Diethylamine

Carcinogenicity

Description of key information

No evidence of carcinogenic activity in rat or mice was evaluated after inhalative exposure.

No liver tumors developed in guinea pigs after exposure via drinking water to DEA alone or in combination with nitrite.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

The study focused on the forming of diethylnitrosamine, a known carcinogen, from the simultaneous administration of the test substance as a hydrochloride and sodium nitrite in drinking-water. The test substance alone was only tested as control in a single dose.

GLP compliance:

no

Specific details on test material used for the study:

hydrochloride of the test material was tested

Species:

guinea pig

Strain:

other: English short hair

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 21-28 days
- Housing: 5 animals per cage
- Diet: Purina guinea-pig chow ad libitum, they also receive once daily fresh lettuce

Route of administration:

oral: drinking water

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Formation of (diethylnitrosamine) DEN in the drinking water was monitored and found to be in between 0.01 and 0.04 ppm for those groups that received DEA and nitrite in combination.
No DEA was lost from the water bottles within 48h at room temperature.

Duration of treatment / exposure:

30 month (between 885 and 911 days)

Frequency of treatment:

continously in drinking water

Post exposure period:

no data

Dose / conc.:

4 000 mg/L drinking water

Remarks:

average intake of 290 mg/day per animal

No. of animals per sex per dose:

20 (males only)

Control animals:

yes, concurrent vehicle

Details on study design:

2 further groups were included in the study to evalute in vivo nitrosamine formation. These animals received on average either 250mg DEA in combination with 50mg nitrite per day (high dose) or 210 mg DEA with 40mg nitrite (low dose). Concentrations in the drinkinge water were selected to achieve a difference in intake by a factor of 2, but due to lower water consumption in the high dose group, intake of the test compounds was almost identical.

Positive control:

Diethylnitrosoamine (average intake of 1.1 mg/day per animal)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily


OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: No data


CLINICAL CHEMISTRY: No data


URINALYSIS: No data


NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, salivary and thyroid gland, lymph nodes, lungs, heart, liver, spleen, adrenals, kidneys and all grossly detectable tumours

Clinical signs:

not specified

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Mortality was observed. Deaths were due mainly to pneumonia or to streptococcal infection of the submaxillary lymph glands.
Surviving animals after
6 month: 18/20
12 month: 14/20
18 month: 11/20
24 month: 5/20
30 month: 4/20
Negative control group: 20/20, 20/20, 17/20, 14/20, 10/20, 5/20 surviving animals at identical time intervals

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Marked decrease in average body weights of the animals.
Due to the unpleasant taste of DEA, water consumption was reduced by at least a factor of 2. Data are only give for the high dose DEA/nitrite mix (4g/l DEA / 0.8g/L nitrite) compared to the low dose DEA/nitrite mix (2g/l DEA / 0.4g/L nitrite). Reduction of the DEA treated animals compared to control could be well above 2.

Food efficiency:

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

no effects observed

Remarks on result:

other: no liver tumors developed in animals treated with DEA or DEA mixed with nitrite.

Positive control animals developed liver tumours (18/20 guinea pigs). The tumours comprised 17 hepatocellular carcinomas and one cholangiocarcinoma.

 

Conclusions:

Under the tested conditions none of the treated animals developed tumors. Due to the observation of treatment-related decreased body weights for animals treated with the tested concentration a NOAEC for systemic effects can not be derived.

Executive summary:

Guinea pigs receiving the test substance (4000 mg/l) developed no tumours after 30 month of treatment via the drinking water (average intake per day and animal 290 mg). No in vivo formation of diehtylnitrosamine was observed when DEA was given in combination with nitrite, i.e., no tumors were detected in these groups as well. In contrast, 18/20 positive control animals exposed to diethylnitrosamine directly (average intake of 1.1 mg/day per animal) developed liver tumours (one of the remaining animals died before tumors had a chance to develop).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug 2003 - Aug 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Version / remarks:

June 2018

Deviations:

yes

Remarks:

Exposure 5 days per week

Principles of method if other than guideline:

Study performed according to standard NTP protocols.

