PDE FOR TRIETHYLAMINE AND 
METHYLISOBUTYLKETONE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This recommendation represents the Food and Drug Administrations (FDAs) current thinking 
on this topic.  It does not create or confer any rights for or on any person and does not operate 
to bind FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the FDA staff responsible for implementing the Q3C guidance.  If you cannot 
identify the appropriate FDA staff, call the appropriate number listed on the title page of the 
guidance.    
 
 
For questions regarding this document, contact (CDER) Timothy J. McGovern 240-402-0477. 
IMPURITIES : RESIDUAL SOLVENTS (MAINTENANCE) 
PDE FOR TRIETHYLAMINE AND PDE OF 
METHYLISOBUTYLKETONE  
TRIETHYLAMINE 
Introduction 
Triethylamine (TEA) is used as catalytic solvent in chemical synthesis (1,2).  It is a 
colourless liquid that is soluble in water, ethanol, carbon tetrachloride, and ethyl 
ether, and very soluble in acetone, benzene, and chloroform.  TEA has a vapour 
pressure of 54 mmHg (20C), and has been reported to be irritating to the lung and 
nasal passage with strong ammoniac odour (2,3).  
 
Data  from  human  studies  show  that  TEA  is  easily  absorbed  via  the  oral  or 
inhalation  route  and  is  rapidly  excreted,  mainly  in  the  urine,  as  the  parent 
compound and/or its N-oxide (4-6).  
In studies in human volunteers, exposures of more than 2.5 ppm (10 mg/m3) caused 
transient  visual  disturbance  (4,7)  due  to  a  locally  induced  cornea  swelling;  no 
systemic effects were observed at the exposures which showed the cornea effect.  The 
odour thresholds ranged from 0.0022 to 0.48 mg/m3 (8-10). 
Genotoxicity 
In an Ames test TEA did not induce mutations in standard Salmonella strains with 
or without metabolic activation (11).  TEA did not induce sister chromatid exchanges 
in Chinese hamster ovary cells with or without metabolic activation (12).  In an in 
vivo study, TEA induced aneuploidy but was not clastogenic in the bone marrow of 
rats exposed to 1 mg/m3 (0.25 ppm) and 10 mg/m3 (2.5 ppm) TEA via continuous 
inhalation for 30 or 90 days (13).  The weak aneugenic effect was observed at the 
low dose and early time point only; due to study deficiencies the relevance of this 
finding is highly questionable. Overall, the available data do not provide evidence 
for a relevant genotoxic potential of TEA. 
Carcinogenicity 
No data available. 
Reproductive toxicity 
No reliable information about reproductive toxicity is available. A three-generation 
reproductive study in which rats (10/sex/group) were administered 0, 2, or 200 ppm 
(c.a. 0, 0.14 or 14 mg/kg/day) TEA in drinking water was cited in the United States 
Environmental  Protection Agency (US EPA) Integrated Risk Information System 
assessment  review  (14).    The  high  dose  was increased to 500 ppm in the third   
generation due to a lack of observed symptoms.  No apparent effects occurred at 200 
ppm through two generations.  However, due to deficiencies in end-points measured 
the  study  data  were  disregarded  from  determining  a  Permitted  Daily  Exposure 
(PDE).  
Repeated dose toxicity 
A sub-chronic inhalation study (similar to Organisation for Economic Cooperation 
and Development [OECD] Test Guideline 413 and OECD Test Guideline 452) in rats 
is considered to be the most relevant published animal study for deriving a PDE.  
F344  rats  (50  rats/group/sex)  were  exposed  by  whole  body  inhalation  at 
concentrations  of  0,  25,  or  247  ppm  (0,  0.10  or  1.02  mg/L)  for  6  hours/day, 5 
days/week for 28 weeks (15).  No statistically significant treatment-related systemic 
effects were observed at all dose groups.  Body weight gain was not statistically 
affected, although a slight dose-related decrease of body weight in male rats was 
observed.  The No Observed Effect Level (NOEL) of this study was 247 ppm.  
 
