Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
88.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Kinetics (absorption for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach was taken forward to DNEL derivation For dermal absorption, based on the physical-chemical properties of the substance (log Kow > 4, poor water solubility 331 mg/l at 20 °C for tests with 10 g test item per 1 L water) uptake is expected. Low dermal absorption is supported by the absence of adverse effects in the acute dermal toxicity study with Soybean oil, epoxidized, reaction products with methanol. Based on the above physical-chemical properties, oral absorption is also expected to be low based on the absence of systemic effects after acute oral exposure. Furthermore, the absence of adverse systemic effects after repeated or chronic exposure at the doses tested in the available oral toxicity studies with a structural analogue epoxidized soybean oil (ESBO) supports low oral absorption. As both oral and dermal absorption are expected to be low a default factor of 1 for oral-to-dermal extrapolation was used for DNEL derivation.

 

Acute toxicity

Soybean oil, epoxidized, reaction products with methanol does not have to be classified for acute toxicity and therefore derivation of a DNELacuteis not necessary.

Irritation

Soybean oil, epoxidized, reaction products with methanol does not have to be classified for irritation/corrosion and therefore derivation of a DNEL is not necessary.

 

Sensitization

Soybean oil, epoxidized, reaction products with methanol does not have to be classified for sensitization and therefore derivation of a DNEL is not necessary.

 

Repeated dose toxicity

No repeated dose oral toxicity study is available for Soybean oil, epoxidized, reaction products with methanol. Therefore data from structural analogues, Epoxidized soybean oil (ESBO) and Fatty acids, tall-oil, epoxidized, 2-ethylhexylesters (ETP), are used.

For ETP a combined repeated dose oral toxicity study with a reproduction/developmental screening study in rats, was performed according to OECD guideline 422. A NOAEL for general systemic toxicity of 1000 mg/kg bw/day was established for male and female.

For ESBO, a combined chronic toxicity/carcinogenicity study was performed in rats, according to OECD guideline 453. NOELs of 1000 mg/kg bw/day for males and 1400 mg/kg bw/day for females were established (BIBRA & Hazelton 1986). In this study the highest dose of ESBO (2.5%) resulted in an significant increase in the incidence of cystic and hyperplastic endometrium when compared to untreated control animals but not compared to the 2.5% Soybean oil treated group. Since there were similar changes in the females given SBO these changes could not be clearly related to ESBO. No treatment-related reactions were observed with respect to clinical symptoms, mortality, food consumption, body weight, clinical laboratory investigations, urinalysis and pathology. In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening with ETP (Marburger et al., 2005) performed according to OECD 422 increased liver weights were noted at concentrations above 100 mg/kg bw/day. These effects were not considered adverse and a NOAEL was derived based on this study of 1000 mg/kg bw/day. Based on the available data the NOAEL of 1000 mg/kg bw/day established in the repeated chronic toxicity/carcinogenicity study was used as starting point for the DNEL derivation.

 

Mutagenicity

Soybean oil, epoxidized, reaction products with methanolis considered not to be mutagenic based on the results of the in the in vitro micronucleus test, the HPRT locus in V79 and the Ames test.

 

Reproduction toxicity

No reproduction and developmental toxicity study is available for Soybean oil, epoxidized, reaction products with methanol. Therefore data from structural analogue Epoxidized soybean oil (ESBO) is used.

A GLP compliant one generation study is performed in rats according OECD guideline 415. The NOAEL/NOEL based on a one generation study in rats exposed by oral gavage was determined to be 1000 mg/kg bw/day.Furthermore, a GLP compliant prenatal developmental toxicity study is performed in rats according OECD guideline 414 with ESBO. The NOAEL is defined as 1000 mg/kg bw/day in terms of maternotoxic effects and embryofetal development. The NOEL is also defined as 1000 mg/kg bw/day in terms of maternotoxic effects and embryofetal development. No specific DNEL has to be derived for developmental and reproductive toxicity.

 

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure, because the substance is not classified for acute toxicity.

 

Oral

For long-term toxicity, regarding systemic effects, a NOAEL of 1000 mg/kg bw/day was observed in a repeated chronic toxicity/carcinogenicity study with ESBO. This NOAEL is used in the derivation of the DNELs. An absorption of 50% is assumed for the oral route.

 

Inhalation

Long-term inhalation toxicity data is not available and therefore route-to-route extrapolation is performed. An absorption of 100% is assumed for the inhalation route.

 

Dermal

Long-term dermal toxicity data is not available and therefore route-to-route extrapolation is performed. Dermal absorption will not be higher than oral absorption. Therefore the ratio of 1 for oral to dermal absorption is provisionally suggested for DNEL derivation.

Worker DNELs

 

Long-term –inhalation, systemic effects (based on repeated chronic toxicity/carcinogenicity study with ESBO in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

2

 

 

 

0.38 m3/kg bw

 

 

 

6.7 m3/10 m3

Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Modified dose-descriptor

(1000 / 2 / 0.38) x (6.7/10) =  882 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

5

Default assessment factor for worker

Exposure duration

1

Endpoint is derived from a chronic (104 weeks) repeated dose study.

Dose response

1

 

Quality of database

2

Factor for read across

DNEL

Value

 

 882 / (1 x 5 x 1 x 1 x 2) = 882 / 10 = 88.2 mg/m3

 

 

Long-term – dermal, systemic effects (based on repeated chronic toxicity/carcinogenicity study with ESBO in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

1

As both oral and dermal absorption are expected to be low adefault factor of 1 for oral-to-dermal extrapolation was used.

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor for worker

Exposure duration

1

Endpoint is derived from a chronic (104 weeks) repeated dose study.

Dose response

1

 

Quality of database

2

Factor for read across

DNEL

Value

 

1000 / (4 x 5 x 1 x 1 x 2) =1000 / 40 = 25 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.75 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
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

Kinetics (absorption for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach was taken forward to DNEL derivation For dermal absorption, based on the physical-chemical properties of the substance (log Kow > 4, poor water solubility 331 mg/l at 20 °C for tests with 10 g test item per 1 L water) uptake is expected. Low dermal absorption is supported by the absence of adverse effects in the acute dermal toxicity study with Soybean oil, epoxidized, reaction products with methanol. Based on the above physical-chemical properties, oral absorption is also expected to be low based on the absence of systemic effects after acute oral exposure. Furthermore, the absence of adverse systemic effects after repeated or chronic exposure at the doses tested in the available oral toxicity studies with a structural analogue epoxidized soybean oil (ESBO) supports low oral absorption. As both oral and dermal absorption are expected to be low a default factor of 1 for oral-to-dermal extrapolation was used for DNEL derivation.

 

Acute toxicity

Soybean oil, epoxidized, reaction products with methanol does not have to be classified for acute toxicity and therefore derivation of aDNELacuteis not necessary.

 

Irritation

Soybean oil, epoxidized, reaction products with methanol does not have to be classified for irritation/corrosion and therefore derivation of a DNEL is not necessary.

 

Sensitization

Soybean oil, epoxidized, reaction products with methanol does not have to be classified for sensitization and therefore derivation of a DNEL is not necessary.

 

Repeated dose toxicity

No repeated dose oral toxicity study is available for Soybean oil, epoxidized, reaction products with methanol. Therefore data from structural analogues, Epoxidized soybean oil (ESBO) and Fatty acids, tall-oil, epoxidized, 2-ethylhexylesters (ETP), is used.

For ETP a combined repeated dose oral toxicity study with a reproduction/developmental screening study in rats, was performed according to OECD guideline 422. A NOAEL for general systemic toxicity of 1000 mg/kg bw/day was established for male and female.

For ESBO, a combined chronic toxicity/carcinogenicity study was performed in rats, according to OECD guideline 453. NOELs of 1000 mg/kg bw/day for males and 1400 mg/kg bw/day for females were established (BIBRA & Hazelton 1986). In this study the highest dose of ESBO (2.5%) resulted in an significant increase in the incidence of cystic and hyperplastic endometrium when compared to untreated control animals but not compared to the 2.5% Soybean oil treated group. Since there were similar changes in the females given SBO these changes could not be clearly related to ESBO. No treatment-related reactions were observed with respect to clinical symptoms, mortality, food consumption, body weight, clinical laboratory investigations, urinalysis and pathology. In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening with ETP (Marburgeret al., 2005) performed according to OECD 422 increased liver weights were noted at concentrations above 100 mg/kg bw/day. These effects were not considered adverse and a NOAEL was derived based on this study of 1000 mg/kg bw/day. Based on the available data the NOAEL of 1000 mg/kg bw/day established in the repeated chronic toxicity/carcinogenicity study was used as starting point for the DNEL derivation.

 

Mutagenicity

Soybean oil, epoxidized, reaction products with methanolis considered not to be mutagenic based on the results of the in the in vitro micronucleus test, the HPRT locus in V79 and the Ames test.

 

Reproduction toxicity

No reproduction and developmental toxicity study is available for Soybean oil, epoxidized, reaction products with methanol. Therefore data from structural analogue Epoxidized soybean oil (ESBO) is used.

A GLP compliant one generation study is performed in rats according OECD guideline 415. The NOAEL/NOEL based on a one generation study in rats exposed by oral gavage was determined to be 1000 mg/kg bw/day.Furthermore, a GLP compliant prenatal developmental toxicity study is performed in rats according OECD guideline 414 with ESBO. The NOAEL is defined as 1000 mg/kg bw/day in terms of maternotoxic effects and embryofetal development. The NOEL is also defined as 1000 mg/kg bw/day in terms of maternotoxic effects and embryofetal development. No specific DNEL has to be derived for developmental and reproductive toxicity.

 

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure, because the substance is not classified for acute toxicity.

 

Oral

For long-term toxicity, regarding systemic effects, a NOAEL of 1000 mg/kg bw/day was observed in a repeated chronic toxicity/carcinogenicity study with ESBO. This NOAEL is used in the derivation of the DNELs. An absorption of 50% is assumed for the oral route.

 

Inhalation

Long-term inhalation toxicity data is not available and therefore route-to-route extrapolation is performed. An absorption of 100% is assumed for the inhalation route.

 

Dermal

Long-term dermal toxicity data is not available and therefore route-to-route extrapolation is performed. Dermal absorption will not be higher than oral absorption. Therefore the ratio of 1 for oral to dermal absorption is provisionally suggested for DNEL derivation.

General population DNELs

Long-term – oral, systemic effects (based on repeated chronic toxicity/carcinogenicity study with ESBO in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor for general population

Exposure duration

1

Endpoint is derived from a chronic (104 weeks) repeated dose study.

Dose response

1

 

Quality of database

2

Factor for read across

DNEL

Value

 

1000 / (4 x 10 x 1 x 1 x 2) =1000 / 80 = 12.5 mg/kg bw/day

 

 

Long-term – inhalation, systemic effects (based on repeated chronic toxicity/carcinogenicity study with ESBO in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

2

 

 

 

1.15 m3/kg bw

 

 

Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)

Modified dose-descriptor

(1000 / 2) x (1/1.15) = 435 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

10

Default assessment factor for general population

Exposure duration

1

Endpoint is derived from a chronic (104 weeks) repeated dose study.

Dose response

1

 

Quality of database

2

Factor for read across

DNEL

Value

 

435 / (1 x 10 x 1 x 1 x 2) = 435 / 20 = 21.75 mg/m3

 

 

Long-term – dermal, systemic effects (based on repeated dose oral toxicity study with read across substance in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

1

As both oral and dermal absorption are expected to be low adefault factor of 1 for oral-to-dermal extrapolation was used

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor for general population

Exposure duration

1

 

Endpoint is derived from a chronic (104 weeks) repeated dose study.

Dose response

1

 

Quality of database

2

Factor for read across

DNEL

Value

 

1000 / (4 x 10 x 1 x 1 x 2) =1000 / 80 = 12.5 mg/kg bw/day