exposure by the dermal route is unlikely. Thus, it is expected that 2-Ethoxynaphthalene shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no dermal absorption data as well as no data available that suggests that 2-Ethoxynaphthalene shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Subchronic toxicity study was performed to determine the toxic nature of test substance
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material: β-Naphthyl ethyl ether
- Molecular formula: C12H12O
- Molecular weight: 172.226 g/mol
- Subsatnce type: Organic
- Physical state: Solid
- Purity: No data
Species:
rat
Strain:
other: FDRL
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation:
59.54±1.5gm(Males) 58.0±1.6gm(females)
- Fasting period before study:No data
- Housing:Animals were housed individually in wiremesh cages.
- Diet (e.g. ad libitum): nutritionally adequate basal ration (Purina Laboratory Chow) ad libitum
- Water (e.g. ad libitum): fresh water ad lib
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data
Route of administration:
oral: feed
Details on route of administration:
No data
Vehicle:
other: Cotton seed oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: β-Naphthyl ethyl ether was diluted in cotton-seed oil in a concentration sufficient to provide the predetermined dosage in 2% of the diet. The oil solutions were incorporated into a nutritionally adequate basal ration at dose levels of 5.1 mg/kg bw/day in males and 5.7 mg/Kg bw/day in females.

DIET PREPARATION-No data
- Rate of preparation of diet (frequency): Biweekly
- Mixing appropriate amounts with (Type of food): Nutritionally adequate basal ration (Purina Laboratory Chow)
- Storage temperature of food: No data

VEHICLE-No data
- Justification for use and choice of vehicle (if other than water): Cotton seed oil
- Concentration in vehicle: 5.1 mg/kg for males and 5.7 mg/kg for females
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
90 days
Frequency of treatment:
Once daily
Dose / conc.:
5 mg/kg bw/day (nominal)
Remarks:
Expected dose (Male/female)
Dose / conc.:
5.1 mg/kg bw/day (actual dose received)
Remarks:
Males
Dose / conc.:
5.7 mg/kg bw/day (actual dose received)
Remarks:
Females
No. of animals per sex per dose:
Total: 60 (15 males and 15 females)
0 mg/Kg bw: 15 males and 15 females
5.1 mg/Kg: 15 males
5.7 mg/Kg: 15 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Single dosage levels for each substance were derived from the total estimated daily intake, calculated on a mg/kg body weight basis assuming 50 kg as the average body weight, and multiplying by 100.
- Rationale for animal assignment (if not random):No data
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data
Positive control:
No data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Not specified
- Time schedule: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

FOOD EFFICIENCY: Not specified
- 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: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):Not specified
- Time schedule for examinations: Not specified

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 6 week and 12 week
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 8 rats of each sex at a 6-wk period, and in all rats at 12 wk
- Parameters checked in table [No.?] were examined. Hematocrit, hemoglobin, RBCs, WBCs, Neutrophils, Lymphocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 6 week and 12 week
- Animals fasted: Not specified
- How many animals: 8 rats of each sex at a 6-wk period, and in all rats at 12 wk
- Parameters checked in table [No.?] were examined. Blood urea nitrogen

URINALYSIS: Not specified
- Time schedule for collection of urine: Not specified
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined. Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Not specified

IMMUNOLOGY: Not specified
- Time schedule for examinations: Not specified
- How many animals: Not specified
- Dose groups that were examined: Not specified
- Parameters checked in table [No.?] were examined. Not specified

