SCOEL/REC/119 N-Methyl-2-Pyrrolidone : recommendation from the Scientific Committee on Occupational Exposure Limits.
Date: 2016-04-26
Institutions: Directorate-General for Employment, Social Affairs and Inclusion
Subjects: chemical product, health risk, occupational health, occupational medicine, occupational safety, toxicology

SCOEL/REC/119  
N-Methyl-2-Pyrrolidone 
Recommendation from the  
Scientific Committee on Occupational Exposure Limits  

H.M. Bolt, H. Greim, J. Cocker, A. Hartwig, S. Hoffmann, G. Johanson, L. Levy, M. Manno, 
T. Santonen, D. Papameletiou, C. L. Klein 
Adopted 23 September 2015 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EUROPEAN COMMISSION 

Directorate-General for Employment, Social Affairs and Inclusion 
Directorate B —Employment 
Unit B.3 — Health and safety 

Contact: Dr. Christoph Klein 

E-mail:  EMPL-SCOEL@ec.europa.eu  

Christoph.Klein@ec.europa.eu 

European Commission 
B-1049 Brussels 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCOEL/REC/119 
N-Methyl-2-Pyrrolidone 

Recommendation from the 
Scientific Committee on Occupational Exposure Limits 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

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Luxembourg: Publications Office of the European Union, 2016 

ISBN: 978-92-79-53351-8 
doi:10.2767/255384 

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Reproduction is authorised provided the source is acknowledged. 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

Contents  

1. 

2. 

3. 

4. 

CHEMICAL AGENT IDENTIFICATION AND PHYSICO-CHEMICAL PROPERTIES ................ 12 

EU HARMONISED CLASSIFICATION AND LABELLING ................................................ 13 

CHEMICAL AGENT AND SCOPE OF LEGISLATION ...................................................... 14 

EXISTING OCCUPATIONAL EXPOSURE LIMITS ......................................................... 15 

5.  OCCURRENCE, USE AND OCCUPATIONAL EXPOSURE ................................................ 17 

5.1.  Occurrence and use .................................................................................... 17 
5.2.  Production and use information .................................................................... 17 
5.3.  Occupational exposure ................................................................................ 18 
5.4.  Routes of exposure and uptake .................................................................... 19 

6.  MONITORING EXPOSURE ...................................................................................... 19 

7.  HEALTH EFFECTS ................................................................................................. 24 

7.4. 

7.1.  Toxicokinetics (absporption, distribution, metabolism, excretion) ...................... 24 
7.1.1.  Human data........................................................................................ 24 
7.1.2.  Animal data ....................................................................................... 25 
7.1.3. 
In vitro data ....................................................................................... 26 
7.1.4.  Toxicokinetic modelling.................................................................... 26 
7.1.5.  Biological monitoring........................................................................ 27 
7.2.  Acute toxicity ............................................................................................. 29 
7.2.1.  Human data........................................................................................ 29 
7.2.2.  Animal data ....................................................................................... 29 
7.3.  Specific Target Organ Toxicity/Repeated Exposure .......................................... 29 
7.3.1.  Human data........................................................................................ 29 
7.3.2.  Animal data ....................................................................................... 30 
7.3.3. 
In vitro data ....................................................................................... 32 
Irritancy and corrosivity .............................................................................. 32 
7.4.1.  Human data........................................................................................ 32 
7.4.2.  Animal data ....................................................................................... 33 
In vitro data ....................................................................................... 33 
7.4.3. 
7.5.  Sensitisation .............................................................................................. 33 
7.5.1.  Human data........................................................................................ 33 
7.5.2.  Animal data ....................................................................................... 33 
In vitro data ....................................................................................... 33 
7.5.3. 
7.6.  Genotoxicity ............................................................................................... 34 
7.6.1.  Human data........................................................................................ 34 
7.6.2.  Animal data ....................................................................................... 34 
In vitro ............................................................................................... 34 
7.6.3. 
7.7.  Carcinogenicity ........................................................................................... 34 
7.7.1.  Human data........................................................................................ 34 
7.7.2.  Animal data ....................................................................................... 34 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

7.8. Reproductive toxicity ..................................................................................... 35 
7.8.1. Human data ........................................................................................... 35 
7.8.2. Animal data ........................................................................................... 35 
7.8.3. In vitro data ........................................................................................... 38 
7.9. Mode of action and adverse outcome pathway considerations ............................. 38 
7.10. Lack of specific scientific information .............................................................. 40 

8. GROUPS AT EXTRA RISK .......................................................................................... 40 

9. REFERENCES .......................................................................................................... 41 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

RECOMMENDATION FROM THE  
SCIENTIFIC COMMITTEE ON OCCUPATIONAL 
EXPOSURE LIMITS  
FOR  
N-METHYL-2-PYRROLIDONE 

8-hour TWA: 

10 ppm (40 mg/m3)  

STEL: 

20 ppm (80 mg/m3) 

20 mg/g creatinine  
2-hydroxy-N-methylsuccinimide (2-HMSI) in 
urine, monitored morning-after-shift (18 h),  

BLV: 

or  

70 mg/g creatinine  
5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) in 
urine, monitored 2-4 h after exposure/shift 

Additional 
categorisation: 

- 

Notation: 

“skin” 

The present Recommendation was adopted by SCOEL on 2015-09-23. 

This  evaluation  is  based  on  a  previous  evaluation  by  SCOEL  (SCOEL/SUM/119;  August 
2007),  further  evaluations  by  Hartwig  (2011)  and  by  the  Swedish  Criteria  Group  for 
Occupational  Standards  (Montelius,  2014),  the  references  cited  in  these  reviews  and  a 
further literature search.  

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

RECOMMENDATION EXECUTIVE SUMMARY 

When  reviewing  the  scientific  data  available  for  NMP,  SCOEL  recognised  that  NMP  is  a 
very  well  investigated  substance,  for  which  a  relatively  high  number  of  reliable  high-
quality studies that is relevant for the occupational situation are available.  

SCOEL  has  assessed  the  available  information.  NMP  has  a  potential  to  cause  adverse 
health  effects  and  is  a  hazardous  chemical  agent.  For  NMP  the  available  information  is 
adequate for deriving a health-based OEL (8-hour TWA and STEL). The database is also 
adequate to derive a BLV and a 'skin' notation. 

NMP shows intrinsic hazardous properties with respect to local and systemic effects. The 
following  key  effects  were  considered  as  being  especially  relevant  for  the  protection  of 
workers and in particular the OEL derivation:  

(a) the potential of the substance to produce respiratory irritation and chemosensory 
effects, both in humans and animals, and 

(b)  the  systemic  toxicity  of  NMP,  in  particular  reproductive  toxicity  in  studies  in 
experimental animals.  

Outcome Considerations 

A  specification  and  discussion  of  these  key  effects  is  provided  in  chapter  7.9  of  this 
document  (“Mode  of  Action  and  Adverse  Outcome  Pathway  Considerations”).  Following 
SCOEL’s Methodology for the Derivation of Occupational Exposure Limits (version 7, June 
2013), the existing human data are considered highly relevant for OEL derivation. 

(a) Local irritancy/chemosensation:  

Subchronic  studies  in  rats  point  to  local  nasal  irritation  by  upon  NMP  exposure, 
with  an  NOAEL  of  125  ppm  (7.3.2.1.).  There  were  no  indications  of  respiratory 
irritation  or  other  health  effects  of  NMP  in  a  study  involving  exposure  of  human 
volunteers  to  10,  25  or  50  mg/m3  [2.5,  6.2  or  12.5  ppm]  over  an  8 hour  period 
(Åkesson  and  Paulsson,  1997).  Workers  exposed  to  levels  of  up  to  280 mg/m3 
[70 ppm]  reported  severe  eye  irritation  and  headache,  but  no  dose-response 
relationship  could  be  established  (Beaulieu  and  Schmerber,  1991).  In  a 
comprehensive experimental study  (van Thriel et al., 2007)  on 15 healthy young 
male volunteers exposed to 10 mg/m3 [2.5 ppm], 40 mg/m3 [10 ppm], 80 mg/m3 
[20  ppm]  and  25/160  mg/m3,  the  latter  including  peak  exposures  up  to 
160 mg/m3 [40 ppm], NMP could be smelled by the subjects, and it was reported 
to  be  slightly  annoying.  For  these  olfactory  symptoms  a  strong  adaptation  was 
observed, especially during the first 4 hours of exposure. SCOEL does not consider 
such  symptoms  as  being  adverse  for  workers  (see  7.9).  Symptoms  indicative  of 
an  irritant  potential,  especially  trigeminal  sensations,  were  not  elicited  by  NMP. 
The conclusion from this well executed and documented study was that NMP is an 
odorous  substance,  but  without  sensory  irritation  potency  up  to  80 mg/m3 
[20 ppm]  and  under  conditions  of  15-min  peak  exposures  to  160 mg/m3 
[40 ppm].  Therefore,  for  local  irritancy  in  humans  a  NOAEC  of  20  ppm  (highest 
concentration tested by van Thriel et al., 2007), is well established. The study of 
van  Thriel  et  al.  (2007)  also  considered  possible  influences  of  physical  workload, 
which was simulated by six 10 min periods of exercise on a bicycle ergometer at 
75 W. 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

(b) Systemic effects 

Developmental  toxicity  and  minor  effects  on  fertility  have  been  reported  in 
reproductive toxicity studies in rats, rabbits and mice, following exposure to NMP 
by  the  inhalation  or  the  oral  route  at  maternally  toxic  doses.    NOAELs  for 
reproductive  effects  range  from  206  to  500  mg/m3  [51  –  125  ppm] in  inhalation 
studies (see 7.8.2). As discussed in chapter 7.9, a NOAEC of 51 ppm (Solomon et 
al., 1995) is related to a borderline and transient and reversible effect on rat pup 
body weight gain. The degree of adversity of this effect for humans is considered 
to  be  borderline,  as  the  effect  seen  at  the  next  higher  concentration  of  116 ppm 
was  borderline,  fully  reversible  and  of  limited  severity.  In  addition,  in  other 
inhalational  developmental  toxicity  studies  effects  were  seen  not  seen  or  were 
seen  only  in  the  presence  of  reduced  food  consumption  and  slight  effects  on 
maternal  body  weight.  The  consideration  of  this  effect  as  being  borderline  is 
supported by oral studies, as even doses up to a level of 250 mg/kg did not show 
this effect. 

In a 2-year chronic toxicity/carcinogenicity study by the inhalation route in rats minimal 
inflammation  of  the  lung  and  slight  systemic  toxicity  was  reported  in  male  rats  at 
18 months, but not at 24 months, at the highest exposure level of 400 mg/m3 [100 ppm] 
(Lee  et  al.,  1987).    The  dose  level  of  400 mg/m3  [100  ppm]  in  this  study  can  be 
considered to be a borderline chronic LOAEL/NOAEL. However, the observed lung effects 
are  likely  based  on  local  irritancy.    There  was  no  indication  of  carcinogenicity  in  this 
2-year study. An increased incidence of hepatocellular adenomas and carcinomas seen in 
a 18-months feeding study in mice (at the top dose of 7200 ppm NMP in the diet; Malley 
et  al.,  2001)  is  not  regarded  as  relevant  for  the  establishment  of  an  OEL  in  humans, 
given the absence of genotoxic activity of NMP, both in vitro and in vivo. In addition, the 
over-sensitivity  of  the  B6C3F1  mouse  and  other  mouse  strains  to  development  of 
hepatocellular  tumours  has  been  recognised.  Therefore,  NMP  is  not  regarded  as  a 
carcinogen for humans. 

The derivation of an OEL considers both (a) acute local irritation effects, for  which solid 
human  data  are  available,  and  (b)  the  developmental  effects  (lower  weight  gain)  upon 
repetitive  dosing,  as  established  in  rats.  For  (a)  local  irritation,  the  conditions  of  the 
study  of  van  Thriel  et  al.  (2007)  of  20  ppm  provide  a  valid  and  well-defined  point  of 
NOAEC for the critical effect. 

The  study  of  van  Thriel  et  al  (2007)  was  a  controlled  human  exposure  study  assessing 
especially  sensitive  and  objectively  verifiable  effects.  The  study  included  experimental 
conditions  of  physical  workload.  It  was  performed  in  young  male  volunteers,  which  are 
considered  as  being  highly  susceptible  to  chemosensory  effects  (Brüning  et  al.  2014). 
Available  data  indicate  that  an  intra-species  uncertainty  factor  >1  may  not  be  needed 
whenever  good  exposure  studies  with  human  volunteers  are  available  (Brüning  et  al. 
2014). Moreover, case studies have led to the conclusion that human acute experimental 
NOAECs  for  chemosensory  effects  are  similar  to  NOAECs  derived  from  exposures  at  the 
workplace (Brüning et al. 2014). 

Therefore, the overall uncertainty factor applied by SCOEL considers possible differences 
due  to  gender  and  any  possible  remaining  uncertainties.  A  factor  of  two  appears 
adequate to account for the identified and remaining uncertainties.  

Derived Limit Values 

An  OEL  (TWA)  of  10  ppm  and  a  STEL  (15  min)  of  20  ppm  is  therefore  considered 
protective for  workers.  The study by van  Thriel et al. revealed that peak concentrations 
of 40 ppm were also without effect, thus supporting a STEL of 20 ppm.   

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

For  (b)  reproductive  toxicity,  the  reproductive  and  developmental  toxicity  study  by 
inhalation in rats of Solomon et al (1995) provides for this critical effect a level of of 51 
ppm as the NOAEC (for discussion/justification, see chapter 7.9). The critical effect was a 
slight  exposure-related  decrease  in  foetal  body  weight  among  the  F1  offspring  whose 
parents  inhaled  NMP  at  116  ppm,  which  persisted  until  weaning  and  was  then  fully 
reversible. As explained in chapter 7.9, the degree  of adversity of this effect for human 
health  appears  to  be  low,  as  (1)  the  magnitude  of  this  experimental  effect  was 
borderline,  (2)  the  effect  was  fully  reversible,  and  (3)  the  effect  as  such  was  not 
supported by a third available  inhalation study.  

A  further  contribution  to  OEL  derivation,  when  based  on  the  body  weight  effects  in  the 
offspring  described  by  Solomon  et  al  (1995)  and  Saillenfait  et  al.  (2003),  is  the 
quantitative risk analysis for NMP using PBPK and benchmark dose modelling by Poet et 
al. (2010; chapter 7.1.4). The modelling results suggest that the effective concentrations 
in humans would be higher as compared to rats. Although there are uncertainties related 
to  the  PBPK-modelling,  these  data  further  reduce  the  uncertainties  related  to  species 
extrapolation. Therefore, no additional uncertainty factor for toxicokinetics is needed. 

