PDEs for Triethylamine and for Methylisobutylketone

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

PDE FOR TRIETHYLAMINE AND
M ETHYLISOBUTYLKETONE
This recommendation represents the Food and Drug Administration’s (FDA’s) 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.
I MPURITIES : R ESIDUAL SOLVENTS (M AINTENANCE )
PDE FOR T RIETHYLAMINE AND PDE OF
M ETHYLISOBUTYLKETONE
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 (20°C), 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
mg/L	022	.	1	mg/m³	1022.2	=
24.45
101.19	x	247
=	ppm	247 	=
mg/L	0.183	=
7	x	24
5	x	6	x	1.022
=	dosing	continuous	For
mg/kg/day	124.9	=
kg	0.425
day	L	290	x	L	0.183mg
=	dose	Daily
-1	-1
Rat respiratory volume: 290 L day -1
Rat body weight: 0.425 kg
mg/day	62.5	=
1	x	1	x	2	x	10	x	5
50	x	124.9
=	PDE
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
ppm	6250	=
10
1000	x	62.5
=	Limit
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.

METHYLISO BUTYLKETO NE
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 α2u-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(CPN) 450 ppm (rat)
mg/L	843	.	1	mg/m³	1843	=
24.45
100.16	x	450
=	ppm	450 	=
mg/L	0.329	=
7	x	24
5	x	6	x	1.843
=	dosing	continuous	For
mg/kg/day	225	=
kg	0.425
day	L	290	x	L	mg	0.329
=	dose	Daily
-1	-1
Rat respiratory volume: 290 L day -1
Rat body weight: 0.425 kg
mg/day	45	=
5	x	1	x	1	x	10	x	5
50	x	225
=	PDE
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
ppm	4500	=
10
1000	x	45
=	Limit
Scenario 2: NOEL(tumor) 900 ppm (rat)
mg/L	687	.	3	mg/m³	3687	=
24.45
100.16	x	900
=	ppm	900 	=
mg/L	0.658	=
7	x	24
5	x	6	x	3.687
=	dosing	continuous	For
mg/kg/day	449	=
kg	0.425
day	L	290	x	L	mg	0.658
=	dose	Daily
-1	-1
Rat respiratory volume: 290 L day -1
Rat body weight: 0.425 kg
mg/day	44.9	=
1	x	10	x	1	x	10	x	5
50	x	449
=	PDE
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
ppm	4490	=
10
1000	x	44.9
=	Limit

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 	α2u-
globulin (α2u) 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.