OTHER: Not specified
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, at autopsy, liver and kidney weights were recorded
HISTOPATHOLOGY: Yes, half the animals in each group were taken for histological examination: liver, kidneys, stomach, small and large intestines, spleen, pancreas, heart, lungs, bone marrow, muscle, brain, spinal cord, bladder, adrenals, thyroid, pituitary, gonads, salivary glands, and lymph nodes.
Other examinations:
No data
Statistics:
No data
Clinical signs:
no effects observed
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
5.1 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No significant alterations were noted in the treated and control animals
Remarks on result:
other: No toxic effect were observed
Dose descriptor:
NOAEL
Effect level:
5.7 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No significant alterations were noted in the treated and control animals
Remarks on result:
other: No toxic effect were observed
Critical effects observed:
no
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
The No Observed Adverse Effect Level (NOAEL) for test substance is considered to be 5.1 mg/Kg in males and 5.7 mg/Kg in females respectivley.
Executive summary:

Repeated dose subchronic toxicity study was performed to determine the toxic nature of test substance.The chemical was dosed to FDRL strain rats at dose levels of 5.1 mg/Kg in males and 5.7 mg/Kg in females for 90 days. Concurrent solvent control was also incorporated in the study. The animals were noted for usual observations (i.e. body weight and food consumption), haematologieal and blood chemical determinations, gross pathology and histopathology respectively. Administration of test substance for 90 days at a level in excess of at least 100 times the maximum estimated daily dietary intake in man evoked no adverse effect on growth, food consumption, haematology, blood chemistry, liver and kidney weights or on gross and microscopic appearance of major organs at autopsy. Hence, the No Observed Adverse Effect Level (NOAEL) for test substance is considered to be 5.1 mg/Kg in males and 5.7 mg/Kg in females.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5.7 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is from peer reviwed publication

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

Repeated dose toxicity: Oral

 

Data from various peer reviewed publications were reviewed to deteremine the toxic nature of 2-Ethoxynaphthalene (CAS no 93 -18 -5). The summary is as mentioned below:

 

Repeated dose subchronic toxicity study was performed by Oser (1965) to determine the toxic nature of test substance. The chemical was dosed to FDRL strain rats at dose levels of 5.1 mg/Kg in males and 5.7 mg/Kg in females for 90 days. Concurrent solvent control was also incorporated in the study. The animals were noted for usual observations (i.e. body weight and food consumption), haematological and blood chemical determinations, gross pathology and histopathology respectively. Administration of test substance for 90 days at a level in excess of at least 100 times the maximum estimated daily dietary intake in man evoked no adverse effect on growth, food consumption, haematology, blood chemistry, liver and kidney weights or on gross and microscopic appearance of major organs at autopsy. Hence, the No Observed Adverse Effect Level (NOAEL) for test substance is considered to be 5.1 mg/Kg in males and 5.7 mg/Kg in females.

 

Supported by other Repeated dose subchronic toxicity study which was performed to determine the toxic nature of test substance . The study was performed on rats by the gavage route of administration. The test chemical was studied at dose levels of 5.0 mg/Kg bw/day. No significant alterations were noted at the mentioned dose level. The No Observed adverse effect level (NOAEL) for test substance is 5.0 mg/Kg bw/day.

 

Another supporting Repeated dose feeding study which was performed to determine the toxic nature of test substance. 5 weanling rats were dosed at dose level of 2% (approximately 2000 mg/Kg bw) in the diet for 2 months. During the 2 months study period, rats developed cataracts and the chemical was considered to be cataractogenic. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for test substance is < 2000 mg/Kg/day.

