Octyl (R)-2-(4-chloro-2-methylphenoxy)propionate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

6

Modified dose descriptor starting point:

NOAEC

Value:

19 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting point was corrected according to Figure R.8-3 in chapter R.8 in the ECHA guidance document (version 2.1, November 2012). For extrapolation of oral to inhalative route it is proposed in the ECHA guidance document, that in the absence of route specific information on the starting route, a factor of 2 should be employed. However, for Mecoprop-P n-octyl ester such informations are available. An in vivo toxicokinetic study shows that absorption after oral administration proceeds to a high extent [> 90% for the for the hydrolysis product Mecoprop-P acid (MCPP-P acid); see endpoint summary toxikokinetics],. Therefore, the assumption that oral absorption is 50% of absorption after inhalation is not justified. Additionally, read-across from supporting substances indicates, that toxicity after inhalative exposure is low compared to a moderate toxicity after oral exposure [cp. Acute inhalation toxicity: LC50 (4h) > 5.6 mg/L for the hydrolysis product Mecoprop-P acid (MCPP-P acid); LC50 (4h) > 4.66 mg/L for the structural analogue substance Mecoprop-P 2-ethylhexyl ester (MCPP-P 2-EHE)]. Overall, a factor of 2 as worst case assumption is not justified and a factor 1 is applied. NOAEL(oral, rat) = 10.8 mg/kg bw/day => NOAEC(corrected, inhalation) = NOAEL(oral, rat) x 1/(0.38 m3/kg bw/day) x 6.7 m3/10 m3 = 19.0 mg/m3

AF for dose response relationship:

1

Justification:

Default value (ECHA)

AF for differences in duration of exposure:

2

Justification:

Default value (ECHA) for subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 is suggested by the ECHA guidance document (version 2.1, November 2012) for remaining interspecies differences, but justified deviations are possible. Interspecies extrapolation for systemic effects has to consider both toxicokinetic and toxicodynamic aspects. Toxicokinetics are already covered by the principle of allometric scaling. According to ECETOC (Technical Report No. 110, 2010) there is scientific evidence that for toxikodynamic aspects the use of a remaining difference factor of 2.5 as a standard procedure is unjustified. Moreover, read-across from a supporting substance shows that for rats, mice and dogs effects of repeated dose toxicity were quite similar with regard to dose level and type of effect. Liver and kidney revealed to be the target organs and the NOAELs were not distinctly different (see chapter repeated dose toxicity). Therefore, an assessment factor of 1 is applied.

AF for intraspecies differences:

3

Justification:

An assessment factor of 5 is suggested by the ECHA guidance document (version 2.1, November 2012) for intraspecies differences in workers, but justified deviations are possible. According to ECETOC (Technical Report No. 110, 2010) a factor of 3 is proposed for workers for intraspecies extrapolation of systemic effects if the POD is derived from animal studies. This is based on a thorough evaluation of scientific literature and therefore, an assessment factor of 3 is applied.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

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:

0.45 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):

24

Modified dose descriptor starting point:

NOAEL

Value:

10.8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For DNEL calculation dermal absorption is assumed to be identical to oral absorption. NOAEL(oral, rat) = 10.8 mg/kg bw/day => NOAEL(dermal, rat) = NOAEL(oral, rat) = 10.8 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default value (ECHA)

AF for differences in duration of exposure:

2

Justification:

Default value (ECHA) for subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (ECHA) for rat versus human

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 is suggested by the ECHA guidance document (version 2.1, November 2012) for remaining interspecies differences, but justified deviations are possible. Interspecies extrapolation for systemic effects has to consider both toxicokinetic and toxicodynamic aspects. Toxicokinetics are already covered by the principle of allometric scaling. According to ECETOC (Technical Report No. 110, 2010) there is scientific evidence that for toxikodynamic aspects the use of a remaining difference factor of 2.5 as a standard procedure is unjustified. Moreover, read-across from a supporting substance shows that for rats, mice and dogs effects of repeated dose toxicity were quite similar with regard to dose level and type of effect. Liver and kidney revealed to be the target organs and the NOAELs were not distinctly different (see chapter repeated dose toxicity). Therefore, an assessment factor of 1 is applied.