Molecular weight of TEA: 101.19 g/mol 
NOEL 247 ppm  
 
247 x 101.19
247 ppm =   = 1022.2 mg/m3=1.022 mg/L 
24.45
 
 
1.022 x 6 x 5
For continuous dosing =   = 0.183 mg/L 
24 x 7
 
 
0.183mg L-1 x 290 L day-1
Daily dose =   = 124.9 mg/kg/day 
0.425 kg
 
Rat respiratory volume: 290 L day-1 
Rat body weight: 0.425 kg   
 
 
124.9 x 50
PDE =   = 62.5 mg/day 
5 x 10 x 2 x 1 x 1
 
F1 = 5 to account for extrapolation from rats to humans 
F2 = 10 to account for differences between individual humans   
F3 = 2 because long duration of treatment (28 weeks) 
F4 = 1 because no severe effects were observed 
F5 = 1 because a NOEL was established 
 
62.5 x 1000
Limit  =   = 6250 ppm 
10
 
Due  to  obvious  study  deficiencies  other  published  animal  toxicity  data  were 
disregarded from determining a PDE. 
Conclusion 
The calculated PDE for TEA based upon the NOEL of the rat sub-chronic inhalation 
study  is  62.5  mg/day.   Since the proposed PDE is greater than 50 mg/day it is 
recommended that TEA be placed into Class 3 (solvents with low toxic potential) in 
Table 3 in the ICH Impurities: Residual Solvents Guideline. 
References 
1.  Lide DR. CRC Handbook of Chemistry and Physics 86th ed. Boca Raton, FL, 
CRC Press, Taylor & Francis; 2005, p. 3-498. 
2.  Lewis RJ. Sr. Hawley's Condensed Chemical Dictionary 14th ed. New York: 
John Wiley & Sons; 2001, p. 1125. 
3.  OECD SIDS Initial Assessment Profile: Tertiary Amines. CoCAM 2, [Online]. 
2012  April  17;  Available  from:  URL: 
http://webnet.oecd.org/hpv/ui/Default.aspx 
4.  Akesson B, Skerfving S, Mattiasson L. Experimental study on the metabolism 
of triethylamine in man. Br J Ind Med 1988;45:262-8.  
5.  Akesson  B,  Vinge  E,  Skerfving  S.  Pharmacokinetics of triethylamine and 
triethylamine-N-oxide in man. Toxicol Appl Pharmacol 1989;100:529-38. 
6.  Akesson B, Skerfving S, Stahlbom B, Lundh T. Metabolism of triethylamine 
in polyurethane foam manufacturing workers. Am J Ind Med 1989;16:255-
65. 
7.  Akesson  B,  Floren  I,  Skerfving  S.  Visual disturbances after experimental 
human exposure to triethylamine. Br J Ind Med 1985;42:848-50. 
8.  Amoore JE, Hautala E. Odor as an aid to chemical safety: Odor thresholds 
compared  with  threshold  limit  values  and  volatilities  for  214  industrial 
chemicals in air and water dilution. J Appl Toxicol 1983;3:272-90. 
9.  Ruth JH. Odor thresholds and irritation levels of several chemical substances: 
A review. Am Ind Hyg Assoc J 1986;47:A142-A151. 
10. Nagata Y. Measurement of odor threshold by triangle odor bag method. In: 
The  Ministry  of  the  Environment  of  Japan:  Odor  measurement  review, 
Booklet of international workshop on odor measurement 2003;118-27. 
11. Zeiger  E,  Anderson  B,  Haworth  S,  Lawlor  T,  Mortelmans  K,  Speck  W. 
Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals.  
Environ Mutagen 1987;9:1-110.   
12. Sorsa  M,  Pyy  L,  Salomaa  S,  Nylund  L,  Yager  JW.  Biological  and 
environmental monitoring of occupational exposure to cyclophosphamide in 
industry and hospitals. Mut Res 1988;204:465-79. 
13. Isakova GE, Ekshtat BY, Kerkis YY. On studies of the mutagenic properties 
of chemical substances in the establishment of hygenic standards. Hygiene 
Saint 1971;36:178-84. 
14. U.S EPA Integrated Risk Information System: Triethylamine (CASRN 121-
44-8)  [Online].  1991  January  4;  Available  from:  URL: 
http://www.epa.gov/iris/subst/0520.htm 
15. Lynch  DW,  Moorman  WJ,  Lewis  TR,  Stober  P,  Hamlin  R,  Schueler  RL. 
Subchronic  inhalation  of  triethylamine  vapor  in  Fisher-344  rats:  Organ 
system toxicity. Toxicol Ind Health 1990;6:403-14.   
METHYLISOBUTYLKETONE 
Introduction 
Methylisobutylketone (MIBK) is listed in the ICH Q3C parent Guideline of 1997 in 
Class  3,  i.e.,  as  a  solvent  with  low  toxicity  based  on  a  review  of  toxicity  data 
available  at  that  time  resulting  in  a Permitted Daily Exposure (PDE) value for 
MIBK of 100 mg/day (1).  Due to new toxicity data including results from National 
Toxicology Program (NTP) 2-year rat and mouse inhalation carcinogenicity studies 
and  published  studies  on  reproductive  and  developmental  toxicity  the  Expert 
Working Group has re-evaluated the PDE value of MIBK. 
Genotoxicity 
No  additional  information  about  genotoxicity  has  been  reported,  since  the  last 
assessment was conducted in 1997.  The available data suggest that MIBK is not 
genotoxic. 
Carcinogenicity 
MIBK has been studied by NTP in 2-year rat and mouse inhalation studies.  F344/N 
rats  and  B6C3F1  mice  (50  animals/sex/group)  were  exposed  to  MIBK  at 
concentrations of 0, 450, 900, or 1800 ppm by inhalation, 6 hours per day, 5 days 
per week for two years.  Survival was decreased in male rats at 1800 ppm (4).  Body 
weight gains were decreased in male rats at 900 and 1800 ppm and in female mice 
at 1800 ppm.  The primary targets of MIBK toxicity and carcinogenicity were the 
kidney in rats and the liver in mice.  The NTP Technical Report concluded that there 
was some evidence of carcinogenic activity of MIBK in rats and mice (4,5).  Based on 
these  NTP  data,  IARC has classified MIBK as a group 2B carcinogen (possibly 
carcinogenic to humans) (6).  
 
In  the  rat  NTP  study,  MIBK  caused  an  increase  in  Chronic  Progressive 
Nephropathy (CPN) and a slight increase in the incidences of renal tubule adenoma 
and carcinomas in males at the highest dose.  Further mechanistic studies provide 
clear evidence that the renal tubular tumors in male rats are most likely caused 
through the well-known male rat specific 2u-nephropathy-mediated mode of action, 
which is considered to be without relevance to humans (7).  Exacerbated CPN was 
also  observed  in  female  rats  (increases  in  the  incidence of CPN in all exposure 
concentrations and in the severity at 1800 ppm) the human relevance of which is 
currently unclear. Increases in mononuclear cell leukemias in male rats at 1800 ppm 
and the occurrence of two renal mesenchymal tumors (very rare tumor, not observed 
in NTP historical control animals) in female rats at 1800 ppm were findings with 
uncertain relationship to MIBK exposure (5).  
 
From the results of the rat carcinogenicity study with MIBK, PDEs are calculated 
based on two different scenarios:    
(i)  tumor  findings  in male and female rats are not treatment-related and/or not 
relevant to humans and therefore the CPN in female rats observed at the lowest 
dose (LOEL1 = 450 ppm) is used for PDE calculation.  
or  
(ii) relationship to MIBK exposure and relevance of rat tumor findings at 1800 ppm 
in males (mononuclear cell leukemias) and/or females (renal mesenchymal tumors) 
to humans cannot be excluded; the NOEL for tumors of 900 ppm is used for PDE 
calculation. 
 
Molecular weight of MIBK: 100.16 g/mol 
 
Scenario 1: LOEL  450 ppm (rat) 
(CPN)
 
450 x 100.16
450 ppm =   = 1843 mg/m3=1.843 mg/L 
24.45
 
 
1.843 x 6 x 5
For continuous dosing =   = 0.329 mg/L 
24 x 7
 
 
0.329 mg L-1 x 290 L day-1
Daily dose =   = 225 mg/kg/day 
0.425 kg
 
Rat respiratory volume: 290 L day-1 
Rat body weight: 0.425 kg 
 
 
 
225  x 50
PDE =   = 45 mg/day 
5 x 10 x 1 x 1 x 5
 
F1 = 5 to account for extrapolation from rats to humans 
F2 = 10 to account for differences between individual humans 
F3 = 1 because long duration of treatment (2 years) 
                                              
1 Lowest Observed Effect Level   
F4  =  1  low  severity  of  effect  (CPN  in  females)  with  unclear 
relevance for humans 
F5 = 5 because a NOEL for CPN was not established 
 
45 x 1000
Limit  =   = 4500 ppm 
10
 
 
Scenario 2: NOEL  900 ppm (rat) 
(tumor)
 
900 x 100.16
900 ppm =   = 3687 mg/m3=3.687 mg/L 
24.45
 
 
3.687 x 6 x 5
For continuous dosing =   = 0.658 mg/L 
24 x 7
 
 
0.658 mg L-1 x 290 L day-1
Daily dose =   = 449 mg/kg/day 
0.425 kg
 
Rat respiratory volume: 290 L day-1 
Rat body weight: 0.425 kg 
 
 
449  x 50
PDE =   = 44.9 mg/day 
5 x 10 x 1 x 10 x 1
 
F1 = 5 to account for extrapolation from rats to humans 
F2 = 10 to account for differences between individual humans 
F3 = 1 because long duration of treatment (2 years) 
F4 = 10 severity of endpoint (cancer) 
F5 = 1 because a NOEL was established 
 
44.9 x 1000
Limit  =   = 4490 ppm 
10  
 
In the mouse study, MIBK increased the incidence of hepatocellular adenomas, and 
adenoma or carcinoma (combined) in male and female mice exposed to 1800 ppm. 
Further  mechanistic  studies  provide  clear  evidence for a constitutive androstane 
receptor (CAR)-mediated mode of action (MOA) for the mouse liver tumors (8). Since 
this MOA has been identified as not relevant for humans (9), no PDE calculation 
was done based on the mouse 2-year study data.   
 
