Registration Dossier

Administrative data

Description of key information

Subacute (28 days study)- oral

In an experimental study conducted by Sustainability Support Services (Europe) AB (2014), NOAEL was considered to be 125 mg/kg bw and LOAEL was considered to be 250 mg/kg body weight/day when Sprague Dawley male and female rats were exposed daily to methyl 2-naphthyl ether by oral route for 28 days.

Subchronic (90 days study)- oral

The experimental study conducted by SHOPP et al(Fundamental and Applied Toxicology 4, 406-419 (1984)) on structurally similar read across substance Napthalene (CAS no 91-20-3), NOAEL was considered to be 133 mg/kg bw when CD-1 ICR male and female mice were treated with Napthalene orally for 90 days.

Metabolite of beta - naphthol is Naphthalene which is chemically a parent ring of target chemical Methyl 2-naphthyl ether as per the details reviewed from Handbook of Biotransformations of Aromatic Compounds, B . L . Goodwin, CRC Press 2004, Print ISBN: 978-0-415-27176-9.

As per criteria of CLP regulation, the test chemical Methyl 2-naphthyl ether (CAS no 93-04-9) does not classify as a toxicant.

Based on the studies available and predictions on Methyl 2-naphthyl ether and its read across substances, it is concluded that NOAEL value for the target chemical is 125 mg/kg bw. The reported use of target chemical as a flavouring agent in US (0.01 µg/kg bw per day) (WHO Food Additives Series: 52, 2004) and which is less when compared with the read across Beta-Naphthyl ethyl ether (CAS no 93-18-5) in rats is >100 000 times the daily per capita intake from its reported use as a flavouring agent in US (4 µg/kg bw per day) with no safety concern. Since the daily per capita consumption of the target chemical is less than that of the read across Beta-Naphthyl ethyl ether (CAS no 93-18-5) which is non toxic, the toxic effect by oral route for the target test chemical is less likely. Hence, Methyl 2-naphthyl ether is likely to be non toxic at its level of use and hence shows a no safety concern.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is form Study report
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
To determine the toxicity likely to arise from the repeated exposure of the test item Methyl 2-naphthyl ether (MNE; CAS No. 93-04-9) over a relatively limited period of time (28 days) in male and female SD rats.
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Methyl 2-naphthyl ether (MNE) (Batch no. 0001)
- Molecular formula (if other than submission substance): C11H10O
- Molecular weight (if other than submission substance): 158.19999999999999 g/mol
- Substance type: Organic
- Physical state: Solid
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: Central Animal Facility (CAF), NIPER, Sector-67, S.A.S. Nagar, Punjab, India.

- Age at study initiation: 7 to 8 weeks old

- Weight at study initiation: Male 184.38-234.56 g, Female 176.90-208.56 g

- Fasting period before study: No data available

- Housing: Four rats per sex per cage were housed in sterilized solid bottom polypropylene cages with stainless steel grill tops with bedding of clean paddy husk. The cages were suspended on stainless steel racks in a controlled environment.

- Diet (e.g. ad libitum): Standard laboratory sterile extruded pelleted rodent feed (Provimi Animal Nutrition India Pvt. Ltd, Bangalore, India), ad libitum

- Water (e.g. ad libitum): Potable tap water filtered through Reviva Reverse Osmosis System (water filter cum purifier), ad libitum.

- Acclimatization period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%):30-70 %
- Air changes (per hr): 25 ± 5 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

IN-LIFE DATES:
From: 11.04.2014 (Male), 13.04.2014 (Female);
To: 17.05.2014 (Male), 19.05.2014 (Female)
Route of administration:
oral: gavage
Vehicle:
other: Groundnut oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 125, 250 and 500 mg was weighed and dissolved in 10 ml of groundnut oil by vortexing the resultant (concentration / dose).

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Groundnut oil
- Concentration in vehicle: 0, 125, 250 and 500 mg/kg body weight/day
- Amount of vehicle (if gavage): 5 ml/kg body weight
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Doses were analyzed by using HPLC system.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Total animals: 56
Control: 7 males, 7 females
125 mg/kg/day: 7males, 7 females
250 mg/kg/day: 7 males, 7 females
500 mg/kg/day: 7 males, 7 females
Control animals:
yes, concurrent vehicle
Details on study design:
Details on study design
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): Animals were randomized by body weight and sex.
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available
Observations and examinations performed and frequency:
Observations and examinations performed & frequency

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations performed: Visual inspection

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily for to characterize the onset and duration of clinical signs. However, detailed physical and clinical observations were conducted before the first exposure of test item and at least once a week thereafter till the end of the study.

BODY WEIGHT: Yes
- Time schedule for examinations: On day 1, 8, 15, 22, 28 and on day 29 before sacrifice.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

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: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Once weekly (on days 2, 9, 16 & 23)

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Fourth week of chemical treatment.
- Dose groups that were examined: All 56 animals were examined.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: On completion of 28 days of treatment and prior to necropsy.
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes, overnight fasting.
- How many animals: All 56 animals were examined.
- Parameters examined: Haemoglobin (Hb) , RBC Count, Total and differential leucocyte count, Haematocrit (Hct /PCV), Mean corpuscular volume (MCV), Mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC) and Platelet Count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On completion of 28 days of treatment and prior to necropsy.
- Animals fasted: Yes, overnight fasting.
- How many animals: All 56 animals were examined.
- Parameters examined: Sodium, Potassium, Glucose, Total Cholesterol, Blood Urea, Creatinine, Total Protein Albumin, SGPT (Serum glutamic pyruvic transaminase)/ALT, SGOT (Serum glutamic oxaloacetic transaminase)/AST, Hormones analysis (testosterone and estrogen) and Total Bile acids.

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters examined: No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Yes, Locomotor activity was observed.

OTHER:
Organ weight were measured.
Sacrifice and pathology:
Sacrifice and pathology
GROSS PATHOLOGY: Yes
On completion of treatment, all surviving rats were sacrificed and a complete necropsy was carried out on all animals. Tissues were collected from brain, stomach, large and small intestine, liver, kidneys, adrenal gland(s), spleen, heart, thymus, lungs, testis/ovary, uterus, lymph nodes, peripheral nerve (sciatic), bone marrow, and other gross lesions, if any.
Tissues were preserved in 10% formal saline. However testes, ovaries and uterus were first fixed in Bouin’s fixative for two hours then transferred to 10% formal saline.

HISTOPATHOLOGY: Yes
Histological examination was conducted on tissues/organs from the control and the high-dose group animals Organ examined: lung, liver, kidney, heart, spleen, testis, ovaries, adrenal glands, large and small intestine, brain, sciatic nerve, lymph nodes, bone marrow, stomach and thymus were examined.
Other examinations:
The collected organs were also weighed.
Statistics:
Statistical analysis was carried out by using Microsoft Excel and IBM SPSS statistics version -20. All analyses and comparisons were evaluated at the 5 % level, statistically significant differences (p0.05) indicated by appropriate notation. PAIRED T-Testing procedure was used to check the significance between above mentioned groups. For multiple comparisons Turkey’s HSD test was applied.
Clinical signs:
no effects observed
Description (incidence and severity):
Abnormalities such as nasal discharge, red crust around the nostrils was observedin all treatment groups. In addition, a few cases of snuffling, eye lid swelling and hunched back posture were also observed in the treated groups.
Mortality:
no mortality observed
Description (incidence):
All animals except animal No. 25 & 26 of high dose survived throughout the treatment period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Treatment with 500 mg/kg body weight/day showed a significant reduction in body weights in male rats on the first, second and fourth week of treatment. In female rats, a significant decrease in body weight was observed on the first, second and third week of treatment.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No difference was observed among the groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No difference in water consumption was observed among the groups.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No difference was observed in opthalmoscopic examination.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In male rats, significant increase in the platelet count was observed along with decrease in MCV and MCH levels at 125 mg/kg body weight/day.

Treatment with 250 mg/kg body weight/day showed significantly decreased values of hemoglobin and MCHC in male rats. The level of MCHC was also found to be significantly decreased when treated with 500 mg/kg body weight/day.

In female rats, treatment with 125 mg/kg body weight/day showed significant alterations in platelet count and MCV.

At 250 mg/kg body weight/day, a significant decrease was noticed in neutrophils along with altered values of MCV in female rats.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In female animals, the level of total bile acid was decreased at 250 mg/kg body weight/day.

A significant increase was noticed in the level of estrogen in the same group. A similar trend was also noticed at 125 and 500 mg/kg body weight/day., but was statistically non-significant.