An  OEL  of  10  ppm  (STEL  of  20  ppm)  as  derived  based  on  absence  of  local  irritation  in 
exposed humans (a), is challenged against the data on experimental reproductive toxicity 
(b) to answer the question whether the level could still be considered protective for this 
endpoint, despite the collected evidence does not support its consideration as such. The 
established  OEL  of  10  ppm  (STEL  of  20  ppm)  would  cover  the  potential  hazard  for  this 
endpoint, too. The margin of 5 between the OEL and the experimental NOAEC (51 ppm) 
is  considered  adequate  because  of  the  low  adversity  of  the  body  weight  effect  with 
limited  relevance  for  human  health  (see  above)  and  the  low  severity  of  the  effects 
observed.  This  is  further  supported  by  the  PBPK  and  benchmark  analysis  of  Poet  et  al 
(see  above),  resulting  in  factors  between  an  OEL  of  10 ppm  and  the  benchmarks 
BMC1SD  (benchmark  concentration  corresponding  to  1 SD)  of  700 ppm  and  BMCL1SD 
(95% lower confidence limit) of 480 ppm, respectively.  

Therefore, having evaluated all data and respective endpoints, SCOEL considers for NMP 
an  OEL  (8h  TWA)  of  10  ppm  and  a  STEL  (15  min)  of  20  ppm  as  being  protective  for 
workers. 

Skin notation 

NMP is well absorbed through the skin, both in humans and in animal studies and some 
systemic  toxicity  (including  developmental  toxicity)  is  seen  following  dermal  uptake.  A 
“skin” notation is therefore considered necessary.  

Biological Monitoring 

and 

(5-HNMP) 

Due  to  the  significant  dermal  uptake  of  NMP,  biological  monitoring  is  recommended.  
5-hydroxy-N-methyl-2-pyrrolidon 
2-hydroxy-N-methylsuccinimide 
(2-HMSI), two key metabolites of NMP, are appropriate biological indicators of exposure, 
and monitoring of either of these metabolites can be undertaken. The optimum sampling 
time for 5-HNMP is the first 2-4 h post-exposure, while in the case of the longer half-life 
metabolite  2-HMSI  a  urine  collection  16  h  post-exposure  (on  the  morning  after  an  8  h 
work-shift)  is  advised.  Both  parameters  should  be  corrected  for  urinary  creatinine  to 
compensate for diuretic variations. The delayed peak maximum at 16-24 h post-exposure 
and  the  long  biological  half-life  makes  urinary  HMSI  especially  suitable  for  the 
surveillance  of  accumulative  effects  during  a  working  week  (Bader  et  al.  2007,  2008a). 
However  either  parameter  may  be  chosen,  depending  on  the  available  analytical 
methodology and the conditions pertaining to the particular workplace.  

For  the  longer  half-life  metabolite  2-HMSI,  an  8-h  TWA  of  10  ppm  (40  mg/m3) 
corresponds  to  a  biological  value  of  approximately  16  mg/g  creatinine,  16  h  post 
exposure for a work scenario without workload and approximately 22 mg/g creatinine for 

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a work scenario with moderate workload (75 Watt).  A Biological Limit Value (BLV) of 20 
mg/g  creatinine  is  recommended  for  2-HMSI,  measured  on  the  morning  after  an  8  h 
work-shift.  This  value  is  intermediate  between  the  work  scenario  without  workload  and 
the work scenario with moderate workload, as assessed by Bader and co-workers (2007, 
2008a),  and  is  likely  to  be  representative  of  a  typical  work  scenario  involving  some 
physical activity. 

For  5-HNMP,  an  8-h  TWA  of  10  ppm  (40  mg/m3)  corresponds  to  a  biological  value  of 
approximately  60 mg/g  creatinine,    2-4 h  post  exposure  for  a  work  scenario  without 
workload  and  approximately  75  mg/g  creatinine  for  a  work  scenario  with  moderate 
workload  (75  Watt).    A  Biological  Limit  Value  (BLV)  of  70 mg/g  creatinine  is 
recommended for 5-HNMP, measured 2-4 hours after the end of exposure. This value is 
intermediate  between  the  work  scenario  without  workload  and  the  work  scenario  with 
moderate workload, as assessed by Bader and co-workers (2007, 2008a), and is likely to 
be representative of a typical work scenario involving some physical activity. 

Analytical  measurement  systems  exist  to  determine  the  recommended  levels  with  an 
appropriate  level  of  precision  and  accuracy.  This  comprises  both  the  measurement  of 
NMP in air and the determination of 5-HNMP or 2-HMSI in urine as a matrix (chapter 6). 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

RECOMMENDATION FROM THE  
SCIENTIFIC COMMITTEE ON OCCUPATIONAL 
EXPOSURE LIMITS  
FOR  
N-METHYL-2-PYRROLIDONE 

RECOMMENDATION REPORT 

1.  CHEMICAL AGENT IDENTIFICATION AND PHYSICO-CHEMICAL PROPERTIES 

N-Methyl-2-pyrrolidone  (NMP)  is  a  water-miscible  colourless  liquid  with  a  characteristic 
amine odour.  The boiling point of NMP is 202oC at 101.3  Pa and its vapour pressure is 
0.39 hPa at 20 oC and 0.45 hPa at 25 oC (IPCS, 2001).   Log Kow is – 0.38 and the density 
is  1.028  g/cm3.  NMP  is  not  flammable    [flash  point,  closed  cup,  90°C,  open  cup  95°C 
(Åkesson, 1994)]. 

Name: 
Synonyms: 

Molecular formula: 
Structural formula: 

N-Methyl-2-pyrrolidone 
NMP,  N-methylpyrrolidone,  1-methyl-2-pyrrolidone,  1-
methyl-2-pyrrolidinone 
C5H9NO 

EC No.: 
CAS No.: 
Molecular weight: 
Conversion factors: 
(20 C, 101.3kPa) 

606-021-00-7 
872-50-4 
99.13 g/mol 
1 ppm = 4.12 mg/m3 
1 mg/m3 = 0.243 ppm 

Note: Some studies, which are evaluated here, give NMP concentrations in mg/m3, others 
in  ppm.  In  this  document,  the  respective  original  values  are  given.  For  information,  the 
corresponding  ppm  or  mg/m3  figure  may  be  calculated  based  on  a  rounded  conversion 
factor of 4 or the exact factors indicated above. 

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2.  EU HARMONISED CLASSIFICATION AND LABELLING 

Information about the  EU harmonised classification and  labelling for  NMP is provided by 
ECHA (2014b), as summarised in Tables 1 and 2. 

Table  1:  Classification  according  to  part  3  of  Annex  VI,  table  3.1  (list  of  harmonised 
classification  and  labelling  of  hazardous  substances  of  Regulation  (EC)  No1272/2008; 
(ECHA, 2014b). 

Index 
no. 

International 
Chemical 
Identification 

EC no. 

CAS 
no. 

606-
021-
00-7 

N-methyl-2-
pyrrolidone, 
1-methyl-2-
pyrrolidone 

212828-
1 

872-
50-4 

Classification 

Hazard 
statement 
code (s) 

H360D*** 
H319 
H335 
H315 

Pictogram 
Signal 
Word 
Code (s) 
GHS08 
GHS07 
Dgr 

Hazard 
Class & 
Category 
Code (s) 
Eye Irrit. 
2 

STOT SE 
3 

Skin 
Irrit. 2 

Suppl. 
Hazard 
statement 
code (s) 

Labelling 

Hazard 
statement 
code (s) 

H360D*** 
H319 
H335 
H315 

Spec. 
Conc. 
Limits, 
M-
factors 

Repr. 
1B 

H360D: 
C ≥ 
5% 

STOT 
SE 3: 
H335: 
C ≥ 
10% 

*** 

Repr. 1B, H360D May damage the unborn child.  
Eye Irrit. 2 H319 Causes serious eye irritation.  
Skin Irrit. 2 H315 Causes skin irritation.  
STOT Single Exp. 3 H335 May cause respiratory irritation. 

Table  2:  Classification  according  to  part  3  of  Annex  VI,  table  3.2  (list  of  harmonised 
classification  and  labelling  of  hazardous  substances  from  Annex  I  of  Council  Directive 
67/548/EEC of Regulation (EC) No1272/2008; (ECHA, 2014b). 

Index 
no. 

International Chemical 
Identification 

EC no. 

CAS 
no. 

Classification 

Labelling 

Concentration 
limits 

606-021-
00-7 

N-methyl-2-
pyrrolidone,  
1-methyl-2-
pyrrolidone 

212-
828-1 

872-
50-4 

Repr. Cat. 2; 
R61 

T 

Repr. Cat. 2; R61: 
C ≥ 5% 

R: 61-
36/37/38 

Xi - R36/37/38 

S: 53-45 

Xi, R36/37/38: 

C ≥ 10% 

Repr. Cat. 2; R61 May cause harm to the unborn child.  
Xi - R36/37/38 Irritating to eyes, respiratory system and skin  

Further  to  the  above  classification,  the  Netherlands  submitted,  in  March  2013,  a 
harmonised  classification  and  labelling  proposal  to  lower  the  specific  concentration  limit 
for reprotoxicity category 1B of NMP to 0.3% (generic value) (RIVM, 2013). 

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3.  CHEMICAL AGENT AND SCOPE OF LEGISLATION 

N-Methyl-2-pyrrolidone is a hazardous chemical agent in accordance with Article 2 (b) of 
Directive 98/24/EC and falls within the scope of this legislation.  

N-Methyl-2-pyrrolidone  is  not  a  carcinogen  or  mutagen  for  humans  in  accordance  with 
Article 2(a) and (b) of Directive 2004/37/EC. 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

4.  EXISTING OCCUPATIONAL EXPOSURE LIMITS  

Occupational  exposure  limits  for  N-methyl-2-pyrrolidone  exist  in  a  number  of  countries, 
as  shown  in  Table  3.  An  IOELV  (indicative  occupational  exposure  limit  value)  has  been 
adopted at EU level (EU, 2009), and national limit values will exist in all Member States. 
The values presented below are presented as examples and are not an exhaustive listing 
of all limit values within the EU and other countries. 

Table 3: Existing OELs for NMP; adapted from the GESTIS database (GESTIS, 2015). 

TWA 
(8 hrs) 

STEL 
(15 min) 

EU countries  

ppm  mg/m³  ppm  mg/m³ 

References 

Austria 

Belgium 

Denmark 

10 

10 

5 

40 

40 

20 

20 

20 

10 

European Union 

10  

40  

20   

10 

10  

20  

40 

40  

82  

20  

20  

40  

80 

80 

40 

80  

80  

80  

GKV (2011) 

Royal Decision (2014) 

BEK (2011) 

SCOEL (2007, 2015) 

MoSH (2012) 

INRS (2012) 

164  

BAUA (2006) 

Finland 

France 

Germany  
(AGS) 

Germany  
(DFG) 

Ireland 

Italy 

Latvia 

Poland 

Spain 

Sweden 

The Netherlands 

20  

82  

40  

164  

DFG (2015) 

10 

10 

25 

50 

40 

40 

100 

40 

103 

200 

40 

20  

20 

80  

80 

80 

HSA (2011) 

SSL (2008) 

GESTIS (2015) 

MLSP (2002) 

75 

309 

INSHT (2010) 

75  

300  

SWEA (2011) 

80 

DLPLV (2007) 

United Kingdom 

25 

103 

75 

309 

HSE (2011) 

Non-EU countries 

Switzerland 

20 

80 

40 

160 

SUVA (2015) 

Australia 

Canada  
(Ontario) 

25 

103  75 

309 

Safe Work Australia (2011) 

400 

Ontario Ministry of Labour (2013) 

New Zealand 

25 

103  75 

309 

Japan 

USA 

1 

10 

HS (2013) 

JSOH (2002) 

AIHA (2013) 

 Page 15 of 56 

 
 
 
 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

In  the  USA,  according  to  EPA  (US  EPA,  2015),  the  Occupational  Safety  and  Health 
Administration (OSHA) has not established regulatory exposure limits for NMP. The only 
recommended  exposure  limit  identified  for  NMP  is  a  non-regulatory  limit  established  by 
the American Industrial Hygiene Association (AIHA, 2013; see Table 3). 

In addition to OELs,  Biological Limit Values (BLVs) have been established/recommended 
by the following bodies: 

SCOEL 

(2015), 

a. 
creatinine 
2-hydroxy-N-methylsuccinimide  (2-HMSI)  in  urine,  measured  morning-after-shift 
(18  hours),  and/or  70  mg/g  creatinine  5-hydroxy-N-methyl-2-pyrrolidone 
(5-HNMP) in urine, measured 2-4 hours after the end of exposure/shift 

(2010): 

INSHT 

mg/g 

20 

b. Germany, DFG (2015): 5-HNMP, 150 mg/l (BAT) 

c.  Danish  EPA  (2014):  A  Biological  Limit  Value  (BLV)  of  20  mg/g  creatinine  is 
recommended for 2-HMSI, measured on the morning after an 8-hr work-shift. For 
5-HNMP,  a  biological  value  of  approximately  60  mg/g  creatinine,  2-4  hrs  post 
exposure  for  a  work  scenario  without  workload  and  approximately  75 mg/g 
creatinine for a work scenario with moderate workload (75 Watt). 

d. USA, ACGIH (2012): 5-HNMP, 100 mg/l (BEI) 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

5.  OCCURRENCE, USE AND OCCUPATIONAL EXPOSURE 

5.1.  Occurrence and use 

NMP does not occur naturally in measurable amounts. There is only one study known to 
have  isolated  NMP  from  a  marine  fungus,  Clathria  frondifera,  which  shows  that  the 
substance  can  be  produced  naturally  (Radhika  et  al.,  2007).  However,  measured  bio-
concentration  studies  were  not  located  and  based  on  available  environmental  fate  data, 
NMP  is  expected  to  have  low  bio-accumulation  potential  and  low  persistence  (US  EPA, 
2015). 

NMP is a synthetized organic substance. It has been manufactured on a commercial scale 
since the 1960s (RTI, 2001).  

The  primary  use  of  NMP  is  as  a  solvent  in  a  wide  range  of  applications  including  the 
paints  and  petrochemical  industries,  for  stripping  and  cleaning  applications  in  the 
microelectronics  industry,  for  the  removal  of  graffiti,  as  a  paint  stripper  and  as  a 
substitute for chlorinated solvents (IPCS, 2001). It is also used as an intermediate in the 
pharmaceutical,  polymer  and  other  chemical  industries  and  as  a  formulating  agent  for 
plant  protection  and  biocidal  actives,  and  as  a  solvent  for  pigments,  dyes  and  inks. 
Further uses include as a penetration enhancer for topically applied pharmaceuticals and 
as  a  vehicle  in  the  cosmetics  industry.  It  is  increasingly  used  as  a  replacement  for 
chlorinated  solvents  because  of  concern  about  the  toxicological  profile  of  some  of  the 
latter, e.g., it has been used to replace dichloromethane as a solvent in paint strippers.  

5.2.  Production and use information 

Recent  information  on  production  and  use  of  NMP  has  been  compiled  by  several  bodies 
(US  EPA,  2015;  ECHA,  2014a;  Danish  EPA,  2014;  NICNAS,  2013;  RIVM,  2013;  SCCS, 
2011; OECD, 2007). 