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): diethylamine
- Physical state: colorless liquid with a strong ammonia odor
- Analytical purity: approximately 99.9%
- Lot/batch No.: BE/07/01
- Stability under test conditions: no degradation of the bulk chemical was detected
- Storage condition of test material: at controlled room temperature

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: males: 23.3 g (mean), female: 19.8 g (mean)
- Housing: individually in stainless steel wire bottom (Lab Products, Inc., Seaford, DE), changed weekly and rotated daily
- Diet: NTP-2000 irradiated wafers (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, except during exposure periods
- Water: Tap water (Richland municipal supply) via automatic watering system (Edstrom Industries, Waterford, WI), available ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3 °C (72°±3 °F)
- Humidity (%): 50% ± 15%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Remarks:

on-line gas chromatograph

Details on analytical verification of doses or concentrations:

Samples were drawn from each exposure chamber approximately every 30 minutes during each 6-hour exposure period using stream-select and gas sampling valves in a separate heated valve oven.

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

6 h/day, 5 days/week

Dose / conc.:

16 ppm (nominal)

Remarks:

analytical concentration 16.1 ± 0.6 ppm

Dose / conc.:

31 ppm (nominal)

Remarks:

analytical concentration 31.1 ± 1.0 ppm

Dose / conc.:

62.5 ppm (nominal)

Remarks:

analytical concentration 62.6 ± 1.9 ppm

No. of animals per sex per dose:

50

Control animals:

yes

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical findings were recorded every 4 weeks for the first 13 weeks; afterwards, clinical findings were recorded every 4 weeks through week 93; then every 2 weeks.

BODY WEIGHT: Yes
- Time schedule for examinations: initially and then weekly for the first 13 weeks, then every 4 weeks through week 93; then every 2 weeks, and at the end of the studies.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, necropsies were performed on all animals

HISTOPATHOLOGY: Yes, complete histopathology was performed on all rats. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, eyes, Harderian gland, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lungs, lymph nodes (bronchial, mandibular, mediastinal, and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, uterus,

Statistics:

- The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Dose related effects on survival were analysed using Cox´s method for testing 2 groups for equality and Taraone´s life table test to identify dose-realted trends.
- Organ and body weight data: multiple comparison procedure of Dunnett (1955) and Williams (1971)
- Fisher exact test and chi-square statistics
- Polyk-test for neoplastic and nonneoplastic lesions prevalence assessment

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Eye abnormality was observed in greater incidence in exposed groups of males compared to the chamber controls, and torso/ventral ulcer/abscess was observed in six 62.5 ppm males compared to none in the chamber controls.

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Mean body weights of males and females were similar to those of the chamber controls throughout the study

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

A spectrum of nonneoplastic lesions was observed in the respiratory and olfactory epithelium of the nose in exposed mice. The lesions included suppurative inflammation, ulceration of the respiratory epithelium, hyaline droplet accumulation in the glands of the respiratory epithelium, necrosis of the turbinates, squamous metaplasia of the respiratory epithelium, hyperplasia of the respiratory epithelium, atrophy of the olfactory epithelium, hyaline droplet accumulation in the respiratory and olfactory epithelium, basal cell hyperplasia of the olfactory epithelium, respiratory metaplasia of the olfactory epithelium, and goblet cell hyperplasia (see details in table in remarks on results). The incidence of necrosis of the respiratory epithelium and chronic active inflammation of the respiratory epithelial glands was significantly increased in 62.5 ppm females. Significantly increased incidences of the respiratory epithelium in 31 and 62.5 ppm animals. Incidences of atrophy of the olfactory epithelium were significantly increased in all animals

Histopathological findings: neoplastic:

no effects observed

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

Cardiomyopathy in th heart significantly increased in 31 ppm males; hyperplasia of the pars distalis in the pituitary gland were significantly increased in 16 and 62.5 ppm males.

