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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
57.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
6
Dose descriptor starting point:
NOAEL
Value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
346.7 mg/m³
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
24
Dose descriptor starting point:
NOAEL
Value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
239.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction for differences between human and experimental exposure conditions is needed.

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
277 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
7.2
Dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day

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)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

For 2 -pyrrolidone, DNELs are needed for chronic exposure by the inhalation and dermal exposure routes. Since 2 -pyrrolidone does not represent an acute hazard (not classified for acute toxicity), no DNELs need to be derived for these endpoints. No DNELs are needed also for local effects because there is no dose-response and route-specific information for these endpoints. Long-term systemic DNEls will cover sufficiently all local effects.

From all available data for the different human health endpoints it is clear that 2 -pyrrolidone exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived from the available toxicity data of 2 -pyrrolidone, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.There are following annotations for each endpoint:

o  2 -pyrrolidone does not show acute hazard by all routes of exposure and therefore is not classified for acute toxicity. DNELs for acute toxicity (systemic dermal) is derived only for comparison with single events. In this case, a LD50 value of 2000 mg/kg bw established in a dermal acute study in rabbits (MB Research Laboratories, Inc., 1992) is identified as a NOAEL because of no mortalities, no systemic signs of toxicity or signs of irritation were observed in treated animals after 24h occlusive application of the test substance.

o   Acute DNELs for inhalation (systemic and local) are not necessary since 2 -pyrrolidone is not toxic by inhalation (BASF, 1961, XI/407). Furthermore, inhalation is not the relevant route of exposure. The DNEL for acute toxicity inhalation (systemic) is derived only for comparison with some single events such as saturated atmosphere.

o  A qualitative approach in hazard assessment for eye and skin irritation/corrosion and skin sensitization is used because no dose descriptors are available on these endpoints.

o  For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No-Effect Level could not be established from the relevant studies. Hence, the hazard characterization is based on a qualitative approach.

o  There is no animal data on repeated dermal and inhalation exposures. To cover these endpoints, data from an oral sub-chronic drinking water study in rats (BASF, 1998, 52S0014/92038) has been used to calculate the long-term DNELs.

First of all, available dose descriptors were converted into a correct starting point to take into account differences in routes of exposure between experimental animals and humans and differences in human and animal exposure conditions. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

The assessment factors are applied in accordance with ECETOC Technical Report No 86, referenced in Table R.8-19 of ECHA guidance document.

Modification of the relevant dose descriptors to the correct starting point:

Bioavailability (absorption)

Midgley et al. reported that absorption of 2 -pyrrolidone in rats was 95% after oral administration and 82% after dermal administration in female animals (Midgley at al, 1992). These values are taken for correction of the starting point. Dermal absorption in rats and humans is assumed to be the same since no information for dermal absorption in humans available. For inhalation, 100% absorption is assumed in humans (worst case).

Route-to-route extrapolation:

o Oral-to-dermal and oral-to-inhalation extrapolations are performed to assess long-term dermal and inhalation effects in humans.

Exposure conditions:

o  Exposure time differed in the oral repeated dose drinking water study. 24 h free access to drinking water with the test substance is the exposure time in the animal study. Therefore, the dose descriptor (the NOAEL of 207 mg/kg bw) was adjusted to 8h exposure relevant for workers by multiplication of the NOAEL by a factor 24/8.

Respiratory volumes:

o  Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the sub-chronic drinking water study was used to assess inhalation exposure in humans. 0.38 and 1.15 m³/kg bw are the standard respiratory volumes in rats during 8h and 24h exposure, respectively. 6.7 and 10 m³ are standard respiratory volumes under normal conditions and by light activity for workers.

Applying of assessment factors:

Interspecies differences:

o  The species-specific default assessment factors of 2.4 and 4 for allometric scaling for rabbits and rats, respectively are applied in case of dermal-to-dermal, and oral-to-dermal extrapolation.

o  No allometric scaling factor is applied in case of oral-to-inhalation extrapolation.

o  No additional assessment factors are applied for remaining interspecies differences.

 

Intraspecies differences

o  Assessment factor of 3 is applied for workers for all endpoints and all exposure routes.

Extrapolation of duration:

o  an assessment factor of 2 was applied in case of sub-chronic to chronic extrapolation.

 

Quality of whole data base:

o The assessment factor for uncertainties to the quality of the data base is regarded to be 1.

 

Issues related to dose response:

o  factor of 1.

Calculation of endpoint-specific DNELs for workers

Acute/short-term exposure systemic dermal

A dermal DNEL is calculated from the dermal acute study in rabbits in which a LD50 of 2000 mg/kg bw was established (MB Research Laboratories, Inc., 1992) No mortality nor clinical signs indicates that LD50 is equivalent a NOAEL. No modification of the starting point is necessary. Dermal absorption is assumed to be the same in rabbits and humans (worst case).

DNEL = 2000 /(2.4 x 3) = 277 mg/kg bw. AFs are: 2.4 (interspecies, rabbit to human), 3 intraspecies (workers). No AF for study duration (acute study and derivation of an acute DNEL for humans).

Acute/short-term exposure systemic inhalation

A LC0 of 61 mg/m³ was established in the 8 h acute inhalation study with rats (BASF AG, 1961; Report No. XI/407). No mortalities occurred during the study. Except intermittent agitation, no clinical signs of toxicity were noted in treated animals. Necropsy revealed no findings. On the basis of intermittent agitation, LC0 is identified as LOAEC. LOAEC has been modified for the differences in respiratory volumes in workers under normal conditions and by light activity:

1. Corrected LOAEC = rat LOAEC x (6.7/10) m³ = 61 mg/m³ x (6.7/10)m³ = 40.87 mg/m³

2. DNEL = 40.87 mg/m³/(3 x 3) = 4.54 mg/m³. AFs are: 3 -intraspecies, 3 - LOAEC to NOEC

Such a DNEL is high uncertain because the value is lower than that for the long-term effects.

Another way, DNEL can be derived from an acute oral study, where a LD50 of greater than 2000 mg/kg bw was established (SafePharm, 1999). Incidences of hunchered posture were observed in the treated animals, which disappeared after one or two days after treatment. Neither clinical abnormalities nor findings by gross pathology were noted. LD >2000 mg/kg bw is considered to be a LOAEL.

1. Corrected LOAEC = oral rat LOAEL x (1/0.38m³) x (ABS oral-rat/ABS inh-human) x (6.7/10)m³ = 2000 mg/kg bw x (1/0.38m³) x (95%/100%) x (6.7/10)m³ = 3.350 mg/m³.

2. DNEL = 3.350 mg/m³/(3 x 3) = 372 mg/m³. AFs are: 3 - intraspecies, 3 - LOAEL to NOEL.

Such a procedure is discouraged and obtained DNEL is high uncertain because it represents 8 hour frame. In case of extrapolation to shorter period (acute DNEL should usually be calculated for 15 min), the DNEL will rise, to a value which in reality will never be reached (technically not achievable concentration). So, the long-term DNEL is sufficient to cover acute exposures.

Long-term exposure - systemic effects (dermal)

Repeated dose toxicity sub-chronic drinking water study in rats (BASF, 1998, 52S0014/92038) was taken for the DNEL derivation:

1. Corrected NOAEL = oral rat NOAEL x (ABS oral-rat/ABSdermal-rat) x (ABS dermal-rat/ABS dermal-human) = 207 mg/kg bw x 95%/82% x 82%/82% = 239.8 mg/kg bw, where 95% is oral absorption in rat and 82% is dermal absorption in female rat. There is no human value for dermal absorption available therefore dermal absorption in rats is assumed to be the same in humans.

2. DNEL = 239.8 mg/kg bw /(4 x 3 x 2) = 10.0 mg/kg bw/day. AFs are: 4 -interspecies, 3 - intraspecies, 2 -sub-chronic-to-chronic.

Long-term exposure - systemic effects (inhalation)

Repeated dose toxicity sub-chronic drinking water study in rats (BASF, 1998, 52S0014/92038) was taken for the DNEL derivation:

1.Corrected NOAEC = oral rat NOAEL x (1/0.38m³) x (ABS oral-rat/ABS inh-human) x (6.7/10)m³ = 207 mg/kg bw x (1/0.38m³) x (95%/100%) x (6.7/10)m³ = 346.7 mg/m³.

2. DNEL = 346.7 mg/m³/ (3 x 2) = 57.8 mg/m³. AFs are: 3 - intraspecies; 2 sub-chronic-to-chronic.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEL
Value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
171 mg/m³
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:
DNEL (Derived No Effect Level)
Value:
6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
Value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
239.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction for differences between human and experimental exposure conditions is needed.

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
167 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
12
Dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day

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:
DNEL (Derived No Effect Level)
Value:
5.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
Value:
207 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
207 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction for differences between human and experimental exposure conditions is needed.

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
33.3 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
60
Dose descriptor starting point:
LOAEL
Value:
2 000 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction for differences between human and experimental exposure conditions is needed.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are some deviations:

o  A higher assessment factor of 5 (in place of 3 for workers) for intraspecies variation/differences of human population was taken (refer to Table R.8-19, ECETOC values).

o  No differences in the respiratory volumes under normal conditions and by light activity in human was taken into account.

o  The conversion of the repeated oral rat NOAEL into inhalation NOAEC was performed as follows:

Corrected inhalation NOAEC = oral rat NOAEC x (1/1.15 m³/kg bw/day x (ABS oral-rat/ABS inhal-human),where 1.15 is standard respiratory volume (m³/kg bw) of rats during 24 h exposure, ABS is absorption (values are the same as described for workers).

o No correction in exposure duration per day was performed (administration of drinking water to rats was 24 hours and exposure for consumers is also 24 hours).