4-methoxybenzyl alcohol

Endpoint summary

Description of key information

Repeated dose toxicity: via oral route;

NOAEL was considered to be in a dose range of  125-625  mg/kg bw  when rodents  were exposed daily to test substance by oral route for repeated dose study.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance 4-methoxybenzyl alcohol (105-13-5 )which is reported as 0.001799398 mmHg at 25 C. Thus, exposure to inhalable dust, mist and vapour of the chemical 4-methoxybenzyl alcohol is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The test substance was evaluated for its repeated dose dermal toxicity study in rabbits for 13 weeks. The test material was exposed to abraded skin of rabbits in the concentration of 0.06mg/Kg for 13 weeks. The animals were observed for clinical sign, mortality, gross and histopathology. Dermal irritation was observed in animals. Somnolence (general depressed activity) was also observed. Therefore LOAEL was considered to be 0.06mg/Kg in rabbits for 13 weeks by dermal exposure. As it is a single dose study and no significant effect were observed. The test substance cannot be classified as per CLP for repeated dose toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data from handbook or collection of data

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Weight of evidence prepared from various studies mention below
1,To determine the toxicity likely to arise from the repeated exposure of the test item over a relatively limited period of time (28 days) in male and female SD rats.
2, To evaluate the toxic nature of test chemical Repeated dose toxicity was conducted in rodent.

GLP compliance:

yes

Limit test:

no

Species:

other: 1,rat 2,mouse

Strain:

other: 1,Sprague-Dawley 2,CB6F1-Tg

Sex:

male/female

Details on test animals or test system and environmental conditions:

1,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)

TEST ANIMALS
- Source: Central Institute for Experimental Animals (Kawasaki, Japan)
- Age at study initiation:≈6 week old
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: housed in polycarbonate cages (singly housed for males and 5:cage
for females) with absorbent hardwood bedding
- Diet (e.g. ad libitum): NIH-07 open formula diet (ad libitum)
- Water (e.g. ad libitum): (ad libitum)
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): continuous temperature monitoring.
- Humidity (%): continuous humidity monitoring.
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-h light:12-h dark cycle

Route of administration:

oral: gavage

Vehicle:

other: Groundnut oil

Details on oral exposure:

1,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

2,PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): p-Anisidine admixed with feed at concentrations of 0.450 and 0.225%
- Mixing appropriate amounts with (Type of food): NIH-07 open formula diet
- Storage temperature of food: 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:

1,28 days
2,18 month period

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)

Remarks:

321.428 And 642.857 mg/kg (0.225 and 0.450%)

No. of animals per sex per dose:

1,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

2,60 animal/sex/dose

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:

1,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.
2,Observation and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data available
DETAILED CLINICAL OBSERVATIONS: No data available
DERMAL IRRITATION (if dermal study): No data available
- Time schedule for examinations: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: No data available
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: 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

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):

1,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.
2,No clinical sighs observed in animals during study.

Mortality:

no mortality observed

Description (incidence):

1,All animals except animal No. 25 & 26 of high dose survived throughout the treatment period.
2,No mortality observed in animals during study.

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:

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

Dose descriptor:

NOAEL

Effect level:

642.857 other: mg/kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effect were observed at this dose

Remarks on result:

other: No toxic effects were observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Conclusions:

NOAEL was considered to be in a dose range of 125-625 mg/kg bw when rodents were exposed daily to test substance by oral route for repeated dose study.

Executive summary:

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.

