N,N-dibutylformamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

182 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study is available. Therefore, the DNEL is derived on basis of observed maternal toxicity in a prenatal developmental toxicity study in the rabbit.

Modification into a correct starting point:  

- Relevant dose descriptor (NOAEL): 125 mg/kg bw/day

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

- Standard respiratory volume of the rabbit (sRVrabbit) for 8 hours: 0.23 m³/kg bw/d

- Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

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

- Corrected NOAEC (inhalation) for workers: 125 mg/kg bw/day × 0.5 × (1 / 0.23 m³/kg bw/day) × (6.7 m³/10 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:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

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 prenatal developmental 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.

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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

180

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction to dose descriptor starting point: NOAEL (oral, rabbit) * 100% dermal resorption (worst case) = 125 mg/kg bw/d * 1

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:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

2.4

Justification:

The default allometric scaling factor for the differences between rabbits 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 prenatal developmental 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.

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:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium 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). The substance is produced under strictly controlled conditions. Transfers, storage tanks, processing equipment and sealing system are all operated in fully closed systems. Exposure is limited to sampling tasks for quality control under strictly controlled conditions (limited exposure probability). Only a small, well-defined and trained group of workers may be exposed occasionally to low levels using appropriate risk management measures to minimize exposure. Therefore, systemic DNELs were calculated only for workers, which is a sufficient conservative approach.

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 studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects. Therefore, it will be necessary to obtain a long-term inhalatory DNEL by route-to route extrapolation.

PoD and most sensitive endpoint: maternal NOAEL (study similar to OECD TG414, oral, rabbit) = 125 mg/kg bw/day

In the OECD 414 guideline similar prenatal developmental toxicity study, the test substance was administrated daily orally to Himalayan rabbits over an exposure time of 13 days from day 6 through day 18 post insemination. Doses of 62, 125, 250 mg/kg bw/day were used.  Maternal toxic effects were not recorded in animals at 62 and 125 mg/kg bw/day. Thus, a NOAEL of 125 mg/kg bw/day was used for risk assessment and calculation of DNEL. The test substance showed a slight maternal toxicity in the highest dose level. Substance-related embryo- or fetotoxicity was not seen in all three dose levels. The NOAEL for prenatal developmental toxicity including teratogenicity was determined to be 250 mg/kg bw/day (1984).

Acute, systemic DNEL- exposure via inhalation (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, "a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute inhalation toxicity. Therefore, a DNEL is not required.

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

A qualitative approach has to be implemented to deal with the serious eye damage as well as skin corrosive properties of the substance. As a result, a medium hazard is derived.

Dermal

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

A dermal prenatal developmental study in rats was published (Stula et al., 1977). However, there is no clear maternal NOAEL in this publication and the doses (1200 and 600 mg/kg bw/d, given once or twice) are well above the NOAEL of 125 mg/kg bw/d from the prenatal developmental study in rabbits (1984). Therefore, it is necessary to obtain a long-term dermal DNEL by route-to route extrapolation.

PoD and most sensitive endpoint: maternal NOAEL (study similar to OECD TG 414, oral, rabbit) = 125 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

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

A qualitative approach has to be implemented to deal with the serious eye damage as well as skin corrosive properties of the substance. As a result, a medium hazard is derived.

Hazard to the eye-local effects (worker)

The test item is classified as skin corrosive and for eye damage (Cat. 1, H314) according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (medium hazard).

 

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 N,N-Dibutylformamide (DBF) is used at industrial domains at strictly controlled conditions only, no exposure of the general population to is expected. Therefore, no DNELs for the general population were calculated.