Reaction mass of Dimethyl [3-[(hydroxymethyl) amino]-3-oxopropyl] phosphonate and Dimethyl (3-amino-3-oxopropyl)phosphonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.67 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

875 mg/m³

Explanation for the modification of the dose descriptor starting point:

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation. Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) is considered to be 0.4 m³/kg bw. Correction for activity driven differences of respiratory volumes in workers compared to workers in rest was considered to be 6.7 m³/10 m³. Therefore, the modified dose descriptor starting point is 875 mg/m³ (= 1000 / 2 / 0.4 x (7/10)).

AF for differences in duration of exposure:

6

Justification:

Difference in duration from subacute to chronic exposure

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Worker population

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20 mg/m³

Most sensitive endpoint:

carcinogenicity

DNEL related information

DNEL derivation method:

other: Based on the DNEL long-term - local effects Inhalation route of 0.5 mg/m³ (= 0.4 ppm).

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

40 mg/m³

Most sensitive endpoint:

carcinogenicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

33.3 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

10 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the low Log Kow and the very high water solubility, dermal absorption is expected to be low. A ration of 0.1 for oral to dermal absorption is therefore provisionally suggested for DNEL derivation.

AF for differences in duration of exposure:

6

Justification:

Difference in duration from subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Rats to humans

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

5

Justification:

Worker population

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. 

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since the substance is not classified for acute dermal, inhalation, and oral toxicity, no short-term DNELs needs to be derived for these routes of exposure. The substance is also not classified as irritating or sensitizing to the skin and therefore no derivation of the DNEL for local dermal effects needs to be derived. No data is available whether the test substance could cause irritation to the respiratory tract and therefore no DNEL could be derived. 

Long-term toxicity

A subacute (28-days) oral toxicity study is available in rats. In none of the dose groups treatment related effects were observed on mortality, clinical signs, body weight, food consumption, ophthalmic examinations, clinical pathology investigations, organ weight, macroscopic and microscopic findings. Therefore, a NOAEL of 1000 mg/kg bw was determined. Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. The low log Pow value and the high water solubility (>10000 mg/L) suggest that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low. In the absence of route-specific information a ratio of 0.1 for oral to dermal absorption is provisionally suggested for the risk assessment of the substance, based on its physical-chemical properties.

Additionally, for the inhalation route of exposure, acute and long-term, local effects, the DNEL values from formaldehyde were taken into consideration. As worst-case scenario the registered substance contains a maximum of 2.5 % of formaldehyde, therefore, the corresponding DNEL value was modified by a factor 40.

DNEL acute local - inhalation

As regards the DNEL short-term inhalation for workers according to the Guidance on information requirements and chemical safety assessment, Chapter R.8; APPENDIX R. 8-13 (Deriving DNELs, when a community/national occupational exposure limit (OEL) is available) the registrant is allowed to use a national occupational exposure limit in place of developing a DNEL.

A national occupational exposure limit (MAK value) has been adopted. Toxicological information and evaluations of health effects used for setting the national OEL are documented and available (German MAK commission; Greim 2000). The study of Lang et al., 2008 reconfirms the MAK value of 0.3 ppm with a short-term excursion factor of 2 (STEL 0.6 ppm) as no objective signs for sensory irritation were found in volunteers exposed to 0.3 ppm with peaks of 0.6 ppm or at 0.5 ppm over 4 h. Recently Müller et al. (2010) defined the NOAEC in more detail. They did not observe objective or subjective signs of irritation at peak exposure concentrations of 0.8 ppm over 15 min and at 0.7 ppm over 4h. These NOAECs pertained likewise to persons with high and low sensitivity for sensory irritation as determined by CO2threshold. In comparison to the findings of Lang et al. (2007) that peak exposures of 1 ppm lead to sensory irritation, this indicates that any irritation occurring in the range between 0.7 and 1 ppm will rapidly subside and that no irritation will occur at 15 min peaks of 0.8 ppm. Therefore, 0.8 ppm is taken as acute DNEL (15 min).

Formaldehyde DNEL short term inhalation worker exposure = STEL (15 minutes) of 0.8 ppm.

Worker-DNEL long-term for inhalation route-local

Derivation of the worker-DNEL long-term for inhalation route-local is driven by effects on the upper respiratory tract especially taking into consideration the development of nasal tumors in rats. According to the Guidance on information requirements and chemical safety assessment, Chapter R.8; APPENDIX R. 8-13 (Deriving DNELs, when a community/national occupational exposure limit (OEL) is available) the registrant is allowed to use a national occupational exposure limit in place of developing a DNEL.