In a 28 days repeated dose toxicity study, the effect of test substance was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight/day. 2 animals died at 500 mg/kg bw as compared to control.Abnormalities such as nasal discharge, red crust around the nostrils was observed in all treatment groups. In addition, a few cases of snuffling, eye lid swelling and hunched back posture were also observed in the treated groups. A significant decrease in body weights in male rats on the first, second and fourth week of treatment and in female rats, a significant decrease in body weight was observed on the first, second and third week of treatment were observed as compared to control. No effects on food and water consumption were observed as compared to control. In addition,In hematology, methyl 2-naphthyl ether resulted in significantly increased platelet count along with decreased MCV, MCH and MCHC levels. Treatment with 250 mg/kg body weight/day resulted in significantly decreased levels of hemoglobin and MCHC in male rats. At 250 mg/kg body weight/day, a significant decrease was noticed in neutrophils along with altered values of MCV in female rats. In clinical chemistry, significantly increased the level of testosterone in the 500 mg/kg body weight/day group in males, as well as it significantly increased the level of estrogen in the 250 mg/kg body weight/day group in females. Significant increased levels in cholesterol, potassium and albumin was also observed. Similarly, Changes in relative and absolute organ weight of spleen, kidney, liver, brain, heart, ovaries and uterus were observed when treated with 125, 250 or 500 mg/kg body weight/day. Nasal discharge, red crust around nostril, perineum wet, bloated stomach, viscous oily secretion was found inside the thoracic cavity. Small white solid mass slightly firm in consistency floating inside the urinary bladder was observed. However, due to adaptive metabolic and physiological changes, anoxic/ hypoxic conditions during anesthesia and terminal sacrifice, these findings were considered to be of no toxicological significance. No remarkable changes observed in control and the 500 mg/kg body weight/day-treated animals. A few microscopic findings observed in 500 mg/kg body weight/day-treated animals included collapsed lung with focal inflammation, focal fatty change and excess of lymphocytes in liver, inflammation in small intestine, reactive spleen and excess of mucous in colon. Since the histopathological changes were not observed in 125 mg/kg bw and these findings were also observed in the control animals. Hence, NOAEL was considered to be 125 mg/kg bw when Sprague Dawley male and female rats were exposed daily to test substance by oral route for 28 days.

 

In repeated toxicity study of test material was performed according OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents). Male and female Crl: CD(SD) of 4 weeks old were used in study. Test material dissolved in corn oil in dose concentration0, 20, 100, 500 mg/kg bw/day and administered in dose volume 10ml/kg by oral gavage route.10 animals/sex/dose for 0 and 500 mg/kg bw/day (5 animals/sex/dose were used as the recovery group). 5 animals/sex/dose for 20 and 100 mg/kg bw/day. All males and females were observed at least three times a day during the administration period and the recovery period. Body weights were measured on days 1, 4, 8, 11, 15, 18, 22, 25 and 28 of administration period and on days 1, 4, 8, 11 and 14 of recovery period. Food consumption of all rats were measured on days 1, 8, 15, 22 and 28 of administration period and on days 1, 8 and 14 of administration. Pathological examinations were performed for all animals and the examination items consisted of organ weight measurements, macroscopic examination and histopathologic examination. The No Observed Adverse Effect Level (NOAEL) was considered to be 100 mg/Kg/day for male and female. When male and female rats were treated with test material orally for 28 days.

 

 

 

Based on the available data summarized, 2-Ethoxynaphthalene (CAS no 93 -18 -5) is not likely to classify as a toxicant upon repeated exposure by oral route of adminsitration.

 

Repeated inhalation

 

According to column 2 of REACH Annex VIII, the acute toxicity inhalation study need not be conducted because exposure of humans via inhalation route is not likely taking into account the low vapour pressure of the substance2-Ethoxynaphthalene,which is reported as 0.5182 Pa. Also considering the particle size distribution of the substance the majority of the particle size was determined to be in the range of 150-53 micron which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical2-Ethoxynaphthaleneis highly unlikely. Therefore this study is considered for waiver.

 

Repeated dermal

 

The acute toxicity value for 2-Ethoxynaphthalene (as provided in section 7.2.3) is >5000 mg/kg body weight.The substance was also found to be not irrtating to skin. Also, given the use of the chemical as dye compound; repeated exposure by the dermal route is unlikely. Thus, it is expected that 2-Ethoxynaphthalene shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no dermal absorption data as well as no data available that suggests that 2-Ethoxynaphthalene shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Justification for classification or non-classification

Based on above annotation and CLP criteria , 2-Ethoxynaphthalene (CAS no 93 -18 -5) is not likely to classify as a toxicant upon repeated exposure by oral,dermal and inhalation route of administration.