Dose descriptor:

NOAEC

Effect level:

62.5 ppm (analytical)

Sex:

male/female

Basis for effect level:

other: carcinogenicity

Remarks on result:

other: highest dose tested

Dose descriptor:

LOAEC

Remarks:

local effects

Effect level:

16 ppm (analytical)

Sex:

male/female

Basis for effect level:

other: gross pathology; histopathology

Tab. 1 Incidences of Nonneoplastic Lesions in Mice in the 2-Year Inhalation Study of Diethylamine

	control		16 ppm		31 ppm		62.5 ppm
	male	female	male	female	male	female	male	female
No. examined	50	50	50	49	50	50	50	50
Glands, Respiratory Epithelium,Accumulation, Hyaline Droplet	5^a(1.0)^b	16 (1.3)	5 (1.0)	28** (1.4)	16** (1.3)	45** (1.9)	33** (1.5)	42**(1.8)
Glands, Respiratory Epithelium,Inflammation, Chronic Active	6 (1.0)	8 (1.0)	9 (1.1)	11 (1.0)	8 (1.3)	16 (1.1)	11 (1.1)	22**(1.1)
Glands, Respiratory Epithelium, Hyperplasia	42 (1.1)	43 (1.2)	41 (1.2)	45 (1.2)	44 (1.1)	47 (1.4)	50** (1.6)	50* (2.0)
Inflammation, Suppurative	6 ( 1.7)	2 (1.0)	5 (1.6)	1 (1.0)	6 (1.7)	3 (1.0)	14* (1.1)	9* (1.1)
Olfactory Epithelium, Atrophy	9 (1.0)	8 (1.0)	19* (1.3)	29** (1.4)	50** (2.0)	49** (2.1)	50** (2.5)	50** (2.6)
Olfactory Epithelium, Respiratory Metaplasia	14 (1.0)	4 (1.0)	15 (1.7)	15** (1.6)	44** (2.3)	48** (2.8)	50** (3.0)	50** (3.0)
Olfactory Epithelium, Necrosis	0	0	2 (1.5)	0	0	2 (1.0)	0	1 (1.0)
Olfactory Epithelium, Vacuolization Cytoplasmic	0	0	5* (1.0)	5* (1.6)	3 (2.0)	1 (2.0)	0	1 (2.0)
Respiratory Epithelium, Accumulation, Hyaline Droplet	11 (1.0)	20 (1.7)	6 (1.3)	33** (1.3)	19 (1.5)	47** (2.2)	30** (1.1)	29 (1.1)
Respiratory Epithelium, Metaplasia, Squamous	4 (1.0)	0	7 (1.0)	0	16** (1.0)	13** (1.1)	34** (1.4)	35** (1.3)
Respiratory Epithelium, Necrosis	2 (1.5)	1 (1.0)	3 (1.3)	0	3 (1.3)	6 (1.5)	8 (1.4)	16** (1.6)
Respiratory Epithelium, Ulcer	1 (1.0)	0	1 (2.0)	0	2 (1.0)	0	4 (1.3)	2 (1.0)
Respiratory Epithelium, Vacuolization Cytoplasmic	0	0	1 (1.0)	2 (2.0)	3 (2.0)	2 (2.5)	0	1 (3.0)
Turbinate, Hyperostosis	5 (1.2)	4 (1.0)	23** (1.1)	23**(1.1)	50** (2.0)	49** (1.8)	50** (3.5)	50** (2.9)
Turbinate, Necrosis	1 (1.0)	0	0	0	0	0	3 (1.0)	1 (1.0)

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

** P≤0.01

^aNumber of animals with lesion

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

Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of diethylamine in male or female mice exposed to 16, 31, or 62.5 ppm.

However, exposure to diethylamine resulted in increased incidences of nonneoplastic lesions of the nose in male and female mice.