AF for intraspecies differences:

3

Justification:

An assessment factor of 5 is suggested by the ECHA guidance document (version 2.1, November 2012) for intraspecies differences in workers, but justified deviations are possible. According to ECETOC (Technical Report No. 110, 2010) a factor of 3 is proposed for workers for intraspecies extrapolation of systemic effects if the POD is derived from animal studies. This is based on a thorough evaluation of scientific literature and therefore, an assessment factor of 3 is applied.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Mecoprop-P n-octyl ester is a liquid substance with a very low vapour pressure (0.00285 Pa at 20°C) at normal ambient conditions, therefore vapour inhalation is an unlikely route of exposure. For assessing occupational risk in humans exposure to dust or liquid aerosol and to the skin is of relevance.

 

Based on the available studies, Mecoprop-P n-octyl ester has a moderate acute toxicity after oral absorption (LD50 = 500 mg/kg bw; cut off level according to OECD TG 423; Gillissen, 2011) and is practically non-toxic after acute dermal exposure (LD50 > 2000 mg/kg bw; Gillissen, 2011). For repeated dose toxicity an oral subchronic (90-day) feeding study establishes NOAELs of 120 ppm for male and female rats based on systemic toxicity (effects on liver and kidney, Popp, 2012). No studies on inhalation toxicity are available for Mecoprop-P n-octyl ester, but route to route extrapolation from oral to inhalation is appropriate, since only systemic and no local effects were observed in the repeated dose study. Furthermore, in vivo studies on irritation/corrosion confirm that distinct local effects are not a property of Mecoprop-P n-octyl ester (no effects at all after 24, 48 or 72 h post-exposure in skin and eye irritation/corrosion study; Leuschner, 2011). Additionally read-across to acute inhalation toxicity of structurally related substances also reveal only indications for slight irritant effects combined with a low toxicity (not justifying classification; HRC, 1992, BASF, 1986).

Mecoprop-P n-octyl ester showed sensitizing properties in a LLNA (Vohr, 2012), therefore the risk of sensitization after dermal exposure has to be assessed.

No indications were seen for genotoxic or carcinogenic effects for Mecoprop-P n-octyl ester (Nern, 2011; Wollny, 2011; Ciethier, 2011; Nern, 2013; and read-across from supporting substance, BASF, 1988, 1996 and 1999).

The NOAEL of 120 ppm is therefore considered to be the point of departure for the determination of long-term systemic DNELs for workers. Conversion of the test substance concentration in feed (ppm) into the daily dose (mg/kg bw/day) equals to 10.8 mg/kg bw/day (Conversion factor 0.09; see EFSA Journal 2012, 10 (3): 2579).

 

Because respiratory irritation potential of Mecoprop-P n-octyl ester is assumed to be low, there is no need to derive an acute DNEL for local toxicity. It is proposed to limit acute/short term (peak) inhalation (systemic) exposure to a value not exceeding the DNEL derived for long term inhalation (systemic) exposure by a factor of 2.

This approach is in line with the regulatory procedure in Germany [see "Technische Regel für Gefahrstoffe" 900 (Technical Rule for Hazardous Substances 900), published by the German "Bundesministerium für Arbeit und Soziales" (Federal Ministry of Labour and Social Affairs)] and is also in accordance with Box 6 in Appendix R.8-8 of the ECHA guidance document (version 2.1, November 2012).

 

The systemic DNELs cover also reproductive toxicity, as systemic effects on kidneys and liver are the most sensitive endpoints and neither effects on fertility nor on teratogenicity were observed at any dose tested.

 

Mecoprop-P n-octyl ester is classified classified for being a skin sensitizers (Skin Sens. 1B, H317), based on a LLNA on mice (EC value = 20.5 %).

However, there are currently no available methods to determine thresholds and DNELs for skin sensitizers. Therefore a quantitative risk assessment for this endpoint is not possible.

According to ECHA guidance on information requirements and chemical safety assessment Part E: Risk characterization (version 2.0, November 2012) an allocation to the moderate (medium) hazard band is appropriate for compounds classified as Skin Sens. 1B, H317.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Value:

9.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting point was corrected according to Figure R.8-3 in chapter R.8 in the ECHA guidance document (version 2.1, November 2012). For extrapolation of oral to inhalative route it is proposed in the ECHA guidance document, that in the absence of route specific information on the starting route, a factor of 2 should be employed. However, for Mecoprop-P n-octyl ester such informations are available. An in vivo toxicokinetic study shows that absorption after oral administration proceeds to a high extent [> 90% for the for the hydrolysis product Mecoprop-P acid (MCPP-P acid); see endpoint summary toxikokinetics],. Therefore, the assumption that oral absorption is 50% of absorption after inhalation is not justified. Additionally, read-across from supporting substances indicates, that toxicity after inhalative exposure is low compared to a moderate toxicity after oral exposure [cp. Acute inhalation toxicity: LC50 (4h) > 5.6 mg/L for the hydrolysis product Mecoprop-P acid (MCPP-P acid); LC50 (4h) > 4.66 mg/L for the structural analogue substance Mecoprop-P 2-ethylhexyl ester (MCPP-P 2-EHE)]. Overall, a factor of 2 as worst case assumption is not justified and a factor 1 is applied. NOAEL(oral, rat) = 10.8 mg/kg bw/day => NOAEC(corrected, inhalation) = NOAEL(oral, rat) x 1/(1.15 m3/kg bw/day) = 9.4 mg/m3

AF for dose response relationship:

1

Justification:

Default value (ECHA)

AF for differences in duration of exposure:

2

Justification:

Default value (ECHA) for subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 is suggested by the ECHA guidance document (version 2.1, November 2012) for remaining interspecies differences, but justified deviations are possible. Interspecies extrapolation for systemic effects has to consider both toxicokinetic and toxicodynamic aspects. Toxicokinetics are already covered by the principle of allometric scaling. According to ECETOC (Technical Report No. 110, 2010) there is scientific evidence that for toxikodynamic aspects the use of a remaining difference factor of 2.5 as a standard procedure is unjustified. Moreover, read-across from a supporting substance shows that for rats, mice and dogs effects of repeated dose toxicity were quite similar with regard to dose level and type of effect. Liver and kidney revealed to be the target organs and the NOAELs were not distinctly different (see chapter repeated dose toxicity). Therefore, an assessment factor of 1 is applied.

AF for intraspecies differences:

5

Justification:

An assessment factor of 10 is suggested by the ECHA guidance document (version 2.1, November 2012) for intraspecies differences in workers, but justified deviations are possible. According to ECETOC (Technical Report No. 110, 2010) a factor of 5 is proposed for workers for intraspecies extrapolation of systemic effects if the POD is derived from animal studies. This is based on a thorough evaluation of scientific literature and therefore, an assessment factor of 5 is applied.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

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:

0.3 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

10.8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For DNEL calculation dermal absorption is assumed to be identical to oral absorption. NOAEL(oral, rat) = 10.8 mg/kg bw/day => NOAEL(dermal, rat) = NOAEL(oral, rat) = 10.8 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default value (ECHA)

AF for differences in duration of exposure:

2

Justification:

Default value (ECHA) for subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (ECHA) for rat versus human

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 is suggested by the ECHA guidance document (version 2.1, November 2012) for remaining interspecies differences, but justified deviations are possible. Interspecies extrapolation for systemic effects has to consider both toxicokinetic and toxicodynamic aspects. Toxicokinetics are already covered by the principle of allometric scaling. According to ECETOC (Technical Report No. 110, 2010) there is scientific evidence that for toxikodynamic aspects the use of a remaining difference factor of 2.5 as a standard procedure is unjustified. Moreover, read-across from a supporting substance shows that for rats, mice and dogs effects of repeated dose toxicity were quite similar with regard to dose level and type of effect. Liver and kidney revealed to be the target organs and the NOAELs were not distinctly different (see chapter repeated dose toxicity). Therefore, an assessment factor of 1 is applied.

AF for intraspecies differences:

5

Justification:

An assessment factor of 10 is suggested by the ECHA guidance document (version 2.1, November 2012) for intraspecies differences in workers, but justified deviations are possible. According to ECETOC (Technical Report No. 110, 2010) a factor of 5 is proposed for workers for intraspecies extrapolation of systemic effects if the POD is derived from animal studies. This is based on a thorough evaluation of scientific literature and therefore, an assessment factor of 5 is applied.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

10.8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:

1

Justification:

Default value (ECHA)

AF for differences in duration of exposure:

2

Justification:

Default value (ECHA) for subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (ECHA) for rat versus human

AF for other interspecies differences:

1

Justification:

An assessment factor of 2.5 is suggested by the ECHA guidance document (version 2.1, November 2012) for remaining interspecies differences, but justified deviations are possible. Interspecies extrapolation for systemic effects has to consider both toxicokinetic and toxicodynamic aspects. Toxicokinetics are already covered by the principle of allometric scaling. According to ECETOC (Technical Report No. 110, 2010) there is scientific evidence that for toxikodynamic aspects the use of a remaining difference factor of 2.5 as a standard procedure is unjustified. Moreover, read-across from a supporting substance shows that for rats, mice and dogs effects of repeated dose toxicity were quite similar with regard to dose level and type of effect. Liver and kidney revealed to be the target organs and the NOAELs were not distinctly different (see chapter repeated dose toxicity). Therefore, an assessment factor of 1 is applied.