At 250 and 500 mg/kg body weight/day the levels of potassium and albumin were found to be significantly increased. The cholesterol level in the 250 mg/kg body weight/day group was noticed to be significantly elevated in the mid-dose group.

In male rats, the level of testosterone was significantly increased after treatment with 500 mg/kg body weight/day.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The weight of spleen was decreased in the 250 mg/kg body weight/day groups while treatment with 500 mg/kg body weight/day resulted in the decreased weight of kidney in both female and male rats. However, the absolute organ weight of male animals does not show any significant difference.

In male rats, the relative weight of liver was noticed to be increased at 125 mg/kg body weight/day. Significant increase in the relative weights of heart and testes was also noticed at 500 mg/kg body weight/day.

In female rats, at all dose levels, the relative weight of ovaries was decreased in comparison to the control group animals. At 250 mg/kg body weight/day, the relative weights of brain and heart were significantly decreased. The relative weight of uterus was also decreased in the 125 or 250 mg/kg body weight/day groups.A significant decrease in the relative weight of spleen was observed at250 or 500 mg/kg body weight/day.

The absolute organ weight of ovaries from all treated groups was found to be decreased significantly in female rats.

The weight of uterus was found to be significantly decreased in 250 or 500 mg/kg body weight/day-treated male and female rats.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
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.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
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. However, these findings were also observed in the control animals.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
haematology
organ weights and organ / body weight ratios
other: Effects observed
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
mortality
ophthalmological examination
organ weights and organ / body weight ratios
water consumption and compound intake
other: No effect observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

SUMMARY OF BODY WEIGHTS(g)

Male

 

 

Group

 

Dose mg/kg

 

 

 

Day1

 

 

Day8

 

 

Day15

 

 

Day22

 

 

Day28

 

Terminal

Day

 

 

1

 

 

Vehicle

Mean

211.80

242.34

262.97

283.01

300.76

296.93

S.D.

14.03

14.91

16.29

24.57

26.41

27.19

 

S.E.M.

6.62

6.15

6.20

8.68

8.78

9.16

 

 

2

 

 

125

Mean

218.02

243.85

260.27

279.35

296.61

291.98

S.D.

9.56

11.42

11.59

14.54

14.88

14.86

 

S.E.M.

4.38

4.68

4.45

5.21

5.02

5.09

 

 

3

 

 

250

Mean

210.57

221.01

241.60

267.42

286.08

282.17

S.D.

9.82

26.98

30.11

23.54

25.05

24.52

 

S.E.M.

4.67

12.21

12.46

8.80

8.76

8.69

 

 

4

 

 

500

Mean

214.35

212.06

223.41

240.97

256.81

256.24

S.D.

10.64

10.08

11.64

13.72

6.86

9.27

 

S.E.M.

4.96

4.76

5.21

5.70

     2.67

3.62

 

SUMMARY OF BODYWEIGHTS(g)

Female

 

 

Group

 

Dose mg/kg

 

 

 

Day1

 

 

Day8

 

 

Day15

 

 

Day22

 

 

Day28

 

Terminal

Day

 

 

1

 

 

Vehicle

Mean

191.17

200.82

208.91

215.94

227.15

219.85

S.D.

7.12

12.39

16.56

15.30

17.64

19.32

 

S.E.M.

3.72

6.17

7.93

7.09

7.77

8.79

 

 

2

 

 

125

Mean

192.17

201.14

208.56

214.38

220.79

216.51

S.D.

9.31

10.16

8.58

7.62

10.76

10.09

 

S.E.M.

4.85

5.05

4.11

3.55

4.87

4.66

 

 

3

 

 

250

Mean

194.94

202.08

209.12

216.24

228.85

226.38

S.D.

9.45

8.89

8.24

7.85

7.51

8.75

 

S.E.M.

4.85

4.40

3.94

3.63

3.28

3.87

 

 

4

 

 

500

Mean

190.49

182.52

192.46

205.74

216.14

212.37

S.D.

8.82

9.74

12.73

11.46

11.61

12.10

 

S.E.M.

4.63

5.34

6.61

5.57

5.37

5.70

SUMMARY OF HEMATOLOGY DATA Male

Group/Dose

 

WBC

3

(x10/

mm3)

RBC

6

(x10/

mm3)

PLT (x10/mm3)

Hct

(%)

Hgb

(g/dl)

MCV(fl)

MCH (pg)

MCHC(g/dl)

Lym

%

Mon

%

Nut

%

Eos

%

 

Bas%

 

 

1/0

 

Mean

12.06

69.49

4.34

23.27

1.17

0.99

10.15

52.77

53.54

16.40

31.07

16.67

600.2

9

±S.D.

2.24

9.56

1.11

9.04

1.07

0.33

0.63

1.40

2.92

0.51

0.97

1.00

76.78

± S.E.M.

18.59

13.76

25.46

38.85

91.51

33.35

6.17

2.65

5.45

3.11

3.12

5.99

12.79

 

 

 

2/125mg/kg

 

Mean

12.09

69.73

4.57

22.04

2.19

0.71

10.16

50.24*

51.00

15.49*

30.83

15.73

1118.

00*

 

±S.D.

2.18

5.30

0.71

6.81

2.70

0.17

0.53

1.93

2.36

0.71

0.83

0.80

383.1

9

±

S.E.M.

0.8

2.0

0.3

2.6

1.0

0.1

0.2

0.7

0.9

0.3

0.3

0.3

144.8

 

 

 

3/250mg/kg

 

Mean

14.97

63.19

4.66

28.04

2.36

0.93

9.93

52.76

52.41

15.81

29.99

15.70

614.8

6

 

±S.D.

2.34

11.26

0.75

12.16

2.83

0.20

0.24

2.50

3.03

0.80

0.18

0.96

173.0

5

±

S.E.M.

0.9

4.3

0.3

4.6

1.1

0.1

0.1

0.9

1.1

0.3

0.1

0.4

65.4

 

 

 

4/ 500mg/kg

 

Mean

9.10

53.17

3.28

16.91

2.29

0.60

7.32

38.41

39.25

11.61

21.62

11.87

476.4

9

 

±S.D.

5.76

31.42

2.26

6.52

1.66

0.35

4.89

25.12

25.52

7.57

14.70

7.70

295.4

8

± S.E.M.

2.6

14.1

1.0

2.9

0.7

0.2

2.2

11.2

11.4

3.4

6.6

3.4

132.1

 

 

SUMMARY OF HEMATOLOGY DATA Female

emaleGroup/Dose

 

WBC (x103/mm3)

RBC (x106/mm3)

PLT (x103/mm3)

 

Hct

(%)

 

Hgb

(g/dl)

 

MCV(fl)

 

MCH (pg)

 

MCHC (g/dl)

 

Lym

%

 

Mon

%

 

Nut

%

 

Eos

%

 

Bas%

 

 

Vehicle

Mean

11.66

62.20

4.41

30.31

1.39

0.87

10.18

49.90

50.74

15.44

30.97

15.71

994.57

±S.D.

2.19

8.62

1.09

8.69

1.61

0.17

0.55

2.34

2.56

0.68

0.31

0.84

520.25

± S..E..M.

 

0.8

 

3.3

 

0.4

 

3.3

 

0.6

 

0.1

 

0.2

 

0.9

 

1.0

 

0.3

 

0.1

 

0.3

 

196.6

 

 

2      /

125mg/kg

 

Mean

 

12.28

 

67.97

 

4.34

 

25.10

 

0.94

 

0.90

 

10.13

 

51.66*

 

52.26

 

15.86

 

30.71

 

16.06

518.71

±S.D.

4.51

6.98

0.78

6.78

0.47

0.18

0.47

1.36

1.39

0.73

0.71

0.45

114.08

±S.E.M.

 

1.7

 

2.6

 

0.3

 

2.6

 

0.2

 

0.1

 

0.2

 

0.5

 

0.5

 

0.3

 

0.3

 

0.2

 

43.1

 

 

3    / 250mg/kg

Mean

11.94

69.24

4.13

21.83*

2.93

1.07

10.18

51.76*

52.76

15.71

30.37

15.99

585.00

±S.D.

3.21

7.96

0.54

7.77

2.71

0.24

0.45

1.55

3.36

0.75

1.44

1.17

213.78

±S.E.M.

 

1.2

 

3.0

 

0.2

 

2.9

 

1.0

 

0.1

 

0.2

 

0.6

 

1.3

 

0.3

 

0.5

 

0.4

 

80.8

 

 

4       /

500mg/kg

Mean

11.37

66.26

4.36

26.57

1.06

1.03

10.00

51.77

51.79

15.79

30.47

15.79

614.29

±S.D.

2.10

9.91

0.99

9.88

1.34

0.19

0.73

0.85

3.90

0.57

0.92

1.41

139.13

±S.E

.M.