According  to  OECD  (2007)  the  annual  world  production  capacity  of  NMP  in  2003  was 
estimated  at  100,000  to  150,000  tons,  subdivided  into  30,000  –  50,000  tons/a  for 
Europe  (3  production  sites),  60,000  –  80,000  tons/a  for  USA  (3  production  sites),  and 
10,000 – 20,000 tons/a for Asia/Pacific (4 production sites).  During 2005, the European 
production capacity was reduced to about 20,000 – 30,000 tons. 

The  main  uses  of  NMP  products  are  summarized  in  Table  4.  The  quantification in  "%  of 
the total" refers to the distribution of NMP across these product uses. This quantification 
has been presented by  OECD  (2007) and is representative at world scale; however it is 
not EU-specific. Further NMP uses identified by NICNAS (2013) and  SCCS (2011) are in 
cosmetics  as  a  solvent,  fragrance  and  surfactant.  Uses  of  NMP  in  road  construction 
applications,  battery  industries,  membrane  manufacturing,  in  functional  fluids,  and  in 
laboratories were reported by ECHA (2014a) and RIVM (2013). According to the US EPA 
(2015),  the  National  Institutes  of  Health  (NIH)  Household  Products  Database  lists  47 
products  containing  NMP,  in  concentrations  ranging  from  1-100  percent.  In  contrast,  in 
the  EU  there  is  only  one  consumer  use  as  a  printing  ink  registered  in  REACH  (Danish 
EPA, 2014). 

According to the SCCS (2011) final concentrations in cosmetic products are not known. A 
survey by the Danish EPA revealed that concentrations of NMP in finished products vary 
from  a  few  percentages  up  to  85%  (Danish  EPA,  2014).  Home  maintenance  products 
may even consist of 100% NMP (US EPA, 2015).  

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

Table 4: Main uses of NMP containing products according to Harreus et al. (2011), OECD 
(2007), and Jouyban et al. (2010) 

Industry 

Application 

Percent of 
Total 

Electronics 

Agricultural chemicals 

Pharmaceuticals 

Coatings 

Cleaning agent for silicon wafers, de-
fluxing, edge bead removal, photoresist 
stripping, auxiliary in printed circuit 
board technology 

Solvent  for  herbicide,  pesticide  and 
fungicide formulations 

Solvent or co-solvent; chemical 
penetration enhancer for 

enhancement of transdermal delivery of 
hydrophilic and 

hydrophobic  drugs  from  an  aqueous 
phase   

Solvent for acrylic and epoxy resins, 
polyurethane paints, waterborne paints 
or finishes, printing inks, 
synthesis/diluent of wire enamels, 
coalescing agent  

Petrochemical processing 

Lube  oil  processing,  natural  and 
synthetic gas purification 

Industrial and consumer 
cleaners 

Paint  removers,  floor  strippers,  graffiti 
degreasing, 
remover, 
cast-molding 
injection 
equipment cleaning 

industrial 
and 

head 

20 

15 

15 

20 

10 

20 

Further  sources  of  information  are  Product  Registers  and  the  Nordic  SPIN  Database. 
Product  Registers  in  Sweden,  Denmark  and  Switzerland  were  interrogated  on  NMP-
containing-product  information  by  OECD  (2007).  The  Nordic  SPIN  Database  was 
interrogated  by  the  Danish  EPA  (2014).  The  registers  include  the  numbers  of  products 
marketed in these countries, the total amount of NMP contained in the products and the 
corresponding NMP concentrations. 

5.3.  Occupational exposure 

Although NMP does not have a high vapour pressure, the pattern and wide range of uses 
results  in  some  potential  for  occupational  exposure  by  inhalation.    Exposure  may  be  to 
NMP  as  a  vapour,  as  an  aerosol  or  as  a  mixture  of  both,  the  relative  proportions  being 
dependent on temperature and relative humidity (DFG, 1998).   

At normal room temperature and humidity (60% relative humidity) and concentrations of 
NMP  below  80  mg/m3,  aerosol  formation  is  unlikely,  however  aerosol  formation  is 
potentiated  at  higher  humidity  and  with  increasing  concentrations  of  NMP  (DFG,  1998). 
Levels  of  up  to  10  mg/m3  NMP  have  been  measured  in  the  breathing  zone  of  workers 
involved  in  the  removal  of  graffiti  (Anundi  et  al.,  1993,  2000),  while  workers  in  the 
microelectronics industry have been exposed to up to 6 mg/m3 (Beaulieu and Schmerber, 
1991). Much higher exposures (up to 280 mg/m3) were reported in the microelectronics 

Page 18 of 56 

 
 
 
 
 
 
 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

industry when NMP was used at a temperature of 80°C (Beaulieu and Schmerber, 1991). 
Exposures  of  up  to  64  mg/m3  have  been  measured  in  the  breathing  zone  of  paint-
strippers, with peak exposures of up to 280 mg/m3 (Åkesson and Jönsson, 2000a).  

Dermal  exposure  to  NMP  in  occupational  settings  is  also  likely,  given  the  pattern  and 
wide range of uses. NMP is readily absorbed through the skin, and dermal exposure thus 
is considered to contribute significantly to the internal NMP dose. There are several older 
reports in the literature of toxic effects resulting from skin contamination through spills, 
inhalation  of  fumes  may  however  have  contributed  to  the  toxicity  seen  (DFG,  1998). 
Additionally,  Bader  and  co-workers  have  reported  dermal  absorption  of  NMP  from  the 
vapour  phase,  equivalent  to  approximately  30 %  of  the  total  inhalation  dose  in  an 
experimental study in human volunteers, the design of which included a phase in which 
inhalational uptake was prevented by face shields (Bader et al., 2008a). 

5.4.  Routes of exposure and uptake 

As  explained  above,  there  is  the  possibility  of  occupational  exposure  by  both  inhalation 
and  dermal  uptake.  In  view  of  potential  high  dermal  exposure  biological  monitoring  is 
recommended (Greim, 1998). 

6.  MONITORING EXPOSURE 

NMP can be monitored in the air at the workplace by applying the following methods: 

  OSHA (1991), OSHA Stopgap method nr. PV2043 

  NIOSH (1998), NIOSH method 1302  

  Breuer et al., (2014), MAK method 1 

  Rosenberger et al., (2014), MAK method 2 

In  all  these  methods  NMP  in  air  is  adsorbed  onto  a  solid  sorbent  (activated  charcoal  or 
silica gel) followed by extraction of the NMP with an organic solvent (either a methylene 
chloride  solution  in  methanol,  pure  methanol  or  a  potassium  hydroxide  solution  in 
methanol). The NMP-containing extract can be then be analysed by gas chromatography 
(GC),  using  either  flame  ionisation  (FID),  nitrogen-phosphorus  (NPD)  or  mass 
spectrometry  (MS)  detection,  each  technique  with  its  limit  of  quantification  (LOQ)  and 
characteristics (see Table 5). 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

Table  5:  Overview  of  sampling  and  analytical  methods  for  monitoring  NMP  at  the 
workplace 

Method  Sorbent  

Desorption 
solution 

Analysis  Recovery 

LOQ 

(%) 

Concentration 
range 

References  

Relativ
e 
standa
rd 
deviati
on 

Activated 
charcoal 

NIOSH 
method 

1302 

Activated 
charcoal 

Silica gel 

MAK 
method 
1* 

methylene 
chloride 
solution  in 
methanol 
(95:5) 

methylene 
chloride 
solution  in 
methanol 
(95:5) 

potassium 
hydroxide 
solution  in 
methanol 

GC-NPD  98.8 

0.02  µg/ 
sample 

5 % 

0.063-25.8 

µg/sample 

GC-FID 

98.8 

0.3  µg/ 
sample 

1% 

0.662-2066 
µg/sample 

NIOSH, 
1998 

GC-NPD  99 

Absolute: 
1.6 ng 

2.3-
5.8% 

9-130 mg/𝑚3 

Breuer 
al., 2014 

et 

Relative: 
0.1 
mg/𝑚3  

Silica gel  methanol 

GC-MS 

92 

MAK 
method 
2* 

Absolute: 
0.3 ng 

4% 

2.5-15  mg/m3  Rosenberge
r  et  al., 
2014 

Relative: 
0.15mg/
𝑚3  

 *  This  method  can  be  used  to  detect  0.1  times  up  to  2  times  the  limit  value  for 
workplace air (MAK value) proposed by the Deutsche Forschungsgemeinschaft (DFG). 

The proposed method 1302 by NIOSH (1998) is considered to be an improvement of the 
OSHA  in-house  method  from  1991,  because  of  their  higher  sensitivity  and  recovery  at 
lower sample levels.  

Alternatively  to  the  above  discontinuous  methods,  airborne  NMP  can  be  analysed  on  a 
continuous  basis  by  photoacoustic  IR  spectrometry  (INNOVA,  1412  Photo  Acoustic  Field 
Gas-Monitor)  with  a  detection  limit  of  0.16-1.24  mg/m3 depending  on  the  optical  filter 
used  (calculated  based  on  the  equation  and  list  of  detection  limits  mentioned  in 
Lumasense, Denmark (2015) (Åkesson and Paulsson 1997; Jönsson and Åkesson, 2003; 
Bader  et  al.,  2007).  There  appears  to  be  no  appropriate  methodological  approach  for 
NMP at the moment using passive air sampling. 

Regarding  biomonitoring  of  NMP,  Bader  et  al.  (2008b)  describes  a  method  for 
measurement  of  5-HNMP  and  2-HMSI  in  urine  using  GC/MS.  The  method  is  based  on 
work  by  Jönsson  and  Åkesson  (1997a).  The  method  involves  addition  of  deuterium-
labeled  5-HNMP  and  2-HMSI  to  the  samples,  as  internal  standards.    Solid  phase 
extraction  (SPE)  is  then  applied  to  separate  the  metabolites  from  the  matrix,  which  is 
followed  by  elution  with  an  ethyl  acetate-methanol  solution.  The  method  has  been 
evaluated  by  the  MAK  Commission,  and  the  evaluation  results  are  summarized  in 
Table 6. 

Page 20 of 56 

 
 
 
 
 
 
 
 
 
 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

Table 6: Evaluation of the MAK method for the determination of 5-HNMP and 2-HMSI in 
urine 

5-Hydroxy-N-methyl-2-pyrrolidon (5-HNMP) 

Precision (series) 

Standard deviation (rel):                 s = 0.9% - 1.2%                       

Confidence interval:                      u = 2.0%- 2.7% 

in  the  concentration  range  from  7.5-75  mg  5-HNMP  per 
liter urine where n=10 determinations 

Precision (day to day) 

Standard deviation (rel):                 s = 1.3% - 2.3% 

Confidence interval:                      u = 2.9% - 5.1%  

in  the  concentration  range  from  7.5-75  mg  5-HNMP  per 
liter urine where n=10 determinations 

Recovery 

r =97% at 150 mg/l 

Detection limit 

1 mg 5-HNMP per liter urine 

2-Hydroxy-N-methylsuccinimide (2-HMSI) 

Precision (series) 

Standard deviation (rel):                 s = 1.4% - 1.7%                       

Confidence interval:                      u = 3.1%- 3.8% 

in  the  concentration  range  from  7.5-75  mg  2-HMSI  per 
liter urine where n=10 determinations 

Precision (day to day) 

Standard deviation (rel):                 s = 3.7% - 4.1% 

Confidence interval:                      u = 8.3% - 9.1%  

in the concentration range from 5-75 mg 2-HMSI per liter 
urine where n=10 determinations 

Recovery 

r =101% at 75 mg/l 

Detection limit 

1 mg 2-HMSI per liter urine 

Åkesson and Jönsson (2000c) and Carnerup et al. (2006) proposed, as an alternative to 
the  MAK  method,  a  concept  using  liquid  chromatography-electrospray  tandem  mass 
spectrometry.  Also  several  concepts  involving  minor  modifications  of  the  basic 
approaches  by  Jönsson  and  Åkesson  (1997a)  and  Bader  et  al.  (2008b),  such  as 
replacement  of  solid  phase  extraction  (SPE)  by  liquid-liquid  extraction  (LLE)  are  applied 
by different authors. An overview of such concepts is provided in Table 7. 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

Table 7: Overview of NMP bio-monitoring concepts applied 

Reference  Compound 
measured 

Method description 

NMP (p + u) 

Åkesson 
and 
Paulsson 
(1997) 

To  2  ml  of  plasma  or  urine,  2  ml  toluene  and  4  ml  12  M 
potassium  hydroxide  (KOH),  containing  0-25%  ammonia 
were  added.  After  shaking  for  10  minutes  the  toluene 
phase  was  transferred  into  glass  vials  with  PFTE  screw 
caps.  The  analyses  of  NMP  were  performed  by  gas  liquid 
chromatography  (GLC)  (Varian  3700;  autosampler  8035) 
with a nitrogen phosphorus detector (NPD; Varian TSD). 

5-HNMP  and 
2-HMSI (u) 

Jönsson 
and 
Åkesson 
(1997a) 

of 
and 

determination 
(5-HNMP) 

5-hydroxy-N-
Simultaneous 
methylpyrrolidone 
2-hydroxy-N-
methylsuccinimide (2-HMSI) in urine involving purification 
from  urine  by  adsorption  to  a  C8  solid-phase  extraction 
column  and  then  elution  by  ethyl  acetate-methanol 
(80:20).  After  evaporation,  the  samples  were  derivatised 
by 
C 
at 
bis(trimethylsilyl)trifluoroacet-  amide.  Ethyl  acetate  was 
then  added  and  the  samples  were  analysed  by  gas 
chromatography-mass  spectrometry 
the  electron 
impact mode.  

degrees 

100 

for 

in 

1 

h 

MSI  and  2-
HMSI (u+p) 

Jönsson 
and 
Åkesson 
(1997b) 

A method for determination of N-methylsuccinimide (MSI) 
and  2-hydroxy-N-methylsuccinimide  (2-HMSI)  in  human 
urine  and  of  MSI  in  human  plasma  was  developed 
involving  purification  from  urine  and  plasma  by  C8  solid-
phase  extraction  and  analysed  by  gas  chromatography-
mass spectrometry in the negative-ion chemical ionisation 
mode 

5-HNMP 
(u+p) 

Åkesson  
and 
Jönsson 
(2000c) 

Blood  and  urine  were  sampled  before,  during,  and  up  to 
40  hours  after  exposure  were  purified,  derivatised,  and 
analysed  for  5-HNMP  on  a  gas  chromatograph/mass 
spectrometer in the electron impact mode. 

Carnerup 
et 
(2001) 

al. 

