tetraethyl N,N'-(methylenedicyclohexane-4,1-diyl)bis-.sc.dl.sc.-aspartate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

28 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):

63

Modified dose descriptor starting point:

LOAEC

Value:

1 763 mg/m³

Explanation for the modification of the dose descriptor starting point:

A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2010) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., 1998, Harkema, 1991). Therefore a factor 1 is chosen for adjusting route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the read across substance is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, Bayer AG, 1998a/b) and that the acute studies that were performed with oral, dermal and inhalation route of exposure did not give evidence for a route specific systemic toxicity.

AF for dose response relationship:

3

Justification:

A LOAEL (mild effects in male rats only) is used as point of departure.

AF for differences in duration of exposure:

1.4

Justification:

For extrapolation of exposure duration subchronic to chronic: The suggested factor 2 for extrapolation of exposure duration subchronic (90 days) to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4. Actually, the exposure duration in the study that leads to the PoD for DNEL derivation was at least for female animals more than 90-days, i.e. 120 days plus mating period, that is in total up to 141 days.

AF for interspecies differences (allometric scaling):

1

Justification:

Already covered by correction of starting point. Correction was according to Figure R.8 in the Guidance Document R.8 (ECHA, 2010): Corrected inhalatory LOAEC = oral LOAEL * 1/0.38 kg/m³ * 6.7 m³/10 m³.

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The read across substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.

AF for intraspecies differences:

5

AF for the quality of the whole database:

3

Justification:

The use of data from another chemical compound that has comparable physical and chemical properties and molecular structure for derivation of a DNEL led to the application of an assessment factor for the quality of the whole database of 3.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

112 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:

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:

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):

252

Modified dose descriptor starting point:

LOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Absorption oral compared to dermal assumed to be identical

AF for dose response relationship:

3

Justification:

A LOAEL (mild effects in male rats only) is used as point of departure

AF for differences in duration of exposure:

1.4

Justification:

For extrapolation of exposure duration subchronic to chronic: The suggested factor 2 for extrapolation of exposure duration subchronic (90 days) to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4. Actually, the exposure duration in the study that leads to the PoD for DNEL derivation was at least for female animals more than 90-days, i.e. 120 days plus mating period, that is in total up to 141 days.

AF for interspecies differences (allometric scaling):

4

Justification:

Differences rat vs. human

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The read across substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.

AF for intraspecies differences:

5

AF for the quality of the whole database:

3

Justification:

The use of data from another chemical compound that has comparable physical and chemical properties and molecular structure for derivation of a DNEL led to the application of an assessment factor for the quality of the whole database of 3.

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

DNEL derivation, Submission 2009, for actualization see below:

For this DNEL delineation toxicology data of the structural analogue aspartic acid, N,N'-[methylenebis(2-methyl-4,1-cyclohexanediyl)]bis-, 1,1',4,4'-tetraethyl ester were used as no data were available for aspartic acid, N,N'-(methylenedi-4,1-cyclohexanediyl)bis-, 1,1',4,4'-tetraethyl ester. The justification to utilise toxicology data for aspartic acid, N,N'-[methylenebis(2-methyl-4,1-cyclohexanediyl)]bis-, 1,1',4,4'-tetraethyl ester, herein after referred to as methyl-cyclohexyl compound, is based primarily on the following statements. Both substances are diethyl esters of aspartic acid linked to a dicyclohexylmethyldiamine moiety. The difference between these two substances is merely the presence of two methyl groups connected to the cyclohexane rings. This structural analogy was confirmed by the Member State responsible for the notification of both substances under the NONS regulation. The Member State decided that test results obtained for one substance can be transferred to the other substance and that testing of both substances is usually not required. This decision is in accordance with the grouping of substances and read-across approach in Annex XI, 1.5 of the REACH Regulation.

No systemic toxicity was observed after an acute oral and dermal toxicity study in rats (Bomhard, Bayer AG, 1990 and 1992a; both LD50 > 2000 mg/kg bw/day) with the methyl-cyclohexyl compound. A subacute oral toxicity study in rats (Bomhard, Bayer AG, 1992b) gave no evidence of a toxicological potential and reveals the NOAEL of 1000 mg/kg bw/day as the starting point for the delineation of the DNEL_{long-term, systemic}for workers. 

