3,7-dimethyl-1-octyl acetate

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg body weight, when Sprague Dawley male and female rats were treated with the given test chemical via oral route, over a period of 90 days.

 

Repeated dose toxicity: Inhalation

A short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the given test chemical has very low vapor pressure 12.93 Pa (0.0900074 mmHg), so the potential for the generation of inhalable vapors is very low. The normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point for repeated inhalation toxicity was considered for waiver.

 

Repeated dose toxicity: Dermal

A short-term toxicity study does not need to be conducted because exposure of humans via dermal in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the acute dermal toxicity value for test chemical (as provided in section 7.2.3) is >2000 mg/kg body weight. Given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that test chemical shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that test chemical shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

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:

sub-chronic 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

Remarks:

Experimental data from various test chemicals

Justification for type of information:

Weight of evidence approach based on the available information from various test chemicals.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

WoE report is based on 2 repeated dose toxicity studies i.e. WoE-2 and WoE-3.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: gavage

Details on route of administration:

No data

Vehicle:

other: 2. water 3. not specified

Details on oral exposure:

2. VEHICLE
- Concentration in vehicle: 100, 500, and 1000 mg/kg/day
- Amount of vehicle (if gavage): 1.111 ml/kg
3. No data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 Days

Frequency of treatment:

2. daily, 5 days/week for 13 weeks
3. once/day, 5 days/wk

Remarks:

0, 100, 500, 1000 mg/kg bw/day

No. of animals per sex per dose:

2. A group of 20 rats/sex/group
3. A group of 20 rats/sex/group

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

2. CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: Yes, all surviving animals were weighed.
- Time schedule for examinations: after 13 weeks

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes, blood samples were collected from the abdominal aortas.
- Time schedule for collection of blood: following an overnight fast
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: No data
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes, clinical laboratory studies (hematology and serum chemistry) were
Performed.
- Time schedule for collection of blood: after 45 days and at study termination.
- Animals fasted: No data
- How many animals: on 5
animals/sex/dose after 45 days (interim sacrifice), and all animals at study termination.
- Parameters checked in table [No.?] were examined.
3. CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: Yes, all surviving animals were weighed.
- Time schedule for examinations: after 13 weeks

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes, blood samples were collected from the abdominal aortas.
- Time schedule for collection of blood: following an overnight fast
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: No data
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes, clinical laboratory studies (hematology and serum chemistry) were
Performed.
- Time schedule for collection of blood: after 45 days and at study termination.
- Animals fasted: No data
- How many animals: on 5
animals/sex/dose after 45 days (interim sacrifice), and all animals at study termination.
- Parameters checked in table [No.?] were examined.

Sacrifice and pathology:

2. GROSS PATHOLOGY: Yes, at 45 days, a complete necropsy was performed and livers were collected, weighed and reserved. After 13 weeks, all surviving animals were weighed, anesthetized and sacrificed by exsanguination. Complete necropsies were performed.
HISTOPATHOLOGY: Yes, microscopic examination was performed.
3. GROSS PATHOLOGY: Yes, at 45 days, a complete necropsy was performed and livers were collected, weighed and reserved. After 13 weeks, all surviving animals were weighed, anesthetized and sacrificed by exsanguination. Complete necropsies were performed.
HISTOPATHOLOGY: Yes, microscopic examination was performed

Other examinations:

2. No data
3. Clinical laboratory studies (hematology and serum chemistry) were performed pretest on 5 males and 5 females (non-study animals).

Statistics:

No data

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

2. Rats produced minimal signs of systemic toxicity.
3. Rats produced minimal signs of systemic toxicity. The in-life clinical observations were primarily oral and dermal irritation (no clear dose response).

Mortality:

no mortality observed

Description (incidence):

2. There was no treatment-related mortality.
3. There was no treatment-related mortality.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

2. Weekly mean body weights were not significantly altered compared to controls.
3. Weekly mean body weights values were not significantly altered compared to controls.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

2. Food consumption values were not significantly altered compared to controls.
3. Food consumption values were not significantly altered compared to controls.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

2. The qualitative hematologic data were unremarkable at all dose levels for the interim and terminal evaluations.
3. The qualitative hematologic data were unremarkable at all dose levels. At the terminal sacrifice, glucose values for the 500, and 1000 mg/kg/day males were lower than controls and the total protein values for the 100 mg/kg/day females were higher than controls.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

2. At the terminal sacrifice, there were no biologically significant differences between treated and control animals for the measured clinical chemistries.
3. not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

2. Terminal liver and kidney weights were elevated in a dose-related manner but were considered to be adaptive changes and not indicative of toxic effects. All other organ weights were comparable to control values.
3. Terminal liver and kidney weights were elevated in a dose-related manner but were considered to be adaptive changes and not indicative of toxic effects.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

2. Microscopic evaluation of the kidneys showed evidence of mild tubular nephropathy only in the high-dose male rats that were consistent with alpha-2u-globulin effects.
3. Microscopic evaluation of the kidneys showed evidence of mild tubular nephropathy in the mid- and high-dose male rats that were consistent with alpha-2uglobulin effects.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

2. Histopathology review of all other tissues from high-dose animals, including reproductive organs (testes, epididymides, prostate, seminal vesicles, ovaries, uterine horns, cervix, and corpus of the uterus, and vagina), showed normal morphology.
3. Histopathology review of all other tissues from high dose animals, including reproductive organs (testes, epididymides, prostate, seminal vesicles, ovaries, uterine horns, cervix/corpus of the uterus, and vagina), showed normal morphology.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Remarks:

2

Effect level:

1 000 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

organ weights and organ / body weight ratios

Dose descriptor:

NOAEL

Remarks:

3

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

Critical effects observed:

not specified

Conclusions:

No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg body weight, when Sprague Dawley male and female rats were treated with the given test chemical via oral route, over a period of 90 days.

Executive summary:

Data available from the various sources was reviewed to determine the toxic nature of the given test chemical. The studies are as mentioned below:

 

90 days repeated oral toxicity study was performed to determine the toxic nature of the given test chemical. The study was performed using male and female Sprague-Dawley rats at dose level of 0 (water) or 100, 500 or 1000 mg/kg/day. Controls received a dose of water volumetrically comparable to the dosage administered to the high dose group, 1.111 ml/kg. Clinical laboratory studies (hematology and serum chemistry) were performed pretest on 5 males and 5 females (non-study animals), on 5 animals/sex/ dose after 45 days (interim sacrifice), and all animals at study termination. Blood samples were collected from the abdominal aortas following an overnight fast. At 45 days, a complete necropsy was performed and livers were collected, weighed and preserved. After 13 weeks, all surviving animals were weighed, anesthetized and sacrificed by exsanguinations. Complete necropsies were performed. Oral administration of the test chemical daily, 5 days/week for 13 weeks, to rats produced minimal signs of systemic toxicity. There was no treatment-related mortality. The in-life clinical observations were primarily oral and dermal irritation (no clear dose response). Weekly mean body weights and food consumption values were not significantly altered compared to controls. The qualitative hematologic data were unremarkable at all dose levels for the interim and terminal evaluations. At the terminal sacrifice, there were no biologically significant differences between treated and control animals for the measured clinical chemistries. Terminal liver and kidney weights were elevated in a dose-related manner but were considered to be adaptive changes and not indicative of toxic effects. All other organ weights were comparable to control values. Microscopic evaluation of the kidneys showed evidence of mild tubular nephropathy only in the high-dose male rats that were consistent with alpha-2u-globulin effects. Histopathology review of all other tissues from high-dose animals, including reproductive organs (testes, epididymides, prostate, seminal vesicles, ovaries, uterine horns, cervix, and corpus of the uterus, and vagina), showed normal morphology. Based on the results of the study, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day, when male and female Sprague-Dawley rats were exposed to the given test chemical for 90 days.

 

In another study, 90 days repeated oral toxicity study was performed to determine the toxic nature of the given test chemical. The study was performed using male and female Sprague-Dawley rats at dose level of 0 (water) or 100, 500 or 1000 mg/kg/day. Controls received a dose of water volumetrically comparable to the dosage administered to the high dose group, 1.111 ml/kg. Clinical laboratory studies (hematology and serum chemistry) were performed pretest on 5 males and 5 females (non-study animals), on 5 animals/sex/dose after 45 days (interim sacrifice), and all animals at study termination. Blood samples were collected from the abdominal aortas following an overnight fast. At 45 days, a complete necropsy was performed and livers were collected, weighed and preserved. After 13 weeks, all surviving animals were weighed, anesthetized and sacrificed by exsanguinations. Complete necropsies were performed. Oral administration of the given test chemical daily, 5 days/week for 13 weeks, to rats produced minimal signs of systemic toxicity. There was no treatment-related mortality. The in-life clinical observations were primarily oral and dermal irritation (no clear dose response). Weekly mean body weights and food consumption values were not significantly altered compared to controls. The qualitative hematologic data were unremarkable at all dose levels. At the terminal sacrifice, glucose values for the 500, and 1000 mg/kg/day males were lower than controls and the total protein values for the 100 mg/kg/day females were higher than controls. Terminal liver and kidney weights were elevated in a dose-related manner but were considered to be adaptive changes and not indicative of toxic effects. Microscopic evaluation of the kidneys showed evidence of mild tubular nephropathy in the mid- and high-dose male rats that were consistent with alpha-2uglobulin effects. Histopathology review of all other tissues from high dose animals, including reproductive organs (testes, epididymides, prostate, seminal vesicles, ovaries, uterine horns, cervix/corpus of the uterus, and vagina), showed normal morphology. Based on the results of the study, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day, when male and female Sprague-Dawley rats were exposed to the given test chemical for 90 days.