A national occupational exposure limit (MAK value) has been adopted. Toxicological information and evaluations of health effects used for setting the national OEL are documented and available (German MAK commission; Greim 2000).

The German MAK commission (2000) developed a detailed mode of action for the induction of nasal tumors in rats after inhalation exposure. For cytotoxicity, cell proliferation and nasal tumor development the NOAECs are in the range between 2 and 6 ppm, while for DNA protein cross link formation (DPX) a clear NOEL could not be established. Most importantly, the proliferation rate of the respiratory epithelium is very low and is not increased up to concentrations of 2 ppm. Therefore, the probability of fixation of DPX into permanent mutations is low taking into account the rapid repair of DPX. The commission concluded that the occurrence of tumors is the result of chronic proliferative processes and that the genotoxicity of formaldehyde plays no or at most a minor part in its carcinogenic potential. Under these considerations the MAK value for the workplace was set at 0.3 ppm with a factor of 2 for peak exposures of 15 min and a ceiling of 1 ppm. The avoidance of cell proliferation in the respiratory tract was decisive for defining the MAK value. Cell proliferation is caused by

cytotoxic irritation of formaldehyde, but data on cytotoxic irritation of the respiratory tract are not available for humans. However, the database for sensory irritation to the eye, a more sensitive parameter, was considered sufficient for setting the MAK value at 0.3 ppm. The review of Paustenbach et al. (1997) was an important consideration of the German MAK commission for defining their MAK value of 0.3 ppm. But according to this review and the review of Arts et al., 2007 appreciable subjective symptoms will only be noted at or above 1 ppm.

As all these studies reviewed only relied on subjective symptoms, much more weight has to be given to the more recent investigations of Lang et al. (2007) and Mueller et al. (2010) because the following important aspects were taken into consideration:

- objective signs of irritation, like eye blinking rate or conjunctival redness

- influence of personality factors

- confounding by odor (Lang-study)

- evaluation of subgroups with high and low sensitivity for nasal irritation (Mueller-study).

The NOAEC for objective or subjective signs of irritation after taking account of personality factors was 0.5 ppm or 0.3 ppm + peaks of 0.6 ppm in the Lang-study. A further refinement of the NOAEC was achieved by Mueller et al., (2010) by using intermediate and higher exposure concentrations. Thereby a NOAEC of 0.7 ppm or 0.4 ppm + peaks of 0.8 ppm was defined.

Based on the MAK value and taking into consideration the most recent study by Mueller et al., (2010) a DNEL of 0.4 ppm is considered appropriate to protect against irritation and thereby also against carcinogenicity in humans after inhalation exposure.

Formaldehyde Worker-DNEL long-term for inhalation route-local: 0.4 ppm

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.9 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

434.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation. Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) is considered to be 1.15 m³/kg bw. Therefore, the modified dose descriptor starting point is 434.8 mg/m3 (= 1000 / 2 / 1.15).

AF for differences in duration of exposure:

6

Justification:

Extrapolation to chronic exposure based on a sub-acute toxicity study

AF for other interspecies differences:

2.5

Justification:

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.

AF for intraspecies differences:

10

Justification:

Default assessment factor for consumers

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

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:

16.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

10 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the low Log Kow and the very high water solubility, dermal absorption is expected to be low. A ratio of 0.1 for oral to dermal absorption is therefore provisionally suggested for DNEL derivation.

AF for differences in duration of exposure:

6

Justification:

Extrapolation to chronic exposure based on a sub-acute toxicity study.

AF for interspecies differences (allometric scaling):

4

Justification:

Assessment factor for allometric scaling.

AF for other interspecies differences:

2.5

Justification:

Assessment factor for allometric scaling.

AF for intraspecies differences:

10

Justification:

Default assessment for consumers.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation is required as it is oral route.

AF for differences in duration of exposure:

6

Justification:

Extrapolation to chronic exposure based on a sub-acute toxicity study

AF for interspecies differences (allometric scaling):

4

Justification:

Assessment factor for allometric scaling.

AF for other interspecies differences:

2.5

Justification:

Remaining differences

AF for intraspecies differences:

10

Justification:

Default assessment factor for consumers.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. 

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since the substance is not classified for acute dermal, inhalation, and oral toxicity, no short-term DNELs needs to be derived for these routes of exposure. The substance is also not classified as irritating or sensitizing to the skin and therefore no derivation of the DNEL for local dermal effects needs to be derived. No data is available whether the test substance could cause irritation to the respiratory tract and therefore no DNEL could be derived. 

Long-term toxicity

A subacute (28-days) oral toxicity study is available in rats. In none of the dosing groups treatment-related effects were observed on mortality, clinical signs, body weight, food consumption, ophthalmic examinations, clinical pathology investigations, organ weight, macroscopic and microscopic findings. Therefore, a NOAEL of 1000 mg/kg bw was determined. Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. The low log Pow value and the high water solubility (>10000 mg/L) suggest that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low. In the absence of route-specific information a ratio of 0.1 for oral to dermal absorption is provisionally suggested for the risk assessment of the substance, based on its physical-chemical properties. Additionally, for the inhalation route of exposure, acute and long-term, local effects, the DNEL values from formaldehyde were taken into consideration. As worst-case scenario the registered substance contains a maximum of 2.5 % of formaldehyde, therefore, the corresponding DNEL value was modified by a factor 40.

DNEL acute local - inhalation

As regards the DNEL short-term inhalation for workers according to the Guidance on information requirements and chemical safety assessment, Chapter R.8; APPENDIX R. 8-13 (Deriving DNELs, when a community/national occupational exposure limit (OEL) is available) the registrant is allowed to use a national occupational exposure limit in place of developing a DNEL.

A national occupational exposure limit (MAK value) has been adopted. Toxicological information and evaluations of health effects used for setting the national OEL are documented and available (German MAK commission; Greim 2000). The study of Lang et al., 2008 reconfirms the MAK value of 0.3 ppm with a short-term excursion factor of 2 (STEL 0.6 ppm) as no objective signs for sensory irritation were found in volunteers exposed to 0.3 ppm with peaks of 0.6 ppm or at 0.5 ppm over 4 h. Recently Müller et al. (2010) defined the NOAEC in more detail. They did not observe objective or subjective signs of irritation at peak exposure concentrations of 0.8 ppm over 15 min and at 0.7 ppm over 4h. These NOAECs pertained likewise to persons with high and low sensitivity for sensory irritation as determined by CO2 threshold. In comparison to the findings of Lang et al. (2007) that peak exposures of 1 ppm lead to sensory irritation, this indicates that any irritation occurring in the range between 0.7 and 1 ppm will rapidly subside and that no irritation will occur at 15 min peaks of 0.8 ppm. Therefore, 0.8 ppm is taken as acute DNEL (15 min).

Formaldehyde DNEL short term inhalation worker exposure = STEL (15 minutes) of 0.8 ppm.

Worker-DNEL long-term for inhalation route-local

Derivation of the worker-DNEL long-term for inhalation route-local is driven by effects on the upper respiratory tract especially taking into consideration the development of nasal tumors in rats. According to the Guidance on information requirements and chemical safety assessment, Chapter R.8; APPENDIX R. 8-13 (Deriving DNELs, when a community/national occupational exposure limit (OEL) is available) the registrant can use a national occupational exposure limit in place of developing a DNEL.

A national occupational exposure limit (MAK value) has been adopted. Toxicological information and evaluations of health effects used for setting the national OEL are documented and available (German MAK commission; Greim 2000). The German MAK commission (2000) developed a detailed mode of action for the induction of nasal tumors in rats after inhalation exposure. For cytotoxicity, cell proliferation and nasal tumor development the NOAECs are in the range between 2 and 6 ppm, while for DNA protein cross link formation (DPX) a clear NOEL could not be established. Most importantly, the proliferation rate of the respiratory epithelium is very low and is not increased up to concentrations of 2 ppm. Therefore, the probability of fixation of DPX into permanent mutations is low considering the rapid repair of DPX. The commission concluded that the occurrence of tumors is the result of chronic proliferative processes and that the genotoxicity of formaldehyde plays no or at most a minor part in its carcinogenic potential. Under these considerations the MAK value for the workplace was set at 0.3 ppm with a factor of 2 for peak exposures of 15 min and a ceiling of 1 ppm. The avoidance of cell proliferation in the respiratory tract was decisive for defining the MAK value. Cell proliferation is caused by cytotoxic irritation of formaldehyde, but data on cytotoxic irritation of the respiratory tract are not available for humans. However, the database for sensory irritation to the eye, a more sensitive parameter, was considered sufficient for setting the MAK value at 0.3 ppm. The review of Paustenbach et al. (1997) was an important consideration of the German MAK commission for defining their MAK value of 0.3 ppm. But according to this review and the review of Arts et al., 2007 appreciable subjective symptoms will only be noted at or above 1 ppm. As all these studies reviewed only relied on subjective symptoms, much more weight has to be given to the more recent investigations of Lang et al. (2007) and Mueller et al. (2010) because the following important aspects were taken into consideration:

- objective signs of irritation, like eye blinking rate or conjunctival redness

- influence of personality factors

- confounding by odor (Lang-study)

- evaluation of subgroups with high and low sensitivity for nasal irritation (Mueller-study).

The NOAEC for objective or subjective signs of irritation after taking account of personality factors was 0.5 ppm or 0.3 ppm + peaks of 0.6 ppm in the Lang-study. A further refinement of the NOAEC was achieved by Mueller et al., (2010) by using intermediate and higher exposure concentrations. Thereby a NOAEC of 0.7 ppm or 0.4 ppm + peaks of 0.8 ppm was defined.

Based on the MAK value and taking into consideration the most recent study by Mueller et al., (2010) a DNEL of 0.4 ppm is considered appropriate to protect against irritation and thereby also against carcinogenicity in humans after inhalation exposure.

Formaldehyde Worker-DNEL long-term for inhalation route-local: 0.4 ppm

 

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation. Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) is considered to be 1.15 m³/kg bw. Therefore, the modified dose descriptor starting point is 434.8 m³/kg bw (= 1000 / 2 / 1.15).

 

A subacute (28-days) oral toxicity study is available in rats. In none of the dose groups treatment related effects were observed on mortality, clinical signs, body weight, food consumption, ophthalmic examinations, clinical pathology investigations, organ weight, macroscopic and microscopic findings. Therefore, a NOAEL of 1000 mg/kg bw was determined. Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route.

 

An acute inhalation study has been performed, however, no effect has been seen on the highest tested concentration (4.83 mg/L air). Moreover, no significant inhalation exposure is expected. The long-term DNEL is normally sufficient to ensure that effects do not occur and to protect workers, if long term DNELs are maintained. Therefore, a DNEL does not need to be derived.

No data on inhalation toxicity after repeated exposure is available as the corresponding test was waved based on exposure considerations. No significant inhalation exposure is expected. As no studies are available on the local effects by inhalation, no DNEL could be derived. An acute inhalation study has been performed, however no effect has been seen on the highest tested concentration (4.83 mg/L). Moreover, no significant inhalation exposure is expected. Therefore, a DNEL does not need to be derived. Based on the low Log Kow and the very high water solubility, dermal absorption is expected to be low. A ratio of 0.1 for oral to dermal absorption is therefore provisionally suggested for DNEL derivation. A subacute (28-days) oral toxicity study is available in rats. In none of the dosing groups treatment-related effects were observed on mortality, clinical signs, body weight, food consumption, ophthalmic examinations, clinical pathology investigations, organ weight, macroscopic and microscopic findings. Therefore, a NOAEL of 1000 mg/kg bw was determined. Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route. The dermal exposure of rats to 2000 mg/kg bw did not cause any deaths or severe signs of toxicity in an OECD TG 402 and GLP compliant test. Accordingly, the substance does not need to be classified and a DNEL does not need to be derived. The long-term DNEL is normally sufficient to ensure that effects do not occur and to protect workers, if long term DNELs are maintained.

The test item is not irritant to the skin and is not a skin sensitizer based on a weight of evidence approach. Accordingly, the substance does not need to be classified and a DNEL does not need to be derived.

A subacute (28-days) oral toxicity study is available in rats. In none of the dosing groups treatment-related effects were observed on mortality, clinical signs, body weight, food consumption, ophthalmic examinations, clinical pathology investigations, organ weight, macroscopic and microscopic findings. Therefore, a NOAEL of 1000 mg/kg bw was determined. No route-to-route extrapolation is needed to derive the DNEL.

 

The oral exposure of rats to 2000 mg/kg bw DMPPA_701-402-5 did not cause any deaths or severe signs of toxicity in an OECD 401 and GLP compliant test. Accordingly, the substance does not need to be classified and a DNEL does not need to be derived. The long-term DNEL is normally sufficient to ensure that effects do not occur if long term DNELs are maintained. According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. 

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since the substance is not classified for acute dermal, inhalation, and oral toxicity, no short-term DNELs needs to be derived for these routes of exposure. The substance is also not classified as irritating or sensitizing to the skin and therefore no derivation of the DNEL for local dermal effects needs to be derived. No data is available whether the test substance could cause irritation to the respiratory tract and therefore no DNEL could be derived. 

Long-term toxicity

A subacute (28-days) oral toxicity study is available in rats. In none of the dose groups treatment related effects were observed on mortality, clinical signs, body weight, food consumption, ophthalmic examinations, clinical pathology investigations, organ weight, macroscopic and microscopic findings. Therefore, a NOAEL of 1000 mg/kg bw was determined. Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. The low log Pow value and the high water solubility (>10000 mg/L) suggest that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low. In the absence of route-specific information a ratio of 0.1 for oral to dermal absorption is provisionally suggested for the risk assessment of the substance, based on its physical-chemical properties.