Assessment of chronic inhalation non-cancer toxicity for diethylamine

Figures & data

Figure 1. Chemical structure of DEA. When amines with a high pKa come in contact with tissues or fluids at physiologic pH, they become protonated and hydroxide ion is released, causing local necrosis.

Table 1. Chemical and physical data.

Parameter	Value	References
Molecular formula	C4H11N	HSDB (2015)
Molecular weight (gmol^−1)	73.1	NIOSH (2011)
Physical state at 25 °C	Liquid	NIOSH (2011)
Color	Colorless	NIOSH (2011)
Odor	Fishy, ammonia-like odor	NIOSH (2011)
CAS registry number	109-89-7	NIOSH (2011)
Synonyms	Diethamine; N,N-diethylamine; ethanamine, N-ethyl; N-ethylethanamine	HSDB (2015)
Solubility in water	Miscible	NIOSH (2011)
Log Kow	0.58	HSDB (2015)
pKa	11.09 at 20 °C	HSDB (2015)
Density (water = 1)	0.71	NIOSH (2011)
Vapor pressure	192 mm Hg	NIOSH (2011)
Melting point	−50 °C	HSDB (2015)
Boiling point	132°F	NIOSH (2011)
Conversion factors	1 ppm = 2.99 mg/m^3; 1 mg/m^3 = 0.33 ppm	NIOSH (2011)

Table 2. Chronic and subchronic inhalation studies.

Exposure concentration (species)	Exposure (number/sex/dose)	NOAEL	LOAEL	Notes (references)
0, 16, 31 or 62.5 ppm (B6C3F1 mice)^a	105 weeks, 6 h/day, 5 days/week (50 M, 50 F)	–	16 ppm^a	A spectrum of non-neoplastic lesions was observed in the respiratory and olfactory EPI of the nose (NTP, 2011)
0, 31, 62.5 or 125 ppm (F344/N rats)	105 weeks, 6 h/day, 5 days/week (50 M, 50 F)	–	31 ppm	A spectrum of non-neoplastic lesions was observed in the respiratory and olfactory EPI of the nose (NTP, 2011)
0, 32, 62 or 125 ppm (B6C3F1 mice)^a	14 weeks, 6 h/day, 5 days/week (10 M, 10 F)	–	32 ppm	Statistical decrease in sperm motility (NTP, 2011)
0, 32, 62 or 125 ppm (F344/N rats)	14 weeks, 6 h/day, 5 days/week (10 M, 10 F)	–	32 ppm	Statistical decrease in sperm motility (NTP, 2011)
50 ppm (rabbits)	6 weeks, 7 h/day, 5 days/week	–	50 ppm	Severe ocular irritation (Brieger & Hodes, 1951; referenced in NTP, 2011)
25 or 250 ppm (Fisher 344 rats)	24 weeks, 6.5 h/day, 5 days/week (M, F)	25 ppm^b	250 ppm	Severe ocular irritation. At 250 ppm, decreased body weights and nasal cavity lesions including squamous metaplasia, rhinitis and lymphoid hyperplasia. Measurements of cardiotoxicity were all negative in exposed rats (Lynch et al., 1986)

^aStudy with lowest LOAEL level.

^bNasal histopathology was not performed at 25 ppm.

Table 3. Incidences of lesions of the nose in rats in 105-week inhalation study.

Non-neoplastic lesion	Sex	0 ppm (49 M, 50 F)	31 ppm (50 M, 49 F)	62.5 ppm (50 M, 50 F)	125 ppm (50 M, 50 F)
Inflammation, suppurative	M	5^a (1.6)^b	5 (1.6)	10 (1.7)	29** (2.6)
	F	6 (2.0)	4 (1.5)	15* (1.5)	34** (2.9)
Atrophy, olfactory EPI	M	2 (1.5)	49** (1.5)	50** (1.8)	50** (2.3)
	F	1 (1.0)	47** (1.9)	48** (2.3)	50** (2.7)
Hyperplasia of the respiratory EPI	M	5 (1.6)	34** (1.2)	35** (1.3)	47** (1.9)
	F	7 (1.4)	31** (1.2)	41** (1.4)	50** (2.4)
Metaplasia, squamous respiratory EPI	M	0	2 (1.0)	6* (1.8)	26** (2.1)
	F	1 (1.0)	1 (1.0)	5 (1.4)	39** (2.3)

^aNumber of animals with lesions.

^bAverage severity grade of lesions in affected animals (in parentheses): 1 = minimal, 2 = mild, 3 = moderate and 4 = marked.

*Significantly different (p ≤ 0.05) from the chamber control group by the Poly-3 test.

**p ≤ 0.01.

Table 4. Incidences of lesions of the nose in mice in 105-week inhalation study.

Non-neoplastic lesion	Sex	0 ppm (50 M, 50 F)	16 ppm (50 M, 49 F)	31 ppm (50 M, 50 F)	62.5 ppm (50 M, 50 F)
Olfactory EPI, atrophy	M	9^a (1.0)^b	19* (1.3)	50** (2.0)	50** (2.5)
	F	8 (1.0)	29** (1.4)	49** (2.1)	50** (2.6)
Olfactory EPI, respiratory metaplasia	M	14 (1.0)	15 (1.7)	44** (2.3)	50** (3.0)
	F	4 (1.0)	15** (1.6)	48** (2.8)	50** (3.0)
Respiratory EPI, metaplasia, squamous	M	4 (1.0)	7 (1.0)	16** (1.0)	34** (1.4)
	F	0	0	13** (1.1)	35** (1.3)
Turbinate, hyperostosis	M	5 (1.2)	23** (1.1)	50** (2.0)	50** (3.5)
	F	4 (1.0)	23** (1.1)	49** (1.8)	50** (2.9)

^aNumber of animals with lesions.