 

0.8

 

3.7

 

0.4

 

3.7

 

0.5

 

0.1

 

0.3

 

0.3

 

1.5

 

0.2

 

0.3

 

0.5

 

52.6

 

SUMMARY OF CLINICAL BIOCHEMISTRY DATA Male Rats

Group/Dose

 

Sod.(mmol/L)

Pot.(mmol/L)

ALB(g%)

CHOL(mg%)

CRT(mg%)

SGOT(IU/L)

SGPT (IU/L)

GLU(mg%)

TP(g%)

BUN(mg%)

TBA

Test

ng/L

nmol/L

 

 

1   /  0

Mean

131.5

7.0

3.9

83.9

0.9

33.1

32.9

117.0

6.5

12.5

490.1

4.363

±S.D.

8.6

0.5

0.3

18.1

0.2

4.0

5.1

7.1

0.4

3.0

44.82

1.02

±S.E.M.

3.2

0.2

0.1

6.8

0.1

1.5

1.9

2.7

0.1

1.1

16.94

0.387

 

 

 

2  /125 mg/kg

Mean

130.0

7.6

3.7

87.6

0.9

33.9

32.5

119.1

6.5

14.4

485.4

5.421

±S.D.

3.3

0.7

0.3

10.7

0.2

8.2

7.6

4.9

0.5

3.0

36.17

1.03

±S.E.M.

1.2

0.3

0.1

4.0

0.1

3.1

2.9

1.9

0.2

1.1

13.67

0.392

 

 

 

 

 

3 /250 mg/kg

Mean

130.1

7.1

3.7

87.7

0.9

65.4

30.0

121.0

6.7

12.1

465.4

4.716

±S.D.

9.8

1.0

0.2

17.4

0.1

90.0

7.0

9.5

0.5

2.8

35.10

1.28

±S.E.M.

3.7

0.4

0.1

6.6

0.1

34.0

2.6

3.6

0.2

1.1

13.26

0.487

 

 

 

4 / 500 mg/kg

 

Mean

 

124.5

 

11.0

 

3.7

 

96.2

 

0.9

 

31.1

 

30.5

 

121.6

 

6.4

 

13.7

485.2

*

 

6.289*

±S.D.

11.1

8.4

0.3

12.1

0.2

7.5

6.4

13.8

0.5

4.0

23.33

0.398

 

±S.E.M.

 

5.0

 

3.8

 

0.1

 

5.4

 

0.1

 

3.3

 

2.8

 

6.2

 

0.2

 

1.8

 

10.43

 

0.178

 

SUMMARY OF CLINICAL BIOCHEMISTRY DATA - Female

 

Group

/Dose

 

Sod.

Pot.

ALB

CHOL

CRT

SGOT

SGPT

GLU

TP

BUN

TBA

Est

(mmol/L)

(mmol/L)

(g%)

(mg%)

(mg%)

(IU/L)

(IU/L)

(mg%)

(g%)

(mg%)

ng/L

ng/L

 

1        /

0 mg/kg

Mean

139.2

7.2

3.3

93.0

1.1

32.3

39.9

110.4

7.0

12.9

485

9.156

±S.D.

9.3

0.6

0.3

14.5

0.2

15.3

21.7

14.2

0.5

4.3

30.60

1.47

±S.E.M.

3.5

0.2

0.1

5.5

0.1

5.8

8.2

5.4

0.2

1.6

11.56

0.558

 

 

2     /

125 mg/kg

Mean

136.6

7.8

3.4

98.0

1.1

28.8

39.6

100.0

7.3

12.5

475.1

9.869

±S.D.

4.3

0.9

0.1

17.1

0.4

7.4

9.0

8.9

0.5

2.1

30.59

1.27

±S.E.M.

1.6

0.3

0.1

6.5

0.1

2.8

3.4

3.4

0.2

0.8

11.56

0.482

 

 

 

 

3     /

250 mg/kg

Mean

141.6

8.1

3.8

119.9

1.1

27.9

40.0

100.2

7.0

12.5

425.5*

10.478*

±S.D.

7.3

0.9

0.4

24.7

0.2

6.0

8.1

9.0

0.6

2.8

52.38

1.33

±S.E.M.

2.8

0.4

0.2

9.3

0.1

2.3

3.0

3.4

0.2

1.1

19.79

0.505

 

 

4     /

500 mg/kg

Mean

137.0

8.1

3.7

113.4

1.1

32.3

43.5

100.1

7.0

14.1

448.5

9.842

±S.D.

5.9

0.8

0.2

23.6

0.2

8.4

9.8

5.8

0.6

2.3

31.16

1.93

 

±S.E.M.

 

2.2

 

0.3

 

0.1

 

8.9

 

0.1

 

3.2

 

3.7

 

2.2

 

0.2

 

0.9

 

13.93

 

0.73

 

SUMMARY OF ABSOLUTE ORGAN WEIGHTS(g) - Male Rats

Group/ Dose

 

 

Brain

 

Thymus

 

Liver

 

Kidneys

 

Adrenals

 

Ovaries

 

Spleen

 

Heart

 

Epididymides

 

 

1

Vehicle

Mean

1.79

0.30

10.72

1.98

0.03

2.79

1.04

0.55

0.88

±S.D.

0.28

0.06

1.48

0.30

0.01

0.27

0.15

0.11

0.09

±S.E.M.

0.11

0.02

0.56

0.11

0.01

0.10

0.05

0.04

0.03

 

 

2

(125) mg/kg

 

Mean

1.89

0.46

11.54

2.09

0.07

2.75

1.05

0.54

0.89

 

±S.D.

0.12

0.16

0.70

0.11

0.08

0.22

0.06

0.13

0.08

±S.E.M.

0.05

0.06

0.26

0.04

0.03

0.08

0.02

0.05

0.03

 

3

(250)mg/kg

 

Mean

1.87

0.32

11.25

2.04

0.04

2.81

1.10

0.63

0.91

 

±S.D.

0.07

0.06

1.96

0.23

0.01

0.14

0.12

0.19

0.10

±S.E.M.

0.02

0.02

0.74

0.09

0.00

0.05

0.05

0.07

0.04

 

 

4

 (500)

mg/kg

Mean

1.79

0.28

10.61

1.93

0.04

2.87

1.03

0.54

0.88

±S.D.

0.07

0.05

0.51

0.17

0.01

0.13

0.06

0.11

0.05

±S.E.M.

0.03

0.02

0.19

0.06

0.00

0.05

0.02

0.04

0.02

 SUMMARY OF ABSOLUTE ORGAN WEIGHTS(g)

 Femalerats

Group/ Dose

 

 

Brain

 

Thymus

 

Liver

 

Kidneys

 

Adrenals

 

Ovaries

 

Spleen

Heart

 

Uterus

1/0

   (mg/kg)

Mean

1.79639

0.69686

8.13916

1.66367

0.0451

0.14289

0.63041

0.79684

0.46711

±S.D.

0.13458

0.547

0.47047

0.18627

0.01172

0.02302

0.11848

0.11455

0.07792

±S.E.M.

0.05087

0.20675

0.17782

0.0704

0.00443

0.0087

0.04478

0.04329

0.02945

 

2/(120)

mg/kg

Mean

1.78147

0.28884

8.15586

1.55246

0.04734

0.08319*

0.63869

0.77013

0.39303

±S.D.

0.11628

0.1304

1.06437

0.16655

0.00937

0.01815

0.24329

0.06459

0.08246

±S.E.M.

0.04395

0.04929

0.40229

0.06295

0.00354

0.00686

0.09196

0.02441

0.03117

 

2/

 

250 mg/kg

Mean

1.6069

0.3289

8.3645

1.566

0.0395

0.0935*

0.4718

0.7185

0.4667*

 

±S.D.

 

0.27569

 

0.12711

 

0.78925

 

0.15522

 

0.01286

 

0.02423

 

0.11176

 

0.06134

 

0.07708

±S.E.M.

0.1042

0.04804

0.29831

0.05867

0.00486

0.00916

0.04224

0.02319

0.02913

 

4  /

(500) mg/kg

Mean

1.75207

0.42151

7.9445

1.525*

0.04407

0.07481

0.49059*

0.70961

0.34757*

±S.D.

0.12692

0.20921

0.63133

0.13336

0.00665

0.01518

0.09178

0.02657

0.10007

±S.E.M.

