2-ethylhexyl salicylate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.03 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

677 mg/m³

Explanation for the modification of the dose descriptor starting point:

no route to route extrapolation but consideration of exposure duration (7 h/d in study to 8h/d per shift) and adjustment to light activity (multiplied by 6.7 m3/10m3) --> NOAEC corr = 1155 mg/m3 * 7/8 *6.7/10 = 677 mg/m3

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEC

AF for differences in duration of exposure:

6

Justification:

extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

allometric scaling factor rat to human

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

5

Justification:

default factor for worker

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

158 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

17.5

Modified dose descriptor starting point:

NOAEL

Value:

2 767 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

According to the toxicokinetic assessment, the absorption rate from dermal route is assumed to be 3% and the absorption rate of oral route is considered to be 100%. Therefore, the oral NOAEL of 83 mg/kg bw/d is converted to a NOAEL of dermal route by multiplying with 100/3.

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

1

Justification:

data from chronic study used

AF for interspecies differences (allometric scaling):

1.4

Justification:

allometric scaling factor dog to human

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

5

Justification:

default factor for worker

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Acute/short-term exposure - local or systemic effects for dermal route:

In a GLP compliant OECD404 guideline study with rabbits, pure 2-ethylhexyl salicylate is considered to be not a skin irritant. In a guideline-compliant primary skin sensitisation study in guinea pigs, 2-ethylhexyl salicylate showed no skin sensitising properties. No short-term local DNEL needs to be derived for cutaneous exposure. Furthermore, in a dermal toxicity study where rats were given a single, 24 -hour, semi-occluded dermal application of the test material to intact skin, at a dose level of 5000 mg/kg body weight no deaths and no evidence of systemic toxicity or dermal irritation were noted. No short-term systemic DNEL needs to be derived for cutaneous exposure.

Acute/short-term exposure - local or systemic effects for inhalation route:

The subacute inhalation toxicity study (Gage, 1970) with methyl salicylate vapour did not demonstrate any adverse effects.

No short-term DNEL needs to be derived for inhalation exposure.

Long-term exposure - local effects for inhalation or dermal route:

Since 2-ethylhexyl is not classified as irritating to the skin, respiratory system or eyes, no long-term local DNEL needs to be derived for inhalation and dermal exposure.

Long-term exposure - systemic effects for dermal route:

The absorption rate from dermal route is assumed to be 3% and the absorption rate of oral route is considered to be 100%. Therefore, the oral NOAEL of 83 mg/kg bw/d is converted to a dermal NOAEL of 2767 mg/kg/day by multiplying by a factor of 100/3.

As basis for dermal DNEL derivation the result from a chronic study with beagle dogs was used, performed by Webb and Hansen in 1963 as conservative approach. In this study, the test item was administered at dosages of 0, 50, 150 and 350 mg/kg bw/day methyl salicylate in capsules daily for 2 years (6 days/week). Controls received diet only.

One high-dose animal died of hepatitis apparently unrelated to methyl salicylate. Hematological analyses at 1, 3, 6, 12 and 24 months and complete necropsy examination were normal, except that dogs treated at 150 and 350 mg/kg body weight/day had enlarged livers, seen microscopically as enlarged hepatic cells. No other pathology was reported in any of the animals. Reduced body weight was reported in the 350 and 150 mg/kg body weight/day groups. Based on this chronic oral study, the NOAEL value is 50 mg/kg body weight/day, being equivalent to 83 mg/kg bw/d 2-ethylhexyl salicylate on an equimolar basis.

An equivalent study with rats was performed, using doses of 0, 50, 250, 500 and 1000 mg/kg bw/d. Also in this study a NOAEL of 50 mg/kg bw/d was established (equivalent to 83 mg/kg bw/d 2-ethylhexyl salicylate). Gross pituitary gland lesions were found in 10 rats at 250 mg/kg bw/day compared to 4 rats in the control groups. Incidence in the 500 mg/kg/day group was similar to controls, while all animals of the 1000 mg/kg/day group died before the usual age at which many spontaneous lesions develop.

