Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.4 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):

50

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

370.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

See "Additional Information" for details.

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:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item was 54 -75 days for females and 42 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (57 days) for females an Assessment factor of 4 is justified.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The study according OECD TG 422 was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.1 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):

200

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

420 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See "Additional Information" for details.

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:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item was 54 -75 days for females and 42 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (57 days) for females an Assessment factor of 4 is justified.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The study according OECD TG 422 was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

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:

low hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term DNEL by route-to-route extrapolation:

An OECD TG 422 study with the test substance is available. Hsd.Han: Wistar rats were administered by oral gavage using doses of 1000, 300 and 100 mg/kg bw/day. High dose was reduced from 1000 mg/kg bw/day to 750 mg/kg bw/day on Day 21 as mortality was observed in male and female animals.

At 750/1000 mg/kg bw/day, clinical signs, reduced body weight development (male) and food consumption, secondarily irregular estrous cycle, changed delivery data of dams, changes in stomach mucosa, which was indicative of localized inflammation of the non-glandular area were observed.

300 mg/kg bw/day caused clinical signs, which recover shortly after administration and changes in stomach mucosa, which was indicative of localized inflammation of the non-glandular area.

The development of the F1 offspring was not impaired from birth to post-natal day 13 at any dose level after repeated oral administration of dams.

Based on these observations the NOAEL for developmental toxicity was 1000 mg/kg bw/day, the NOAEL for systemic toxicity and reproductive performance was 300 mg/kg bw/day and the NOAEL for local toxicity was 100 mg/kg bw/day. The NOAEL of 300 mg/kg bw/day is used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 300 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume, human (sRVhuman): 6.7 m3

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m3/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m3

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human):50%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 300 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 370.2 mg/m3

Step 3: Overall AF= 50

Intraspecies AF (workers): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study performed with the test item was 54 -75 days for females and 42 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (57 days) for females an Assessment factor of 4 is justified.

Whole database AF: 1

The OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion,long term systemic inhalation DNEL, workers = 7.4 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

No data for the classification and labelling of the test substance for acute inhalation toxicity is available. The substance is not classified for acute oral toxicity, therefore no adverse result for inhalation toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Due to the extremely low vapour pressure (0.0159 Pa at 20 °C and 0.0216 Pa at 25°C) of the test item inhalation exposure is not considered as relevant. Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is unlikely to be available as a vapor. Furthermore, the substance is a waxy liquid and no generation of dust is expected. Therefore, no DNEL was derived.

Long term & acute, local DNEL- exposure via inhalation (workers)

The substance is classified for eye irritation Cat.2 and in conclusion local mucosal membrane damage of the respiratory membranes might be possible (in accordance with "Guidance on information requirements and chemical safety assessment, chapter R8"). However, due to the extremely low vapour pressure of the substance, inhalation exposure is not considered as relevant and local respiratory irritation is expected to be low. Furthermore, as the substance is marketed in a non-solid form no dust formation is expected. Therefore, no DNEL was derived.

Dermal

Long term, systemic DNEL- exposure via dermal route (workers)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOAEL of 300 mg/kg bw/day derived from an OECD TG 422 study performed with the test item was used as the PoD.

Step 1: PoD: NOAEL = 300 mg/kg bw/day

Step 2: Modification into a correct starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

= 300 mg/kg bw/day x 1.4

= 420 mg/kg bw/day

Step 3:Overall AF= 200

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study performed with the test item was 54 -75 days for females and 42 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and reproduction of the parental generation and furthermore information on developmental toxicity of the offspring. Together with the longer exposure duration (57 days) for females an Assessment factor of 4 is justified.

In conclusion,long term systemic dermal DNEL, workers = 2.1 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

Long term & acute, local DNEL- dermal exposure (workers)

Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is classified for skin sensitization Cat 1B and skin irritation Cat 2. Therefore the substance is allocated to the medium hazard band (according to "Guidance on Information Requirements and Chemical Safety Assessment Part E: Risk Characterisation", May 2016). A qualitative risk assessment is conducted.

Hazard to the eye-local effects (workers)

The test item is classified for skin and eye irritation Cat 2 (H319:”Causes serious eye irritation”) under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.

Thus, a qualitative risk assessment is done and the substance is assigned to the low hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Since Reaction mass of lauric acid, compound with morpholine (1:1) and 2-ethylhexyl dihydrogen phosphate, compound with morpholine (1:2) and bis(2-ethylhexyl) hydrogen phosphate, compound with morpholine (1:1) is used at industrial and professional domains at strictly controlled conditions only, no exposure of the general population to is expected. Therefore, no DNELs for the general population were calculated.