5-HNMP  and 
2-HMSI 
(u+p) 

and 

(5-HNMP) 

Simultaneous  determination  of  5-hydroxy-N-methyl-2-
pyrrolidone 
2-hydroxy-N-
methylsuccinimide  (2-HMSI)  was  developed  involving 
purification 
from  plasma  and  urine  by  solid-phase 
extraction  using  Isolute  ENV+  columns,  and  analysis  by 
liquid  chromatography  coupled  to  a  mass  spectrometer 
fitted  with  an  atmospheric  pressure  turbo  ion  spray 
ionisation interface in the positive ion mode. 

Ligocka  et 
al. (2002) 

5-HNMP (u)  Different  solvents  and  alternative  methods  of  extraction 
including  liquid-liquid  extraction  (LLE)  on  Chem  Elut  and 
solid-phase  extraction  (SPE)  on  Oasis  HLB  columns  were 
tested. 

Page 22 of 56 

 
 
 
 
 
 
 
 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

Åkesson 
et 
(2004) 

al. 

NMP (u+p) 

MSI (u+p) 

NMP was measured in plasma and urine using the method 
described by Åkesson and Paulsson (1997). 

MSI  in  plasma  and  urine  was  measured  using  the 
measured described by Jönsson and Akesson (1997). 

Carnerup 
et 
(2006) 

al. 

NMP,5-
2-
HNMP, 
HMSI,  MSI 
and 
2-
Pyrrolidone 
(2-P) (u+p)  

Liquid  chromatography  with  tandem  mass  spectrometry 
(LC-MS/MS). 

Bader  et 
al. (2007) 

NMP, 
HNMP 
2-HMSI (u) 

5-
and 

Urinary  NMP  and  its  metabolites  5-HNMP  and  2-HMSI 
were  measured  according  to  Åkesson  and  Paulsson 
(1997). 

Kubota  et 
al. (2007) 

NMP,  MSI 
and  2-HMSI 
(u) 

Combination  of  solid-phase  extraction  (SPE)  and  gas 
chromatography  with  a 
thermionic  detector 
(GC/FTD) was developed for determination of N-methyl-2-
pyrrolidone  (NMP),  N-methylsuccinimide  (MSI),  and  2-
hydroxy-N-methylsuccinimide (2-HMSI) in human urine. 

flame 

Suzuki    et 
al. (2009)  

5-
NMP, 
HNMP,  MSI 
and  2-HMSI 
(u) 

Urinary  concentrations  of  NMP  and  its  metabolites  5-
hydoxy-N-methyl-2-pyrrolidone 
(5-HNMP),  N-methyl-
succinimide  (MSI),  and  2-hydroxy-N-methylsuccinimide 
(2-HMSI)  were  determined.  Development  of  a  HPLC-ESI-
MS/MS method that excluded using SPE, but included the 
use  of  deuterium-labeled  compounds  to  directly  correct 
the  remaining  matrix  effect  for  electrospray  ionization 
(ESI) detection. 

Meier 
et 
al. (2013) 

5-HNMP  and 
2-HMSI (u) 

5-Hydroxy-N-methyl-2-pyrrolidone 
(5-HNMP)  and  2-
hydroxy-N-methyl-succinimide  (2-HMSI  were  analyzed  in 
urine based on Bader et al. (2008b) 

Haufroid 
et 
(2014) 

al. 

5-HNMP  and 
2-HMSI (u) 

Urinary 5-HNMP and 2-HMSI were determined using liquid 
chromatography with tandem mass spectrometry. 

p: plasma, u: urine 

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 SCOEL/REC/119 N-Methyl-2-Pyrrolidone 

7.  HEALTH EFFECTS 

7.1.  Toxicokinetics (absporption, distribution, metabolism, excretion) 

7.1.1.  Human data 

to 

Human volunteer studies have shown that NMP is rapidly absorbed following exposure by 
the  inhalation,  dermal  or  oral  route  (Ursin  et  al.,  1995;  Åkesson  and  Paulsson,  1997; 
Åkesson and Jönsson, 1997; Åkesson and Jönsson, 2000b,c; Akrill et al., 2002; Jönsson 
and  Åkesson,  2003;  Åkesson  et  al.,  2004;  Bader  et  al.,  2008a).  A  study  involving 
exposure  of  six  healthy  male  volunteers  to  NMP  in  an  exposure  chamber  for  8  h  at 
concentrations  of  10,  25  and  50 mg/m3  showed  rapid  uptake  following  inhalation,  with 
metabolism 
the  mono-hydroxy  metabolite  5-hydroxy-N-methyl-2-pyrrolidone 
(5-HNMP),  which  was  further  metabolised  to  N-methylsuccinimide  (MSI)  and  then  to 
2-hydroxy-N-methylsuccinimide  (2-HMSI)  (Åkesson  and  Paulsson,  1997;  Åkesson  and 
Jönsson,  2000c,  Jönsson  and  Åkesson,  2003).  The  half-lives  of  NMP,  HNMP,  MSI  and 
2-HMSI  following  inhalation  of  NMP  were  4,  6,  8  and  16 h,  respectively,  with  100% 
urinary excretion, and the relative proportions  of  NMP and its metabolites in urine were 
2%  NMP,  60%  5-HNMP,  0.1%  MSI  and  37%  2-HMSI  (Åkesson  and  Paulsson,  1997). 
Carnerup  and  co-workers  have  identified  2-pyrrolidone  (2-P)  as  a  minor  metabolite  in 
both  humans  and  in  rats  (Carnerup  et  al.,  2005,  2006).  2-P  has  been  reported  to  be  a 
developmental toxicant and may possibly be responsible for the reproductive effects seen 
in animal studies with NMP (Carnerup et al., 2005, 2006).  

Bader  and  co-workers  have  confirmed  5-HNMP,  2-HMSI  and  free  NMP  as  the  major 
urinary metabolites following inhalation exposure of 16 male volunteers to concentrations 
of 10, 40, 80 and 25/160 mg/m3 NMP (Bader  et al., 2008a). The relative proportions of 
these urinary metabolites were approximately 68:31:1 at the exposure level of 40 mg/m3 
NMP under  resting conditions. Half-lives  of 3.9, 7.5 and 28 hours for NMP, 5-HNMP and 
2-HMSI  respectively  at  the  exposure  level  of  40  mg/m3  NMP  under  resting  conditions 
were  reported  by  Bader  et  al.  (2008a).  Bader  and  co-workers  also  reported  delayed 
elimination  of  NMP  following  dermal-only  exposure  to  NMP  vapour,  with  peak  times  for 
free  NMP,  5-HNMP  and  2-HMSI  being  delayed  by  approximately  4  hours  (Bader  et  al., 
2007, 2008a). 

Xiaofei and co-workers studied the pharmacokinetics of NMP in four workers exposed to 
0.46  –  2.84  mg/m3  for  12  hours  per  day  for  a  5  day  working  week  and  five  volunteers 
who  observed  the  work  processes  for  a  single 8  hour  day  and  were  exposed  to  a  mean 
concentration of 1.15 mg/m3 (Xiaofei et al., 2000). NMP levels in plasma and urine were 
monitored in both workers and volunteers and the data used to derive a pharmacokinetic 
model  for  NMP.    Metabolic  saturation  was  not  predicted  at  concentrations  below 
approximately  40  mg/m3.  The  predictability  of  the  model  was  demonstrated  by 
monitoring of NMP levels in plasma and urine in a second set of workers.  

After  oral  administration  of  100  mg  NMP  to  three  healthy  male  volunteers,  65%  of  the 
administered dose was recovered in urine, comprising 2% NMP, 67% 5-HNMP, 0.1% MSI 
and  31%  2-HMSI  (Åkesson  and  Jönsson,  1997).  One  third  of  the  oral  dose  of  NMP  was 
not  found  as  any  of  these  metabolites,  the  lack  of  mass  balance  possibly  indicating 
incomplete  absorption  from  the  gastrointestinal  tract  or  the  presence  of  unidentified 
metabolites (Åkesson and Jönsson, 1997). 

A  6-h  topical  study  in  male  and  female  volunteers  using  a  single  dose  of  300 mg 
undiluted NMP showed peak plasma concentrations of NMP three hours after application.  
A  fraction  of  22  to  24%  of  the  total  dose  was  recovered  in  the  urine  for  females  and 
males  respectively  (Åkesson  and  Jönsson,  2000b).  Mean  peak  plasma  levels  of  5-HNMP 
were  observed  after  4 hours  in  females  and  after  6  in  males,  while  plasma  MSI  and  2-
HMSI peaked after 8 hours and 24 hours respectively (Åkesson et al., 2004). The authors 
compared  the  pharmacokinetics  of  50%  aqueous  dermally  applied  NMP  in  a  group  of  6 
male volunteers with the results obtained with undiluted NMP and showed peak levels of 
NMP  8  hours  after  application,  MSI  after  12  hours  and  2-HMSI  after  24  –  30  hours 

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(Åkesson  et  al.,  2004).    The  results  indicated  delayed  absorption  of  NMP  in  aqueous 
formulations, a result also found in animal studies. 

Akrill  and  co-workers  examined  the  excretion  of  5-HNMP  in  2  volunteers  exposed  for 
15 minutes  to  aqueous  NMP  solutions  (5  –  25%:  one  hand)  followed  by  urine  collection 
for  48  hours  (Akrill  et  al.,  2002).    They  found  that  urinary  levels  of  5-HNMP  were  at  a 
maximum after about 10 h and excretion continued for 48 h after exposure. The half-life 
of  5-HNMP    was    approximately  11  h,  confirming  the  delayed  absorption  of  NMP  and 
prolonged  half  life  of  NMP  and  its  metabolites  observed  by  Åkesson  and  co-workers 
following dermal exposure compared with inhalation, particularly for aqueous solutions of 
NMP.  It  can  be  estimated  from  these  data  that  15  minutes  exposure  to  15%  aqueous 
NMP  is  equivalent  to  inhalation  of  10  mg/m3  NMP  with  respect  to  absorption  and 
elimination profile (Akrill et al., 2002). 

A  permeability  rate  through  human  skin  of  171  +  59  g/m3  has  been  derived  for  NMP 
(Ursin et al., 1995). Ligocka and co-workers demonstrated a mean 67.9% absorption of 
NMP through the skin in 12 human volunteers exposed to 300 mg NMP via a skin patch 
(Ligocka  et  al.,  2003).  Of  the  total  dose  12.6%  was  excreted  as  5-HNMP,  6-12  hours 
after  exposure,  while  2-HMSI  peaked  at  2  time  periods,  12-24  hours  after  exposure 
(3.3%  of  dose)  and  36-48  hours  after  exposure  (3.2%  of  dose).  The  authors  also 
demonstrated  a  significant  relationship  between  CYP2E1  mRNA  content  in  peripheral 
blood  lymphocytes  and  levels  of  5-HNMP  and  2-HMSI  excreted  in  urine  within  24  hours 
and  suggested  that  the  activity  of  this  enzyme  in  an  individual  should  be  taken  into 
account  when  interpreting  the  results  of  biological  monitoring  of  exposure  to  NMP 
(Ligocka et al., 2003). 

7.1.2.  Animal data  

Toxicokinetic  studies  have  been  carried  out  in  rats  using  the  dermal,  inhalation,  oral  or 
intravenous  routes,  with  similar  results.    As  in  humans,  NMP  was  rapidly  absorbed  and 
distributed, with 80 - 90% excretion in urine within 24 h (Wells and Digenis, 1988; RTI, 
1990, cited in IPCS, 2001); Midgley et al., 1992; Ravn-Jonsen et al., 1992; Payan et al., 
2003). Faecal excretion was 2  – 4% of total dose, and there was very limited excretion 
as  CO2  (0.9  –  1.7%)  or  volatile  organic  compounds.  A  distribution  study  following 
intravenous  administration  of  radio-labelled  NMP  showed  distribution  to  all  tissues,  with 
highest  levels  of  radioactivity  being  observed  in  the  liver,  bile  and  small  intestine, 
kidneys, stomach and testis (Wells and Digenis, 1988). 

Following topical administration of NMP radio-labelled with  14C on the C2 atom to rat skin 
at  doses  of  0.2,  2  and  20  mg/cm2,  applied  to  an  area  of  12  cm2,  there  was  50% 
absorption  of  the  2  lower  doses  while  75%  of  the  20  mg/cm2  dose  was  absorbed, 
suggesting that NMP promotes its own absorption. Maximum blood levels were observed 
approximately 8 hours after application (RTI, 1990, cited in IPCS, 2001). A percutaneous 
absorption study applying NMP as the pure substance, as a 30% solution in water and as 
a  30%  solution  in  limonene,  showed  uptakes  of  31%,  3.5%  and  72%  respectively, 
suggesting that the use and nature of the vehicle also influences uptake (Huntingdon Life 
Sciences,  1998,  cited  in  IPCS,  2001).  Payan  and  co-workers  demonstrated  that 
percutaneous absorption flux in rats was proportional to the concentration of NMP applied 
and  was  dependent  on  skin  thickness,  suggesting  a  passive  diffusion  process  (Payan  et 
al., 2003).  Maximum absorption fluxes of 10 and 20 mg/cm2 NMP were determined for 
20 μl/cm2 and 40 μl/cm2 respectively. Absorption decreased when neat NMP was diluted. 

In  a  study  in  which  rats  were  exposed  to  618 mg/m3  NMP  (whole  body)  for  6  h,  NMP 
crossed  the  placental  barrier,  with  an  equilibrium  being  reached  between  foetal  and 
maternal  blood.  Elimination  of  NMP  was  slower  in  pregnant  than  non-pregnant  rats 
(Ravn-Jonsen et al., 1992). 

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As  also  observed  in  the  human  volunteer  studies  reported  by  Åkesson  and  co-workers, 
the main urinary metabolite in rats was 5-HNMP, amounting to 70 – 75% of administered 
dose following intravenous administration (Wells et al., 1992) and 60% after an oral dose 
of  500  mg/kg  (RTI,  1990  cited  in  IPCS,  2001).  In  the  latter  study,  a  further  10  –  15% 
was  a  metabolite  of  5-HNMP  and  5%  was  unchanged  NMP.  At  the  lower  oral  dose  of 
5 mg/kg,  NMP  was  completely  metabolised  and  at  least  4  urinary  metabolites  were 
detected,  indicating  that  metabolic  pathways  may  become  saturated  at  higher  dose 
levels.  The  study  did  not  identify  the  2-HMSI  metabolite  demonstrated  in  humans 
(Åkesson and Paulsson, 1997). Ligocka and co-workers also demonstrated that the main 
metabolite  in  rats  following  dermal  administration  of  NMP  was  5-HNMP  (Ligocka  et  al. 
2003). Excretion of this metabolite was significantly reduced in rats pre-treated with the 
CYP2E1  inhibitor  diethyldithiocarbamate,  confirming  that  CYP2E1  is  involved  in  the 
metabolism of NMP (Ligocka et al. 2003; see also 7.1.1.). 

7.1.3.  In vitro data 

A  study  by  Dick  et  al  (2001)  has  been  assessed  by  the  Swedish  Criteria  Group  for 
Occupational  Standards  (Johanson  and  Rauma  2008,  Montelius  2014)  as  being  suitable 
for  an  estimation  of  dermal  absorption  of  NMP  by  human  skin  in  vitro.  The  rate  of 
absorption of undiluted NMP was calculated as 10 mg/cm2 per hour. Extrapolation of data 
to 2000 cm2 skin (equivalent to both hands and forearms) and 1 hour of exposure gave a 
dermal absorption of 20,000 mg (20 g). This uptake was estimated to be about 10 times 
higher  than  the  uptake  within  8  h  of  inhalation  at  the  Swedish  OEL  of  50  ppm 
[200 mg/m3]. 

7.1.4.  Toxicokinetic modelling 

Poet and coworkers (2010) applied PBPK- and benchmark dose modelling to calculate the 
point of departure (POD) as the area under the blood concentration-time curve (AUC) for 
NMP  in  blood.  The  application  focussed  on  two  experimental  inhalation  studies  on 
developmental  toxicity  in  rats  (Saillenfait  et  al  2003,  Solomon  et  al  1995;  see  7.8.2). 
Since  in  utero  exposures  were  of  concern,  the  models  considered  major  physiological 
changes  occurring  in  the  dam  or  mother  over  the  course  of  gestation.  The  rat  PBPK 
model  was  used  to  determine  the  relationship  between  NMP  concentrations  in  maternal 
blood  and  decrements  in  foetal/pup  body  weights  following  exposures  to  NMP  vapour. 
Body weight decrements seen after vapour exposures occurred at lower NMP blood levels 
than  those  observed  after  oral  and  dermal  exposures.  Benchmark  dose  modelling  was 
used to define a point of departure (POD) for  foetal/pup body weight changes based on 
dose-response  information  from  two  inhalation  studies  in  rats.  In  this  analysis,  dose-
response models were used to predict from the experimental data of both Solomon et al. 
and  Saillenfait  et  al.  the  benchmark  concentrations  (BMC)  resulting  in  a  decrease  in 
mean  body  weight  (foetal/pup)  corresponding  to  1  SD  (BMC1SD)  and  its  95%  lower 
confidence  limit  (BMCL1SD).  The  calculated  human  equivalent  concentration  (HEC,  for 
8h/d and 5d/wk) for BMC1SD was 700 ppm and for BMCL1SD 480 ppm. Although there 
are  uncertainties  related  to  these  PBPK  modelling,  these  modelling  results  basically 
suggest  that  the  effective  concentrations  in  humans  would  be  higher  as  compared  to 
rats. 

For  the  U.S.  Environmental  Protection  Agency  (EPA),  this  PBPK  model  was  further 
optimised by Poet (2013, as cited in Lumpkin and Gentry 2013; Schlosser 2013). In the 
following evaluation by EPA, it was noted that the model generally produced very similar 
simulations  (compared  to  the  originally  published  version)  following  i.v.  and  dermal 
exposures in rats and for inhalation and dermal exposures in humans. Also, the modified 
model code was considered to be capable of predicting parent compound and metabolite 
profiles from multiple data sets, providing blood and urine measurements in rodents and 
humans  exposed  to  NMP  by  multiple  routes  of  exposure  (i.v.,  dermal  and  inhalation).  

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EPA especially recognised that the model described well the urinary clearance of 5-HNMP 
after  a  range  of  i.v.  and  inhalation  exposures  (Lumpkin  and  Gentry  2013;  Schlosser 
2013). 

7.1.5.  Biological monitoring  

Studies in both humans and animals show that NMP is readily absorbed through the skin 
(RTI,  1990,  cited  in  IPCS,  2001;  Midgely  et  al,  1992;  Åkesson  and  Jönsson,  2000b).  
Bader and co-workers have measured dermal absorption of NMP from the vapour phase, 
equivalent to approximately ~ 30 % of the total inhalation dose in an experimental study 
in  human  volunteers,  the  design  of  which  included  a  phase,  in  which  uptake  through 
inhalation was prevented by face shields and absorption of NMP vapour was likely to have 
occurred  mainly  through  the  exposed  skin  areas  of  the  hands,  arms  and  lower  neck 
(Bader  et  al.,  2008a).    Dermal  absorption  can  therefore  contribute  significantly  to  body 
burden. Measurement of non-metabolised NMP in plasma or urine has been proposed as 
a  biological  monitor,  reflecting  exposure  from  both  the  inhalation  and  dermal  routes 
(Åkesson  and  Paulsson,  1997;  Xiaofei  et  al.,  2000),  but  has  several  disadvantages, 
including the comparatively short half-life of NMP and the low concentrations in urine.  

The  metabolites  of  NMP  are  more  appropriate  biological  indicators  of  exposure,  and 
measurement of the major metabolite 5-HNMP, with a half-life of 6-7  hours, in urine or 
plasma  has  been  proposed  as  a  suitable  method  for  biological  monitoring  (Åkesson  and 
Jönsson,  2000c;  Jönsson  and  Åkesson,  2003).  The  same  group  has  also  suggested 
measurement  of  MSI,  given  the  readily  available  analytical  method  for  this  metabolite 
(Jönsson  and  Åkesson,  2001).    However  MSI  has  a  somewhat  larger  volume  of 
distribution and levels in urine are low.   

In an 8-hour inhalation study in male volunteers exposed to NMP at concentrations of 10, 
25 and 50 mg/m3, Åkesson and Jönsson reported an excellent correlation between NMP 
air  levels  and  plasma  or  urinary  5-HNMP  (Åkesson  and  Jönsson,  2000c).  An  8-hour 
exposure  to  an  air  concentration  of  10  mg/m3  NMP  resulted  in  a  level  of  22  mmol 
5-HNMP/mol creatinine in urinary samples collected during the last 2 hours of exposure, 
while  exposure  to  50  mg/m3  NMP  resulted  in  a  level  of  110  mmol/mol  creatinine.  The 
same group also proposed 2-HMSI in urine as an appropriate biological marker for NMP 
exposure, as sensitive analytical methods were available (Carnerup et al, 2001; Jönsson 
and Åkesson, 2003; Carnerup et al., 2005, 2006). Given the long half-life of 2-HMSI, this 
metabolite  may  be  advantageous  over  5-HNMP  as  a  biological  marker,  particularly  in 
situations where workers may be exposed topically to aqueous solutions of NMP. In such 
situations, dermal absorption of NMP is delayed (Åkesson et al., 2004), but the impact of 
this on peak levels of 2-HMSI is much less marked than for 5-HNMP. 

A  comprehensive  study  in  16  human  volunteers  (see  section  7.1.1  for  methodological 
details  of  this  study),  Bader  and  co-workers  have  confirmed  that  levels  of  urinary  NMP, 
5-HNMP and 2-HMSI show close correlations to airborne NMP. In this study, the authors 
considered  that  5-HNMP  and  2-HMSI  were  preferable  biomarkers  for  workplace 
surveillance  (Bader  et  al.,  2008a).    The  delayed  peak  maximum  of  16-24  h  post-
exposure and the long biological half-life makes urinary HMSI especially suitable for the 
surveillance  of  accumulative  effects  during  a  working  week  (Bader  et  al.  2008a).  The 
results of Bader and co-workers indicate that the optimum sampling time for 5-HNMP is 
2-4 h post-exposure, while in the case of 2-HMSI, a urine collection 16 h post-exposure 
(i.e.  on  the  morning  after  an  8  h  work-shift)  is  indicated.  Although  Åkesson  and  co-
workers  have  proposed  that  results  of  biological  monitoring  should  be  expressed  as 
absolute urinary concentrations of 2-HMSI or 5-HNMP, adjusted for urine density, rather 
than  relative  to  urinary  creatinine  levels  (Åkesson  et  al.,  2004),  Bader  and  co-workers 
corrected  both  parameters  for  urinary  creatinine  to  compensate  for  diuretic  variations 
(Bader et al., 2007, 2008a). 

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Linear  regression  analysis  of  NMP  in  air  and  of  post-exposure  5-HNMP  in  urine  in  the 
above  study  indicated  an  average  concentration  of  approximately  60  mg/g  creatinine 
(post exposure) for an  exposure of 40 mg/m3 NMP without workload and approximately 
75 mg/g creatinine in a work scenario with moderate workload [six 10 minute periods of 
exercise during the 8-hour exposure period, on a bicycle ergometer (75 Watt)] (Bader et 
al., 2008a). The regression curve reported by Åkesson and Jönsson (2000c) for a series 
of 8 h exposures to 10, 25 and 50 mg/m3 NMP was considerably steeper than the curve 
calculated  in  the  Bader  and  co-workers  study,  and  provided  an  estimate  of  90 mg/g 
creatinine  for  urinary  5-HNMP  after  an  8  h  exposure  to  40  mg/m3  NMP.  Similarly, 
regression analyses between NMP in air and urinary 2-HMSI peak values (16 – 24 h post-
exposure)  in  the  Bader  et  al.  study  pointed  to  an  average  concentration  of  16  mg/g 
creatinine  (without  workload)  and  to  22  mg/g  creatinine  (moderate  workload)  for  a 
whole-body  exposure  at  20  mg/m3  NMP.  Comparable  to  the  situation  with  5-HNMP,  the 
results from an inhalation study by Jönsson and Åkesson (2003) point to higher urinary 
2-HMSI concentrations than in the Bader and co-workers study, with an estimated level 
of  40  mg  2-HMSI/g  creatinine  at  40  mg/m3  NMP.  These  differences  may  be  due  to 
methodological differences between the two studies although Bader and co-workers also 
suggest that differences in the dermal absorption of NMP are likely to have contributed to 
the discrepancies between the studies (Bader et al., 2007, 2008a). 

'cleaning'  of 

tasks  ('loading'  and 

Meier  et  al  (2013)  reported  on  a  study  investigating  current  exposures  to  NMP  in  the 
spraying  department  of  an  automobile  plant  using  biological  monitoring.  5-HNMP  and 
2-HMSI were analysed in 69 urine samples of 14 workers exposed to NMP and of 9 non-
exposed  controls.  Measurements  of  airborne  exposure  levels  were  not  included.  Three 
different  working 
the  sprayer  system  and 
'wiping/packing' of the sprayed materials) and three sampling times (pre-shift, post-shift, 
and  pre-shift  of  the  following  day)  were  studied  in  exposed  workers.  Median  levels  of 
5-HNMP  and  2-HMSI  in  post-shift  urine  of  exposed  workers  were  0.91  and  0.52  mg/g 
creatinine,  respectively,  whereas  median  levels  in  controls  were  below  the  limit  of 
detection.  Decreased  levels  of  5-HNMP  were  observed  in  pre-shift  urine  samples  on  the 
following  day  (0.39  mg/g  creatinine)  in  exposed  workers,  while  the  concentration  of 
2-HMSI  did  not  change  (0.49  mg/g  creatinine).  Highest  exposures  occurred  during 
sprayer cleaning with a maximum level of 8.31 mg/g creatinine of 5-HNMP in post-shift 
urine. In contrast to 'wipers/packers', no decrease in 5-HNMP could be observed in pre-
shift urine samples on day 2 of the 'loaders' and 'cleaners'. Overall, exposure in terms of 
5-HNMP  post-shift  and  2-HMSI  pre-shift  of  the  following  day  were  well  below  existing 
biological limit values  of the  European Union (70 and 20 mg/g  creatinine, respectively). 
The  authors  suggested  that  the  analysis  of  5-HNMP  in  pre-shift  samples  also  provided 
essential  information,  particularly  in  situations  involving  direct  handling  of  liquid  NMP-
containing formulations. 

Haufroid  et  al  (2014)  conducted  a  field  study  to  examine  the  value  of  urinary  5-HNMP 
and 2-HMSI in workers exposed to  N-methyl-2-pyrrolidone (NMP) and to look for health 
effects  of  exposure.  Airborne  NMP  was  determined  according  to  the  NIOSH  method. 
Urinary  5-HNMP  and  2-HMSI  (after  and  before  next  shift)  were  determined  by  liquid 
chromatography  with  tandem  mass  spectrometry.  Outcomes  were  effects  on  lung, 
kidney,  skin  and  mucous  membranes,  nervous  system,  haematopoiesis  and  liver 
determined  by  clinical  examination  and  laboratory  measurements.  Univariate  statistical 
methods and multiple regressions were used to analyse results. Skin absorption, smoking 
and  other  potential  confounders  were  taken  into  account.  Three-hundred-twenty-seven 
workers were eligible out of which 207 workers (63%) participated. Ninety-one of these 
worked  with  NMP.  Occupational  exposure  to  NMP  did  often  not  occur  daily  and  ranged 
from non-detectable to 25.8 mg/m3 (median = 0.18). Urinary 2-HMSI (mg/l; before next 
shift) was the best biomarker of exposure to NMP, explaining about 70% of the variance, 
but most likelihood ratios did not allow for ruling exposure in or out, at these low levels 
of  exposure.  Creatinine  adjustment  did  not  improve  the  results  clearly.  No  clear  and 
consistent health effects could be associated with NMP exposure. No indication for a bias 
due  to  non-participation  was  found.  It  was  concluded  by  the  authors  that  biological 
monitoring, primarily urinary 2-HMSI (before next shift), is of value to estimate exposure 
to NMP, even when exposure is irregular and low. No irritant or other health effects were 
found. 

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7.2.  Acute toxicity 

7.2.1.  Human data 

No information is available on the acute toxicity of NMP in humans, but the substance is 
of low acute toxicity in animals. 

7.2.2.  Animal data 

Oral  LD50  values  in  rats,  mice,  rabbits  and  guinea  pigs  are  reported  to  lie  in  the  range 
3500  –  7900  mg/kg  bw  (Bartsch  et  al.,  1976;  Ansell  and  Fowler,  1988)  while  dermal 
LD50 in rats and rabbits are in the range 4000 – 10,000 mg/kg bw (Bartsch et al., 1976; 
Weisbrod,  1981;  Clark,  1984,  cited  in  Greim,  1998).  No  deaths  occurred  in  an  acute 
inhalation study in rats exposed nose-only to a 5100 mg/m3 vapour/ aerosol mixture with 
a mass median aerodynamic diameter (MMAD) of 4.6 µm (respirable fraction 87%), the 
LC50 was >5100 mg/m3 (BASF, 1988, cited in IPCS, 2001). LC50s in the range of 3100 – 
8800 mg/m3 were determined in another study also involving exposure to an aerosol (du 
Pont,  1988,  cited  in  Greim,  1998).  Effects  seen  following  oral  or  inhalational  exposure 
included mucosal irritancy, narcosis and non-specific symptoms of toxicity (BASF, 1988, 
cited in IPCS, 2001; Ansell and Fowler, 1988). 

7.3.  Specific Target Organ Toxicity/Repeated Exposure 

7.3.1.  Human data 

In a human volunteer study, involving six subjects exposed to 10, 25, or 50 mg/m3  [2.5, 
6.25 or 12.5 ppm] NMP over an 8 hour period, there were no acute changes in the nasal 
cavity as assessed by continuous acoustic rhinometry, and no significant differences were 
observed  in  FEV1  (forced  expiratory  volume  in  1  s),  vital  capacity  or  forced  expiratory 
capacity,  measured  by  spirometry  (Åkesson  and  Paulsson,  1997).  Two  volunteers 
reported  detecting  an  odour  at  50  mg/m3  [12.5  ppm].  The  subjects  did  not  experience 
any  symptoms  of  eye  or  respiratory  tract  irritation,  or  other  symptoms  such  as 
headache, dizziness, and nausea.  

Workers  exposed  to  up  to  280  mg/m3  [70  ppm]  NMP  in  working  areas  in  the 
microelectronics  fabrication  industry  where  warm  NMP  (80  °C)  was  being  handled 
reported  severe  eye  irritation  and  headache  (Beaulieu  and  Schmerber,  1991).  Due  to 
methodological deficiencies, an exposure – response relationship could not be established 
in this study.  

In  a  study  of  38  graffiti  removers,  working  8  hour  shifts  in  the  Stockholm  underground 
system  and  exposed  to  a  mixture  of  solvents  including  NMP,  there  was  a  significantly 
higher  prevalence  of  tiredness,  headaches  and  symptoms  affecting  airways,  eyes  and 
skin  than  population  controls  (Langworth  et  al.,  2001).    Eight-hour  exposures  (TWA) 
were  below  20%  of  the  Swedish  Permissible  Exposure  Limit  for  all  solvents  measured, 
but  short-term  exposures  occasionally  exceeded  the  short-term  exposure  limits.  Mean 
short-term exposure to NMP over 15 minutes was 4.71 + 6.17 mg/m3 (AM), with a range 
of  0.01  –  24.61.  The  relationship  between  the  different  exposure  measurements  and 
reported symptoms were generally weak, and no specific relationship with NMP exposure 
could be identified. 

A  comprehensive  study  in  15  healthy  young  male  volunteers  has  been  undertaken,  in 
order  to  investigate  possible  chemosensory  effects  of  NMP  under  workplace  conditions 
(van  Thriel  et  al.,  2007).  One  subject,  out  of  16  subjects  initially,  dropped  out  of  the 

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study at an early stage for reasons unrelated to NMP exposure.  Exposure scenarios used 
in  the  study  were  10  mg/m3,  40  mg/m3,  80  mg/m3  and  25/160  mg/m3,  the  latter 
including  peak  exposures  up  to  160  mg/m3.  The  10  mg/m3  condition  was  defined  as  a 
non-irritating odorous control condition. The subjects were exposed for an 8-hour (typical 
shift) period once a week over an 8 week period, with an exposure-free period of 1 week 
between  two  subsequent  sessions,  i.e.  a  total  of  4  exposures  during  the  experimental 
period.    All  four  inhalational  conditions  were  investigated  with  and  without  additional 
physical  workload.  The  physical  workload  consisted  of  six  10  minute  periods  of  exercise 
during  the  8-hour  exposure  period  on  a  bicycle  ergometer  (75  Watt).  [The  toxicokinetic 
aspects  of  this  study  are  discussed  in  7.1.1,  the  biomonitoring  aspects  in  7.1.5.] 
Chemosensory effects of NMP were assessed using the following measures: (1) eye blink 
rates,  based  on  EMG  recordings,  (2)  nasal  air 
flow,  assessed  by  anterior 
rhinomanometry,  (3)  breathing  rates,  based  on  electrophysiological  measurements,  (4) 
neurobehavioral/psychological  tests  of  attentional  functions  (chemosensory  mediated 
distraction),  (5)  subjective  acute  symptoms  (including  acute  symptoms  of  odour  and 
trigeminally  mediated  health  effects)  according  to  the  Swedish  Performance  Evaluation 
System (SPES), (6) intensity of chemosensory sensations (e.g. odour intensity, intensity 
of eye irritations) based on ratings assessed with the labelled magnitude scale (LMS) and 
(7)  odour  threshold  shifts  measured  by  flow-olfactometry  (self-  and  cross-adaptation). 
The  study  included  a  dermal-only  exposure  phase  in  which  inhalational  uptake  was 
prevented  by  face  shields,  in  order  to  measure  dermal  uptake  of  NMP  from  the  vapour 
phase,  and  urine  samples  were  taken  in  order  to  investigate  the  absorption  and 
elimination  of  NMP  in  humans  under  workplace-oriented  conditions.  The  results  showed 
that NMP could be smelled by the subjects (odour intensity, showing some adaption over 
the 8 hour exposure period) and it was reported to be slightly annoying. However other 
symptomology  indicative  of  an  irritant  potential,  especially  trigeminal  sensations,  were 
not  elicited  by  NMP.  Median  intensity  ratings  of  annoyance  only  reached  “moderate” 
intensities. The odour intensity was rated slightly higher than annoyance, but the ratings 
exceeded  “moderate”  only  during  exposure  peaks.  The  peak  concentrations  were 
mirrored  by  the  ratings  of  odour  intensity  and  annoyance.  However,  neither  nasal  flow 
values  (AAR),  nor  eye  blink  rates,  and  breathing  rates  showed  any  dose-related 
response, even at the peak exposure of 160 mg/m3. None of the neuropsychological tests 
revealed any NMP-related effect with respect to cognitive abilities of the subjects during 
the exposures. The authors of the study concluded that NMP can be characterised as an 
odorous  substance  without  irritant  potency  even  during  peak  exposures  of  160  mg/m 3 
(van Thriel et al., 2007). 

A Japanese study of 15 workers, who cleaned components with an NMP solution (>90%), 
examined  clinical  effects  (urine  and  blood  status)  and  effects  on  motor  and  cognitive 
functions. Exposure, which was mainly by inhalation, was measured at about 0.13 – 0.25 
ppm  [0.6  –  1  mg/m3]  (8  h  TWA,  5  days).  The  authors  reported  no  effects  when 
compared with a control group (Nishimura et al 2009). 

7.3.2.  Animal data 

7.3.2.1. Inhalation 

A series of subacute, subchronic and chronic inhalation toxicity studies have been carried 
out in rats involving exposure to NMF as an aerosol or as a vapour.  Of these, the studies 
of Lee and co-workers (Lee et al., 1987) and the 1992–1995 studies carried out by BASF 
are  considered  to  be  the  most  reliable  for  determining  a  No-Adverse-Effect-Level 
(NOAEL). 

Lee  and  co-workers  exposed  rats  to  100,  500,  or  1000  mg/m3  NMP  for  6  h/day, 
5 days/week, for 4 weeks, using whole-body exposure (Lee  et al., 1987). Exposure was 
predominantly  to  an  aerosol,  with  >95%  of  droplets  <10  µm.  Deaths  were  seen  at 
1000 mg/m3  NMP,  accompanied  by  bone  marrow  hypoplasia  and  evidence  of  toxicity  in 
lymphoid  tissue  (thymus,  spleen,  and  lymph  nodes)  Concentration-related  lethargy  and 

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irregular  respiration  were  observed  at  all  dose  levels,  reversible  within  30  –  45  min  of 
exposure  at  the  100  and  500  mg/m3  exposure  levels.    No  treatment-related 
histopathological changes were reported at these dose levels.   

Irritation  of  the  nasal  passages  at  levels  of  1000  mg/m3  and  above  was  observed  in 
inhalational  toxicity  studies  carried  out  using  exposure  levels  of  between  10  and 
10,000 mg/m3 NMP as a liquid aerosol, head-only exposure, 6 h/day, 5 days/week for 2, 
4  or  13  weeks  (BASF,  1992,  1993b,  1993c,  1994,  cited  in  Greim,  1998).  Deaths  were 
seen at 7000 mg/m3 NMP and above, with female rats being more sensitive than males, 
while  exposure  to  3000  mg/m3  for  13  weeks  or  to  4000  mg/m3  and  above  for  14  days 
caused  respiratory  tract,  decreased  testis  weights  associated  with  histopathological 
changes including cell loss in the germinal cell epithelium and evidence of mild systemic 
toxicity, comprising body weight loss, mild hepatotoxicity and treatment-related changes 
in  haematological  parameters.  In  the  13-week  study,  3000  mg/m3  NMP  aerosol 
(6h/working  day)  caused  clinical  symptoms  of  upper  respiratory  tract  irritation,  general 
unspecific systemic toxicity, and in some male animals cellular depletion of the germinal 
epithelium  of  the  testes.  Whereas  the  symptoms  of  general  toxicity  were  mostly 
reversible during a 4-week recovery period, the testes damage persisted. The NOAEC for 
systemic toxicity was 1000 mg/m3, but there were slight signs of local nasal irritation at 
1000 mg/m3 without histopathological correlate. Therefore, the NOAEC for local effects to 
the upper respiratory tract was judged to be 500 mg/m3 [125 ppm] (BASF 1994). Yellow 
discoloration  of  the  urine  noted  at  levels  of  100  mg/m3  and  higher  may  be  due  to  a 
coloured  unidentified  metabolite  or  to  hepatic  dysfunction  (IPCS,  2001).  In  a  series  of 
whole-body  inhalation  studies  in  rats,  comparing  fine  aerosols  with  coarse  aerosols  and 
varying  humidity  conditions,  toxicity  was  more  marked  when  exposure  was  to  coarse 
droplets and high relative humidity (BASF, 1995a , b, c, d, e, f, g, cited in IPCS, 2001).  

Exposure  of  rats  to  NMP  vapour  at  a  level  of  1750  mg/m3  for  6  h/day,  5  days/week  for 
6 weeks  caused  only  slight  irritation  of  nasal  passages  (BASF,  1983,  cited  in  Greim, 
1998), while repeated exposure to 6600 mg/m3 was lethal to mice but without effect on 
rats, guinea pigs, rabbits or cats (BASF, 1964a, cited in Greim, 1998). 

In  a  2-year  inhalation  study,  CD-1  rats  (120  per  sex  per  dose  level)  were  exposed  to 
NMP as a vapour at levels of 0, 40, or 400 mg/m3 for 6 h/day, 5 days/week, whole body 
exposure (Lee et al., 1987). Ten rats per sex were subjected to haematology and blood 
and urine chemistry analysis after 1, 3, 6, 12, and 18 months of exposure and ten  rats 
per  sex were sacrificed after 3, 12, and 18 months. All surviving rats were killed at the 
end of 24 months of exposure.  Lee et al noted "alveolitis, acute, focal" in 2/84 male and 
in  13/84  female  controls,  and  in  10/85  and  12/85  male  and  female  400  mg/m3  rats. 
There  was  "alveolar  cell  hyperplasia/aggregated  macrophages"  in  0/84  male  and 
4/85 female  controls  and  in  4/84  and  9/84  male  and  female  400  mg/m3  rats.  Other 
histological  lung  effects  were  not  observed.  Male  rats  exposed  to  400  mg/m3  for 
18 months  showed  slight  body  weight  loss,  higher  haematocrit  and  higher  alkaline 
phosphatase levels in serum than were observed in the control group. There was no such 
difference  after  24  months  of  exposure.  At  the  400  mg/m3  exposure  level,  male  rats 
excreted larger urine volumes, and both males and females excreted dark yellow urine.  

7.3.2.2. Oral exposure 

Repeat-dose  oral  toxicity  studies  have  been  carried  out  in  rats,  mice,  rabbits,  guinea 
pigs, dogs, and cats (BASF 1964b, 1978a, cited in Greim, 1998; Meleschtschenko, 1970; 
Becci  et  al.,  1983;  GAF,  1990,  cited  in  Greim,  1998;  Malek  et  al.,  1997);  Malley  et  al., 
1999, 2001). Of these, only the BASF (1978a) gavage study in rats and the 28-day, 90-
day  and  18-month/2  year  dietary  studies  of  Malek,  Malley  and  co-workers  provide 
adequate detail about methodology and results obtained.   

In  a  28-day  study  in  rats  administered  0,  257,  514,  1028,  or  2060  mg/kg  bw/day  NMP 
for  5  days/week  by  oral  gavage  (BASF,  1978a,  cited  in  Greim,  1998),  dose-related 

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changes included tremor, restlessness, ruffled fur, and defensive reactions, decreases in 
body  weight  gain  and  increases  in  relative  liver  and  kidney  weights.    Relative  and 
absolute  testis  weights  were  decreased  in  males  receiving  2060  mg/kg  bw/day, 
accompanied by histological changes in the testis. The NOAEL in this study was 514 mg 
NMP/kg bw (BASF, 1978a, cited in Greim, 1998).    

The feeding studies in rats carried out more recently by the NMP Producers Group (Malek 
et al.,1997; Malley et al., 1999, 2001) at dietary dose levels up to 30,000 mg NMP/kg for 
28  days,  18,000  mg  NMP/kg  for  90  days  and  15,000  mg  NMP/kg  for  2  years  showed 
sedative effects and consistent decreases in body weight and body weight gain at higher 
dose  levels,  accompanied  by  lower  food  consumption.    Centrilobular  hypertrophy 
accompanied  by  increases  in  liver  weight  was  reported  in  high  dose  females  in  the  90-
day  study,  while  increases  in  kidney  weight  in  both  sexes  were  not  associated  with 
histopathological  changes.  At  2  years,  male  rats  at  the  highest  dose  level  showed  a 
significantly  increased  incidence  of  severe  progressive  nephropathy,  accompanied  by 
decreased  survival.  In  addition,  top  dose  males  showed  increased  incidences  of 
polyarteritis  in  the  caecum,  mesenteric  lymph  node  and  testis  and  accumulation  of 
pigment-containing macrophages in the spleen. While the kidney was concluded to be the 
main  target  organ  in  male  rats,  testicular  degeneration  and  atrophy  in  top  dose  males 
was  also  a  consistent  finding.  Top  dose  females  showed  lymphoid  depletion  of  the 
mesenteric  lymph  node  and  accumulation  of  pigment-containing  macrophages  in  the 
spleen at 2 years. Although there were dose-related trends in the incidence of a number 
of these changes in lower dose groups, none were statistically significant. The NOAEL in 
the  90-day  study  was  3000  mg/kg  diet,  equivalent  to  169  mg/kg  bw/day  in  male  rats 
and  217  mg/kg  bw/day  in  female  rats,  and  in  the  2-year  study  was  reported  to  be 
5000 mg/kg,  equivalent  to  207  mg/kg  bw/day  in  male  rats  and  283  mg/kg  bw/day  in 
female rats (Malley et al., 1999, 2001). 

In 28-day, 90-day and 18-month studies in mice (Malek et al., 1997; Malley et al., 1999, 
2001),  effects  on  body  weight  change  and  food  consumption  were  less  marked  than 
those  seen  in  rats.  Centrilobular  hypertrophy  accompanied  by  increases  in  liver  weight 
were seen in male and female B6C3F1 mice administered NMP at levels of 7500 mg/kg in 
the diet for 90 days or 2 years (equivalent to 1931 mg/kg bw/day) and at 1200 mg/kg in 
the diet (males only) for 2 years, while histological changes were reported in the kidneys 
of  mice  receiving  2030  mg/kg  diet  and  above  for  28  days.      The  NOAEL  in  the  90-day 
study was 1000 mg/kg diet, equivalent to 277 mg/kg bw/day, and in the 18-month study 
was  600  mg/kg  in  male  mice  (equivalent  to  89  mg/kg  bw/day)  and  1200  mg/kg  in 
female mice (equivalent to 115 mg/kg bw/day) (Malley et al., 1999, 2001). 