Similar kinds and numbers of tumors occurred in rats of all diets except the 1000 mg/kg/day group (premature decedents), with mammary tumors of the females being the most common. Benign pituitary tumors occurred in similar numbers of surviving rats on all diets, with occurrence predominantly in females. Malignant pituitary tumors occurred in one male and two females receiving 250 mg/kg/day. Since no such tumors were reported in either the lower or higher dose groups (50 and 500 mg/kg/day), this low incidence does not clearly indicate any relation with methyl salicylate treatment. The NOAEL was set to 50 mg/kg bw/d equivalent to 83 mg/kg bw/d if adjusted equimolar to 2-ethylhexyl salicylate.

Compared to the NOAEL seen in the subchronic study in rats with 2-ethylhexyl salicylate, where no test article-related effects including clinical observations, survival, body weights, food consumption, water consumption, clinical pathology determinations, ophthalmoscopic examinations, macroscopic pathology, organ weight determinations and microscopic pathology were noted at the high-dose level and the NOAEL (No Observed Adverse Effect Level) for general toxicity in rats was considered to be 250 mg/kg bw/day, the adjusted NOAEL of 83 mg/kg bw/d found in the chronic study with rats and dogs is considered a conservative worst case value and is used to derive the dermal DNEL by route to route extrapolation.

Factors for allometric scaling from dog to human (1.4), other interspecies differences (2.5) and intraspecies differences for workers (5) were applied to receive a DNEL of 158 mg/kg.

Long-term exposure - systemic effects for inhalation route:

The derivation of the DNEL inhalative is based on an available subacute inhalative study with methyl salicylate, as read-across substance. Methyl salicylate at 700 mg/m³ (120 ppm), the maximum achievable atmosphere, did not cause any adverse effects (Gage, 1970). The adjusted NOAEC (equimolar) to 2-ethylhexyl salicylate is 1155 mg/m³ and is used as basis to derive the inhalative DNEL for workers. Consideration of exposure duration (7 h/d in study to 8h/d per shift) and adjustment to light activity was done (multiplied by 6.7 m3/10m3) --> NOAEC corr = 1155 mg/m3 * 7/8 *6.7/10 = 677 mg/m3. Factors for duration of exposure (6), other interspecies differences (2.5) and intraspecies differences for workers (5) were applied leading to a DNEL of 9.03 mg/m3.

Alternative calculations of the dermal and inhalative DNELs:

An alternative dermal DNEL calculation was performed using the NOAEL of 25 mg/kg received from the reproductive toxicity study (OECD 421). The absorption rate from dermal route is assumed to be 3% and the absorption rate of oral route is considered to be 100%. Therefore, the oral NOAEL of 25 mg/kg bw/d is converted to a dermal NOAEL of 833.4 mg/kg/day by multiplying by a factor of 100/3. No factors for duration of exposure were applied since it was a reproductive effect and the duration of treatment in the study covered the whole period of pregancy. No interspecies differences were applied since considerable species differences in sensitivity were described with the rat being more sensitive than humans. A factor of 5 was applied for intraspecies differences leading to DNEL of 166 mg/kg being a value close to 158 mg/kg.

The same was performed for the inhalative DNEL calculation using the NOAEL of 25 mg/kg received from the reproductive toxicity study (OECD 421). A route to route extrapolation must be performed and adjustment to light activity was done (multiplied by 6.7 m3/10m3) --> NOAEL corr = 25 mg/kg *1/0.38 m3*6.7/10 = 44 mg/m3.

No factors for duration of exposure were applied since it was a reproductive effect and the duration of treatment in the study covered the whole period of pregancy. No interspecies differences were applied since considerable species differences in sensitivity were described with the rat being more sensitive than humans. A factor of 5 was applied for intraspecies differences leading to DNEL of 8.8 mg/m3 being a value close to 9.03 mg/m3. Alternative DNEL calculations under consideration of the reproductive effects confirm the calculated DNEL values.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.25 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

NOAEC

Value:

337 mg/m³

Explanation for the modification of the dose descriptor starting point:

no route to route extrapolation but consideration of exposure duration (7 h/d in study to 24h/d ) --> NOAEC corr = 1155 mg/m3 * 7/24 = 337 mg/m3

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEC

AF for differences in duration of exposure:

6

Justification:

extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

not required for airborne concentrations

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

10

Justification:

default factor for general population

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

79.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

35

Modified dose descriptor starting point:

NOAEL

Value:

2 767 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

According to the toxicokinetic assessment, the absorption rate from dermal route is assumed to be 3% and the absorption rate of oral route is considered to be 100%. Therefore, the oral NOAEL of 83 mg/kg bw/d is converted to a NOAEL of dermal route by multiplying by 100/3.

