Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

383 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

24

Modified dose descriptor starting point:

NOAEL

Value:

9 202 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (endpoint). This is in line with the ECHA R8 guidance document.)

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used. This is in line with the ECHA R8 guidance document.

AF for other interspecies differences:

1

Justification:

Based on the absence of evident organ specific toxicity, an additional AF for interspecies differences other than allometric scaling is not considered necessary.

AF for intraspecies differences:

3

Justification:

Substance specific assessment factor: No relevant adverse organ toxicity was observed. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 3 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

AF for the quality of the whole database:

1

Justification:

The quality of the whole database is considered to be sufficient.

AF for remaining uncertainties:

1

Justification:

Substance specific assessment factor: Subchronic administration of C-1701 B_C_3 resulted in no evident organ toxicity in rats. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure – systemic and local effects

No acute toxicity study is available for 2-ethoxyethyl (2Z)-2-cyano-2-[3-(3-methoxypropylamino) cyclohex-2-en-1-ylidene]acetate (C-1701 B_C_3). However, assessment of this endpoint has been made on acute oral toxicity data of a structural analogue via read-across and the available repeated dose toxicity data for C-1701 B_C_3 in a weight of evidence. No mortality or evident organ toxicity was observed in an oral repeated dose rat bone marrow micronucleus test (BioReliance, 2012) at the limit dose level of 2000 mg/kg bw as well as in oral subacute and subchronic toxicity studies in rats tested up to 1000 mg/kg bw/day. Low acute toxicity of C-1701 B_C_3 is supported by data from a structural analogue, i.e. C-1523 (CAS 1243654-84-3) via read-across. In a respective acute oral toxicity study, the LD50 is >2000 mg/kg bw for C-1523.

In view of the absence of any mortality or evident organ toxicity after repeated oral dosing up to 2000 mg/kg of C-1701 B_C_3 and with special regard to its low percutaneous absorption determined in human skin in vitro with a dermal delivery (mean) of 1.63 % or 1.08 µg/cm² after 24 hours (Charles River Laboratories, 2013), acute toxicity after short term exposure is unlikely. Based on the low bioavailability after dermal application and the absence of mortality after oral administration, no acute dermal toxicity is to be expected.

In light of the present data from oral toxicity studies, the substance characteristics (low vapour pressure, high melting point) and the fact, that inhalative exposure is not considered to be the major route of exposure, inhalation of toxicologically significant amounts of t C-1701 B_C_3 is unlikely. C-1701 B_C_3 did not induce skin or eye irritation and was not sensitising in the LLNA. As the test item did neither show acute systemic nor acute local toxicity, the derivation of acute DNELs for systemic and local effects is not considered mandatory.

Long-term exposure – systemic effects

Inhalation:

There are no experimental data on repeated dose exposure by inhalation. For derivation of a long-term systemic inhalation DNEL, 10 mg/m3 has been defined. This value is based on the general dust limit value (TRGS 900, established by AGS (Ausschuß für Gefahrstoffe), published by the German BMAS (Bundesministerium für Arbeit und Soziales")), since C-1701 B_C_3 does not pose any intrinsic hazard, i.e. is not classified according to 67/548/EEC and regulation (EU) 1272/2008 regarding a health hazard. Furthermore, the substance characteristics (low vapour pressure, high melting point) indicate that an inhalation absorption of toxicologically significant amounts of C-1701 B_C_3 is unlikely.

Dermal:

The basis of the derived systemic dermal DNEL for C-1701 B_C_3 form the available oral repeated dose toxicity studies in rats:

In an oral 90 day repeated dose toxicity study in Wistar rats, clinical signs (urine-stained abdominal fur, increased incidence of dehydration and excess salivation), decreases in body weight gains and food consumption, clinical pathology (decreased red blood cell parameters, increased reticulocyte and leucocyte counts, increased bilirubin concentration) were the major adverse test substance related effects and a NOAEL of 300 mg/kg bw/d has been set (Charles River Laboratories (2013), 20027338).

In an oral reproduction/developmental toxicity screening study in Wistar rats, decreased body weight parameters and decreased food consumption were identified as relevant adverse effects in parental animals, associated with reductions in pup weights. A NOAEL of 250 mg/kg bw/d has been set for general systemic toxicity in parents and developmental toxicity, whereas the NOAEL for fertility was set at 700 mg/kg bw/day, i.e. the highest dose tested (Charles River Laboratories (2012), 20027631).

In an oral developmental toxicity study in Wistar rats, decreased bodyweight parameters and food consumption and clinical signs (dehydration, urine-stained abdominal fur, red perinasal substance) associated with reduction in fetal weights and delayed ossification in the offspring was observed (Charles River Laboratories (2013), 20027630). The NOAEL for maternal and embryo-fetal toxicity was 250 mg/kg bw/day.