7.3.2.3. Dermal exposure 

Summary  details  only  of  a  repeat-dose  dermal  toxicity  study  in  rabbits  are  provided  in 
the 1990 report of GAF (GAF, 1990, cited in Greim, 1998).  Undiluted NMF applied to the 
intact or abraded skin of rabbits at levels of 0, 411, 822 or 1645 mg/kg/day for 20 days 
produced local irritancy but there were no signs of systemic toxicity although one animal 
treated with 1645 mg/kg/day (abraded skin) died.   

7.3.3.  In vitro data 

There are no in vitro toxicity data, which are relevant for the current evaluation. 

7.4.  Irritancy and corrosivity 

7.4.1.  Human data 

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 

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workers  in  the  paint-stripping  industry  coming  into  contact  with  NMP  (Åkesson  & 
Jönsson,  2000a),  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).  

7.4.2.  Animal data 

7.4.2.1. Skin 

Several skin irritation studies in rabbits involving a single application of 0.5 ml NMP under 
an occlusive dressing have shown a low potential for irritancy (Draize et al., 1944; Ansell 
& Fowler, 1988). In contrast, severe erythema and subsequent scaling at the application 
site was reported in a study in rabbits carried out by BASF (BASF, 1963, cited in Greim, 
1998).    Repeated  daily  dermal  administration  of  450  mg/kg  body  weight  to  rabbits 
caused  painful  and  severe  haemorrhage  and  eschar  formation  after  four  doses;  the 
reaction  to  a  dose  of  150  mg/kg  body  weight  per  day  was  less  marked  (BASF,  1993a, 
cited in IPCS (2001).  Application of 20 daily doses of undiluted NMF at dose levels up to 
1645  mg/kg  bw/day  to  the  intact  or  abraded  skin  of  rabbits  caused  only  mild  irritation 
(GAF, 1990, cited in Greim, 1998).  

7.4.2.2. Eyes 

Following  instillation  of  0.1  ml  NMP  into  the  eyes  of  New  Zealand  White  marked 
conjunctival  irritancy  including  corneal  opacity,  iritis,  and  conjunctivitis  was  observed 
(Draize et al., 1944).  The effects were reversible within the 21 day observation period of 
the  study.  Moderate  to  marked  eye  irritancy  was  also  reported  in  studies  carried  out  in 
rabbits by BASF (1951, 1963, cited in Greim, 1998), Ansell and Fowler (1988) and GAF 
(GAF, 1990, cited in Greim, 1998). 

7.4.3.  In vitro data 

No data found. 

7.5.  Sensitisation 

7.5.1.  Human data 

There are no reports of sensitisation in workers following dermal contact with NMP. NMP 
produced  no  signs  of  contact  sensitisation  in  a  repeated-insult  patch  test  in  human 
subjects, although minor to moderate transient irritation was observed (Lee et al., 1987). 

7.5.2.  Animal data 

In  a  modified  Draize  test  in  guinea  pigs,  repeated  application  of  a  5%  NMP  solution  did 
not  produce  any  signs  of  sensitisation  (Lee  et  al.,  1987).  No  further  details  were 
provided.      Similarly,  no  evidence  of  sensitisation  was  observed  in  an  intradermal 
sensitisation  potential  test  involving  4  intradermal  injections  of  0.1  ml  of  1%  NMP  in 
saline in Guinea pigs, followed by application of a 5% or a 50% aqueous solution of NMP 
and  examination  after  24  and  48  h  (du  Pont,  1976a,  cited  in  IARC,  2001).  The  50% 
solution produced slight irritancy at the application site.  

7.5.3.  In vitro data 

Shortt  et  al  (2014)  described  antineoplastic  and  immune-modulatory  activity  in  a  cMYC 
driven  myeloma  model  in  vitro.  The  authors  challenged  the  use  of  NMP  as  an  "inert" 
drug-delivery vehicle. 

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7.6.  Genotoxicity 

7.6.1.  Human data  

There are no human studies known on genotoxicity of NMP. 

7.6.2.  Animal data 

No  evidence  of  clastogenicity  or  aneugenicity  was  seen  in  a  micronucleus  test  in  which 
male  and  female  NMRI  mice  were  administered  single  oral  doses  (by  gavage)  of  950, 
1900, or 3800 mg NMP/kg body weight. The animals showed signs of systemic toxicity as 
evidenced  by  irregular  respiration,  coloured  urine,  and  general  poor  health  (Engelhardt 
and Fleig, 1993).  Similarly, no evidence of clastogenicity or aneugenicity was seen in a 
bone marrow chromosomal aberration study in which male and female Chinese hamsters 
were  administered  single  oral  doses  of  1900  or  3800  mg  NMP/kg  body  weight,  dose 
levels which produced signs of systemic toxicity (Engelhardt and Fleig, 1993).  

Significantly increased post-implantation losses were observed compared with controls in 
a  dominant  lethal  test  in  male  NMRI  mice  given  391  mg  NMP/kg  body  weight 
intraperitoneally  once  per  week  for  8  consecutive  weeks  (BASF,  1976a,  cited  in  Greim, 
1998). In a micronucleus test in male and female Chinese hamsters exposed for 6 weeks 
(6  h/day,  5  days/week)  to  3300  mg  NMP/m3  a  slight  but  non-significant  increase  in 
structural  chromosomal  aberrations  in  the  bone  marrow  was  reported  (BASF,  1976b, 
cited  in  Greim,  1998).    None  of  the  studies  was  performed  according  to  current 
regulatory standards, and therefore they are not adequate for the purposes of evaluation 
of the mutagenicity of NMP. 

7.6.3.  In vitro 

A number of bacterial mutagenicity studies have been carried out, using tester strains TA 
97,  98,  100,  102,  104,  1535,  1537  and  NMP  dose  levels  in  the  range  of  0.01–1000 
µmol/plate, equivalent to 0.99 µg/plate to 99 mg/plate, with cytotoxicity being evident at 
the  highest  dose  levels  (BASF,  1978b,  cited  in  Greim,  1998;  Maron  et  al.,  1981; 
Mortelmans  et  al.,  1986;  Wells  et  al.,  1988).  All  tests  gave  negative  results  with  and 
without metabolic activation. Negative results were also obtained in mammalian cells, in 
the  L5178Y  mouse  lymphoma  test  (du  Pont,  1976b,  cited  in  IPCS,  2001),  in  the  HPRT 
(hypoxanthine  guanine  phosphoribosyl  transferase)  test  in  CHO  cells  and  in  the  UDS 
(unscheduled DNA synthesis) assay in rat primary hepatocyte cultures (GAF, 1990, cited 
in Greim, 1998). NMP at high concentrations of 77 230 mmol/l, equivalent to 7.6–23 g/l, 
has however been reported to induce aneuploidy in Saccharomyces cerevisiae strain D61 
(Mayer et al., 1986, 1988; Mayer and Goin, 1988; Zimmermann et al., 1988).  

7.7.  Carcinogenicity 

7.7.1.  Human data 

There are no epidemiological studies known on carcinogenicity of NMP. 

7.7.2.  Animal data 

In a 2-year inhalation study, groups of 120 male and 120 female Charles River CD  rats 
were  exposed  to  NMP  as  a  vapour  at  levels  of  0,  40,  or  400  mg/m3  for  6  h/day, 
5 days/week,  whole  body  exposure,  as  already  detailed  in  section  7.3.2  (Lee  et  al., 
1987).    Male  rats  exposed  to  400  mg/m3  showed  slight  body  weight  loss,  higher 
haematocrit  and  higher  alkaline  phosphatase  levels  in  serum  and  they  excreted  larger 

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urine volumes than did the control group. Both males and females excreted dark yellow 
urine.  Minimal  inflammation  in  the  lung  was  observed  at  the  highest  exposure  level  of 
400  mg/m3.  There  were  no  significant  differences  in  morbidity  or  mortality  and  no 
evidence of carcinogenic effects of NMP in this study. 

Carcinogenicity  studies  in  rats  and  mice  commissioned  by  the  NMP  Producers  Group 
showed  no  evidence  of  a  carcinogenic  effect  in  rats  at  dietary  concentrations  of  15000 
mg/kg  and  below  (Malley  et  al.,  2001).    Male  B6C3F1  mice  receiving  NMP  at  levels  of 
7200 mg/kg in the diet (equivalent to 1089 mg/kg bw/day) showed a significant increase 
in hepatocellular carcinoma (13/50 compared  with 4/50 in the control group) (Malley et 
al.,  2001).    Female  mice  in  this  dose  group  also  showed  a  significant  increase  in 
hepatocellular  carcinoma  (3/50  compared  with  0/50  in  the  control  group),  however  the 
incidence fell within the historical control.  Hepatocellular adenomas were also increased 
in both male and female mice. The authors considered that these tumours were produced 
by a non-genotoxic mechanism, due to enhanced  cell proliferation in the liver (Parod  et 
al., 2001). 

7.8. Reproductive toxicity 

7.8.1. Human data 

A  23-year  old  laboratory  technician  was  occupationally  exposed  to  NMP  during  her  first 
20  weeks  of  pregnancy,  in  particular  due  to  an  NMP  spill in  week  16  of  pregnancy.  She 
experienced malaise, headache, and nausea during the 4 days following the spill, and at 
week  25,  signs  of  delayed  foetal  development  were  observed.    A  stillborn  foetus  was 
delivered  at  week  31.    No  information  on  the  mother’s  level  of  exposure  to  NMP  is 
available, and it was concluded that it was impossible to establish if exposure to NMP was 
the causative factor (Solomon et al., 1996; Bower, 1997). 

7.8.2. Animal data 

7.7.2.1. Fertility 

The  repeat  dose  toxicity  studies  summarised  in  section  7.3.2  indicate  that  exposure  of 
male  rats  to  high  levels  of  NMP  is  associated  with  decreased  testicular  weight  and 
histopathological changes including cell loss in the germinal cell epithelium (BASF, 1978a, 
cited  in  Greim,  1998,  1992,  cited  in  IPCS,  2001,  1993b,  1993c,  1994,  cited  in  Greim, 
1998;  Malek  et  al.,  1997).  A  toxicokinetic  study  in  rats  with  radio-labelled  NMP  showed 
highest  levels  of  radioactivity  in  the  testis,  liver,  bile,  small  intestine,  kidneys  and 
stomach,  with  0.9%  of  the  administered  dose  being  recovered  in  the  testis  (Wells  and 
Digenis, 1988).   

However,  Fries  and  co-workers  reported  no  effect  on  testis  or  sperm  morphology  and 
sperm count in 24 male Wistar rats exposed to NMP vapour at a level of 618 mg/m3 (150 
ml/ m3) for 90 days (Fries et al. 1992, cited in Greim, 1998).  

7.7.2.2. Developmental toxicity 

NMP  has  been  shown  to  cross  the  placental  barrier,  with  an  equilibrium  between  foetal 
and maternal blood (Ravn-Jonsen et al., 1992).  

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7.7.2.3. Inhalation 

In  a  two-generation  reproduction  study  in  rats  10  males  and  20  females  per  dose  level 
were  exposed whole body to 0, 10, 51 or 116  ppm [0, 41, 206, or 478 mg/m3] of NMP 
vapour  (relative  humidity  40–60%)  for  6  h/day,  7  days/week,  for  a  minimum  of 
14 weeks (Solomon et al., 1995). Animals were mated after a 12-week exposure period 
and  both  parents  and  offspring  were  examined  for  adverse  effects  on  reproduction.  No 
effects  on  reproductive  ability  were  recorded.  However,  a  very  slight  but  statistically 
significant reduced body weight gain was evident in the F1 pups whose parents had been 
exposed  to  116  ppm  [478  mg/m3].  P0  dams  showed  reduced  sensitivity  to  noise.  The 
NOAEL  for  both  reproductive  and  maternal  toxicity  was  reported  to  be  51  ppm  [206 
mg/m3] (Solomon et al., 1995). 

A developmental toxicity study by the inhalation route, at exposure levels of 0, 10, 51 or 
116 ppm [0, 41, 206, or 478 mg/m3] of NMP vapour, was carried out in rats by Solomon 
and co-workers as part of the two-generation reproductive toxicity study reported above 
(Solomon et al., 1995). No effects on pregnancy rate, numbers of viable litters, corpora 
lutea,  implantations,  foetal  deaths,  resorptions,  litter  size,  or  incidence  of  foetal 
malformations or variations were reported, although the mean foetal weight was slightly, 
but statistically significantly decreased in the highest dose group.  

NMP was  reported to have no embryotoxic, foetotoxic or teratogenic effects in pregnant 
rats exposed whole body to 0, 100, or 360 mg /m3 [0, 25 or 90 ppm] for 6 h/day on days 
6–15 of gestation (Lee et al., 1987).  Maternal toxicity was not observed in this study.   

Whole body exposure of pregnant rats to 680 mg/m3 [170 ppm] NMP vapour for 6 h/day 
on days 4–20 of gestation resulted in increased pre-implantation loss compared with the 
control group, there was no significant effect on the number of implantations per dam or 
on number of live foetuses (Fries et al., 1992, cited in Greim, 1998; Hass et al., 1995). 
Delayed  ossification  of  the  skull,  cervical  vertebrae,  sternebrae,  and  metatarsal  and 
digital  bones  was  also  observed,  in  the  absence  of  clinical  signs  of  maternal  toxicity, 
malformations were not increased.   

In  a  study  conducted  by  Saillenfait  and  co-workers,  pregnant  rats  were  exposed  whole 
body  to  NMP  vapour  at  concentrations  of  0,  30,  60  and  120  ppm  [0,  125,  250,  500 
mg/m3]  for  6  h/day,  on  days  6  –  20  of  gestation  (Saillenfait  et  al.,  2003).  Significant 
decreases  in  maternal  body  weight  gain  and  food  consumption  were  seen  at  120  ppm, 
with some slight decrease in body weight gain also being evident at 60 ppm.  There were 
no  adverse  effects  on  embryo/foetal  viability  or  evidence  of  teratogenicity  at  any 
concentration tested. A marginal foetal toxicity was indicated by reduced foetal weight at 
120  ppm  (5.52  ±  0.4  g  vs.  5.81  ±  0.39  g  in  controls).  No  maternal  or  developmental 
toxicity was recorded at 30 and 60 ppm [125 and 250 mg/m3], respectively. 