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

1

Justification:

data from chronic study used

AF for interspecies differences (allometric scaling):

1.4

Justification:

allometric scaling factor dog to human

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

10

Justification:

default factor for general population

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

35

Modified dose descriptor starting point:

NOAEL

Value:

83 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route to route

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

1

Justification:

data from chronic study used

AF for interspecies differences (allometric scaling):

1.4

Justification:

allometric scaling factor dog to human

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

10

Justification:

default factor for general population

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Acute/short-term exposure - local or systemic effects for dermal route:

In a GLP compliant OECD404 guideline study with rabbits, pure 2-ethylhexyl salicylate is considered to be not a skin irritant. In a guideline-compliant primary skin sensitisation study in guinea pigs, 2-ethylhexyl salicylate showed no skin sensitising properties. No short-term local DNEL needs to be derived for cutaneous exposure. Furthermore, in a dermal toxicity study where rats were given a single, 24 -hour, semi-occluded dermal application of the test material to intact skin, at a dose level of 5000 mg/kg body weight no deaths and no evidence of systemic toxicity or dermal irritation were noted.No short-term systemic DNEL needs to be derived for cutaneous exposure.

Acute/short-term exposure - local or systemic effects for inhalation route:

The subacute inhalation toxicity study (Gage, 1970) with methyl salicylate vapour did not demonstrate any adverse effects.

No short-term DNEL needs to be derived for inhalation exposure.

Long-term exposure - local effects for inhalation or dermal route:

Since 2-ethylhexyl is not classified as irritating to the skin, respiratory system or eyes, no long-term local DNEL needs to be derived for inhalation and dermal exposure.

Long-term exposure - systemic effects for dermal route:

The absorption rate from dermal route is assumed to be 3% and the absorption rate of oral route is considered to be 100%. Therefore, the oral NOAEL of 83 mg/kg bw/d is converted to a dermal NOAEL of 2767 mg/kg/day by multiplying by a factor of 100/3.

As basis for DNELdermal derivation the result from a chronic study with beagle dogs was used, performed by Webb and Hansen in 1963 as conservative approach. In this study, the test item was administered at dosages of 0, 50, 150 and 350 mg/kg bw/day methyl salicylate in capsules daily for 2 years (6 days/week). Controls received diet only.

One high-dose animal died of hepatitis apparently unrelated to methyl salicylate. Hematological analyses at 1, 3, 6, 12 and 24 months and complete necropsy examination were normal, except that dogs treated at 150 and 350 mg/kg body weight/day had enlarged livers, seen microscopically as enlarged hepatic cells. No other pathology was reported in any of the animals. Reduced body weight was reported in the 350 and 150 mg/kg body weight/day groups. Based on this chronic oral study, the NOAEL value is 50 mg/kg body weight/day, being equivalent to 83 mg/kg bw/d 2-ethylhexyl salicylate on an equimolar basis.

An equivalent study with rats was performed, using doses of 0, 50, 250, 500 and 1000 mg/kg bw/d. Also in this study a NOAEL of 50 mg/kg bw/d was established (equivalent to 83 mg/kg bw/d 2-ethylhexyl salicylate).

Gross pituitary gland lesions were found in 10 rats at 250 mg/kg bw/day compared to 4 rats in the control groups. Incidence in the 500 mg/kg/day group was similar to controls, while all animals of the 1000 mg/kg/day group died before the usual age at which many spontaneous lesions develop.