Due to the low vapour pressure of the liquid substance an inhalation exposure via vapour is not assumed. An acute inhalation toxicity study in rats with exposure to a highly respirable aerosol (Pauluhn, Bayer AG, 1998a; LC50 (4h) > 4224 mg/m³ air, NO(A)EL 1436 mg/m³ air) gave no mortality and also no evidence of a systemic toxicity. 

The major signs in the acute aerosol inhalation study (Pauluhn, Bayer AG, 1998a) were only observed at the highest concentration (4224 mg/m³ air) and could be seen as a consequence of the local irritating properties of the substance. Consistent to that the methyl-cyclohexyl compound was described to have a low potential to elicit upper respiratory tract sensory irritation (Pauluhn, Bayer AG, 1998b; RD₅₀: 841 mg/m³ air). Furthermore, the substance was reported to be “slightly to moderately irritating to the skin" of rabbits (Maertins, Bayer AG, 1991).

The DNEL_{long-term, systemic} for workers for oral/dermal exposure and for inhalative exposure is derived as follows:

 

DNEL_{long-term, systemic} for workers for oral/dermal exposure using default extrapolation factors¹:

Oral NOAEL (rat) from a subacute toxicity study:                                1000 mg/kg bw/day

Absorption oral compared to dermal assumed to be identical                1

For interspecies differences rat vs. human (allometric scaling):               4

²For remaining interspecies differences:                                                1

For intraspecies differences in workers:                                                5

³For extrapolation of exposure duration subacute to chronic:                 4.2

For reliability of dose-response:                                                            1

⁴For quality of whole database:                                                             3

Overall factor:                                                                                   252

Worker DNEL_{long-term, systemic} for oral/dermal exposure:      4.0 mg/kg bw/day

 

DNEL_{long-term, systemic} for workers for inhalative exposure using default extrapolation factors¹:

Oral NOAEL (rat) from a subacute toxicity study:                                1000 mg/kg bw/day

Correction of the starting point according to Figure R.8 in the Guidance Document R.8 (ECHA, 2008c)

Corrected inhalatory NOAEL = oral NOAEL * 1/0.38 m³/kg * 6.7m³/10m³

Corrected inhalatory NOAEL for workers =                1763 mg/m³

⁵Absorption oral compared to inhalative                                                  1

For interspecies differences rat vs. human (allometric scaling):                   1 (already covered by correction of starting point)

²For remaining interspecies differences:                                                    1

For intraspecies differences in workers:                                                    5

³For extrapolation of exposure duration subacute to chronic:                    4.2

For reliability of dose-response:                                                               1

⁴For quality of whole database:                                                                3

Overall factor:                                                                                        63

Worker DNEL_{long-term, systemic} for inhalative exposure:              28.0 mg/m³ air

¹: default factors according to the Guidance Document R.8 (ECHA, 2008c);

²: A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2008c) for

remaining interspecies differences, but justified deviations are possible. The methyl-cyclohexyl compound showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects. The DNEL derivation based on a NOAEL with no LOAEL, is already very conservative, therefore no correction for remaining interspecies differences has to be done → factor 1.

³: The suggested factor 6 for extrapolation of exposure duration subacute to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 6 * 0.7 = 4.2.

⁴: The use of data from another chemical compound that has comparable physical and chemical properties and molecular structures for derivation of a DNEL led to the application of an assessment factor for the quality of the whole database of 3.

⁵: A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2008c) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., 1998, Harkema, 1991). Therefore a factor 1 is chosen for adjusting route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the methyl-cyclohexyl compound is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, Bayer AG, 1998a/b) and that the acute studies that were performed with oral, dermal and inhalation route of exposure did not give evidence for a route specific systemic toxicity.

