Glycerol, ethoxylated, esters with acrylic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.46 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

25.5

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.46 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

25.5

Dose descriptor:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.8 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

9

Dose descriptor starting point:

LOAEC

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - workers

Worker:

 

Based on the available data glycerol, ethoxylated, esters with acrylic acid, has to be considered as toxic by inhalation (R23 according to Directive 67/548/EEC annex VI; Cat. 3 according to EC/1271/2008), harmful if swallowed (R22; Cat. 4), to be irritating to the respiratory tract (R37; STOT SE Cat. 3), to have the potential to cause serious damage to the eyes (R41; Cat.1), and potentially skin sensitizing (R43; Cat. 1A), respectively.

 

The primary routes of anticipated industrial exposure to glycerol, ethoxylated, esters with acrylic acid, are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see below).

 

 

Inhalation short-term exposure – local effects:

Local irritating effects to eyes, nasal and respiratory tract during inhalation of the substance were considered to be a further critical endpoint for workers.

No valid sub-chronic or chronic animal study by the inhalation route, suitable for DNEL derivation, is available for glycerol, ethoxylated, esters with acrylic acid.

 

For inhalative short-term exposure, the LC0 of 51 mg/m³for local effects after single exposure to an aerosol in rats (= LOAEL) was converted into the corrected inhalatory LOAEC taking into account the differences between experimental and human exposure conditions by the factor 6.7 m³/10 m³(respiratory volume) according to the ECHA GD R.8 (2010) resulting in a corrected starting point of 34.2 mg/m³. The following assessment factors were taken into account for the final DNEL calculation: intraspecies differences (3), dose-response relationship (LOAEC to the NOAEC) (3) (AF = 3 X 3 = 9). These assessment factors are sufficient as outlined in the Technical Report No. 110 of ECETOC in 2010. Thus, the DNEL for short-term inhalative local effects is 3.8 mg/m³.

 

Inhalation long-term exposure – local and systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 422 (BASF SE 2010) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 150 mg/kg bw/d for male and female rats based on clinical chemistry changes at the next higher dose level of 500 mg/kg bw/d. Local irritation in fore- and glandular stomach lead to mortality at 500 mg/kg bw/d and adverse clinical observations as well as hematological changes at 150 and 500 mg/kg bw/d. Thus, the NOAEL for local irritation effects was 50 mg/kg bw/d. For DNEL derivation the NOAEL of 50 mg/kg bw/d was considered the most appropriate point of departure covering both local and systemic effects.

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). Since no considerable systemic uptake was observed after oral and inhalative exposure, respectively, no additional assessment factor for differences between oral absorption in rats and inhalative absorption in humans was used. The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 88.16 mg/m³.

 

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

 

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

 

- Intraspecies factor: 3

Systemic effects in the repeated dose study with rats were minimal and restricted to changes in clinical chemistry probably as a secondary effect following local irritation in the fore- and glandular stomach of rats. Furthermore, since the test substance is considered to be a local irritant without much specific systemic toxicity, not much variation of the irritant effect of the test substance in human workers is expected. Therefore an intraspecies factor of 3 is considered to be sufficient.

 

- Exposure duration: 3.4 (Batke et al. 2010 cited in ECETOC TR 110, 2010)

Local effects on the respiratory tract or forestomach appear to be more related to the concentration than to the total dose (AUC). In fact, studies with many irritating chemicals have shown that there is little influence of exposure time on the NOAELs, although increased exposure times for effective concentrations may influence the severity of effects. When effective concentrations are likely to be achieved, it is deemed necessary to apply an assessment factor to account for exposure duration. The ERASM project suggests values of 1.9 (sub-acute to sub-chronic), 2.7 (sub-chronic to chronic) and 3.4 (sub-acute to chronic) for local effects following exposure via the inhalation route (Batke et al. 2010 cited in ECETOC TR 110, 2010). Thus, for the present data, an assessment factor of 3.4 for exposure duration was considered sufficient.

 

- Dose-response: 1 (default)

- Uncertainty factor: 2.5 (default)

 

Total AF = 3 x 3.4 x 2.5 = 25.5

Based on this calculation the resulting DNEL is 3.46 mg/m³.

 

 

This value is considered protective for both local and systemic effects by the inhalation route.

 

 

 

·        Batke et al. (2010). Evaluation of time extrapolation factors: analysis of distributions based on the database RepDose. Manuscript submitted. Cited in ECETOC (2010). Technical Report No. 110,, October 2010.

·        ECHA (2010). REACh Guidance document R.8. December 2010

·        ECETOC (2003).Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

·        ECETOC (2010). Guidance on Assessment Factors to Derive DNELs. Technical Report No. 110,, October 2010.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.02 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

42.5

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.02 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

42.5

Dose descriptor:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.4 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

15

Dose descriptor starting point:

LOAEC

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.74 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

68

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Additional information - General Population

General population:

 

Based on the available data glycerol, ethoxylated, esters with acrylic acid, has to be considered as toxic by inhalation (R23 according to Directive 67/548/EEC annex VI; Cat. 3 according to EC/1271/2008), harmful if swallowed (R22; Cat. 4), to be irritating to the respiratory tract (R37; STOT SE Cat. 3), to have the potential to cause serious damage to the eyes (R41; Cat.1), and potentially skin sensitizing (R43; Cat. 1A), respectively.

 

For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account.

 

 

Inhalation short-term exposure – local effects:

Local irritating effects to eyes, nasal and respiratory tract during inhalation of the substance were considered to be a further critical endpoint.

No valid sub-chronic or chronic animal study by the inhalation route, suitable for DNEL derivation, is available for glycerol, ethoxylated, esters with acrylic acid.