0.04797

0.07907

0.23862

0.05041

0.00251

0.00574

0.03469

0.01004

0.03782

SUMMARY OF RELATIVE ORGAN WEIGHTS Male Rats

 

Group/Dose

 

 

Brain

 

Thymus

 

Liver

 

Kidneys

 

Adrenals

 

Testes

 

Splee n

 

Heart

 

epididymide s

 

1/

 

0

Mean

0.6051

0.1009

3.6170

0.6680

0.0110

0.9447

0.1846

0.2970

0.3521

±S.D.

 

0.1132

 

0.0236

 

0.4211

 

0.0880

 

0.0052

 

0.1114

 

0.0407

 

0.0210

 

0.0527

±S.E.M.

 

0.0428

 

0.0089

 

0.1592

 

0.0333

 

0.0020

 

0.0421

 

0.0154

 

0.0079

 

0.0199

 

 

 

 

2/

125 mg/kg

Mean

 

0.6466

 

0.1549

 

3.9569*

 

0.7236

 

0.0243

 

0.9377

 

0.1856

 

0.3060

 

0.3599

±S.D.

 

0.0330

 

0.0515

 

0.2711

 

0.0369

 

0.0274

 

0.0434

 

0.0428

 

0.0262

 

0.0299

±S.E.M.

 

0.0125

 

0.0195

 

0.1025

 

0.0139

 

0.0104

 

0.0164

 

0.0162

 

0.0099

 

0.0113

 

 

 

3  /

250 mg/kg

Mean

 

0.6674

 

0.1140

 

3.9886

 

0.7207

 

0.0143

 

1.0007

 

0.2209

 

0.3220

 

0.3883

±S.D.

 

0.0627

 

0.0252

 

0.6023

 

0.0431

 

0.0021

 

0.0816

 

0.0608

 

0.0367

 

0.0346

±S.E.M.

 

0.0237

 

0.0095

 

0.2277

 

0.0163

 

0.0008

 

0.0309

 

0.0230

 

0.0139

 

0.0131

 

 

 

4   /

500 mg/kg

Mean

 

0.5317

 

0.0868

 

3.1877

 

0.5684

 

0.0110

 

0.8401

 

0.1709

 

0.2618*

 

0.3071*

±S.D.

 

0.3033

 

0.0461

 

1.7161

 

0.3359

 

0.0062

 

0.4873

 

0.0898

 

0.1468

 

0.1775

±S.E.M.

 

0.1357

 

0.0206

 

0.7675

 

0.1502

 

0.0028

 

0.2179

 

0.0402

 

0.0656

 

0.0794

SUMMARY OF RELATIVE ORGAN WEIGHTS- Females

Group/Dose

 

 

Brain

Thymu s

 

Liver

 

Kidneys

Adrenal s

 

Ovaries

 

uterus

 

Spleen

 

Heart

 

 

1/0

Mean

 

0.8181

 

0.3176

 

3.7199

 

0.7573

 

0.0200

 

0.0654

 

0.2107

 

0.2849

 

0.3614

±S.D.

0.0380

0.2566

0.3170

0.0667

0.0045

0.0141

0.0202

0.0354

0.0334

±S.E.M.

0.0144

0.0970

0.1198

0.0252

0.0017

0.0053

0.0076

0.0134

0.0126

 

 

2 / 125 mg/kg

Mean

 

0.8227

 

0.1324

 

3.7541

 

113.7454

 

0.0214

 

*0.0380

 

0.1824

 

0.2926

 

0.3557

±S.D.

0.0439

0.0598

0.3280

299.0822

0.0053

0.0090

0.0439

0.1052

0.0323

±S.E.M.

0.0166

0.0226

0.1240

113.0424

0.0020

0.0034

0.0166

0.0398

0.0122

 

3  /          250 mg/kg

Mean

 

0.7137

 

0.1443

 

3.6900

 

0.6917

 

0.0171

 

0.0406*

 

0.2054

 

0.2077*

 

0.3169*

±S.D.

0.1425

0.0553

0.2348

0.0629

0.0053

0.0089

0.0298

0.0487

0.0212

±S.E.M.

0.0539

0.0209

0.0887

0.0238

0.0020

0.0034

0.0113

0.0184

0.0080

 

4    /  500mg/kg

Mean

0.8253

0.1970

3.7417

0.7173

0.0203

0.0349*

0.1636

0.2304*

0.3341

±S.D.

0.0546

0.0920

0.2484

0.0423

0.0028

0.0080

0.0463

0.0405

0.0130

±S.E.M.

0.0206

0.0348

0.0939

0.0160

0.0011

0.0030

0.0175

0.0153

0.0049

Conclusions:
NOAEL was considered to be 125 mg/kg bw and LOAEL was considered to be 250 mg/kg body weight/day when Sprague Dawley male and female rats were exposed daily to methyl 2-naphthyl ether by oral route for 28 days.
Executive summary:

In a 28 days repeated dose toxicity study, the effect of methyl 2-naphthyl ether 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 and LOAEL was considered to be 250 mg/kg body weight/day when Sprague Dawley male and female rats were exposed daily to methyl 2-naphthyl ether by oral route for 28 days.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is from GLP laboratory

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity: Oral

In different studies, Methyl 2-naphthyl ether has been investigated for repeated dose oral toxicity to a greater or lesser extent. Often are the 28 and 90 day studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in mice and rats for 4 Methyl 2-naphthyl ether along with the study available on structurally similar read across substance Phenyl Beta-Naphthyl ethyl ether (CAS no 93-18-5), 1-Methoxynaphthalene (CAS no 2216-69-5), 2-naphthyloxyacetic acid (CAS no 120-23-0), 2-Naphthalenol (CAS no 135-19-3), 2-naphthylisobutyl ether (CAS no 2137-57-1), 2-(2-naphthyloxy)ethano (CAS no 93-20-9), (7-methoxynaphthalen-1-yl)acetonitrile (CAS no 138113-08-3), β-Naphthyl ethyl ether (CAS no 93-18-5), methyl beta-naphthyl ketone (CAS no 93-08-3), Napthalene (CAS no 91-20-3) and 2-(phenylmethoxy)naphthalene (CAS no 613-62-7). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. These RA are based on structural and functional group similarity further they are also assessed throgh metabolic pathways. The detailed justifcation is attached in section 13 of the dossier with title as category justifcation.

28 days repeated dose studies:

In a experimental study conducted by Sustainability Support Services (Europe) AB (2014), male and female Sprague Dawley rats treated with methyl 2-naphthyl ether 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 and LOAEL was considered to be 250 mg/kg body weight/day when Sprague Dawley male and female rats were exposed daily to methyl 2-naphthyl ether by oral route for 28 days.

In another experimental study given by OECD HPV Chemicals Programme (OECD HPV Chemicals Programme, SIDS Dossier, 09-FEB-2006) and European Chemicals Bureau (European Commission – European Chemicals Bureau, 18–FEB–2000) on structurally similar read across substance 2–naphthol (CAS no 135-19-3), Sprague-Dawley male and female rats were treated with 2–naphthol in the concentration of 0, 50, 150 and 450 mg/kg bw orally by gavage in CMC (carboxymethyl cellulose) for 28 days. No effect on survival was observed in treated rats. No signs of adverse reactions to treatment were observed in the male rats. Among females, the only sign observed was brown staining of the coat in animals from the high dose group. This sign occurred only during the 4th week of treatment and the first 2 weeks of the recovery period. No significant effect on body weight, Food consumption, water consumption, ophthalmic and haematological and urinalysis parameters were observed in treated male and female rats. Significant increase in creatinine, sodium and calcium levels, together with a significant decrease in potassium levels in male rat and significantly decreased Creatinine levels in female rats at 450 mg/kg bw were observed as compared to control. at the end of both the treatment and recovery periods. Similarly, All treated groups showed a slight and not dose-dependent increase in absolute and relative adrenal weights, the significance of this finding is unclear. In addition, no gross pathological and histopathological changes were observed in treated male and female rats. Therefore, NOAEL was considered to be 150 mg/kg bw when Sprague-Dawley male and female rats were treated with 2–naphthol orally by gavage for 28 days.

Further supported by by experimental study given by Infineum UK Ltd (2-(2-naphthyloxy) ethanol, Infineum UK Ltd, 2012) on structurally similar read across substance 2-(2-naphthyloxy) ethanol (CAS no 93-20-9), Crj: CD(SD) male and female Rats were administered the test substance at 50, 150 and 450 mg/kg bw and/or the vehicle, corn oil, once daily by oral gavage from Days 1 through 28 of study. The dose volume was 5 mL/kg and doses were based on the most recent body weights recorded prior to dose administration and given at approximately the same time each day. The following parameters and end points were evaluated in this study: viability, clinical signs, body weights, body weight changes, food consumption, functional observational battery, motor activity, clinical pathology, gross necropsy findings, histology and histopathology. On Day 29 of study (main study) or Day 43 of study (recovery portion), all surviving rats were anesthetized under isoflurane/oxygen and following blood collection from the inferior vena cava, were subsequently euthanized by an injection of sodium pentobarbital into the inferior vena cava. Examination for gross lesions, and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. No deaths related to the test substance occurred. One male rat in the 450 mg/kg/day dose group was found dead on Day 10 of study (DS 10). Necropsy revealed that all lobes of the lungs were mottled red and dark red. Based on the necropsy observation, this death was considered to be the result of an intubation error. There was an increase or statistically significant increase in the number of male and female rats in the 450 mg/kg/day dose groups observed with excess salivation (slight, moderate or extreme) and low carriage. There was also an increase in the number of male and female rats observed with mild or moderate dehydration and the number of male rats observed with urine-stained abdominal fur. In the male rats at 450 mg/kg/day, there were statistically significantly reduced mean body weights and body weight gains observed at all intervals during the dose period. Absolute and relative food consumption values were also reduced or statistically significantly reduced in the male rats at 450 mg/kg/day at all intervals during the dose period. At the end of the dose period, changes in serum chemistry that were considered to be test substance-related included a decrease in aspartate aminotransferase and an increase in triglyceride in the male and female rats at 150 and 450 mg/kg/day. There was an increase in glucose observed in the male and female rats at 450 mg/kg/day. In the male rats at 450 mg/kg/day, there was also an increase in the albumin/globulin ratio and the total bilirubin observed at the end of the dose period. These changes in serum chemistry had resolved by the end of the recovery period. Doses of the test substance as high as 450 mg/kg/day for 28 consecutive days did not cause any findings during the FOB and motor activity evaluations on DS 28. Likewise, the urinalysis performed at the end of dose period for both male and female rats showed no adverse effects. There were no adverse gross lesions observed at necropsy, effects on the organ weights, hematology or gross or microscopic histopathologic changes that were attributed to exposure to the test substance.  The no-observed-adverse-effect-level (NOAEL) for systemic toxicity produced by oral exposure to the test substance is considered to be at least 50 mg/kg/day for male and female rats.

Again supported by experimental study given by EGIS Pharmaceuticals PLC ((7-methoxynaphthalen-1-yl)acetonitrile, EGIS Pharmaceuticals PLC, 2005) on structurally similar read across substance (7-methoxynaphthalen-1-yl)acetonitrile (CAS no 138113-08-3, EC number: 461-670-1), Sprague-Dawley male and female rat were treated with 7-methoxynaphthalen-1-yl)acetonitrile in the concentration of 0, 50, 150 and 300 mg/kg bw orally by gavage in 0. 5 % methylcellulose. At 300 mg/kg including piloerection, hunched posture, thin appearance, soiled regions, cold to the touch and/or ptyalism, change in body weight and Food consumption and compound intake were observed. No salient changes were observed hematology and neurologic observation (FOB) of treated rats. Slightly high level of cholesterol (x1,3) and bilirubin (x1,7) serum concentration observed at 300 mg/kg. Increased liver weight were observed at 150 mg/kg (x1,2) and 300 mg/kg (x1,5). No salient findings were observed in treated rats. Non-neoplastic centrilobular hepatocellular hypertrophy was observed at 150 and 300 mg/kg. No changes in reproductive parameters such as vaginal cyclic or in sperm count and morphology. Therefore, NOEL was considered to be 50 mg/kg bw when Sprague-Dawley male and female rat were treated with 7-methoxynaphthalen-1-yl)acetonitrile orally by gavage for 28 days.

Again further supported by experimental study summarized by European Commission (Additional report to the Draft assessment report prepared in the context of the possible inclusion of the following active substance in Annex I of Council Directive 91/414/EEC; Rapporteur Member State: Italy April 2010) on structurally similar read across substance 2-naphthyloxyacetic acid (CAS no 120-23-0), rats were administered 0 (vehicle control), 50, 100, 250 and 500 mg/kg b.w./d of 2-naphthyloxyacetic acid orally for 28 days. Up to 500 mg/kg during 28 days, 2-Naphtyloxyacetic acid caused in rats slight clinical signs. It induced retardation in body weight growth and decreased food consumption. Some haematological disorders including a decrease in the red blood cell mean corpuscular volume, in the haemoglobin concentration and in the platelets number were seen. All these changes were evident at the 250 and 500 mg/kg b.w./d. dose levels; the involvement at 100 mg/kg b.w./d. was slight and only a few changes were observed at 50 mg/kg b.w./d. The target organs seem to be the stomach where microscopic changes were found at 100 mg/kg and higher, the liver whose weight was increased at the two top doses and the kidney. Kidney relative weight was increased in doses from 50 mg/kg in males and some histological findings including tubular dilation associated with eosinophilic material in tubules and hydronephrosis were seen above 100 mg/kg b.w./d in females. Based on the results of this study, the NOAEL for repeated dose toxicity study was estimated to be < 50 mg/kg bw/d.