Conclusions:

No evidence of carcinogenic activity in male or female mice expsosed to 16, 31, 62.5 ppm of the test substance for 2 years.

Executive summary:

Groups of 50 male and 50 female mice were exposed to vapourized test substance at concentrations of 0, 16, 31, or 62.5 ppm, 6 hours plus T90(15 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups of mice was similar to that of the chamber control groups. Mean body weights of males and females were similar to those of the chamber controls. Eye abnormality was observed in greater incidence in exposed groups of males than in the chamber controls, and torso/ventral ulcer/abscess was observed in six 62.5 ppm males compared to none in the chamber controls. A similar spectrum of nonneoplastic lesions was seen in the nose of exposed mice as was seen in rats.  There was no evidence of carcinogenic activity in male or female mice under experimental conditions

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug 2003 - Aug 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Version / remarks:

June 2018

Deviations:

yes

Remarks:

Exposure 5 days per week (no justification)

Principles of method if other than guideline:

Study performed according to standard NTP protocols.

GLP compliance:

yes

Specific details on test material used for the study:

- Physical state: colorless liquid with a strong ammonia odor
- Analytical purity: approximately 99.9%
- Lot/batch No.: BE/07/01
- Stability under test conditions: no degradation of the bulk chemical was detected
- Storage condition of test material: at controlled room temperature

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: males: 110 g (mean), female: 93 g (mean)
- Housing: individually in stainless steel wire bottom (Lab Products, Inc., Seaford, DE), changed weekly and rotated daily
- Diet: NTP-2000 irradiated wafers (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, except during exposure periods
- Water: Tap water (Richland municipal supply) via automatic watering system (Edstrom Industries, Waterford, WI), available ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3 °C (72°±3 °F)
- Humidity (%): 50% ± 15%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Remarks:

on-line gas chromatograph

Details on analytical verification of doses or concentrations:

Samples were drawn from each exposure chamber approximately every 30 minutes during each 6-hour exposure period using stream-select and gas sampling valves in a separate heated valve oven.

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

6 h/day, 5 days/week

Dose / conc.:

31 ppm (nominal)

Remarks:

analytical concentration 31 ± 1.1 ppm

Dose / conc.:

62.5 ppm (nominal)

Remarks:

analytical concentration 62.5 ± 2.3 ppm

Dose / conc.:

125 ppm (nominal)

Remarks:

analytical concentration 125 ± 4 ppm

No. of animals per sex per dose:

50

Control animals:

yes

Details on study design:

- Dose selection rationale: Chemical-related microscopic lesions were only present in the nasal cavity of rats exposed to the test substance for 3 months. Lesions consisted of turbinate necrosis, suppurative inflammation, hyperplasia and squamous metaplasia of the respiratory epithelium, and atrophy of the olfactory epithelium. Turbinate necrosis was limited to one male and one female exposed to 125 ppm. The severity of these lesions was not considered severe enough to compromise a 2-year study. Exposure concentrations of 0, 31, 62.5, and 125 ppm were selected for the 2-year study in rats.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical findings were recorded every 4 weeks for the first 13 weeks; afterwards, clinical findings were recorded every 4 weeks through week 93; then every 2 weeks.

BODY WEIGHT: Yes
- Time schedule for examinations: initially and then weekly for the first 13 weeks, then every 4 weeks through week 93; then every 2 weeks, and at the end of the studies.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, necropsies were performed on all animals

HISTOPATHOLOGY: Yes, complete histopathology was performed on all rats. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, eyes, Harderian gland, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lungs, lymph nodes (bronchial, mandibular, mediastinal, and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, uterus, and Zymbal’s gland

Statistics:

- The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Dose related effects on survival were analysed using Cox´s method for testing 2 groups for equality and Taraone´s life table test to identify dose-realted trends.
- Organ and body weight data: multiple comparison procedure of Dunnett (1955) and Williams (1971)
- Fisher exact test and chi-square statistics
- Polyk-test for neoplastic and nonneoplastic lesions prevalence assessment

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Icreased incidences of eye abnormalities occured in exposed males and females, lethargy was more common in 125 ppm males than in chamber controls. Clonic seizures in a few chamber control and expsosed males (19/200 animals) and females (33/ 200 animals)

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Survival of exposed groups of rats was similar to that of the chamber control groups. Lethargy was more common in 125 ppm males than in the chamber controls.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of males and females exposed to 125 ppm were less (10 %) than those of the chamber controls after week 57.

