3-[[3-(dimethylamino)propyl]amino]propiononitrile

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.32 mg/m³

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

132.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

The reproductive toxicity of 3-[[3-(dimethylamino)propyl]amino]propiononitrile was determined using a 2 -generation test design that pre-dates current OECD guidelines but following interpretation the study provided adequate data for use. The NOAEL was determined to be 150 mg/kg bw day, this was also the maximum tested dose.

Since only a sub-chronic oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation routes. 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-inhalation extrapolation. On the assumption, that in general, dermal absorption will not be higher than oral absorption, no default factor is introduced for the oral to dermal extrapolation. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation. This approach will be taken forward to DNEL derivation.

AF for differences in duration of exposure:

2

Justification:

Assessment factor of two included due to extrapolation from a sub-chronic to chronic endpoint

AF for interspecies differences (allometric scaling):

2.5

Justification:

Default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). As described in R.8.4.3.1 Assessment factors relating to the extrapolation procedure of the REACH Guidance

AF for other interspecies differences:

4

Justification:

Assuming body weight of rat 0.250 kg an allometric scaling factor of 4 is applied based on the assumed Human weight of 70 kg (as detailed in Table R8-3 of REACH Guidance on information requirements and chemical safety assessment)

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

Justification:

The database is considered to be of good and there is no need to include an assessment factor.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.6 mg/m³

Most sensitive endpoint:

acute 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

881.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

The acute oral toxicity to the rat was assessed over a 14 -day period, Animals were dosed at 1000, 2150, 2780, 3170, 3590 and 4640 mg/kg bw d. Mortalities occured at doses >1000 mg/kg bw day and the LD50 was determined to be 2284 mg/kg bw/d. Due to a lack of effects at 1000 mg/kg bw day this dose has been used to derive DNEL values for acute/short term exposure.

An toxicity study by the inhalation is not available so a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation routes. 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-inhalation extrapolation.

1000/2 (absorption rate) / 0.38 m3/kg bw = Inhalation NOAEL Rat of 1315.8 mg/m3 (8h)

1315.8 x 0.67 = 881.6 mg/m3

Justification:

Assessment factor for dose response is not required, the NOAEL from a 14-day acute study has been used for derivation of the DNEL/NOAEC. The acute laboratoiy endpoint is considered to reflect the most appropriate endpoint for assessing acute risk.

AF for interspecies differences (allometric scaling):

2.5

Justification:

Default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). As described in R.8.4.3.1 Assessment factors relating to the extrapolation procedure of the REACH Guidance

AF for other interspecies differences:

4

Justification:

Assuming body weight of rat 0.250 kg an allometric scaling factor of 4 is applied based on the assumed Human weight of 70 kg (as detailed in Table R8-3 of REACH Guidance on information requirements and chemical safety assessment)

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

Justification:

The database is considered to be of good and there is no need to include an assessment factor.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 mg/kg bw/day

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The acute dermal LD50 of TK 12271 in rats of both sexes observed over a period of 14 days is greater than 4000 mg/kg, The test material has therefore practically no acute toxicity to the rat by this route of application. Skin irritation was also no observed. As a ong term dermal toxicity study is not available the oral reproductive toxicity endpoint determined using a 2 -generation test design will be used for assessment purposes. The NOAEL was determined to be 150 mg/kg bw day, this was also the maximum tested dose.

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor is introduced for the oral to dermal extrapolation. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation. However, based on the log Kow of 0.492 and molecular weight of the substance (155.24), the skin permeability according to Fitzpatrick et al (2004) of the substance is considered to be slightly permeable to the skin based on a calculated Log skin permeation coefficient of -4.18. Therefore, a ratio of 0.5 for oral to dermal absorption is provisonally suggested for DNEL derivation.

Modified dose descriptor (dermal) = 150/0.5 (skin absorption rate for slightly permeable substance) = 300 mg/kg bw

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

2.5

Justification:

Default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). As described in R.8.4.3.1 Assessment factors relating to the extrapolation procedure of the REACH Guidance

AF for other interspecies differences:

4

Justification:

Assuming body weight of rat 0.250 kg an allometric scaling factor of 4 is applied based on the assumed Human weight of 70 kg (as detailed in Table R8-3 of REACH Guidance on information requirements and chemical safety assessment)

AF for intraspecies differences:

5

Justification:

For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

Justification:

The database is considered to be of good and there is no need to include an assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Explanation for the modification of the dose descriptor starting point:

The results of three acute (14-day) dermal tests indicated that slight irritation accured at concentrations >4000 mg/kg bw day based on the professional use pattern of the substance acute exposure to high concentrations is unlikely and therefore the risk management measures enforced based on the long term DNEL are considered adequate for protection against acute hazard/exposure.

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

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 "Guidance on information requirements and chemical safety assessment, Part B: Hazard Assessment", above 10 t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on long-term exposure is normally sufficient to ensure that adverse effects do not occur. Thus, acute DNELs should default to the long term systemic DNELs.

For local effects, a DNEL was not quantifiable; however, as the substance is classified as Cat 1 for eye damage and as Cat 2 skin irritant and, local effects must be assessed qualitatively and risk management measures applied as necessary. The potential for respiratory sensitization is unknown; however, given its skin sensitization potential, this endpoint also is assessed qualitatively.

 

Long-term toxicity:

A two-generation reproduction study is available. A NOAEL of 150 mg/kg bw was determined this was the maximum tested concentration and used to derive the DNEL.

 

Since only a sub-chronic 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. On the assumption that, in general, dermal absorption will not be higher than oral absorption, The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation. However, based on the log Kow of 0.492 and molecular weight of the substance (155.24), the skin permeability according to Fitzpatrick et al (2004) of the substance is considered to be slightly permeable to the skin. Therefore, a ratio of 0.5 for oral to dermal absorption is provisonally suggested for DNEL derivation

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

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:

no hazard identified

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

The substance is not intended to be marketed for consumer use.‬