This is again supported experimental study summarized by Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation (Japan Chemicals Collaborative Knowledge database, J-CHECK, 2010) on structurally similar read across substance 1-Methoxynaphthalene (CAS no 2216-69-5), Crj: CD(SD) male and female rats were treated with 1-Methoxynaphthalene in the concentration of 0, 30, 100, 300, 1000 mg/kg bw orally by gavge in corn oil for 28 days. Salivation until the end of the administration period were observed at 100, 300 and 1000 mg/kg bw. Eyelid ptosis was observed almost continuously from 1 to 2 days after administration in female at 300 mg / kg and in male and female at 1000 mg / kg p until the end of the administration period. Lacrimation was observed on the first day of administration in females of 300 and 1000 mg / kg. Coat of the coat was observed in males of the 300 mg / kg almost continuously from 23 days of administration, 17 days of administration in males at 1000 mg / kg, from 3 days of administration in female until the end of the administration period. Besides, a decline in locomotor activity was observed in one male in 1 to 17 days on treatment at 1000 mg / kg, and epidermal decline was observed in 1 case on 17thadministration. During the recovery period, no abnormal symptoms were observed in both sexes in the control group. In the sexes of the coat, one case was seen on each day at 1000 mg/ kg,, but no abnormality was observed after 2 days of recovery. No significant effect on body weight of treated male and female rats were observed at 30 and 100 mg/kg bw. At 300 mg/kg bw, tendency to suppress weight gain from around 5 days after administration were observed as compared to control group. At 1000 mg/kg bw in male rats, significant decrease in body weight from the 5thday of administration to the final administration day and in female rats suppression of body weight gain was observed from the 5thadministration day, and a significant decrease was observed on administration days 26 and 28 as compared to control. During the recovery period, significant decrease in body weight was observed in male and female rats at 1000 mg / kg from recovery 1 day to recovery 14 days as compared to control. No significant effect on food intake of treated male and female rats were observed at 30 and 100 mg/kg bw. At 300 mg / kg bw, significant decrease in food intake were observed on days 3 and 10 in male and in female on the 3rdday of administration as compared to control. At 1000 mg / kg, significant lower values of food intake were observed on 3 to 17 days of administration in male and on the 3rdday in female as compared to control. During the recovery period, there was no significant difference in feeding intake on either measurement day in male or female at 1000 mg / kg as compared to control. During the administration period, no significant difference was observed in the water intake amount on any measurement day in males at 30, 100 and 300 mg / kg and in females at 30 and 100 mg / kg as compared to control. In females of the 300 mg / kg group, a significant increase in water intake was observed on the 24thday of administration as compared to control. In males, significant decrease in water intake on day 3 of administration and a significant increase in water intake on Days 17 and 24 and in females a significant increase in water intake was observed on 10 to 24 days of administration at 1000 mg / kg as compared to control. During the recovery period, there was no significant difference in the water intake amount for any measurement day in males at 1000 mg / kg as compared to the control. In female at 1000 mg / kg, the trend of high water consumption was observed on recovery days 3 and 10 as compared to control. Before the end of the administration period, there was no significant difference in urine volume and specific gravity in male and female at 30, 100 and 300 mg / kg were observed as compared to control. In male and female of the 1000 mg / kg group, a significant increase in urine volume was observed as compared to the control. The color tone, pH, protein, sugar, ketone bodies, bilirubin, occult blood, urobilinogen and sediment were almost the same as in the control group in male and female at 30, 100 and 300 mg / kg. Increased tendency of acidic side of pH in sex, increasing tendency of epithelial cell appearance in sediment, increasing tendency of mild and moderate bilirubin in male were observed at of 1000 mg / kg bw. Before the end of the recovery period, there was no significant difference in urine volume and urine specific gravity were observed as compared to control in both sexes at 1000 mg / kg. The color tone, pH, protein, sugar, ketone bodies, bilirubin, occult blood, urobilinogen and sediment were almost the same as in the control in both sexes of 1000 mg / kg. Similarly, at the end of the administration period, red blood cell count, hemoglobin level, hematocrit value and significant decrease in MCHC and significant increase in reticulocyte count were observed in male and female at 300 and 1000 mg / kg as comparison to control. In male and female at 1000 mg / kg, a significant increase in methaemoglobin value was observed as compared to control. In addition, a significant shortening of prothrombin time and activated partial thromboplastin time in male at 30, 100, 300 and 1000 mg / kg were observed as compared to control, significant prolongation of prothrombin time in female at 30, 100 and 300 mg / kg, A significant high value of platelet number in male and female, and a significant high value of fibrinogen in females at 1000 mg / kg were observed, but it was numerical value within the range of our company's accumulated data of almost the same age-old rat. At the end of the recovery period, there was a significant decrease in MCHC in males and a significant increase in MCV in females at 1000 mg / kg as compared to control, but the accumulation of our almost same weekly rats it was numerical value within the range of data. At the end of the administration period, at 300 and 1000 mg/kg bw significant decrease in total protein, α1-globulin rate and α3-globulin rate, albumin ratio, β-globulin ratio, A / G ratio, Significant bilirubin and K were observed. In males, a significant high value of GPT, α 2 - globulin rate was observed at 1000 mg / kg as compared to control. In females, the β-globulin ratio and the total high bilirubin value were higher at at 300 and 1000 mg / kg as compared to control. Significant lower values of α1-globulin rate, α3-globulin rate, GPT, α2-globulin ratio, total cholesterol and K were observed in females at 1000 mg / kg as compared to control. At the end of the recovery period, there was a significant low value of glucose, a significant high value of glucose, ALP, K and inorganic phosphorus in males in the 1000 mg / kg group, significantly lower Ca in females in the same group However, it was within the range of agglomeration data of the same age-old rat. In addition, at the end of the administration period in gross pathology, dark reddening of the spleen was observed at 300 mg / kg in 9 males and 10 females and in 10 males and 10 females each at 1000 mg / kg. A large size of the spleen was found in one male in the 1000 mg / kg. Besides, unilateral pyeloid dilatation was observed in males at 100 and 1000 mg / kg, 1 in each case, dark red spots in the glandular gastric mucosa in 300 mg / kg males and 1 in 1000 mg / kg. One case in males, a bilateral testis and a small size of epididymis in 300 mg / kg group were observed in one case, but the appearance rate was low, not dependent on the dose. At the end of the recovery period, there was no abnormality in both sexes in either group. At the end of the administration period, there was no significant difference in weight of any organs were observed as compared to control at 30 and 100 mg / kg in both males and females. In male, at 300 and 1000 mg / kg, a significant high value of the absolute and relative weight of the spleen, a significant high value of the relative weight of the kidney, a significant high value of the absolute weight of the kidney at 300 mg / kg were observed. In the 1000 mg / kg, a significant high value of the relative weight of the liver, a high tendency of absolute weight of the liver was observed. Besides, at 300 mg / kg, a significant decrease in absolute weight of heart were observed as compared to control, a significant decrease in absolute weight of heart and Significantly high relative weight of the brain, testis and epididymis was observed at 1000 mg/ kg, but it was not absolute weight and relative weight in a fixed direction, or it was a slight difference. In females, a significant elevation of relative liver and kidney weight were observed as compared to control at 300 and 1000 mg / kg, a significant high value of the absolute and relative weight of the spleen, absolute weight of the liver and kidney were observed at 1000 mg / kg. Besides, in the 1000 mg / kg, the absolute weight of the thymus was significantly lower than that of the control group, but there was no difference in the relative weight. At the end of the recovery period, significant increase in absolute weights of the liver and adrenal glands were observed at 1000 mg / kg males as compared to control group, with significant high values of relative weights of the brain, spleen, kidney, testis and epididymis Although in absolute weight and relative weight, it was not a change in a certain direction, or it was a slight difference. In females, significant decrease in absolute weight of the brain, kidney and ovary and a significant increase in relative weight of the liver were observed as compared to control, but in the case of the absolute weight and the relative weight in the fixed direction. There was nothing or a slight difference. At the end of the administration period, in male, hemosiderin deposition was observed in the liver in 1 of 30 mg / kg, 6 cases of 300 mg / kg, 10 cases of 1000 mg / kg in the liver. In females in 2 cases at 100 mg / kg, 7 cases at 300 mg / kg, and 8 cases at 1000 mg / kg, and the change was significant at 300 mg / kg or more compared with the control group Differences were observed, and dose correlation was also confirmed. 10 cases of hepatocytes in the control, 5 cases in 30 mg / kg, 2 cases in the 100 mg / kg, 1 case in the 300 mg / kg, 5 in the 1000 mg /kg were observed. As seen in the example, a significant difference was observed in the 100 and 300 mg / kg as compared to the control, but dose correlation was not observed. This change was seen in females in 6 cases in the control, 5 cases at 30 mg / kg group, 6 cases at 100 mg / kg group and 3 cases at 300 mg / kg group, A significant difference was observed at 1000 mg kg, but dose correlation was not observed. All of the sexes were positive at 1000 mg / kg by iron staining, but in the biliary pigment staining, all cases were negative in the control and 1000 mg / kg. In the spleen, hemosiderin deposition was observed in 9 cases at 300 mg / kg group and 10 cases at 1000 mg / kg group in males, a significant difference was observed at 300 and 1000 mg / kg as compared to control, dose correlation. The sex was also confirmed. This change was seen in females in 8 cases at 100 mg / kg group, 10 cases at 300 mg / kg, 10 cases in the 1000 mg / kg, significant at 300 and 1000 mg / kg as compared to control. Differences were observed and dose correlation was also confirmed. Stasis was seen in males in 6 cases at 300 mg / kg and in 10 cases in 1000 mg / kg, significant difference was observed at 1000 mg / kg group, dose correlation was also confirmed. In females, this change was seen in 10 cases at 1000 mg / kg, a significant difference was observed as compared to control, and dose correlation was also confirmed. In the 1000 mg / kg by iron staining, all males and females were positive. In the kidney, the vitreous degeneration of renal tubules was observed in 1 at 30 mg / kg, 4 subjects at 100 mg / kg, 4 cases at 300 mg / kg, and 5 cases at 1000 mg / kg, A significant difference was observed at 1000 mg / kg group as compared to control, but dose correlation was not observed. This change was not seen in any group in females. In addition, 1 pelvic dilation was observed at 100 mg / kg, 1 in the 1000 mg / kg, 1 in the lime deposit at 100 mg/kg bw in the female, 1 in the female, cysts at 1,000 mg / kg and basophilization of renal tubules and renal tubular dilation were observed in one males in the 1000 mg / kg. In the biliary pigment staining, all cases were negative in the control. In the heart, granulomas were found in one male in the control group. There was no abnormality in the adrenal gland and bone marrow in the control group and in both sexes in the 1000 mg / kg. Others showed atrophy of seminiferous tubules and sperm disappearance in epididymal ducts in the testis and epididymis at 300 mg / kg in which abnormality was observed at necropsy. No changes were observed in the male stomach at 300 mg / kg and in female stomach at 1000 mg / kg. At the end of the recovery period, hemosiderin deposition was observed in liver in 4 cases at 1000 mg / kg in females, and a significant difference was observed as compared to control. Vacuolation of hepatocytes was observed in 3 males and 1 female in the control group. In the spleen, hemosiderin deposition was observed in 5 male at 1000 mg / kg, a significant difference was observed as compared to control. This change was seen in 5 female at 1000 mg / kg, and a significant difference was observed as compared to control. Therefore, NOAEL was considered to be 30 mg/kg bw when Crj: CD (SD) male and female rats were treated with 1-Methoxynaphthalene orally by gavage for 28 days.

Again supported by experimental study given by J-check (Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation, J-check, 2010) and OECD SIDS (SIAM 32, OECD SIDS, 2012) on structurally similar read across substance 2-naphthylisobutyl ether (CAS no 2173-57-1), Crj: CD(SD) male and female rats were treated with 2-naphthylisobutyl ether in the concentration of 0, 20, 100 and 500 mg/kg bw orally by gavage in corn oil for 28 days. In the 500 mg/kg group, loose stools, mucous feces, watery diarrhea and salivation were observed during the administration period in both males and females. Two females were found dead each on days 6 and 7 of administration. In the 500 mg/kg bw/day group, lower body weight was seen from day 4 of administration to the end of 14-day recovery period in males and on days 4-11 of administration in females. Food consumption was decreased on days 1-8 and days 15-28 of administration and on days 29-36 of recovery in males and on days 1-8 of administration in females at 500 mg/kg bw/day. Similarly, Decreases in red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT) and mean corpuscular hemoglobin concentration (MCHC) in females at 500 mg/kg bw/day. Other dose-related changes found at the end of recovery period included decreases in RBC and MCHC, increases in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) at 500 mg/kg bw/day. Blood biochemical test revealed a decrease in glucose and increase in ALT in males and decrease in total protein and increases in triglyceride and ALP in females at 500 mg/kg bw/day. Other dose-related changes found at the end of recovery period included decrease in blood glucose, increase in blood triglyceride level and total cholesterol in females at 500 mg/kg bw/day. At the end of administration period, urinalysis showed, at 500 mg/kg bw/day, an increase in urine volume in both sexes (not statistically significant for males) and, a decrease in osmotic pressure in both sexes and, in males, decreases in daily sodium and potassium excretion and neutralization of urine in males at 500 mg/kg bw/day. Further, browning of urine was found in both sexes at 100 mg/kg bw/day and above, and a positive bilirubin reaction was increased in both sexes at 500 mg/kg bw/day. In the functional observational battery (FOB) conducted during the fourth week of administration, the motor activity was decreased in males at 500 mg/kg bw/day , and no reaction to approach contact or touch stimuli and freezing to touch stimuli was found each in one male at this dose. In the recovery period, there were no differences between controls and treated groups in the FOB. In addition, Increases in the relative liver weight in males at 500 mg/kg bw/day and in females at 100 and 500 mg/kg bw/day, in the relative kidney weight in males at 100 mg/kg bw/day and above, in the relative spleen weight in both sexes at 500 mg/kg bw/day and in the relative adrenal weight in males at 500 mg/kg bw/day. Decreases in the absolute weight of the kidney, heart, thymus, epididymis and mandibular gland and increases in the relative weight of the brain and mandibular bland were also found in males and/or females at 500 mg/kg bw/day, but these changes were considered to be secondary effects due to the lowered body weight at necropsy. Other dose-related changes found at the end of recovery period included increase in the relative spleen weight, decrease in sperm in the epididymis and increase in the relative liver weight in females at 500 mg/kg bw/day. Small-sized prostate and seminal vesicle were observed at 500 mg/kg bw/day in males. There were also darkening of the spleen in both sexes, white patch/zone in the stomach, small-sized testis and scarred adrenal gland in males, and hypertrophic and scarred heart with nodules in females in the 500 mg/kg bw/day. Change in the heart was observed only in one female at 500 mg/kg bw/day, and accompanied with histopathological changes (i.e., fibrosis, hypertrophy of myocardium, pericarditis, myxoid change), but this change is not considered to be dose-related based on the severity and/or frequency. Other dose-related changes found at the end of recovery period included grossly small-sized testis, prostate and seminal vesicle grossly small-sized testis, prostate and seminal vesicle at 500 mg/kg bw/day. Dose-related changes were observed in the stomach, cecum, colon, liver, spleen, adrenal glands, prostate and seminal vesicle, as follows. -Forestomach: squamous hyperplasia in both sexes, hemorrhage and fibrosis in male, and edema and ulcer in female at 500 mg/kg bw/day -Glandular stomach: edema in female at 500 mg/kg bw/day -Cecum: increase in mitosis and basophilic change in the mucosal epithelial cells in males at 500 mg/kg bw/day -Colon: increase in mitosis in the mucosal epithelial cells in male at 100 mg/kg bw/day and in both sexes at 500 mg/kg bw/day, and basophilic change in the mucosal epithelial cells in both sexes at 500 mg/kg bw/day. -Liver: eosinophilic change and centrilobular hypertrophy of hepatocyte in both sexes of the 500 mg/kg bw/day group -Spleen: congestion and pigment deposition in both sexes and atrophy of white pulp in female at 500 mg/kg bw/day. -Adrenal gland: angiectasis, vacuolar degeneration, necrosis, and accumulation of macrophage and hypertrophy of cortex in both sexe at 500 mg/kg bw/day -Prostate: acinar atrophy in males of the 500 mg/kg bw/day group -Seminal vesicle: acinar atrophy in males in the 500 mg/kg bw/day group. After the 14-day recovery period, histopathological changes remained in the spleen (i.e. pigment deposition) and in the adrenal glands (i.e. angiectasisale, vacuolar degeneration, accumulation of macrophage, and necrosis and hypertrophy of cortex) in the 500 mg/kg bw/day group. Therefore, NOAEL was considered to be 20 mg/kg bw when Crj: CD (SD) male and female rats were treated with 2-naphthylisobutyl ether orally by gavage for 28 days.

90 days repeated dose studies:

In a experimental study conducted by Fitzhughet al(Arch Ophthalmol. 1949; 41(5):572-582) Repeated dose feeding study was performed to determine the toxic nature of Methyl 2-naphthyl ether. 5 weanling rats were dosed at dose level of 2% (approximately 1000 mg/Kg bw) in the diet for 2 months. During the 2 months rats developed cataracts and the chemical was considered to be cataractogenic. Based on the observations made, The No Observed Adverse Effect Level (NOAEL) was considered to be < 1000 mg/Kg/day when 5 weanling rats treated with Methyl 2-naphthyl ether orally in feed for 2 months.

In another prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for Methyl 2-naphthyl ether. The NOAEL was estimated to be 231 mg/kg bw when Fischer 344 male and female rats were orally exposed with Methyl 2-naphthyl ether.

Further supported by experimental study conducted by SHOPP et al (Fundamental and Applied Toxicology 4, 406-419 (1984)) on structurally similar read across substance Napthalene (CAS no 91-20-3), CD-1 ICR male and female mice were treated with Napthalene in the concentration of 0, 5.3, 53 and 133 mg/kg bw orally by gavage in corn oil for 90 days. No mortality was observed in treated male and female mice as compared to control. Aggressive behavior and biting were observed in male mice of all the treated groups. No Significant effect on body weight was observed in treated male and female mice as compared to control. Similarly, Slight but significant increase in hemoglobin and APTT and significant increase in Eosmophil numbers were observed in female mice at 133 mg/kg bw as compared to control. No significant changes were observed in the males as compared to control. In female mice, decrease in BUN at 5.3, 53 and 133 mg/kg, Increase in albumin levels and creatinine values and decrease in calcium levels in males and Increase in Total serum protein and increased globulin levels were observed in male and female at 53 and 133 mg/kg. Although there appeared to be increases in serum protein levels, the serum chemistry parameters gave little evidence of significant toxicity at any dosage and the nature of the noted changes does not allow detection of specific organ site toxicity. No significantly effect on the immune system was observed. The positive control, cyclophosphamide, suppressed the immune system. In addition, No effect on microsomal protein, cytochrome P-450, and cytochrome b3 and Hepatic glutathione levels were observed in treated male and female mice as compared to control. Aniline hydroxylation appeared to be increased in the 133 mg/kg bw female mice when expressed per nanomole cytochrome P-450, but the biological significance of this increase is doubtful. On the other hand, benzo(a)pyrene hydroxylase was depressed in a dose-dependent manner in both males and females. The mechanisms associated with this decrease will require further investigation, but competitive inhibition produced by residual naphthalene associated with the microsomes can be ruled out by the rapid hepatic clearance of naphthalene. Significant decrease in absolute brain, liver, and spleen weights and relative weight of spleen was observed in female at 133 mg/kg bw as compared to control. No significant changes in organ weights were observed in the males as compared to control. Although an organ associated with immune function showed a decreased weight, there was no evidence of immunotoxicity in any treatment group of either sex. Cataract formation was observed in treated mice. An interesting finding in this study was the lack of either naphthalene induced hemolytic anemia or cataract formation in CD 1 mice at the dosage levels employed. Therefore, NOAEL was considered to be 133 mg/kg bw when CD-1 ICR male and female mice were treated with Napthalene orally for 90 days.

Again supported by experimental study conducted by Koppers Netherlands B.V (Naphthalene, Koppers Netherlands B.V, 1980) on structurally similar read across substance Napthalene (CAS no 91-20-3), Fischer 344 male and female rats were treated with Napthalene in the concentration of 0, 25, 50, 100, 200, 400 mg/kg bw orally in corn oil for 1x/d, five consecutive days per week for 13 weeks. Mortality was noted for two male rats in the 400 mg/kg bw in the last week of the experiment. In one of the dead animals, renal lesions were found Signs of discomfort and disorder, Diarrhoea, lethargy, hunched posture and roughened haircoats were observed in 400 mg/kg bw treated male and female rats. Dose-related effects on body weights were observed at the 400 mg/kg and 200 mg/kg dose groups: in male rats significant decreases in body weight of -60% and -24% were observed in the 400 mg/kg and 200 mg/kg dose groups, respectively. In female rats, both doses caused a decrease in body weight of -69% and -15%, respectively. No substance-specific trends in diet consumption were observed in treated rats. Similarly, Marginal decrease in haemoglobin and haematocrit in the male and female and Considerable effects on lymphocyte and neutrophil values were observed in male at 400 mg/kg bw were observed. In addition, Lesions in kidneys from male animals (score 3 = moderate) and thymus glands from female animals (score 3 = moderate) was observed at 400 mg/kg bw in treated rats. Therefore, NOAEL was considered to be 200 mg/kg bw when Fischer 344 male and female rats were treated with Napthalene orally by gavage for 13 weeks. 

Above studies are further supported by experimental study conducted by Koppers Netherlands B.V (Naphthalene, Koppers Netherlands B.V, 1980) on structurally similar read across substance Napthalene (CAS no 91-20-3), B6C3F1 male and female mice were treated with Napthalene in the concentration of 0, 12.5, 25, 50, 100 and 200mg/kg bw orally in corn oil for 1x/d, five consecutive days per week for 13 weeks. 7 animals died: These early-death animals were attributed to gavage trauma or accident and included 3/10 males at 200 mg/kg bw, 2/10 females at 200 mg/kg bw, 1/10 female at 825 mg/kg bw, and 1/10 male in control. Signs of discomfort and physiologic disorders, predominantly in male mice were observed. Rough hair coats were observed in two female mice at 200 mg/kg group, whereas all male mice of the same dose group showed rough coats and lethargy. Two of these male mice exhibited slow, shallow breathing and mucous-coated eyes. No dose-related trends evident. Observed effects on body weight are not considered to be large enough to conclusively indicate a toxic effect. Dose-related decreasing trend in body-weight gains were observed in female mice. Similarly, No dose-related effect on diet consumption were observed in treated mice. Male mouse in 200 mg/kg group show a drop in diet consumed during week 5. In addition, slight increase in lymphocytes count and slight decrease in segmented neutrophiles count were observed at 200 mg/kg male mice; however, these effects are considered to be not biologically significant. Therefore, no clinically significant or dose-related trends have been identified. No gross pathological and histopathological changes were observed in treated mice. Therefore, NOAEL was considered to be 200 mg/kg bw when B6C3F1 male and female mice were treated with Napthalene orally by gavage for 13 weeks.

Further in another experimental study conducted by OSER et al (Food Cosmetic Toxicology. Vol. 3, pp. 563-569.1965) on structurally similar read across substance Beta-Naphthyl ethyl ether (CAS no 93-18-5), FDRL male and female rats were treated with Beta-Naphthyl ethyl ether in the concentration of 5.1 mg/kg for males and 5.7 mg/kg for females orally by feed for 90 days. No adverse effects on body weight and food consumption or food efficiency throughout the administration period were observed in treated rats as compared to control. Similarly, No effect on Hematological parameters and organ weight of treated male and female rats were observed as compared to control. In addition, No gross pathological and histopathological changes were observed in treated male and female rats in liver, kidneys, stomach, small and large intestines, spleen, pancreas, heart, lungs, bone marrow, muscle, brain, spinal cord, bladder, adrenals, thyroid, pituitary, reproductive organs (gonads), salivary glands, and lymph nodes as compared to control. Therefore, No adverse effect level (NOAEL) was considered to be 5.1 mg/kg for males and 5.7 mg/kg for females when FDRL male and female rats were treated with Beta-Naphthyl ethyl ether orally in feed for 90 days. The NOAEL of 5.1 mg/kg for males and 5.7 mg/kg for females in the study in rats is >100 000 times the daily per capita intake of Beta-Naphthyl ethyl ether from its reported use as a flavouring agent in US (0.06 µg/kg bw per day).

Further supported by experimental study conducted by Fitzhughet al(Arch Ophthalmol. 1949;41(5):572-582) on structurally similar read across substance Beta-Naphthyl ethyl ether (CAS no 93-18-5), 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 β-naphthyl ethyl ether is < 2000 mg/Kg/day.

Again supported by experimental study conducted by Fitzhugh et al (Arch Ophthalmol. 1949;41(5):572-582) on structurally similar read across substance 1-Methoxynaphthalene (CAS no 2216-69-5), 5 weanling rats were dosed at dose level of 2% (approximately 1000 mg/Kg bw) in the diet for 2 months. During the 2 months rats not developed cataracts and the chemical was considered to be not cataractogenic. Based on the observations made, The No Observed Adverse Effect Level (NOAEL) was considered to be > 1000 mg/Kg/day when 5 weanling rats treated with 1-Methoxynaphthalene orally in feed for 2 months.

Further again supported by experimental study given by Nagase GmbH (2-(phenylmethoxy)naphthalene, Nagase GmbH, 1994) on structurally similar read across substance 2-(phenylmethoxy)naphthalene (CAS no 613-62-7), SPF-bred Wistar rats were treated with 2-(phenylmethoxy)naphthalene was included in the diet at exposure levels of 0, 200, 1000, 5000 and 20000 ppm and fedad libitum.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 measured 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 recovery 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 high dose groups and samples of the lungs, 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. Therefore, from the results presented in the report a definitive No Observed Adverse Effect Level (NOAEL) was considered to be 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.

Again experimental study conducted by OSER et al (Food Cosmetic Toxicology. Vol. 3, pp. 563-569.1965) on structurally similar read across substance methyl beta-naphthyl ketone (CAS no 93-08-3), FDRL male and female rats were treated with methyl beta-naphthyl ketone in the concentration of 33 mg/kg for males and 37 mg/kg for females orally by feed for 90 days. No adverse effects on body weight and food consumption or food efficiency throughout the administration period were observed in treated rats as compared to control. Similarly, No effect on Hematological parameters and organ weight of treated male and female rats were observed as compared to control. In addition, No gross pathological and histopathological changes were observed in treated male and female rats in 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 as compared to control. Therefore, No adverse effect level (NOAEL) was considered to be 33 mg/kg for males and 37 mg/kg for females when FDRL male and female rats were treated with methyl beta-naphthyl ketone orally in feed for 90 days.

This above studies again supported by experimental study summarized by European Commission (Additional report to the Draft assessment report prepared in the context of the possible inclusion of the following active substance in Annex I of Council Directive 91/414/EEC; Rapporteur Member State: Italy April 2010) on structurally similar read across substance 2-naphthyloxyacetic acid (CAS no 120-23-0), rats were administered 0 (vehicle control), 10, 50 and 200 mg/kg b.w./d of 2-naphthyloxyacetic acid orally for 90 days. At 200 mg/kg, liver showed slight (in males) or moderate (in females) increase in weight due to slight centrilobular hepatocellular hypertrophy concomitant with increase in ALP and SGPT. Kidneys were slightly increased in weight and histology showed slight or moderate increase in frequency and degree of tubular dilation associated with presence of eosinophilic material within the tubular lumen. Furthermore, increase in urea and creatinine levels were noted at 200 mg/kg bw. A slight increase in comparison with controls of gastric slight dilation and repletion was seen in some animals in most cases associated with glandular mucosa erosion. At 50 mg/kg bw/day, morphological changes were limited to a slight increase in frequency when compared with the controls of the above-mentioned renal tubular changes, without any renal weight variation. The dose of 50 mg/kg b.w./d induced a few slight modifications indicating a mild renal involvement, but their reversibility was complete. The dose of 200 mg/kg b.w./d induced changes indicative of hepatic, renal and gastric effects, as well as a few haematological changes consisting of a slight decrease in platelet and leukocyte count (bone marrow was normal), and a slight body weight gain reduction in males. However, no severe toxic effects were noted, and all the above changes, particularly the morphological ones, proved capable of complete recovery after withdrawal of the compound. Under the experimental conditions applied, the NOEL for 2-Naphthyloxyacetic acid after 13-week repeated oral administration in rats was 10 mg/kg b.w. /d.

Based on the data available for the target chemical and its read across, the test chemical Methyl 2-naphthyl ether (CAS no 93-04-9) does not classify as a toxicant as per the criteria mentioned in CLP regulation

Justification for classification or non-classification

Based on the data available for the target chemical ans its read across, the test chemical Methyl 2-naphthyl ether (CAS no 93-04-9) does not classify as a toxicant as per the crietria mentioned in CLP regulation.