Diisopropylamine

Carcinogenicity

Description of key information

No data was generated on Diisopropylamine (DIPA). However, results from repeated dose toxicity studies indicate that other than local irritative effects, DIPA does not cause any significant systemic toxicity resulting from prolonged exposure. The consistently negative results from the series of in vitro genotoxicity tests assessing gene mutation and chromosomal damage do not suggest any cause for concern with respect to carcinogenicity. In addition, two carcinogenicity studies by inhalation  in rats and mice were realized by the NTP (2011) on Diethylamine (DEA), a structural analogue of DIPA. Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of diethylamine in male or female F344/N rats exposed to 31, 62.5, or 125 ppm and in male or female B6C3F1 mice exposed to 16, 31, or 62.5 ppm.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented report which meets basic scientific principles. Study performed according to standard NTP protocols.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Principles of method if other than guideline:

NTP standard protocol

GLP compliance:

yes

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)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The study laboratory designed the inhalation exposure chamber (Harford Systems Division of Lab Products, Inc., Aberdeen, MD) so that uniform vapor concen-trations could be maintained throughout the chamber with the catch pans in place. The total active mixing volume of each chamber was 1.7 m3
- Method of holding animals in test chamber: no data
- Source and rate of air: no data
- Method of conditioning air: no data
- System of generating vapors: Diethylamine was pumped onto glass beads in a heated glass column where it was vaporized. Heated nitrogen flowed through the column and carried the vapor into a short vapor distribution manifold. Concentration in the manifold was determined by the chemical pump rate and nitrogen flow rate. The pressure in the distribution manifold was kept fixed to ensure constant flow through the manifold and into all chambers as the flow of vapor to each chamber was adjusted. Individual Teflon® delivery lines carried the vapor from the manifold to three-way exposure valves at the chamber inlets. The exposure valves diverted vapor delivery to the exposure chamber exhaust until the generation system was stable and exposures were ready to proceed. A metering valve with a flow indicator at the manifold controlled the flow rate to each chamber. To initiate exposure, the chamber exposure valves were rotated to allow the vapor to flow to each exposure chamber inlet duct where it was further diluted with HEPA®-filtered, conditioned air to achieve the desired exposure concentration.
- Temperature, humidity, pressure in air chamber: no data
- Air flow rate: no data
- Air change rate: 15 air changes per hour
- Method of particle size determination: A small particle detector was used with and without animals in the exposure chambers to ensure that diethylamine vapor, and not aerosol, was produced. No particle counts above the minimum resolvable level (approximately 200 particles/cm3) were detected
- Treatment of exhaust air:

TEST ATMOSPHERE
- Brief description of analytical method used: Samples of the test atmosphere from the distribution lines and the low and high exposure concentration chambers were collected prior to the 3-month and also at the beginning and end of one generation day during the 3-month study. The atmosphere samples were collected with adsorbent gas sampling tubes containing an acrylic ester, followed by a tube containing activated coconut charcoal, and extracted with methylene chloride. Chamber and room concentrations of diethylamine were monitored by an on-line gas chromatograph.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

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:

109 to 111 weeks

Frequency of treatment:

6 h/day, 5 days/week

Remarks:

Doses / Concentrations:
31, 62.5 and 125 ppm (65.1, 131.25 and 262.5 mg/m3)
Basis:
other: target conc.

Remarks:

Doses / Concentrations:
31.0 ± 1.1, 62.5 ± 2.3 and 125 ± 4 ppm
Basis:
analytical conc.

No. of animals per sex per dose:

50

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: Chemical-related microscopic lesions were only present in the nasal cavity of rats exposed to diethylamine 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 diethylamine 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

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
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. Increased incidences of eye abnormality occurred in exposed males and females (males: chamber control, 0/50; 31 ppm, 3/50; 62.5 ppm, 1/50; 125 ppm, 3/50; females: 1/50; 3/50; 7/50; 5/50). Lethargy was more common in 125 ppm males than in the chamber controls. Clonic seizures, usually observed during routine animal care, were noted in a few chamber control and exposed males (1/50, 2/50, 7/50, 9/50) and females (2/50, 7/50, 11/50, 13/50). More females (33) than males (19) developed seizures. There was an increased incidence of seizures with increasing exposure concentration in both males and females. The seizures were initially observed during week 23. No evidence of brain lesions was found to account for the cause or effect of the seizures.

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


HISTOPATHOLOGY: NON-NEOPLASTIC:

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).

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).

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 (see details in table in remarks on results).

Relevance of carcinogenic effects / potential:

Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of diethylamine in male or female F344/N rats exposed to 31, 62.5, or 125 ppm. 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.

Dose descriptor:

NOAEC

Effect level:

> 125 other: ppm (analytical) (>262.5 mg/m3)

Sex:

male/female

Basis for effect level:

other: no evidence for carcinogenicity

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

LOAEC

Effect level:

< 31 other: ppm (analytical) (< 65.1 mg/m3)

Sex:

male/female

Basis for effect level:

other: increased incidences of nonneoplastic lesions of the nose in male and female rats and of the pleura and lung in female rats

Remarks on result:

other:

Remarks:

Effect type: other: local irritation (migrated information)

Dose descriptor:

NOAEC

Effect level:

62.5 other: ppm (analytical) (131.25 mg/m3)

Sex:

male/female

Basis for effect level:

other: Decreased body weight gain and clinical signs at 125 ppm

Remarks on result:

other:

Remarks:

Effect type: other: systemic toxicity (migrated information)

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

Executive summary:

In a study conducted similar to OECD TG 451, groups of 50 male and 50 female rats were exposed to diethylamine vapor 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. In 125 ppm males, the incidence of suppurative inflammation of the cornea was significantly increased.

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

According to CLP criteria, no classification is warranted for carcinogenicity.

Additional information

Two carcinogenicity studies by inhalation were realized by the NTP (2011) on Diethylamine (DEA), a structural analogue of DIPA, in rats and mice:

In a study conducted similar to OECD TG 451, groups of 50 male and 50 female rats were exposed to diethylamine vapor 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.

In a study conducted similar to OECD TG 451, groups of 50 male and 50 female mice were exposed to diethylamine vapor 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.