Due to the low sensory irritation potential of the methyl-cyclohexyl compound (RD₅₀: 841 mg/m³) there is no need to derive an acute DNEL for local toxicity. As there are no data available for aspartic acid, N,N'-(methylenedi-4,1-cyclohexanediyl)bis-, 1,1',4,4'-tetraethyl ester and as there is no evidence of toxicity for the methyl-cyclohexyl compound up to the highest dose tested in the repeated dose toxicity study it is proposed to limit exposure peaks to a factor of 4. This approach is in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900, published by the German Federal Ministry of Labour and Social Affairs).

According to the potency categorisation approach the methyl-cyclohexyl compound is classified as a moderate skin sensitiser (category 1), based on a guinea pig maximisation test (5% intradermal concentration during induction; 85% incidence of sensitisation).

DNEL-derivation, additional remarks for submission 2012:

The justification for DNELs above was part of the data submission for aspartic acid, N,N'-(methylenedi-4,1-cyclohexanediyl)bis-, 1,1',4,4'-tetraethyl ester according to REACH in 2009. Meanwhile, results of a two-generation reproduction toxicity study on the structural analogue aspartic acid, N,N'-[methylenebis(2 -methyl-4,1-cyclohexanediyl)]bis-, 1,1',4,4'-tetraethyl ester reveal a NOAEL of 200 mg/kg (Doses 0, 40, 200 and 1000 mg/kg) for general toxicity (for reproduction toxicity 1000 mg/kg) due to signs of kidney damage in F0 males and indications of changes in kidney function in F0 females and F1 rats both at 1000 mg/kg.

More detailed, in males of F0-generation basophilic tubules were slightly increased by severity at 1000 mg/kg and minimal focal tubular dilation/casts were slightly more frequent at 1000 mg/kg.

 

		0 mg/kg	40 mg/kg	200 mg/kg*	1000 mg/kg
Male animals without kidney findings		3	-	1	-
Male animals with Basophilic Tubules	Grade 1	18	18	18	6
	Grade 2	4	6	5	16
	Grade 3	-	-	-	2
	Grade 4	-	1	-	-
Male animals with Foc. Tub. Dil./Casts	Grade 1	8	7	10	13
	Grade 2	1	-	-	3

                                                        *in total kidneys of 24 animals examined

 

Although basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. For F0 females slightly more frequent slight non-adverse tubular change of inner renal cortex were found at 1000 mg/kg and for F1 rats kidney histopathology was inconspicuous.

Taking into account the large spacing between the NOAEC and LOAEC in the two-generation reproduction toxicity study of 5 – instead of typically a factor of 3, and the mild response at the LOAEC, which revealed adverse effects for male F0-animals only, a DNEL based on the NOAEL of this study would overestimate the risk. By comparison starting with the LOAEC of 1000 mg/kg of this two-generation (subchronic) study and setting an extrapolation factor of 3 for reliability of dose-response would result exactly in the initial derived DNEL of 4 mg/kg.

 

Oral LOAEL (rat) from a 2-Gen.- study:                                        1000 mg/kg bw/day

¹Absorption oral compared to dermal assumed to be identical                   1

For interspecies differences rat vs. human (allometric scaling):                   4

²For remaining interspecies differences:                                                     1

For intraspecies differences in workers:                                                     5

³For extrapolation of exposure duration subchronic to chronic:                  1.4
           (2 * 0.7 = 1.4)

⁴For reliability of dose-response:                                                               3

⁵For quality of whole database:                                                                 3

Overall factor:                                                                                       252

Worker DNEL_{long-term, systemic}for oral/dermal exposure:       4 mg/kg bw/day

Due to the moderate skin sensitization potential the risk management measures and operational conditions set for the substance lead to avoidance of exposure, anyway.

Overall it was concluded not to deviate from the initial DNELs.

 

¹: A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2008c) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., Toxicol.Appl. Pharmacol. 152, 211 -231, 1998; Harkema, Toxicol. Pathol. 19, 4, 321 -336, 1991). Therefore a factor 1 is chosen for adjusting route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the methyl-cyclohexyl compound is characterized by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, Bayer AG, 1998a/b) and that the acute studies that were performed with oral, dermal and inhalation route of exposure did not give evidence for a route specific systemic toxicity.

²: A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2008c) for remaining interspecies differences, but justified deviations are possible. The methyl-cyclohexyl compound showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.

³: The suggested factor 2 for extrapolation of exposure duration subchronic (90 days) to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4. Actually, the exposure duration was at least for female animals more than 90-days, i.e. 120 days plus mating period, that is in total up to 141 days.

⁴: A LOAEL (mild effects in male rats only) is used as point of departure.

⁵: The use of data from another chemical compound that has comparable physical and chemical properties and molecular structure for derivation of a DNEL led to the application of an assessment factor for the quality of the whole database of 3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.8 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):

180

Modified dose descriptor starting point:

LOAEC

Value:

870 mg/m³

Explanation for the modification of the dose descriptor starting point:

A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2008c) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., 1998, Harkema, 1991). Therefore a factor 1 is chosen for adjusting route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the methyl-cyclohexyl compound is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, Bayer AG, 1998a/b) and that the acute studies that were performed with oral, dermal and inhalation route of exposure did not give evidence for a route specific systemic toxicity.

AF for dose response relationship:

3

Justification:

A LOAEL (mild effects in male rats only) is used as point of departure

AF for differences in duration of exposure:

2

Justification:

For extrapolation of exposure duration subchronic to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Already covered by correction of starting point. Correction was according to Figure R.8 in the Guidance Document R.8 (ECHA, 2010): Corrected inhalatory LOAEC = oral LOAEL * 1/1.15 m³/kg.

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The read across substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.

AF for intraspecies differences:

10

AF for the quality of the whole database:

3

Justification:

The use of data from another chemical compound that has comparable physical and chemical properties and molecular structure for derivation of a DNEL led to the application of an assessment factor for the quality of the whole database of 3.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

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:

1.4 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):

720

Modified dose descriptor starting point:

LOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Absorption oral compared to dermal assumed to be identical

AF for dose response relationship:

3

Justification:

A LOAEL (mild effects in male rats only) is used as point of departure.

AF for differences in duration of exposure:

2

Justification:

For extrapolation of exposure duration subchronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Differences rat vs. human

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The read across substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.

AF for intraspecies differences:

10

AF for the quality of the whole database:

3

Justification:

The use of data from another chemical compound that has comparable physical and chemical properties and molecular structure for derivation of a DNEL led to the application of an assessment factor for the quality of the whole database of 3.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

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:

1.4 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):

720

Modified dose descriptor starting point:

LOAEL

Value:

1 000 mg/kg bw/day

AF for dose response relationship:

3

Justification:

A LOAEL (mild effects in male rats only) is used as point of departure.

AF for differences in duration of exposure:

2

Justification:

For extrapolation of exposure duration subchronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Differences rat vs. human

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by the Guidance Document R.8 (ECHA, 2010) for remaining interspecies differences, but justified deviations are possible. The read across substance showed no evidence of systemic availability or toxicity in an acute oral, dermal or aerosol inhalation study and even up to the limit dose of 1000 mg/kg bw/day a subacute toxicity study did not reveal adverse effects; in a two generation reproductive toxicity study mild kidney effects were seen in males only at a dose of 1000 mg/kg bw/day. The basophilic tubules and focal tubular dilation/hyaline casts are common spontaneous findings in male rats of this age but as a worst case assumption these findings were concluded to be adverse, since they correlated with statistically significantly elevated absolute and/or relative kidney weights, evident for F0 and F1 rats at 1000 mg/kg. Overall, as the male rat is highly sensitive to such kidney responses the use of a LOAEL based on such effects as a point of departure for derivation of a human DNEL is regarded to be highly conservative, therefore there is no need for an additional interspecies extrapolation factor.

AF for intraspecies differences:

10

AF for the quality of the whole database:

3

Justification:

The use of data from another chemical compound that has comparable physical and chemical properties and molecular structure for derivation of a DNEL led to the application of an assessment factor for the quality of the whole database of 3.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified