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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
DNEL derivation method:
other: The DNEL is derived from the results of the 28-day cell proliferation test with a NOEC of 0.2 ppm, which is about 25-fold below the LOAEC in the carcinogenicity study and 5-fold below the overall NOAEC from all classical subchronic studies.
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
2.5
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor:
other: NOAEC of 0.2 ppm (0.92 mg/m3) for histological findings in nasal cavity
AF for intraspecies differences:
3
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
2.5
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.014 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

N-Vinylpyrrolidone-2 (NVP) was pronouncedly carcinogenic in a rat 24 months inhalation study at all 3 air-borne concentrations investigated, namely 5, 10, and 20 ppm, and in a concentration-related incidence (Klimisch et al. 1997 a). For this long-term study the most sensitive animal strain (Sprague-Dawley rats) had been selected from a number of prechronic studies in rats and mice (Klimisch et al., 1997 b; see also chapter 7.5.) Malignant tumors were found in liver, larynx and nasal sinuses. Liver tumors have also been obtained in a stop-experiment with a limited exposure phase of 45 ppm NVP for 3 months and a post-observation period of 21 months. In the preceeding subchronic experiments NVP had shown liver toxicity from 10 ppm onwards but no clear effects at 5 ppm; inflammatory and hyperplastic responses in the nasal tissues were seen at 5 ppm but not at 1 ppm.

 

A DMEL may be calculated from the tumor incidences in the different dose groups by means of a linear low dose extrapolation. At 5 ppm there were still 19/120 animals with exposure-related tumors at the end of the study (appr. 16%). 3 ppm may be associated with an appr. 10 % tumor risk which would indicate a risk of 1:1000 at 0.03 ppm. On the other hand, there is also experimental evidence for non-linear elements in the dose-response relation which indicates that the factual risk of exposure levels in the range of 0.03 ppm should be considerably lower and probably remote.

The existing genotoxicity studies did not demonstrate a genotoxic effect of NVP. It is, however, assumed that NVP may under certain circumstances release acetic aldehyde which is a pronouncedly mitogenic and under certain circumstances also clastogenic agent. However, the carcinogenic potential of NVP appears to be stronger than that of acetic aldehyde (Woutersen et al., 1986). This may be explainable by a higher intracellular bioavailability of acetic aldehyde if released from NVP with a metabolically competent target cell.

For further investigation of the effects of NVP on cell proliferation/apoptosis in the liver and histological changes in the nasal cavity of rats, eight male Wistar rats per test group were whole-body exposed to vapor on 6 hours per day, 5 days a week for up to 28 days (BASF, 2011/2012). The target concentrations from NVP were 0.5, 1, 5 and 10 ppm. Control animals were exposed to conditioned air. To determine the time course of liver cell proliferation during the 4 week exposure period, satellite animals were sacrificed on study day 7, whereas the main group animals were sacrificed on study day 28. For each examination time point, a concurrent control group was conducted. BrdU minipumps were implanted 7 days before necropsy. On exposure days clinical examination was performed before, during and after exposure. Body weight of the animals was determined once prior to preflow, on start of exposure, once a week during exposure period and before necropsy. Animals were necropsied and the liver was investigated for cell proliferation and apoptotic cell death by BrdU staining and TUNEL labeling. The histological examination of the nasal cavity of main group animals was performed after hematoxylin and eosin stain (H&E) by light microscopy.To establish a No Observed Adverse Effect Concentration (NOAEC) two additional groups were exposed to 0.2 and 0.5 ppm test substance to a later time point. For the later two groups, a concurrent control group was exposed to conditioned air.The desired atmospheric concentrations were maintained throughout the study. There were no clinical signs of toxicity observed throughout the study. At the highest concentration of 10 ppm, the body weight change was significantly reduced from study day 7 onward (not significant on study day 21). This effect indicates the slight general toxicity of the test substance and was considered to be an exposure–related adverse effect. Concerning the determination of cell proliferation (S-Phase response), 7-day exposure with the test article led to an increased cell proliferation already at a concentration of 1 ppm and, with a concentration-dependent enhancement, at concentrations of 5 ppm and 10 ppm. No increased cell proliferation was noted when exposed with a concentration of 0.2 ppm.Concerning the determination of apoptosis (TUNEL stain), 7-day exposure with the test article led to an increased apoptotic cell death at concentrations of 1 and 5 ppm. 28-day exposure with the test article led to an increased apoptotic cell death at concentrations of 1, 5 and 10 ppm. This increase is interpreted as a secondary, counter balancing induction of apoptosis due to the primary induction of cell proliferation. Exposure with a low concentration of 0.2 ppm of the test substance over a period of 28 days resulted in no increased apoptotic cell death. Treatment-related findings were noted in level I of the nasal cavity in animals at concentrations of 0.5 to 10 ppm.In level II, III and IV of the nasal cavity, findings were noted in all animals only at the highest concentration (10ppm). In level II, degeneration of the respiratory epithelium, degeneration of the olfactory epithelium, hyperplasia of the respiratory, olfactory and transitional epithelium and squamous metaplasia of the respiratory epithelium was found. These findings were graded minimal to slight. In level III and IV, degeneration of the olfactory epithelium was seen in most animals and hyperplasia of the basal cells of the olfactory epithelium was also seen in all animals of this group (10 ppm), mostly graded minimal to slight. There were no substance-related findings observed at 0.2 ppm (NOAEC).