Similar kinds and numbers of tumors occurred in rats of all diets except the 1000 mg/kg/day group (premature decedents), with mammary tumors of the females being the most common. Benign pituitary tumors occurred in similar numbers of surviving rats on all diets, with occurrence predominantly in females. Malignant pituitary tumors occurred in one male and two females receiving 250 mg/kg/day. Since no such tumors were reported in either the lower or higher dose groups (50 and 500 mg/kg/day), this low incidence does not clearly indicate any relation with methyl salicylate treatment. The NOAEL was set to 50 mg/kg bw/d equivalent to 83 mg/kg bw/d if adjusted equimolar to 2-ethylhexyl salicylate.

Compared to the NOAEL seen in the subchronic study in rats with 2-ethylhexyl salicylate, where no test article-related effects including clinical observations, survival, body weights, food consumption, water consumption, clinical pathology determinations, ophthalmoscopic examinations, macroscopic pathology, organ weight determinations and microscopic pathology were noted at the high-dose level and the NOAEL (No Observed Adverse Effect Level) for general toxicity in rats was considered to be 250 mg/kg bw/day, the adjusted NOAEL of 83 mg/kg bw/d found in the chronic study with rats and dogs is considered a conservative worst case value and is used to derive the DNELdermal by route to route extrapolation.

Factors for allometric scaling from dog to human (1.4), other interspecies differences (2.5) and intraspecies differences for general population (10) were applied to receive a DNEL of 79.1 mg/kg.

The derivation of the DNEL inhalative is based on an available subacute inhalative study with methyl salicylate, as read-across substance.Methyl salicylate at 700 mg/m³ (120 ppm), the maximum achievable atmosphere, did not cause any adverse effects (Gage, 1970). The adjusted NOAEC (equimolar) to 2-ethylhexyl salicylate is 1155 mg/m³ and is used as basis to derive the inhalative DNEL for workers.Consideration of exposure duration(7 h/d in study to 24h/d ) is done --> NOAEC corr = 1155 mg/m3 * 7/24 = 337 mg/m3. Factors for duration of exposure (6), other interspecies differences (2.5) and intraspecies differences for general population (10) were applied leading to a DNEL of 2.25 mg/m3.

Alternative calculations of the dermal, oral and inhalative DNELs:

An alternative calculation for the dermal DNEL was performed using the NOAEL of 25 mg/kg received from the reproductive toxicity study (OECD 421). The absorption rate from dermal route is assumed to be 3% and the absorption rate of oral route is considered to be 100%. Therefore, the oral NOAEL of 25 mg/kg bw/d is converted to a dermal NOAEL of 833.4 mg/kg/day by multiplying by a factor of 100/3. No factors for duration of exposure were applied since it was a reproductive effect and the duration of treatment in the study covered the whole period of pregancy. No interspecies differences were applied since considerable species differences in sensitivity were described with the rat being more sensitive than humans. A factor of 10 was applied for intraspecies differences leading to DNEL of 80 mg/kg being a value close to 79.1 mg/kg.

An alternative calculation was also performed for the oral DNEL using the NOAEL of 25 mg/kg received from the reproductive toxicity study (OECD 421). No factors for duration of exposure were applied since it was a reproductive effect and the duration of treatment in the study covered the whole period of pregancy. No interspecies differences were applied since considerable species differences in sensitivity were described with the rat being more sensitive than humans. A factor of 10 was applied for intraspecies differences (general population) leading to DNEL of 2.5 mg/kg being a value close to 2.4 mg/kg.

The same was performed for the inhalative DNEL calculation using the NOAEL of 25 mg/kg received from the reproductive toxicity study (OECD 421). A route to route extrapolation must be performed --> NOAEL corr = 25 mg/kg *1/1.15 m3 = 21 mg/m3.

No factors for duration of exposure were applied since it was a reproductive effect and the duration of treatment in the study covered the whole period of pregancy. No interspecies differences were applied since considerable species differences in sensitivity were described with the rat being more sensitive than humans. A factor of 10 was applied for intraspecies differences (general population) leading to DNEL of 2.1 mg/m3 being a value close to 2.25 mg/m3. Alternative DNEL calculations under consideration of the reproductive effects confirm the calculated DNEL values.