 

For inhalative short-term exposure, the LC0 of 51 mg/m³for local effects after single exposure to an aerosol in rats (= LOAEL) was considered as appropriate starting point for derivation of a short-term DNEL. The following assessment factors were taken into account for the final DNEL calculation: intraspecies differences (5), dose-response relationship (LOAEC to the NOAEC) (3) (AF = 5 x 3 = 15). These assessment factors are sufficient as outlined in the Technical Report No. 110 of ECETOC in 2010. Thus, the DNEL for short-term inhalative local effects is 3.4 mg/m³.

 

Oral short-term –systemic effects:

In addition, a DNEL for oral short-term exposure was derived from the no observed adverse effect level obtained in an acute toxicity study conducted with the substance in rats according to OECD TG 423 (BASF SE, 2005). At the dose of 300 mg/kg bw no mortality, clinical signs or any gross-pathological abnormalities were observed. Thus, this dose can be considered to be the NOAEL in rats after a single gavage administration of the substance.

The NOAEL of 300 mg/kg bw/d was considered appropriate as point of departure for DNEL derivation. Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the oral route: interspecies differences (4), remaining differences (1), intraspecies differences (5) (AF = 4 x 1 x 5 = 20). These assessment factors are sufficient as outlined in the Technical Report No. 110 of ECETOC in 2010. As a consequence, the resulting DNEL for short-term oral systemic effects is 15 mg/kg bw/d for the general population.

 

Inhalation long-term exposure – local and systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 422 (BASF SE 2010) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 150 mg/kg bw/d for male and female rats based on clinical chemistry changes at the next higher dose level of 500 mg/kg bw/d. Local irritation in fore- and glandular stomach lead to mortality at 500 mg/kg bw/d and adverse clinical observations as well as hematological changes at 150 and 500 mg/kg bw/d. Thus, the NOAEL for local irritation effects was 50 mg/kg bw/d. For DNEL derivation the NOAEL of 50 mg/kg bw/d was considered the most appropriate point of departure covering both local and systemic effects.

This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). Since no considerable systemic uptake was observed after oral and inhalative exposure, respectively, no additional assessment factor for differences between oral absorption in rats and inhalative absorption in humans was used. The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 43.5 mg/m³.

 

For DNEL derivation, the following assessment factors (AF) were applied to the correct starting point:

 

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and human have to be taken into account.

 

- Intraspecies factor: 5

Systemic effects in the repeated dose study with rats were minimal and restricted to changes in clinical chemistry probably as a secondary effect following local irritation in the fore- and glandular stomach of rats. Furthermore, since the test substance is considered to be a local irritant without much specific systemic toxicity, not much variation of the irritant effect of the test substance in human workers is expected. Therefore an intraspecies factor of 5 is considered to be sufficient.

 

- Exposure duration: 3.4 (Batke et al. 2010 cited in ECETOC TR 110, 2010)

Local effects on the respiratory tract or forestomach appear to be more related to the concentration than to the total dose (AUC). In fact, studies with many irritating chemicals have shown that there is little influence of exposure time on the NOAELs, although increased exposure times for effective concentrations may influence the severity of effects. When effective concentrations are likely to be achieved, it is deemed necessary to apply an assessment factor to account for exposure duration. The ERASM project suggests values of 1.9 (sub-acute to sub-chronic), 2.7 (sub-chronic to chronic) and 3.4 (sub-acute to chronic) for local effects following exposure via the inhalation route (Batke et al. 2010 cited in ECETOC TR 110, 2010). Thus, for the present data, an assessment factor of 3.4 for exposure duration was considered sufficient.

 

- Dose-response: 1 (default)

- Uncertainty factor: 2.5 (default)

 

Total AF = 5 x 3.4 x 2.5 = 42.5

Based on this calculation the resulting DNEL is 1.02 mg/m³.

 

Oral long-term exposure – local and systemic effects:

In addition, the DNEL for oral long-term exposure was derived from the no observed adverse effect level obtained in a gavage study conducted with the substance in rats according to OECD TG 422 (BASF SE, 2010). The NOAEL for general, systemic toxicity of the test substance was 150 mg/kg bw/d for male and female rats based on clinical chemistry changes at the next higher dose level of 500 mg/kg bw/d. Local irritation in fore- and glandular stomach lead to mortality at 500 mg/kg bw/d and adverse clinical observations as well as hematological changes at 150 and 500 mg/kg bw/d. Up to the highest dose tested, no adverse effects on reproduction or development of the offspring were observed. Thus, the NOAEL for toxicity to reproduction / developmental toxicity was 500 mg/kg bw/d.

The NOAEL for local effects of 50 mg/kg bw/d was considered appropriate as point of departure for DNEL derivation. Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the oral route: interspecies differences (4), remaining differences (1), intraspecies differences (5), exposure duration (3.4) (AF = 4 x 1 x 5 x 3.4 x 1 x 1 = 68). These assessment factors are sufficient as outlined in the Technical Report No. 86 of ECETOC in 2003 and in the ECETOC TR 110, 2010. As a consequence, the resulting DNEL for long-term oral local and systemic effects is 0.74 mg/kg bw/d for the general population.

 

 

 

·        Batke et al. (2010). Evaluation of time extrapolation factors: analysis of distributions based on the database RepDose. Manuscript submitted. Cited in ECETOC (2010). Technical Report No. 110,, October 2010.

·        ECHA (2010). REACh Guidance document R.8. December 2010

·        ECETOC (2003).Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

·        ECETOC (2010). Guidance on Assessment Factors to Derive DNELs. Technical Report No. 110,, October 2010.