N-acetylhexanelactam

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.47 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):

120

Dose descriptor starting point:

LOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

176.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

In accordance with ECHA REACH TGD R8 and ECETOC technical report 110 Inhalation long-term systemic DNEL based on NOAEL (OECD 407 and OECD 421, oral) in rats: Wheras a NOAEL of 1000 mg/kg bw/day could be derived from a subacute repeated oral dose study in rats, a NOAEL of 300 mg/kg bw/day for males and no NOAEL for

females could be derived from the OECD 421 screening study, due to effects seen in dams of the low dose (i.e. 100 mg/kg bw). Acc to ECHA guidance, the OECD 421 study was used for DNEL derivation as this repeated dosing regimen provides the lowest effect level.

Following effects were described for females at OECD421 study:

Changes observed in females include severe clinical signs and mortality at ≥ 300 mg/kg Bwt/day females. Further, clinical signs, decreased body weight, food consumption and reticulocytes count at 1000 mg/kg Bwt/day, gross pathological changes such as not prominent/small thymus, small spleen, and multiple focus and/ or thickening in glandular/non-glandular stomach at ≥100 mg/kg Bwt/day were observed. Microscopically, atrophy of thymus and mucosal necrosis/epithelial hyperplasia/leukocytic infiltration-sub mucosa-glandular and/or nonglandular in stomach at ≥ 100 mg/kg Bwt/day and atrophy/ decreased red pulp cellularity in spleen at ≥ 300 mg/kg Bwt/day were observed. Based on these observations, the no observed adverse effect level (NOAEL) for maternal toxicity could not be determined. The LOAEL (lowest observed adverse effect level) of 100 mg/kg Bwt/day is derived.

Thus, taking into account the effects seen in females of the OECD 421 the LOAEL of 100 mg/kg bw/day is considered the most appropriate starting point.

- LOAEC (inhalation derived according to ECHA Guidance TGD R8: "Guidance on information requirements and chemical safety assessment", Chapter R.8.4.2, Figure R.8-3)

corrected LOAEC(inhalation) = LOAEL(oral,rat) *1 / sRVrat * ABS(oral-rat)/ABS(inhalation-human) * sRVhuman / wRV

= 100 mg/kg * 1/0.38 m3/kg/d x 100% /100% * 6.7 m3 /10 m3

= 176.3 mg/ m3

(with sRV: standard respiratory volume; ABS: Absorption; wRV: worker respiratory Volume)

AF for dose response relationship:

10

Justification:

according to ECETOC technical report 110; the LOAEL is considered the most appropriate starting point.

AF for differences in duration of exposure:

4

Justification:

According to ECHA TGD and ECETOC technical report 110. Treatment of females of the OECD 421 study, lasted at least about 48 to 60 days (i.e. 14 days premating, 1 to14 days mating, 22 days gestation plus 13 days lactation), which is about two third of a 90 day sub-chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

according to ECETOC technical report 110; ECHA REACH TGD; Allometric scaling is not applied. Factor of 2,5 for interspecies difference is included in the calculation by correcting the respiratory volumes of rat and man.

AF for other interspecies differences:

1

Justification:

according to ECETOC technical report 110; ECHA REACH TGD; Allometric scaling is not applied. Factor of 2,5 for interspecies difference is included in the calculation by correcting the respiratory volumes of rat and man.

AF for intraspecies differences:

3

Justification:

ECHA REACH TGD. Findings in pregnant rats of the OECD 421 study already considered with the LOAEL, indicating this group as the most sensitive population.

AF for the quality of the whole database:

1

Justification:

ECHA REACH TGD and ECETOC technical report 110

AF for remaining uncertainties:

1

Justification:

ECHA REACH TGD and ECETOC technical report 110

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.47 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):

120

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.47 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

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:

0.42 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):

480

Dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Worker:

The test substance is not a skin sensitizer nor irritating to skin. The LD 50 dermal is > 2000 mg/kg bw. In accordance with ECHA REACH TGD R8 and ECETOC technical report 110 dermal long-term systemic DNEL is based on NOAEL (OECD 407 and OECD 421, oral) in rats: Whereas a NOAEL of 1000 mg/kg bw/day could be derived from a subacute repeated oral dose study in rats, a NOAEL of 300 mg/kg bw/day for males and no NOAEL for females could be derived from the OECD 421 screening study, due to effects seen in dams of the low dose (i.e. 100 mg/kg bw). According to ECHA guidance, the OECD 421 study was used for DNEL derivation as this repeated dosing regimen provides the lowest effect level.

Following effects were described for females at OECD421 study:

Changes observed in females include severe clinical signs and mortality at ≥ 300 mg/kg Bwt/day females. Further, clinical signs, decreased body weight, food consumption and reticulocytes count at 1000 mg/kg Bwt/day, gross pathological changes such as not prominent/small thymus, small spleen, and multiple focus and/ or thickening in glandular/non-glandular stomach at ≥100 mg/kg Bwt/day were observed. Microscopically, atrophy of thymus and mucosal necrosis/epithelial hyperplasia/leukocytic infiltration-sub mucosa-glandular and/or non-glandular in stomach at ≥ 100 mg/kg Bwt/day and atrophy/ decreased red pulp cellularity in spleen at ≥ 300 mg/kg Bwt/day were observed. Based on these observations, the no observed adverse effect level (NOAEL) for maternal toxicity could not be determined. The LOAEL (lowest observed adverse effect level) of 100 mg/kg Bwt/day is derived.

Thus, taking into account the effects seen in females of the OECD 421 the LOAEL of 100 mg/kg bw/day is considered the most appropriate starting point.

- LOAEL (dermal) derived according to ECHA Guidance TGD R8: "Guidance on information requirements and chemical safety assessment", Appendix R.8-2, Example B.5

corrected LOAEL(dermal) = LOAEL(oral,rat) * Absorption(oral, rat)/Absorption (dermal, human)

= 100 mg/kg bw * 100% / 50%

= 200 mg/kg bw

AF for dose response relationship:

10

Justification:

according to ECHA REACH TGD R8 and ECETOC technical report 110. The LOAEL is considered the most appropriate starting point.

AF for differences in duration of exposure:

4

Justification:

according to ECHA REACH TGD R8 and ECETOC technical report 110. Treatment of female rats of the OECD 421 study, lasted at least about 48 to 60 days (i.e. 14 days premating, 1 to14 days mating, 22 days gestation plus 13 day lactation), which is about two third of a 90 day sub-chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

according to ECHA REACH TGD R8 and ECETOC technical report 110; Allometric scaling from rat to human => factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration

AF for other interspecies differences:

1

Justification:

according to ECHA REACH TGD R8 and ECETOC technical report 110: factor of 2.5 for remaining interspecies differences not taken but included into intraspecies variability consideration

AF for intraspecies differences:

3

Justification:

according to ECHA REACH TGD R8 and ECETOC technical report 110; Findings in pregnant rats of the OECD 421 study already considered with the LOAEL, indicating this group as the most sensitive population.

AF for the quality of the whole database:

1

Justification:

according to ECHA REACH TGD R8 and ECETOC technical report 110: Good /standard quality of database

AF for remaining uncertainties:

1

Justification:

according to ECHA REACH TGD R8 and ECETOC technical report 110: Good /standard quality of database

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

DNEL extrapolated from long term DNEL

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:

low hazard (no threshold derived)

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

DNEL extrapolated from long term DNEL

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

DNEL extrapolated from long term DNEL

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

DNEL extrapolated from long term DNEL

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

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

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