In conclusion, the NOAEC for liver cell proliferation/apoptosis and histological changes in the nasal cavity was determined to be 0.2 ppm.

This concentration is about 25-fold below the LOAEC in the carcinogenicity study and 5-fold below the overall NOAEC from all classical subchronic studies.

In a kinetic study in dogs, NVP was detectable in the serum at the end of a 6 hrs exposure phase from 1 ppm onwards but not at 0.1 ppm (BASF, 1992). This experiment indicates that NVP is rapidely eliminated at 0.1 ppm. Dose levels which are not eliminated within the exposure time (> 0.1 ppm over 6 hrs) are considered to be more prone to certain saturation phenomena such as parent substance accumulation, enzyme induction and / or onset of adverse effects.

The NOEC from the cell proliferation study (0.2 ppm; about 1 mg/m3; BASF 2011/2012) was taken as a factual NOAEC also for carcinogenicity and as a point of departure for the DNEL calculation. 0.2 ppm were divided by a factor of 3 in order to extrapolate from 28 days to a chronic exposure time. This factor 3 is considered to be sufficient since already the differences on the LOAEC and NOAEC levels between 7 and 28 days were not more than 2 - 2.5. A further factor of 3 for interindividual variation is proposed. This is considered to be sufficient since already the most sensitive animal strain had been selected from several prechronic studies. Both factors multiplied would result in an overall approximate assessment factor of 10 and in a proposed chronic inhalation DNEL of 0.1 mg/m3. This chronic inhalation DNEL for systemic effects does also cover the DNEL for long term local effects (0.3 mg/m3; based on the NOAEC of 0.2 ppm (0.92 mg/m3) for histological findings in nasal cavity and a factor of 3 for interindividual variation and without a further time extrapolation factor).For short exposure times (15 min, 4 times a day) a short-term DNEL of 0.4 mg/m3 is proposed. This level of short-term exposure results in a total uptake during the working shift that is one-half of the 8 hour time-weighted average (TWA) DNEL, assuming no other exposures during the shift.

Dermal exposure should be minimized due to the irritating properties and the inherent carcinogenicity of the material. For systemic toxicity, a dermal DNEL can be derived using the systemic long term inhalation DNEL of 0.1 mg/m3 as the starting point such that an equivalent internal dose results and assuming 100% of the external dose is absorbed. On this basis, a dermal DNEL for chronic systemic toxicity of 0.014 mg/kg-bw/day has been derived by correcting the units of the starting point (m3 to L), multiplying by a 480 minute workday, and then multiplying by a default inhalation rate (for light work) of 0.3 lpm/kg-bw-day from the ECHA R.8 guidance document (May 2008). Short-term dermal DNELs have not been derived on the basis that the substance is a carcinogen and data are not sufficient from which to derive reliable short-term DNELs for this route of exposure.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

No general population DNELs/DMELs are proposed since there is no designed exposure of the general public towards this material.