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Nose: A spectrum of nonneoplastic lesions was observed in the respiratory and olfactory epithelium of the nose in exposed rats. The lesions included suppurative inflammation, ulceration of the respiratory epithelium, hyaline droplet accumulation in the glands of the respiratory epithelium, necrosis of the turbinates, squamous metaplasia of the respiratory epithelium, hyperplasia of the respiratory epithelium, atrophy of the olfactory epithelium, hyaline droplet accumulation in the respiratory and olfactory epithelium, basal cell hyperplasia of the olfactory epithelium, respiratory metaplasia of the olfactory epithelium, and goblet cell hyperplasia (see details in table in remarks on results). The incidences of ulceration of the respirathory epithelium were significantly increased in 125 ppm males and females. Significantly increased incedences of necrosis of the turbinates in 125 ppm males and females. Incedences of squamous metaplasia of the respiratory epithelium were significantly increased in 125 ppm males and females and 62.5 ppm males compared to the controls. Olfactory epithelium atrophy occured in most exposed animals and increased in severity with concentration.

Eye: Increased incidences of eye abnormality (suppurative inflammation, cataracts and retinal atrophy) occurred in exposed males and females (see details in table in remarks on results).

Lung and Pleura: The incidence of chronic inflammation of the pleura was significantly increased in 31 ppm and 125 ppm females. The incidences of histiocytic cellular infiltration of the alveolus of the lung were significantly increased in all exposed groups of females and the incidence of chronic inflammation was significantly increased in 125 ppm females (see details in table in remarks on results).

Histopathological findings: neoplastic:

no effects observed

Dose descriptor:

NOAEC

Effect level:

125 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: carcinogenicity

Remarks on result:

other: highest dose tested

Dose descriptor:

LOAEC

Remarks:

local effects

Effect level:

31 ppm (analytical)

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Tab. 1 Incidences of Nonneoplastic Lesions in Rats in the 2-Year Inhalation Study of Diethylamine

	control		31 ppm		62.5 ppm		125 ppm
	male	female	male	female	make	female	male	female
No. examined	49	50	50	49	50	50	50	50
Glands, Respiratory Epithelium, Accumulation, Hyaline Droplet	6^a (1.0)^b	9 (1.0)	45** (1.2)	46** (1.6)	42** (1.6)	45** (1.7)	45** (1.5)	44** (1.6)
Glands, Respiratory Epithelium, Hyperplasia	44  (1.0)	45 (1.0)	46 (1.2)	49* (1.7)	46 (1.7)	48 (1.9)	48 (1.7)	49 (2.1)
Goblet Cell, Hyperplasia	0	1 (2.0)	0	0	2 (1.5)	4 (1.8)	13** (2.2)	20** (2.5)
Inflammation, Suppurative	5 (1.6)	6 (2.0)	5 (1.6)	4 (1.5)	10 (1.7)	15* (1.5)	29 (2.6)	34** (2.9)
Olfactory Epithelium, Accumulation, Hyaline Droplet	8 (1.0)	11 (1.3)	49** (2.4)	49** (2.6)	49** (2.1)	50** (2.6)	42** (1.7)	48** (2.4)
Olfactory Epithelium, Atrophy	2 (1.5)	1 (1.0)	49** (1.5)	47** (1.9)	50 ** (1.8)	48** (2.3)	50** (2.3)	50** (2.7)
Olfactory Epithelium, Hyperplasia, Basal Cell	0	0	0	3 (1.0)	22 ** (1.8)	29** (1.7)	50** (2.4)	48** (2.9)
Olfactory Epithelium, Respiratory Metaplasia	2 (1.5)	3 (1.7)	2 (1.0)	1 (2.0)	2 (1.5)	2 (1.0)	37** (1.6)	19** (1.7)
Olfactory Epithelium, Vacuolization Cytoplasmic	0	0	2 (4.0)	1 (4.0)	8** (3.8)	4 (3.8)	1 (4.0)	3 (3.3.)
Respiratory Epithelium, Accumulation, Hyaline Droplet	0	4 (1.0)	29** (1.2)	48** (1.9)	42** (1.4)	46** (1.2)	11** (1.5)	39** (1.4)
Respiratory Epithelium, Hyperplasia	5 (1.6)	7 (1.4)	34** (1.2)	31** (1.2)	35** (1.3)	41** (1.4)	47** (1.9)	50** (2.4)
Respiratory Epithelium, Metaplasia, Squamous	0	1 (1.0)	2 (1.0)	1 (1.0)	6* (1.8)	5 (1.4)	26** (2.1)	39** (2.3)
Respiratory Epithelium, Necrosis	0	0	0	0	1 (1.0)	1 (1.0)	4 (1.3)	4 (1.8)
Respiratory Epithelium, Ulcer	0	0	0	0	2 (2.5)	0	22** (3.3)	34** (3.1)
Turbinate, Hyperostosis	0	0	0	0	0	0	3 ( 2.3)	2 (2.0)
Turbinate, Necrosis	0	0	0	0	1 (2.0)	0	19** (2.9)	32** (3.0)
EYE
Cornea, Inflammation, Suppurative	0	0	0	2 (2.5)	1 (2.0)	2 (2.5)	5* (2.4)	1 (3.0)
Cornea, Inflammation, Chronic	0	-	0	-	0	-	3 (1.7)	-
Lens, Cataract	1 (2.0)	3 (2.0)	3 (4.0)	2 (4.0)	1 (3.0)	6 (3.7)	5 (2.6)	4 (3.5)
Retina, Atrophy	1 (2.0)	4 (2.5)	3 (4.0)	2 (4.0)	1 (3.0)	8 (3.3)	3 (3.3)	6 (3.0)
LUNG
Alveolus, Infiltration Cellular, Histiocyte	-	13 (1.2)	-	24* (1.3)	-	27** (1.3)	-	35** (1.4)
Inflammation, Chronic	-	4 (1.5)	-	11 (1.3)	-	7 (1.4)	-	24** (1.3)
PLEURA
Inflammation, Chronic	-	6 (1.2)	-	14* (1.2)	-	12 (1.3)	-	21** (1.3)

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

** P≤0.01

^a Number of animals with lesion

^b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked

Conclusions:

Under the conditions of this 2-year inhalation study, there was no evidence of carcinogenic activity in male and female rats.
However, exposure to diethylamine resulted in increased incidences of nonneoplastic lesions of the nose in male and female rats and of the pleura and lung in female rats.

Executive summary:

In this GLP-compliant NTP-study groups of 50 male and 50 female rats were exposed to the vapourized test substance at concentrations of 0, 31, 62.5, or 125 ppm, 6 hours plus T₉₀(15 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups of rats was similar to that of the chamber control groups. Mean body weights of males and females exposed to 125 ppm were less than those of the chamber controls after week 57. Increased incidences of eye abnormality occurred in exposed males and females.

A spectrum of nonneoplastic lesions was observed in the respiratory and olfactory epithelium of the nose in exposed rats. The lesions included suppurative inflammation, ulceration of the respiratory epithelium, hyaline droplet accumulation in the glands of the respiratory epithelium, necrosis of the turbinates, squamous metaplasia of the respiratory epithelium, hyperplasia of the respiratory epithelium, atrophy of the olfactory epithelium, hyaline droplet accumulation in the respiratory and olfactory epithelium, basal cell hyperplasia of the olfactory epithelium, respiratory metaplasia of the olfactory epithelium, and goblet cell hyperplasia.

