1-methyl-2-pyrrolidone

Endpoint summary

Description of key information

NMP is suggested to be rapidly absorbed orally and dermally. A good absorption via inhalation is also described in literature (further information are given in the "Toxicokinetics" chapter).

The principal metabolite of NMP was found to be 5 -HNMP. Besides, a good correlation between NMP and 2-HMSI is discussed in various studies.

In occupational case reports irritational effects and/or headaches or unspecific symptoms (e.g. fatigue) after direct contact at workplaces (paint strippers, graffiti removers, workers gluing packages at a circuit board factory) are described. In some cases, the irritating symptom did lead to contact dermatitis. These observations are taken into consideration together with the animal results for the classification of NMP on respiratory irritation.

However, no respiratory irritation or headaches are described in volunteer studies under controlled conditions (Bader 2003, Bader 2006/2007/2008 van Thriel 2007, Johnsson 2003). There were only olfactory mediated health symptoms described by individuals in these studies.

In the key study van Thriel (van Thriel et al., 2007) described air concentrations of up to 160 mg/m3 that caused no adverse sensory irritation or undue annoyance. These findings are the basis for the joint opinion of RAC and SCOEL for N-Methyl-2 -Pyrrolidone from 30 November 2016 to define a NOAEC for chemosensory effects and thus an OEL for acute local irritation effects.

Additional information

Irritancy

There are several observatory studies in human specifically at workplaces discussed in literature concerning local irritation. Human case reports support this observation. Following the recommendation of the 'Joint Opinion to resolve differences in scientific opinion as regards exposure levels for N-Methyl-2-Pyrrolidone' by the ECHA RAC and SCOEL from 2016, the chemosensory irritation effects of the studies from Baders and van Thriel (Bader et al. 2006/2007/2008, van Thriel et al., 2007) are considered as being adverse and local irritation is defined as the most critical effect. However, for RAC irritation effects are not demonstrated in animal studies (refer to the chapters Acute toxicity, Irritation/corrosion, Repeated dose toxicity and Toxicity to reproduction).

Leira and co-workers reported development of skin irritancy and contact dermatitis in 10/12 workers exposed to NMP 8 hours a day for 2 days (Leira et al., 1992). Åkesson & Jönsson observed redness, swelling and thickening and vesiculation of the skin in workers in the paint-stripping industry coming into contact with NMP (Akesson and Jonsson, 2000), while irritant contact dermatitis was seen in three workers newly exposed to NMP; this was attributed to a hygroscopic effect of the solvent on the stratum corneum (Jungbauer et al. 2001).

Biomonitoring

Exposure to NMP can be evaluated by combining standard toxicokinetic methodologies with measurements of the level of 5-hydroxy-N-methyl-2-pyrrolidone (5 -HNMP), the principal metabolite of NMP, in plasma or urine. There is also a very good correlation between NMP exposure and the metabolites N-methylsuccinimide (MSI) and 2-HMSI (Akesson and Paulsson, 1997; Jonsson and Akesson, 2003; Akesson and Jonsson, 2000; Jonsson and Akesson, 2001; Anundi et al., 2000; Meier et al., 2013; Haufroid et al., 2014).

Within the frame work of an occupational field study, individual exposures to NMP were investigated in 7 workers and 3 scientific co-workers, who used a cleaner containing NMP to remove resin from mixing drums and tools. The average NMP concentration in the ambient air was about 3 mg/m³ in the mixing area with short-term peak concentrations of up to 19 mg/m³ in the vicinity of the cleaning activity. The average post shift urinary concentration of NMP was 0.27 mg/L (< 0.01 – 1.4 mg/L) or 0.21 mg/g creatinine (0.10 – 0.71 mg/g creatinine); the average urinary 5-HNMP concentration was 45 mg/L (4 – 241 mg/L) or 28 mg/g creatinine (4 – 128 mg/g creatinine). None of the exposed workers reported symptoms such as respiratory irritation or headache. Air measurements and biomonitoring results were comparable to those reported by other working groups (Akesson and Jonsson, 2000; Anundi et al., 2000). Furthermore, it was demonstrated that dermal absorption accounts for the majority of the internal NMP burden (Bader et al., 2003).

A representative end user exposure to NMP was investigated in 4 male volunteers during paint stripping of furniture using a commercial product containing NMP (19 %), limonene (< 1 %), and dibasic ester (75 %). The air concentrations of NMP during the 2 – 3 hour exposure period averaged between 0.4 – 3.8 mg/m³. As an indication of dermal and inhalation uptake, the maximum urinary levels of NMP and 5-HNMP were 0.11 mg NMP/L and 7.4 mg 5-HNMP/L, respectively. Valid values for 2-HMSI could not be obtained (BASF SE, 2003).

In the UK, the occupational respiratory and dermal exposure to NMP was analyzed during different procedures of graffiti removal (brushing on, spraying off, wiping on and off) and dipping for paint stripping. 28 volunteers provided urine samples. The cleaning agents used for graffiti removal contained 10 % – 30 % NMP. The dipping tanks for paint stripping contained up to 90 % NMP. The average NMP concentration in air during graffiti removal was 0.24 mg/m³ (0.008 – 30 mg/m³); during dipping the average was 0.033 mg/m³ (0.006 – 5.7 mg/m³). The levels of 5-HNMP in the urine varied considerably (< limit of detection – 47.4 mmol/mol creatinine corresponding to 48.2 mg/g creatinine at maximum). These variations reflect the large differences in dermal NMP uptake associated with the various removal procedures. PBPK modeling showed that inhalation exposures alone could not account for the systemic bioavailability of NMP, indicating that dermal absorption also played a role in the uptake process. However, the nature of the occupational settings of this study made it difficult to monitor exposures to NMP over the whole working day.This was especially the case for graffiti removal where workers were visiting multiple sites during the course of the day (Health and Safety Laboratory, 2003¸ Akrill et al., 2002).

Recently, the effect of internal glove contamination was investigated and showed that the main routes were found to be self contamination, cuff entry and failed gloves. Wearing internally contaminated gloves led to a higher systemic absorption than was gained from the equivalent skin contamination when not wearing gloves. Repeat wetting of fingers with aqueous NMP, when gloves were not worn, gave higher systemic absorption than the equivalent continuous exposure, probably due to the low volatility of NMP leading to increased concentration and longer residence time on the skin (Rawson et al., 2005).

A cross-sectional study was carried out between 2006 and 2011 in northeast Switzerland including 21 firms representing a large spectrum of activities and 91 workers exposed to NMP. The external and internal exposure to NMP was investigated. Airborne NMP was collected by personal sampling over a whole workday. Urinary 5-HNMP and 2-HMSI were examined for assessing an occupational exposure to NMP and to look for health effects. Urinary metabolites correlated very well with the airborne NMP concentrations, although these concentrations were low. At the low levels found in this study, no irritation, renal, haematological or neurobiological effects could be found (Haufroid et al., 2014).

In another study the NMP exposure in the spraying department of an automobile plant using biological monitoring was investigated.Two specific metabolites, 5-HNMP and 2-HMSI, were analyzed in 69 urine samples of 14 workers exposed to NMP and 9 nonexposed controls. Three sampling times were studied: preshift, postshift and preshift of the following day (8-h shift). Three different working tasks were studied: loading and cleaning of the sprayer system and wiping/packing of the sprayed materials. The results show that workers in the spraying department of automobile plants can be exposed to NMP and suggest that 2-HMSI in preshift samples of the following day is supposed to be the critical parameter for exposure assessment due to its prolonged excretion half-life compared to 5-HNMP. Although the analysis of 5-HNMP in preshift samples also provides essential information, particularly in situations involving direct handling of liquid NMP-containing formulations (Meier et al., 2013).