^bAverage severity grade of lesions in affected animals (in parentheses): 1 = minimal, 2 = mild, 3 = moderate and 4 = marked.

*Significantly different (p ≤ 0.05) from the chamber control group by the Poly-3 test.

**p ≤ 0.01.

Table 5. Concentration-dependent decrease in percent sperm motility from a 14-week study (NTP, 2011).

Concentration (number of animals)	Control (10)	32 ppm (10)	62 ppm (10)	125 ppm (10)
Rat sperm motility (%)	93.01 ± 0.72*	88.60 ± 1.45**	87.27 ± 1.57**	68.44 ± 2.78**
Mouse sperm motility (%)	86.66 ± 1.45	80.60 ± 1.41**	78.47 ± 1.51**	73.65 ± 2.04**

*Means ± SE.

**Significantly different (p < 0.01) from the chamber control group by Shirley’s test.

Table 6. BMC results for the best-fit model for the examined endpoints.

Endpoint	Best model	p value	AIC	Scaled residual	BMC10 (ppm)	BMCL10 (ppm)
Rat inflammation, suppurative	Dichotomous-Hill	0.637	379.87	<|2|	60.3	48.8
Rat atrophy of olfactory EPI	No acceptable models	–	–	–	LOAEL 31	–
Rat hyperplasia of the respiratory EPI	Gamma multistage 2°	0.150	345.37	<|2|	4.23	3.66
Rat metaplasia squamous of the respiratory EPI	Logistic	0.981	240.90	<|2|	61.5	54.1
Mouse atrophy in the olfactory EPI	Multistage 3°	0.746	244.16	<|2|	9.30	6.08
Mouse respiratory metaplasia in the olfactory EPI	Gamma	0.935	299.94	<|2|	17.1	14.3
Mouse metaplasia squamous of the respiratory EPI	Multistage 2°	0.480	333.99	<|2|	19.0	15.3
Mouse hyperostosis in the turbinates^a	Multistage 3°	0.866	212.76	<|2|	9.13	5.71
Rat sperm motility	No acceptable continuous models	–	–	–	LOAEL 32	–
Mouse sperm motility	No acceptable continuous models	–	–	–	LOAEL 32	–

^aChosen as the critical effect.

Table 7. Derivation of the chronic ReV.

Parameter	Summary
Study	105-week bioassay (NTP, 2011)
Study population	F344/N rats and B6C3F1 mice, 50 males and 50 females/group
Exposure method	Exposures via inhalation to analytical concentrations of DEA vapor Rats: 0, 31, 62.5 or 125 ppm Mice: 0, 16, 31 or 62.5 ppm
Critical effect	Hyperostosis in the turbinates in mouse
BMC10	9.13 ppm
POD (BMCL10)	5.71 ppm
Exposure duration	6 h/day, 5 days/week for 105 weeks
Extrapolation to continuous exposure (PODADJ)	1.020 ppm or 1020 ppb
PODHEC	1020 ppb
Total UFs	90
Intraspecies UF	10
Interspecies UF	3
LOAEL UF	1
Database UF	3
Chronic ReV	11 ppb (33 µg/m^3)

Table 8. Confidence in the chronic toxicity assessment.

Not evaluated Toxicity value comparison	Low confidence Systematic review Peer review Validation	Medium confidence Database completeness Human equivalent POD Sensitive populations	High confidence Key study quality Critical effect Relevance of critical effect Point of departure
Element	Score* (1–5)	Basis
Database completeness	3 Medium	Short-term developmental and one- or two-generation reproductive  studies were not conducted. MOA information is adequate.  One chronic study in rats and mice, and one chronic study in rats.
Systematic review	1 Low	At the time of this assessment, TCEQ did not employ a systematic  procedure for data gathering, analysis and internal review.
Key study quality	5 High	The chosen study is well done.
Critical effect	5 High	Studies are sufficient to assess the critical effect  with confidence based on MOA.
Relevance of critical effect	5 High	The critical effect of adverse upper respiratory effects is relevant  to humans based on knowledge of MOA.  Critical effect matches human experience.
Point of departure (POD)	5 High	A BMCL10 was used as the POD. Multiple dose groups.  Difference between BMC and BMCL was less than a factor of two.
Human equivalent POD (PODHEC)	3 Medium	Default duration and dosimetric adjustments were made,  which are assumed to be conservative.
Sensitive populations	2 Medium	There was no data to evaluate sensitive subpopulations or increased childhood  susceptibility. The TCEQ assumed the UFH of 10 was adequate.
Peer review	+ Low	Peer input was received. The Development  Support Document was posted for public comment.
Validation	+ Low	Ambient air concentrations were determined in one study  (Key et al., 2011). Measured concentrations are well below the ReV.  Biological indices are not available for comparison.
Toxicity value comparison	–	No other agencies have derived DEA chronic inhalation toxicity values.

*Criteria for scoring the individual elements are discussed in Grant et al. (2015). For the first eight elements: low (1), medium (2–3) and high (4–5). For peer review, validation and toxicity value comparison: low (+), medium (++), high (+++) or not evaluated (–).

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