The incidence of chronic inflammation of the pleura was significantly increased in 125 ppm females. The incidences of histiocytic cellular infiltration of the alveolus of the lung were significantly increased in all exposed groups of females and the incidence of chronic inflammation was significantly increased in 125 ppm females. Evidence of eye irritation was observed in some rats exposed to 125 ppm test substance (mild to moderate suppurative inflammation and chronic inflammation of the cornea). Although the respiratory tract was a major target site for the inhaled test substance, no treatment related neoplasms were observed in the nose, larynx, or lung of rats for 2 years.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. No carcinogenic effects were observed in rats and mice after 2 years of inhalative exposure. As a result, the substance is not classified for carcinogenicity under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) No. 2018/1480.

Additional information

Under the conditions of two available GLP-compliant 2-year inhalation studies similar to OECD TG 451 in rat and mice (2005, reliability 2), there was no evidence of carcinogenic activity of the test substance after inhalative exposure.

In this NTP-study, groups of 50 male and 50 female rats were exposed to the vapourized test substance at concentrations of 0, 31, 62.5, or 125 ppm, 6 hours plus T₉₀(15 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups of rats was similar to that of the chamber control groups. Mean body weights of males and females exposed to 125 ppm were less than those of the chamber controls after week 57. Increased incidences of eye abnormality occurred in exposed males and females.

A spectrum of nonneoplastic lesions was observed in the respiratory and olfactory epithelium of the nose in exposed rats. The lesions included suppurative inflammation, ulceration of the respiratory epithelium, hyaline droplet accumulation in the glands of the respiratory epithelium, necrosis of the turbinates, squamous metaplasia of the respiratory epithelium, hyperplasia of the respiratory epithelium, atrophy of the olfactory epithelium, hyaline droplet accumulation in the respiratory and olfactory epithelium, basal cell hyperplasia of the olfactory epithelium, respiratory metaplasia of the olfactory epithelium, and goblet cell hyperplasia. The incidence of chronic inflammation of the pleura was significantly increased in 125 ppm females. The incidences of histiocytic cellular infiltration of the alveolus of the lung were significantly increased in all exposed groups of females and the incidence of chronic inflammation was significantly increased in 125 ppm females. Evidence of eye irritation was observed in some rats exposed to 125 ppm test substance (mild to moderate suppurative inflammation and chronic inflammation of the cornea). Although the respiratory tract was a major target site for the inhaled test substance, no treatment related neoplasms were observed in the nose, larynx, or lung of rats for 2 years.

The NTP-study also included a cancerogenicity study with 50 male and 50 female mice which were exposed to the vapourized test substance at concentrations of 0, 16, 31, or 62.5 ppm, 6 hours plus T90 (15 minutes) per day, 5 days per week for 105 weeks. Survival of exposed groups of mice was similar to that of the chamber control groups. Mean body weights of males and females were similar to those of the chamber controls. Eye abnormality was observed in greater incidence in exposed groups of males than in the chamber controls, and torso/ventral ulcer/abscess was observed in six 62.5 ppm males compared to none in the chamber controls. A similar spectrum of nonneoplastic lesions was seen in the nose of exposed mice as was seen in rats.  There was no evidence of carcinogenic activity in male or female mice under experimental conditions

Another study conducted with the hydrochloride of diethylamine was published in Food Cosmetic Toxicology 13, 423-425 (1975, reliability 2). Guinea pigs recieved the test substance via the drinking water (4g/l, average daily intake 290mg) alone or in combination with app. 50mg nitrite per day to check, if diethylnitrosamines can from in vivo. None of these animals developed tumours after 30 month of treatment. In contrast, 18 of 20 positive control animals exposed to diethylnitrosamine (average intake of 1.1 mg/day per animal) developed liver tumours within this study.