As a point of departure for the derivation of the worker DNEL long-term for dermal route – systemic, a NOAEL of 300 mg/kg bw/d from the 90 day study has been taken. On the basis of the comparability of type and potency of findings in parental animals between the reproductive/developmental toxicity studies (relevant adverse effects observed at 700 mg/kg bw/d) versus the 90 day repeated dose study, parental adverse effects and associated offspring effects are considered to be covered by the choice of this point of departure for the DNEL derivation.

Route to route extrapolation:

Concerning dermal penetration potential an in vitro dermal penetration study is available for human skin. The percutaneous absorption determined, i.e. a dermal delivery (mean) was 1.63 % after 24 hours (Charles River Laboratories, 2013). Based on the physicochemical properties of C-1701 B_C_3, i.e. moderate log Pow (1.7 at 20°C), low molecular weight (322.41) and moderate water solubility (450 mg/l at 20°C), a good oral bioavailability via passive diffusion is considered likely, justifying an oral absorption rate in rats of 50%.

The dermal NOAEL was calculated by means of route-to-route extrapolation as follows:

NOAEL_dermal

= NOAEL_oral*ABS_oral-rat/ABS_dermal-human

= 300 mg/kg bw/day*50%/1.63%

= 9202 mg/kg bw/day

Long-term exposure – local effects

According to the available databasis, C-1701 B_C_3 did not give any indication for evident local toxicity. The substance does not pose any hazard, leading to a non-classification according to the criteria laid down under67/548/ECC and CLP. Thus, the derivation of a long-term DNEL for local effects is considered not mandatory.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Value:

130 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (endpoint). This is in line with the ECHA R8 guidance document.

AF for interspecies differences (allometric scaling):

1

Justification:

In line with the ECHA R8 guidance document, allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.

AF for other interspecies differences:

1

Justification:

Based on the absence of evident organ specific toxicity, an additional AF for interspecies differences is not considered necessary.

AF for intraspecies differences:

5

Justification:

Substance specific assessment factor: No relevant adverse organ toxicity was observed. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 3 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

AF for the quality of the whole database:

1

Justification:

The quality of the whole database is considered to be sufficient.

AF for remaining uncertainties:

1

Justification:

Substance specific assessment factor: Subchronic administration of C-1701 B_C_3 resulted in no evident organ toxicity in rats. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

230 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Value:

9 202 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (endpoint). This is in line with the ECHA R8 guidance document.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used. This is in line with the ECHA R8 guidance document.

AF for other interspecies differences:

1

Justification:

Based on the absence of evident organ specific toxicity, an additional AF for interspecies differences other than allometric scaling is not considered necessary.

AF for intraspecies differences:

5

Justification:

Substance specific assessment factor: No relevant adverse organ toxicity was observed. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 3 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

AF for the quality of the whole database:

1

Justification:

The quality of the whole database is considered to be sufficient.

AF for remaining uncertainties:

1

Justification:

Substance specific assessment factor: Subchronic administration of C-1701 B_C_3 resulted in no evident organ toxicity in rats. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (endpoint). This is in line with the ECHA R8 guidance document.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used. This is in line with the ECHA R8 guidance document.

AF for other interspecies differences:

1

Justification:

Based on the absence of evident organ specific toxicity, an additional AF for interspecies differences other than allometric scaling is not considered necessary.

AF for intraspecies differences:

5

Justification:

Substance specific assessment factor: No relevant adverse organ toxicity was observed. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 3 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

AF for the quality of the whole database:

1

Justification:

The quality of the whole database is considered to be sufficient.

AF for remaining uncertainties:

1

Justification:

Substance specific assessment factor: Subchronic administration of C-1701 B_C_3 resulted in no evident organ toxicity in rats. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure – systemic and local effects

No acute toxicity study is available for 2-ethoxyethyl (2Z)-2-cyano-2-[3-(3-methoxypropylamino) cyclohex-2-en-1-ylidene]acetate (C-1701 B_C_3). However, assessment of this endpoint has been made on acute oral toxicity data of a structural analogue via read-across and the available repeated dose toxicity data for C-1701 B_C_3 in a weight of evidence. No mortality or evident organ toxicity was observed in an oral repeated dose rat bone marrow micronucleus test (BioReliance, 2012) at the limit dose level of 2000 mg/kg bw as well as in oral subacute and subchronic toxicity studies in rats tested up to 1000 mg/kg bw/day. Low acute toxicity of C-1701 B_C_3 is supported by data from a structural analogue, i.e. C-1523 (CAS 1243654-84-3) via read-across. In a respective acute oral toxicity study, the LD50 is >2000 mg/kg bw for C-1523.

In view of the absence of any mortality or evident organ toxicity after repeated oral dosing up to 2000 mg/kg of C-1701 B_C_3 and with special regard to its low percutaneous absorption determined in human skin in vitro with a dermal delivery (mean) of 1.63 % or 1.08 µg/cm² after 24 hours (Charles River Laboratories, 2013), acute toxicity after short term exposure is unlikely. Based on the low bioavailability after dermal application and the absence of mortality after oral administration, no acute dermal toxicity is to be expected.

