Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.5 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):
25
Modified dose descriptor starting point:
NOAEC
Value:
261.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL (90d oral, rat) / [sRV * time] *absorption oral/absorption inhal. * no/light work

= NOAEL / [0.8 L/min/kg bw rat * 8*60 min] *50%/100% * 6.7m3/10m3
= 300 mg/kg bw/d /0.384 m3/kg /2 *0.67 = 261.7 mg/m3

AF for dose response relationship:
1
Justification:
The NOAEL of 300 mg/kg bw/d is the mid-dose of a GLP compliant OECD408 study.
AF for differences in duration of exposure:
2
Justification:
default for subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
default after correction to NOAEC by route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
Justification:
Study according to GLP and OECD TG guideline
AF for remaining uncertainties:
1
Justification:
default
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)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
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):
100
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Worst case: oral = dermal absorption --> dermal NOAEL = 1 * oral NOAEL

AF for dose response relationship:
1
Justification:
The NOAEL of 200 mg/kg bw/d is the mid-dose of a GLP OECD407 study.
AF for differences in duration of exposure:
2
Justification:
default for subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: rat to man
AF for other interspecies differences:
2.5
Justification:
EACH REACH Guidance
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
Justification:
GLP guidline studies
AF for remaining uncertainties:
1
Justification:
EACH REACH Guidance
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)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General considerations

As N-(3-Aminopropyl)-imidazol, CAS 5036-48-6 (API) is classified as Skin Corr. 1B, H314 (CLP EU), it should be attributed to a moderate hazard class according to the Guidance on information requirements and chemical safety assessment, Part E - Risk Characterisation, E.3.4 (ECHA, May 2008). Appropriate RMMs (risk management measures) and OCs (operational conditions) should therefore be implemented, when developing exposure scenarios.

The primary route of anticipated occupational exposure to API is via skin contact. Given its low vapour pressure at room temperature (0.12 Pa), inhalation of API vapour is not likely to be high. As API is used as an additive in polymerization processes, spraying uses can occur. However, the exposition to aerosols or droplets of an inhalable size is rather unlikely due to the operational conditions and risk management measures, protecting against the corrosivity.

Concerning acute toxicity API is moderate toxic after single ingestion (LD50 (oral, rat) > 1780 mg/kg bw). According to the REACh regulation, annex VIII, 8.5 column 2, inhalation or dermal study does not need to be conducted due to the corrosivity of API to the skin. Furthermore, according to the REACh regulation, annex VII+VIII, 8.2 and annex VII, 8.3, column 2 neither an eye irritation / corrosion study nor a skin sensitization study was performed due to the corrosivity.

DNEL derivation: Point of departure

The starting point for the systemic long term inhalation and dermal DNEL is a NOAEL of 300 mg/kg bw/d, obtained by Wistar rats from an oral 90-d study (OECD TG 408 with exposure via gavage; 2019; RL1). The local irritation of the mucosa of the stomach/forestomach in the high dose group (1000 mg/kg bw/d) was considered to be the main effect of the test substance. This might be the reason for the general systemic toxicity (clinical findings, decrased BW gain and grip strength of hindlimbs in males, decrased MA measurements). However, incrased liver weights in the high dose females were also observed and some changes in clinical chemistry (lower total protein, albumin and globulin levels in males and females, higher urea levels in males and higher triglyceride levels in females) indicated a dysregulation of the liver cells.

Supportingly, the NOAEL in an oral 28 -d study was 200 mg/kg bw (OECD407, 1999; RL1) and the maternal NOAEL in an oral OECD414 was 300 mg/kg bw/d (2019; RL1). The developmental NOAEL of this OECD414 study was 1000 mg/kg bw/d. No adverse effects of API were found in an oral OECD421 stud y (2012; RL1) up to the highest dose tested (1000 mg/kg bw).

No local (long term or acute/short term) DNELs and no systemic short term DNELs were derived, because API is classified as Skin Corr. 1B, H314 (GHS EU) and dose-response information is not available (Guidance on information requirements and chemical safety assessment, Part R.8 - Characterisation of dose [concentration]-response for human health; ECHA, v 2.1, November 2012).

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

There are no consumer uses known for API. Thus, no DNELs for the general population were derived.