AF for intraspecies differences:

5

Justification:

An assessment factor of 10 is suggested by the ECHA guidance document (version 2.1, November 2012) for intraspecies differences in workers, but justified deviations are possible. According to ECETOC (Technical Report No. 110, 2010) a factor of 5 is proposed for workers for intraspecies extrapolation of systemic effects if the POD is derived from animal studies. This is based on a thorough evaluation of scientific literature and therefore, an assessment factor of 5 is applied.

AF for the quality of the whole database:

1

Justification:

A GLP guideline study is used.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Mecoprop-P n-octyl ester is a liquid substance with a very low vapour pressure (0.00285 Pa at 20°C) at normal ambient conditions, therefore vapour inhalation is an unlikely route of exposure. For assessing occupational risk in humans exposure to dust or liquid aerosol and to the skin is of relevance.

 

Based on the available studies, Mecoprop-P n-octyl ester has a moderate acute toxicity after oral absorption (LD50 = 500 mg/kg bw; cut off level according to OECD TG 423; Gillissen, 2011) and is practically non-toxic after acute dermal exposure (LD50 > 2000 mg/kg bw; Gillissen, 2011). For repeated dose toxicity an oral subchronic (90-day) feeding study establishes NOAELs of 120 ppm for male and female rats based on systemic toxicity (effects on liver and kidney, Popp, 2012). No studies on inhalation toxicity are available for Mecoprop-P n-octyl ester, but route to route extrapolation from oral to inhalation is appropriate, since only systemic and no local effects were observed in the repeated dose study. Furthermore, in vivo studies on irritation/corrosion confirm that distinct local effects are not a property of Mecoprop-P n-octyl ester (no effects at all after 24, 48 or 72 h post-exposure in skin and eye irritation/corrosion study; Leuschner, 2011). Additionally read-across to acute inhalation toxicity of structurally related substances also reveal only indications for slight irritant effects combined with a low toxicity (not justifying classification; HRC, 1992, BASF, 1986).

Mecoprop-P n-octyl ester showed sensitizing properties in a LLNA (Vohr, 2012), therefore the risk of sensitization after dermal exposure has to be assessed.

No indications were seen for genotoxic or carcinogenic effects for Mecoprop-P n-octyl ester (Nern, 2011; Wollny, 2011; Ciethier, 2011; Nern, 2013; and read-across from supporting substance, BASF, 1988, 1996 and 1999).

The NOAEL of 120 ppm is therefore considered to be the point of departure for the determination of long-term systemic DNELs for workers. Conversion of the test substance concentration in feed (ppm) into the daily dose (mg/kg bw/day) equals to 10.8 mg/kg bw/day (Conversion factor 0.09; see EFSA Journal 2012, 10 (3): 2579).

 

Because respiratory irritation potential of Mecoprop-P n-octyl ester is assumed to be low, there is no need to derive an acute DNEL for local toxicity. It is proposed to limit acute/short term (peak) inhalation (systemic) exposure to a value not exceeding the DNEL derived for long term inhalation (systemic) exposure by a factor of 2.

This approach is in line with the regulatory procedure in Germany [see "Technische Regel für Gefahrstoffe" 900 (Technical Rule for Hazardous Substances 900), published by the German "Bundesministerium für Arbeit und Soziales" (Federal Ministry of Labour and Social Affairs)] and is also in accordance with Box 6 in Appendix R.8-8 of the ECHA guidance document (version 2.1, November 2012).

 

The systemic DNELs cover also reproductive toxicity, as systemic effects on kidneys and liver are the most sensitive endpoints and neither effects on fertility nor on teratogenicity were observed at any dose tested.

 

Mecoprop-P n-octyl ester is classified classified for being a skin sensitizers (Skin Sens. 1B, H317), based on a LLNA on mice (EC value = 20.5 %).

However, there are currently no available methods to determine thresholds and DNELs for skin sensitizers. Therefore a quantitative risk assessment for this endpoint is not possible.

According to ECHA guidance on information requirements and chemical safety assessment Part E: Risk characterization (version 2.0, November 2012) an allocation to the moderate (medium) hazard band is appropriate for compounds classified as Skin Sens. 1B, H317.