 

Thus based on the above studies, the No Observed Adverse Effect Level (NOAEL) is considered to be 1000 mg / kg body weight and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from handbook or collection of data.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Endpoint conclusion:

no study available

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:

chronic toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

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

Data available from the various sources was reviewed to determine the toxic nature of the given test chemical. The studies are as mentioned below:

 

90 days repeated oral toxicity study was performed to determine the toxic nature of the given test chemical. The study was performed using male and female Sprague-Dawley rats at dose level of 0 (water) or 100, 500 or 1000 mg/kg/day. Controls received a dose of water volumetrically comparable to the dosage administered to the high dose group, 1.111 ml/kg. Clinical laboratory studies (hematology and serum chemistry) were performed pretest on 5 males and 5 females (non-study animals), on 5 animals/sex/ dose after 45 days (interim sacrifice), and all animals at study termination. Blood samples were collected from the abdominal aortas following an overnight fast. At 45 days, a complete necropsy was performed and livers were collected, weighed and preserved. After 13 weeks, all surviving animals were weighed, anesthetized and sacrificed by exsanguinations. Complete necropsies were performed. Oral administration of the test chemical daily, 5 days/week for 13 weeks, to rats produced minimal signs of systemic toxicity. There was no treatment-related mortality. The in-life clinical observations were primarily oral and dermal irritation (no clear dose response). Weekly mean body weights and food consumption values were not significantly altered compared to controls. The qualitative hematologic data were unremarkable at all dose levels for the interim and terminal evaluations. At the terminal sacrifice, there were no biologically significant differences between treated and control animals for the measured clinical chemistries. Terminal liver and kidney weights were elevated in a dose-related manner but were considered to be adaptive changes and not indicative of toxic effects. All other organ weights were comparable to control values. Microscopic evaluation of the kidneys showed evidence of mild tubular nephropathy only in the high-dose male rats that were consistent with alpha-2u-globulin effects. Histopathology review of all other tissues from high-dose animals, including reproductive organs (testes, epididymides, prostate, seminal vesicles, ovaries, uterine horns, cervix, and corpus of the uterus, and vagina), showed normal morphology. Based on the results of the study, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day, when male and female Sprague-Dawley rats were exposed to the given test chemical for 90 days.

 

In another study, 90 days repeated oral toxicity study was performed to determine the toxic nature of the given test chemical. The study was performed using male and female Sprague-Dawley rats at dose level of 0 (water) or 100, 500 or 1000 mg/kg/day. Controls received a dose of water volumetrically comparable to the dosage administered to the high dose group, 1.111 ml/kg. Clinical laboratory studies (hematology and serum chemistry) were performed pretest on 5 males and 5 females (non-study animals), on 5 animals/sex/dose after 45 days (interim sacrifice), and all animals at study termination. Blood samples were collected from the abdominal aortas following an overnight fast. At 45 days, a complete necropsy was performed and livers were collected, weighed and preserved. After 13 weeks, all surviving animals were weighed, anesthetized and sacrificed by exsanguinations. Complete necropsies were performed. Oral administration of the given test chemical daily, 5 days/week for 13 weeks, to rats produced minimal signs of systemic toxicity. There was no treatment-related mortality. The in-life clinical observations were primarily oral and dermal irritation (no clear dose response). Weekly mean body weights and food consumption values were not significantly altered compared to controls. The qualitative hematologic data were unremarkable at all dose levels. At the terminal sacrifice, glucose values for the 500, and 1000 mg/kg/day males were lower than controls and the total protein values for the 100 mg/kg/day females were higher than controls. Terminal liver and kidney weights were elevated in a dose-related manner but were considered to be adaptive changes and not indicative of toxic effects. Microscopic evaluation of the kidneys showed evidence of mild tubular nephropathy in the mid- and high-dose male rats that were consistent with alpha-2uglobulin effects. Histopathology review of all other tissues from high dose animals, including reproductive organs (testes, epididymides, prostate, seminal vesicles, ovaries, uterine horns, cervix/corpus of the uterus, and vagina), showed normal morphology. Based on the results of the study, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day, when male and female Sprague-Dawley rats were exposed to the given test chemical for 90 days.

 

Thus based on the above studies, the No Observed Adverse Effect Level (NOAEL) is considered to be 1000 mg / kg body weight and hence is not likely to classify as per the criteria mentioned in CLP regulation.

 

Repeated dose toxicity: Inhalation

A short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the given test chemical has very low vapor pressure 12.93 Pa (0.0900074 mmHg), so the potential for the generation of inhalable vapors is very low. The normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point for repeated inhalation toxicity was considered for waiver.

 

Repeated dose toxicity: Dermal

A short-term toxicity study does not need to be conducted because exposure of humans via dermal in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the acute dermal toxicity value for test chemical (as provided in section 7.2.3) is >2000 mg/kg body weight. Given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that test chemical shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that test chemical shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

 

Justification for classification or non-classification

Based on the data available and applying the weight of evidence approach, the given test chemical does not exhibit toxic nature upon repeated exposure by oral route of exposure. Hence, it is not likely to classify as toxic as per the criteria mentioned in CLP regulation. For repeated inhalation and repeated dermal toxicity wavier was added so, not possible to classify.