In  a  neurobehavioural  teratology  study  in  pregnant  rats  exposed  whole  body  to 
622 mg/m3  [156  ppm]  NMP  vapour  for  6  h/day  on  days  7–20  of  gestation,  most  of  the 
behavioural  tests  gave  similar  results  for  the  exposed  and  control  animals  (Hass  et  al., 
1994).    An  occasionally  increased  latency  in  Morris  swimming  maze  and  a  statistically 
borderline  impairment  in  operant  behaviour  with  delayed  spatial  alternation  were 
however noted among the exposed offspring.  Pups had a somewhat lower body weight 
and slight delay in achieving some developmental milestones in the pre-weaning period.  

Pregnant rabbits were exposed head only for 6 h/day to 0, 200, 500, or 1000 mg/m3 [50, 
125  or  250  ppm]  NMP  (vapour/aerosol;  MMAD  2.7–3.5  µm)  on  days  7–19  post-
insemination.  Slight  developmental  toxicity  in  the  absence  of  maternal  toxicity  was 
manifest  as  an  increased  occurrence  of  supernumerary  13th  ribs  in  the  1000  mg/m3 
[250 ppm] group (BASF, 1993d, cited in IPCS, 2001). No malformations were observed. 
The NOAEL for developmental and maternal toxicity was 500 mg/m3 [125 ppm]. 

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7.7.2.4. Oral 

In a multi-generation reproduction study by the oral route, in which rats were exposed in 
the diet to NMP at doses of 50, 160, or 500 mg/kg bw/day, the highest dose level caused 
an  increased  incidence  of  stillbirths,  decreased  parental  body  weight  and  food 
consumption,  slightly  lower  male  fertility  and  female  fecundity  (Exxon,  1991,  cited  in 
IPCS, 2001).  Because of pup toxicity at the 500 mg/kg bw level, the dose was decreased 
to 350 mg/kg bw. for the remainder of the study. There was a concomitant reduction in 
survival  and  growth  rates  in  the  F1  generation  and  testis  weights  were  reduced  in  the 
male  pups.  No  effect  was  seen  in  the  50  and 160  mg/kg  bw  per  day  groups.  When  the 
dose was reduced to 350 mg/kg bw/day, NMP did not cause maternal toxicity or reduced 
pup survival. The NOEL for parental and reproductive effects was 350 mg/kg bw/day and 
that for growth and development of the offspring was 160 mg/kg bw/day. 

Pregnant  rats  were  given  daily  NMP  doses  of  0,  40,  125,  or  400  mg/kg  bw/day  by  oral 
gavage  on  days  6–15  of  gestation.  Maternal  and  foetotoxicity  were  observed  at  the 
highest  dose  level  compared  with  control,  as  evidenced  by  decreases  in  maternal  body 
weight  gain  decrement,  reduced  foetal  body  weights  and  increased  incidence  of  foetal 
stunting (EXXON, 1992, cited in IPCS, 2001).  Oral gavage administration of 997 mg/kg 
bw/day  to  rats  on  days  6–15  of  gestation  caused  increased  resorptions  (95%)  and 
malformations  in  8  out  of  15  surviving  foetuses,  accompanied  by  foetal  mortality, 
reduced  placental  and  foetal  weights,  and  reduced  foetal  lengths    (BASF,  1971,  cited in 
Greim,  1998).  Insufficient  detail  was  provided  on  maternal  toxicity in this  study.    In  an 
oral  developmental  toxicity  study  in  Sprague  Dawley  rats,  using  dose  levels  of    0,  125, 
250,  500  and  750  mg/kg  body  weight  by  gavage,  significant  impairments  in  maternal 
body weight gain and food consumption were noted at doses of 500 mg/kg body weight 
and above (Saillenfait et al. 2002). At the 250 mg/kg dose, effects on body weight gain 
(day  6  –  21)  and  absolute  weight  gain  were  about  10%  below  control  and  associated 
with  a  reduction  in  foetal  weight  at  this  dose  level.  Only  the  latter  gained  statistical 
significance.  Foetal  body  weight  was  dose  dependently  decreased  at  250  mg/kg  (10%) 
and 500 (30%) or 750 mg/kg (47% less than control) as was maternal body weight gain. 
A  significant  increase  (p  0.01  or  0.05)  in  malformations  was  observed  at  500  and 
750 mg/kg and consisted of external (anasarca, anal atresia, the latter considered not to 
be dose-related), soft tissue (persistent truncus arteriosus) and skeletal findings (fusion 
or absence of cervical arches were most prominent). 

In rabbits, gavage administration of 55, 175 or 540 mg/kg bw/day NMP on days 6–18 of 
gestation  caused  developmental  toxicity  as  evidenced  by  post-implantation loss,  altered 
foetal morphology, and increased incidences of cardiovascular and skull malformations at 
540 mg/kg body weight per day (GAF, 1991). The NOAEL for developmental toxicity was 
175 mg/kg bw/day.  Maternal toxicity as evidenced by decreased body weight gain was 
apparent at 175 and 540 mg/kg bw/day. 

In  mice,  oral  doses  of  0,  1055,  or  2637  mg/kg  bw/day  on  days  11–15  of  gestation 
caused an increase in resorptions, increased incidence of runts, diminished foetal weight 
and  length,  and  an  increased  rate  of  malformations  including  as  cleft  palate  at  the 
highest  dose  level  (BASF,  1970,  cited  in  Greim,  1998).  The  lower  dose  level  caused  no 
apparent  foetotoxicity,  however  insufficient  detail  was  provided  on  maternal  toxicity  in 
this study. 

7.7.2.5. Dermal 

Pregnant rats were administered daily dermal doses of 0, 75, 237, or 750 mg/kg bw/day 
NMP on days 6-15 of gestation (Becci et al., 1982). Maternal and developmental toxicity 
were  evident  at  the  highest  dose  level,  evidenced  by  decreased  maternal  body  weight 
gain,  increased  resorptions  and  decreased  foetal  body  weight,  skeletal  abnormalities 

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including  missing  sternebrae  and  fused/split/extra  ribs,  incomplete  closing  of  the  skull, 
incomplete  ossification  of  vertebrae,  fused  atlas  and  occipital  bones,  and  reduced  or 
incomplete hyoid bone on day 20 of gestation. There was no increase in the incidence of 
soft  tissue  anomalies.  The  NOAEL  for  maternal  and  developmental  toxicity  was  237 
mg/kg body weight per day.  

In  rabbits  dermally  exposed  to  0,  100,  300,  or  1000  mg/kg  bw/day  NMP  as  a  40% 
aqueous  solution  for  6  h/day  on  days  7–19  post-insemination,  slight  foetal  toxicity  as 
evidenced by an increased occurrence of supernumerary 13th ribs was apparent at 1000 
mg/kg  bw/day  (BASF,  1993a,  cited  in  IPCS,  2001).    There  were  no  signs  of  maternal 
toxicity. The NOAEL for maternal and developmental toxicity was 300 mg/kg body weight 
per day.  

7.7.2.6. Other routes 

Intraperitoneal  studies  in  mice  have  shown  evidence  of  developmental  toxicity  of  NMP, 
evidenced  by  exencephaly,  open  eyelids,  microphthalmia,  cleft  palate,  oligodactyly, 
shortened or kinked tails, fusions and curvature of neck and chest vertebrae, and fusion 
of  sternebrae  and  ribs  (BASF,  1970,  cited  in  Greim,  1998;  Schmidt,  1976).  Conclusions 
cannot  be  drawn  from  these  studies,  due  to  the  inappropriate  method  of  exposure  and 
lack of detail on maternal toxicity. 

7.8.3. In vitro data 

Flick  and  coworkers  (Flick  et  al.,  2009)  studied  the  toxicity  of  NMP  and  3  metabolites 
(5-HNMP, MSI, 2-HMSI) in an in vitro culture system comprising whole rat embryos. The 
embryos  were  exposed  to  up  to  0.06%  NMP,  equivalent  to  0.006  mol/l  in  the  medium, 
and  up  to  0.44%  5-HNMP,  MSI  or  2-HMSI  on  days  9.5-11.5  of  pregnancy.  The  results 
showed  that  exposure  to  NMP  (≥0.03%  or  0.003  mol/l)  and  5-HNMP  (≥0.10%)  cause 
foetal  injuries  comprising  abnormalities  of  the  cranium,  abnormal  development  of  the 
second  visceral  arch  and  delayed  anterior  neuropore  closure.  On  this  basis  the  authors 
concluded that NMP and 5-HNMP could be classified as weak teratogens, and that 2-HMSI 
and MSI have no teratogenic effects. [Note: The extremely high NMP concentrations used 
in  this  study  should  be  recognised,  0.003  mol/l  equalling  300  mg/l.  In  the  human 
biomonitoring study of Xiaofei et al. (2000), an 8 h TWA exposure to 0.5 ppm resulted in 
a  plasma  concentration  of  0.1  mg  NMP  per  litre.  Upon  linear  extrapolation,  a  human 
exposure (8 h TWA) to  the  proposed OEL  of 10 ppm would therefore result in a plasma 
NMP concentration of only 2 mg/l. Therefore, the findings of this study cannot be related 
to any human exposure condition.] 

7.9. Mode of action and adverse outcome pathway considerations 

NMP is an aprotic solvent miscible with both water and lipophilic solvents. Owing to these 
properties,  it  has  a  high  potential  to  penetrate  the  human  skin  barrier  and  to  act 
systemically.  

NMP  has  a  characteristic  amine-like  ”fishy”  odour.  In  terms  of  criteria  of  the  current 
SCOEL “Methodology for the Derivation of Occupational Exposure Limits” (version 7, June 
2013;  chapter  3.1)  this  effect  in  humans  is  very  slight,  leading  to  an  awareness  of 
exposure. Such an effect is not considered as being adverse for workers.  

The  key  toxicity  observed  in  humans  is  local  irritation,  based  on  data  both  in  humans 
(upper  airways)  and  in  experimental  animals  (lung).  Workers  exposed  to  up  to 
280 mg/m3  NMP  at  80  °C  reported  severe  eye  irritation  and  headache  (Beaulieu  and 
Schmerber, 1991), although an exposure–response relationship could not be established. 

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A  carefully  designed  human  volunteer  study  (van  Thriel  et  al.,  2007)  has  indicated  the 
absence  of  irritation  at  mean  airborne  concentrations  up  to  80  mg/m3  [20  ppm]  (with 
15 min peaks of 160 mg/m3 [40 ppm]).  

Experimentally,  there  are  a  number  of  animal  studies  by  the  inhalation  route,  which  is 
the  generally  preferred  exposure  route  to  derive  an  OEL  (SCOEL  Methodology,  chapter 
3.3.2). A common effect across most of these studies is slight retardation in body weight 
gain.  Considering  this  effect  (among  others),  in  a  90-day  rat  inhalation  study  (BASF 
1994,  cited  in  Greim,  1998;  7.3.2)  the  NOAEC  was  assessed  to  be  500  mg/m3  [125 
ppm].  

Upon a 2 years inhalation study in rats (Lee et al., 1987) there was minimal inflammation 
in  the lung  at  the  highest  exposure  level  of  400  mg/m3  (100  ppm).  This  effect  appears 
generally  compatible  with  the  local  irritating  properties  of  NMP.  Also,  at  this  highest 
concentration male rats showed slight reduction in mean body weight. It must be noted 
that  there  was  a  wide  dose-spacing in  the  study  of  the  2-years  study  of  Lee  et  al,  with 
the next lower concentration (with no such effect) at 40 mg/m3 [10 ppm]. 

The  central  studies  are  three  rat  developmental  toxicity  studies  upon  inhalation.  Slight 
retardation  in  foetal  and  pup  weight  gain  was  reported  in  two  studies  (Solomon  et  al., 
1995; Saillenfait et al., 2003; 7.8.2), but not in a third study (Lee et al., 1987):  

(1) Saillenfait et al. (2003) reported on reduced food consumption, reduced maternal 
body  weight  gain,  and  reduced  foetal  weight  at  120  ppm  [480 mg/m3].  At  60 ppm 
[240 mg/m3] there was only a slight reduction in maternal body weight gain on days 
6-13 of gestation, but no significant later reduction on days 13-21.  

(2) Solomon et al. (1995) reported a very slight decrease in foetal weight in the F1 
offspring  at  116  ppm  [464  mg/m3],  with  NOAEC  being  51  ppm  [204 mg/m3].  This 
slight effect also appeared at birth among the pups of the reproductive phase where 
it  persisted  for  21  days  after  birth,  when  NMP  inhalation  of  the  mother  ceased. 
Thereafter,  the  body  weight  of  the  offspring  was  within  the  range  of  the  control 
values. [A low palatability of the mother’s milk might be a factor contributing to this 
effect.] Again, no developmental effects appeared in the 10 ppm [41  mg/m3] or 51 
ppm [210 mg/m3] groups.  

(3) In the rat developmental toxicity study by Lee et al. (1987) exposure to 100 [24 
ppm]  or  360  mg/m3  [87  ppm]  (6  h/d  on  days  6  through  15  of  gestation)  did  not 
affect either the outcome of pregnancy or the embryonal growth rate.  

Thus,  the  results  of  all these  three  developmental  toxicity  studies  show  only  very  slight 
or no effects at doses up to 120 ppm. Considering the overall weight of evidence, there 
might  be  a  tentative,  borderline  and  transient  and  reversible  effect  on  the  pup  weight, 
with a NOAEC of 51 ppm, based on the study of Solomon et al. (1995). However, if such 
an effect would be assumed to  exist, the degree of adversity for humans appears to be 
very low, as the effect is slight/borderline and fully reversible. It is not supported by all 
inhalation studies performed. In the study by Saillenfait et al, there was some decrease 
in foetal BW at 120 ppm, but in the presence of reduced maternal food consumption and 
small  reductions  in  maternal  body  weight.  As  the  studies  by  Lee  et  al  (1987)  and  by 
Solomon  et  al  (1995)  were  performed  at  the  same  laboratory,  one  would  expect  no 
relevant methodological differences between these studies.  

In  summary,  for  local  irritancy  in  humans  a  NOAEC  of  20 ppm  (highest  concentration 
tested, with peak concentrations of 40 ppm, van Thriel et al., 2007) is well established. 
Experimentally,  a  NOAEC  of  51  ppm  is  only  related  to  a  borderline,  transient  and 
reversible effect on pup weight, with a very low toxicological significance for workers and 
humans in general.  

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7.10. Lack of specific scientific information 

Overall,  for  NMP,  a  very  well  investigated  chemical  substance.  The  specific  scientific 
information  currently  available  is  considered  to  be  adequate  for  the  recommendation  of 
an OEL. 

8. GROUPS AT EXTRA RISK 

NMP  is  largely  metabolised  via  CYP2E1  (7.1.1;  7.1.2),  an  isoform  that  displays  some 
metabolic  variability in humans  (Bolt  et  al.,  2003).  However,  the  biological  relevance  of 
this phenomenon for solvent metabolism in workers, if any, is controversial (Lucas et al., 
2001; Haufroid et al., 2002). Therefore, no practical conclusions can be drawn, as far as 
specific  individual  situations  of  a  potential  metabolic  hyper-susceptibility  to  NMP  are 
concerned.  

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