In light of the present data from oral toxicity studies, the substance characteristics (low vapour pressure, high melting point) and the fact, that inhalative exposure is not considered to be the major route of exposure, inhalation of toxicologically significant amounts of t C-1701 B_C_3 is unlikely. C-1701 B_C_3 did not induce skin or eye irritation and was not sensitising in the LLNA. As the test item did neither show acute systemic nor acute local toxicity, the derivation of acute DNELs for systemic and local effects is not considered mandatory.

Long-term exposure – systemic effects

The basis of the derived systemic DNELs, long-term exposure for C-1701 B_C_3 form the available oral repeated dose toxicity studies in rats:

In an oral 90 day repeated dose toxicity study in Wistar rats, clinical signs (urine-stained abdominal fur, increased incidence of dehydration and excess salivation), decreases in body weight gains and food consumption, clinical pathology (decreased red blood cell parameters, increased reticulocyte and leucocyte counts, increased bilirubin concentration) were the major adverse test substance related effects and a NOAEL of 300 mg/kg bw/d has been set (Charles River Laboratories (2013), 20027338).

In an oral reproduction/developmental toxicity screening study in Wistar rats, decreased body weight parameters and decreased food consumption were identified as relevant adverse effects in parental animals, associated with reductions in pup weights. A NOAEL of 250 mg/kg bw/d has been set for general systemic toxicity in parents and developmental toxicity, whereas the NOAEL for fertility was set at 700 mg/kg bw/day, i.e. the highest dose tested (Charles River Laboratories (2012), 20027631).

In an oral developmental toxicity study in Wistar rats, decreased bodyweight parameters and food consumption and clinical signs (dehydration, urine-stained abdominal fur, red perinasal substance) associated with reduction in fetal weights and delayed ossification in the offspring was observed (Charles River Laboratories (2013), 20027630). The NOAEL for maternal and embryo-fetal toxicity was 250 mg/kg bw/day.

As a point of departure for the derivation of the systemic DNELs, long-term exposure, a NOAEL of 300 mg/kg bw/d from the 90 day study has been taken. On the basis of the comparability of type and potency of findings in parental animals between the reproductive/developmental toxicity studies (relevant adverse effects observed at 700 mg/kg bw/d) versus the 90 day repeated dose study, parental adverse effects and associated offspring effects are considered to be covered by the choice of this point of departure for the DNEL derivation.

Route to route extrapolation:

Concerning dermal penetration potential an in vitro dermal penetration study is available for human skin. The percutaneous absorption determined, i.e. a dermal delivery (mean) was 1.63 % after 24 hours (Charles River Laboratories, 2013). Based on the physicochemical properties of C-1701 B_C_3, i.e. moderate log Pow (1.7 at 20°C), low molecular weight (322.41) and moderate water solubility (450 mg/l at 20°C), a good oral bioavailability via passive diffusion is considered likely, justifying an oral absorption rate in rats of 100%.

The substance characteristics (low vapour pressure, high melting point) indicate that an inhalation absorption of toxicologically significant amounts of C-1701 B_C_3 is unlikely. However, 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 to include a default factor in the case of inhalation-to-oral extrapolation, assuming a 2 fold higher inhalation absorption compared to oral absorption.

Inhalation:

There are no experimental data on repeated dose exposure by inhalation. C-1701 B_C_3 does not pose any intrinsic hazard, i.e. is not classified according to 67/548/EEC and regulation (EU) 1272/2008 regarding a health hazard.

A corrected inhalatory NOAEC was calculated as follows:

NOAEC_inhal

= NOAEL_oral* (1 / sRV_rat) * (ABS_oral-rat/ ABS_inhal-human)

= 300 mg/kg bw/d * (1/1.15 m³/kg bw/d)* (1/2)

= 130 mg/m³

Dermal:

The dermal NOAEL was calculated by means of route-to-route extrapolation as follows:

NOAEL_dermal

= NOAEL_oral*ABS_oral-rat/ABS_dermal-human

= 300 mg/kg bw/day*50%/1.63%

= 9202 mg/kg bw/day

Long-term exposure – local effects

According to the available databasis, C-1701 B_C_3 did not give any indication for evident local toxicity. The substance does not pose any hazard, leading to a non-classification according to the criteria laid down under67/548/ECC and CLP. Thus, the derivation of a long-term DNEL for local effects is considered not mandatory.

Registration Dossier

Registration Dossier

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Diss Factsheets

Acetic acid, 2-cyano-2-[3-[(3-methoxypropyl)amino]-2-cyclohexen-1-ylidene]-, 2-ethoxyethyl ester, (2Z)-

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

Workers - Hazard for the eyes

Local effects

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

General Population - Hazard via oral route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Additional information - General Population