Repeated dose toxicity test was performed on CB6F1 males and female at two different laboratories in Japan and USA. Test substance was mixed with feed and given to animals at two different concentrations as 321.428 and 642.857 mg/kg and observed for 18 months. After 18 months all mice were necropsied and observed histopathologically. Standard hematoxylin and Eosin-stained slides were also evaluated. After 18 months no clinical effects were observed in male and female mice. Decrease in body weight in males and some females of low dose concentration were also observed. On gross pathology dark red spleens and small lung nodules in a few mice and no significant dose-related trends for either pulmonary or splenic tumors were observed. Some effects were also observed in control also. So on the basis of above experimental results it was concluded that the No Observed Adverse Effect Level (NOAEL) at 642.857 mg/kg concentration of test substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

125 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Weight of evidence prepared from vaeious qulified 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

Link to relevant study records

Reference

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Data is from RTECS Database

GLP compliance:

not specified

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

intermittent

Remarks:

0.06mg/Kg

Control animals:

not specified

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

ehavioral - somnolence (general depressed activity) was observed.

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Yes ,Dermal irritation was moderatley observed on abrraded skin by repeated application.

Mortality:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

No Leasion was observed in survived animals.

Details on results:

OTHER FINDINGS : Toxic Effects : B
Related to Chronic Data - death

Key result

Dose descriptor:

LOAEL

Effect level:

0.06 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: overall effects : Toxic Effects : Behavioral - somnolence (general depressed activity) Related to Chronic Data - death

Remarks on result:

other: Low adverse effects were observed

Critical effects observed:

not specified

Conclusions:

The chronic toxicity study for test substance was tested in rabbit by dermal exposure of 0.06mg/Kg of substance for 13 weeks. The LOAEL was considered to be 0.06mg/Kg in rabbits by dermal exposure.

Executive summary:

The test substance was evaluated for its repeated dose dermal toxicity study in rabbits for 13 weeks. The test material was exposed to abraded skin of rabbits in the concentration of 0.06mg/Kg for 13 weeks. The animals were observed for clinical sign, mortality, gross and histopathology. Dermal irritation was observed in animals. Somnolence (general depressed activity) was also observed. Therefore LOAEL was considered to be 0.06mg/Kg in rabbits for 13 weeks by dermal exposure. As it is a single dose study and no significant effect were observed. The test substance cannot be classified as per CLP for repeated dose toxicity.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

0.06 mg/kg bw/day

Study duration:

subchronic

Species:

rabbit

Quality of whole database:

Data is from publication

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The data available for the test chemical was reviewed to determine the toxic nature of p-Anisidine (104-94-9) repeated exposure by oral route. The study is as mentioned below:

Repeated dose toxicity: via oral route;

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.

Repeated dose toxicity test was performed on CB6F1 males and female at two different laboratories in Japan and USA. Test substance was mixed with feed and given to animals at two different concentrations as 321.428 and 642.857 mg/kg and observed for 18 months. After 18 months all mice were necropsied and observed histopathologically. Standard hematoxylin and Eosin-stained slides were also evaluated. After 18 months no clinical effects were observed in male and female mice. Decrease in body weight in males and some females of low dose concentration were also observed. On gross pathology dark red spleens and small lung nodules in a few mice and no significant dose-related trends for either pulmonary or splenic tumors were observed. Some effects were also observed in control also. So on the basis of above experimental results it was concluded that the No Observed Adverse Effect Level (NOAEL) at 642.857 mg/kg concentration of test substance.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance 4-methoxybenzyl alcohol (105-13-5 )which is reported as 0.001799398 mmHg at 25 C. Thus, exposure to inhalable dust, mist and vapour of the chemical 4-methoxybenzyl alcohol is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The test substance was evaluated for its repeated dose dermal toxicity study in rabbits for 13 weeks. The test material was exposed to abraded skin of rabbits in the concentration of 0.06mg/Kg for 13 weeks. The animals were observed for clinical sign, mortality, gross and histopathology. Dermal irritation was observed in animals. Somnolence (general depressed activity) was also observed. Therefore LOAEL was considered to be 0.06mg/Kg in rabbits for 13 weeks by dermal exposure. As it is a single dose study and no significant effect were observed. The test substance cannot be classified as per CLP for repeated dose toxicity.

.

Based on the data available for the test chemical not likely to exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available, the test chemical is not likely to exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation