Pentanedioic acid, compd. with (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1:1)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

304 µg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12 500

Modified dose descriptor starting point:

T25

Value:

929 mg/m³

Explanation for the modification of the dose descriptor starting point:

from oral study T25 = 156 mg/kg; 1.176: AF of 100 % absorption by inhalation / 85 % oral absorption; 70 kg body weight; breathing volume of 10 m3 for workers (light activity, 8 h)

AF for dose response relationship:

25

Justification:

10: point of comparison x 2.5: case where the T25 is used instead of the BMDL10

AF for differences in duration of exposure:

0.4

Justification:

5 d/wk, 48/52 wks, 40/75 yrs => 1/2.8

AF for interspecies differences (allometric scaling):

1

Justification:

allometric scaling implicity taken into account (see other interspecies differences)

AF for other interspecies differences:

10

Justification:

remaining differences

AF for intraspecies differences:

5

Justification:

for workers

AF for the quality of the whole database:

1

Justification:

a good oncogenicity study in mice

AF for remaining uncertainties:

10

Justification:

nature of carcinogenic process => default AF

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

86.9 µg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12 500

Modified dose descriptor starting point:

T25

Value:

265 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

0.588: AF of 50 % dermal absorption / 85 % oral absorption

AF for dose response relationship:

25

Justification:

10: point of comparison x 2.5: case where the T25 is used instead of the BMDL10

AF for differences in duration of exposure:

0.4

Justification:

5 d/wk, 48/52 wks, 40/75 yrs => 1/2.8

AF for interspecies differences (allometric scaling):

1

Justification:

allometric scaling implicity taken into account (see other interspecies differences)

AF for other interspecies differences:

10

Justification:

remaining diferences

AF for intraspecies differences:

5

Justification:

for workers

AF for the quality of the whole database:

1

Justification:

a good oncogenicity study in mice

AF for remaining uncertainties:

10

Justification:

nature of carcinogenic process => default AF

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

No threshold effect and/or no dose-response information is available for local and systemic effects caused by acute inhalation and dermal exposure. No DNELs/DMELs for systemic effects due to acute exposure were derived since in the key study on acute oral toxicity the LD50 was greater than 2000 mg/kg bw and the substance is not cassified for actue toxicity according to EU criteria. No DNELs/DMELs for local effects due to acute exposure were derived as the respective skin irritation study did not produce any signs of local irritation.

No mutations were observed in the Ames test at the dose of 5000 µg/plate with and without S9 mix (Lawlor 1993, Williams & Gatehouse 1998). However, the in vivo micronucleus test following OECD guideline 474 produced chromosome damage at 1000 mg/kg/d Abacavir (3 days) (Allen 1996). In 104-week oncogenicity studies with rats and mice (Gardner 2001), statistically significant neoplasic histopathology findings (increased tumour incidence) were made in the high dose group animals, i.e. at 600 mg/kg bw/day in rats and at 330 mg/kg bw/day in mice. The indicative tolerable risks of potential cancerogens for the health hazard information is expressed as the Derived Minimal Effect Level (DMEL). A DMEL was derived from the effect level seen in the oral 104-week oncogenicity study in mice (Gardner 2001) since the quality of data was better than in the oral 104-week oncogenicity study in rats (Gardner 2001).

For DMEL derivation the 'Large Assessment Factor' approach was applied since the mode of action of Abacavir was assumed as clastogenic rather than DNA damaging. The starting point is based on T25 (dose rate that will give 25% of the animals tumours at a specific tissue site) calculated from the data given in the oral 104-week oncogenicity study in mice (Gardner, 2001), where squamous cell carcinoma of preputial gland was observed in 27 out of 51 examined males receiving 330 mg/kg/day Abacavir dose (control 0 out of 50 males). This 53% incidence value was interpolated following ECHA guideline R.8 to 25% incidence value giving a dosis of 156 mg/kg/day Abacavir (calculated for free base). The dose descriptor was modified according to ECHA guideline R.8 before the DMELs for long-term systemic effects were derived for the dermal and inhalation routes. The modified dose descriptor for systemic effects due to long-term dermal exposure was 743 mg/kg bw/day and the overall assessment factor was 12500. The modified dose descriptor for systemic effects due to long-term inhalation exposure was 2601 mg/m3 and the overall assessment factor was 12500.

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

Abacavir glutarate is used as an intermediate in the manufacture of a drug. The substance is consumed in the chemical reactions used in the making of the drug. Release of substance to the environment is strictly avoided. Therefore, the general population will experience neither direct exposure to the susbtance nor indirect exposure via the environment.

With the exception of the acute oral study, all studies were carried out one of the analogue materials, the analogues are considered to be sufficiently similar to the substance of interest (please see attached data matrix and justification in Section 13 for additional details) for them to be used for the purposes of health and environment risk assessments.