Reproductive and developmental toxicity 
In a developmental toxicity study, pregnant F-344 rats were exposed to MIBK by 
inhalation at doses 0, 300, 1000, or 3000 ppm, 6 hours/day on gestational day 6 
through  15.    Some  fetotoxicities  (reduced  fetal  body  weight  and  reductions  in 
skeletal  ossification)  observed  at  3000  ppm  are  considered  to  be  secondary  to 
maternal toxicities.  There was no maternal, embryo, or fetal toxicity at 1000 ppm 
(2).   
 
In a two-generation reproduction study, SD rats were exposed to MIBK via whole-
body inhalation at concentrations of 0, 500, 1000, or 2000 ppm, 6 hours/day, for 70 
days  covering the period prior to mating of F0 generation through the lactation 
period of F2 generation.  The NOEL for reproductive effects was 2000 ppm, the 
highest concentration tested; the NOEL for neonatal toxicity was 1000 ppm, based 
on acute Central Nervous System depressive effects (3).  
Conclusion 
The former PDE of MIBK was greater than 50 mg/day (100 mg/day) and the solvent 
was placed in Class 3.  The newly calculated PDE of MIBK is based upon the NOEL 
for  tumors  in  male  and  female  rats  and  the  LOEL  for  chronic  progressive 
nephropathy in female rats from the NTP 2-year inhalation study; in both cases a 
PDE  of  45  mg/day  was  calculated.  Therefore,  it  is recommended that MIBK be 
placed into Class 2 in Table 2 in the ICH Impurities: Residual Solvents Guideline. 
References 
1.  Connelly JC, Hasegawa R, McArdle JV, Tucker ML. ICH Guideline Residual 
Solvents. Pharmeuropa 1997;Suppl 9:57. 
2.  Tyl  RW,  France  KA,  Fisher  LC,  Pritts  IM,  Tyler  TR,  Phillips  RD,  et  al. 
Developmental toxicity evaluation of inhaled methyl isbutyl ketone in Fisher 
344 rats and CD-1 Mice. Fundam Appl Toxicol 1987;8:310-27. 
3.  Nemec MD, Pitt JA, Topping DC, Gingell R, Pavkov KL, Rauckman EJ, et al. 
Inhalation  two-generation  reproductive  toxicity  study  of  methyl  isobutyl 
ketone in rats. Int J Toxicol 2004;23:127-43. 
4.  NTP. Toxicology and Carcinogenesis Studies of Methyl Isobutyl Ketone (CAS 
No. 108-10-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). US 
Department of Health and Human Services, Public Health Service, National 
Institutes  of  Health;  Research Triangle Park, NC: 2007. Technical Report 
Series No. 538. 
5.  Stout MD, Herbert RA, Kissling GE, Suarez F, Roycroft JH, Chhabra RS et 
al. Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and   
B6C3F1 mice following 2-year inhalation exposure. Toxicology 2008;244:209
19. 
6.  IARC. Some Chemicals Present in Industrial and Consumer Products, Food 
and Drinking-water. IARC Monographs 2012;101:305-24. 
7.  Borghoff SJ, Poet TS, Green S, Davis J, Hughes B, Mensing T, et al. Methyl 
isobutyl  ketone  exposure-related  increases  in  specific  measures  of  2u-
globulin  (2u)  nephropathy  in  male  rats  along  with  in  vitro  evidence of 
reversible protein binding. Toxicology 2015;333:1-13. 
8.  Hughes BJ, Thomas J, Lynch AM, Borghoff SJ, Green S, Mensing T, et al. 
Methyl  isobutyl  ketone-induced  hepatocellular  carcinogenesis  in B6C3F(1) 
mice:  A  constitutive  androstane  receptor  (Car)  -mediated  mode  of  action. 
Regul Toxicol Pharmacol. 2016;doi:10.1016/j.yrtph.2016.09.024. [Epub ahead 
of print] PubMed PMID: 27664318. 
9.  Elcombe CR, Peffer RC, Wolf DC, Bailey J, Bars R, Bell D, et al. Mode of 
action  and  human  relevance  analysis  for  nuclear  receptor-mediated  liver 
toxicity: A case study with phenobarbital as a model constitutive androstane 
receptor (CAR) activator. Crit Rev Toxicol 2014;44:64-82.