Tripropylamine

Endpoint summary

Description of key information

Tripropylamine was highly irritating if applied to the skin of rabbits. The structural analogue TEA was corrosive while another structural analogue TBA was irritating to skin. In a BASF test, exposure of rabbit's eyes to tripropylamine resulted in the average conjunctivae score of 0.75 in two animals at 24-h and at 48-h reading time points. The erythema was fully reversible within 8 days. In a supporting study, tripropylamine produced a very small area of necrosis in the eyes of rabbits. TEA was highly irritating/corrosive to eyes, while TBA was not irritating to eyes. 
Based on the available data, TnPA is considered to be corrosive to skin and in analogy to its tertiary analogue amines should be classified accordingly. TnPA induced irritation effects to respiratory tract in animals in the acute inhalation toxicity studies. Moreover,  TEA and TBA are classified as irritating to the respiratory tract and therefore tripropylamine, in analogy to its nearest analogues, should also be classified as H335 (may cause respiratory irritation). 

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

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 (72 hour reading time point is missing).

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: BASF-Test: Two animals were treated for 1, 5, 15 min or 20 h using occlusive conditions. An application site of 2.5x2.5 cm was covered with the liquid test substance. After the application time the skin was washed with Lutrol (conc.) and Lutrol/water (1:1). The animals were observed for 8 days and skin changes were recorded daily. The report describes findings after 24 and 48 hours and at the end of the observation period (8 days).

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 3.0 and 3.15 kg

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated skin sites of the same animal served as control

Duration of treatment / exposure:

1, 5, 15 min and 20 h

Observation period:

24 h, 48 h, 8 days

Number of animals:

2

Details on study design:

TEST SITE
- Area of exposure: back: 2.5 x 2.5 cm

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with Lutrol (conc.) and Lutrol/water (1:1)
- Time after start of exposure: after the exposure time: 1, 5, 15 min

Irritation parameter:

erythema score

Remarks:

20 h exposure

Basis:

mean

Time point:

other: 24, 48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 8 days

Remarks on result:

other: 72 hour reading point missing, leathery necrosis after 8 days

Irritation parameter:

edema score

Remarks:

20 h exposure

Basis:

mean

Time point:

other: 24, 48 h

Score:

2.5

Max. score:

4

Reversibility:

fully reversible within: 8 days

Irritant / corrosive response data:

Exposure to the substance for 15 minutes resulted in one animal in a leathery necrosis which was not reversible within 8 days. A 20-hour exposure resulted in both tested animals in leathery necrosis which was not reversible within 8 days.

Detailed results:

			Duration of treatment
Animal	Reading after		1 min	5 min	15 min	20 hours
1	24 hours	Erythema	1	1	4	2
		Edema	0	1	2	2
		other	Spotted	-		Partly grey necrosis
	48 hours	Erythema	0	1	2	2
		Edema	0	1	1	2
		other		spotted		Partly necrosis
	8 days	Erythema	0	0	0	0
		Edema	0	0	0	0
		other		Slight scaling	marked scaling (parchmenty)	Leathery necrosis, surrounding: slight scaling
2	24 hours	Erythema	1	2	3	2
		Edema	1	2	2	3
		Other				Grey soft necrosis
	48 hours	Erythema	1	2	2	2
		Edema	0	2	1	3
		Other	spotted			Partly parchmenty necrosis
	8 days	Erythema	0	0	0	0
		Edema	0	0	0	0
		Other	scaling	marked scaling (parchmenty)	Leathery necrosis	Comprehensive leathery necrosis

Interpretation of results:

corrosive

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Exposure of skin of rabbits to tripropylamine for 15 minutes resulted in necrosis which was not reversible within 8 days.

Executive summary:

The skin irritation potential of tripropylamine was determined in a test according to an internal BASF method. Two animals (Vienna White rabbits) were treated with the test substance for 1, 5, 15 min or 20 h using occlusive conditions. An application site of 2.5 x 2.5 cm was covered with the liquid test substance. After the application time the skin was washed with Lutrol (conc.) and Lutrol/water (1:1). The animals were observed for 8 days and skin changes were recorded daily. The report describes findings after 24 and 48 hours and at the end of the observation period (8 days). The 1 -min and 5 -min exposure of the animal skin to tripropylamine resulted in skin reactions which were fully reversible within 8 days. Exposure to the substance for 15 minutes resulted in one animal in a leathery necrosis which was not reversible within 8 days. A 20-hour exposure resulted in both tested animals in leathery necrosis which was not reversible within 8 days.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

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 (72 hour reading point is missing).

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: BASF-Test: 50 µL of the test substance were applied to the conjunctival sac of one eye in 2 animals. The animals were observed after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The eyes were not washed out after 24 hours as specified in OECD Guideline 405.

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.38 and 2.49 kg

Vehicle:

unchanged (no vehicle)

Controls:

other: The adjacent eye served as control and was treated with 0.9 % NaCl (saline).

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 µL

Duration of treatment / exposure:

single application

Observation period (in vivo):

8 days

Number of animals or in vitro replicates:

2

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

A first test was done with 2 animals. In this test, both animals displayed erythema of similar severity and thus, similar scoring, in the control (0.9% NaCl) eye and the eye treated with the test item. Therefore, the test was repeated with a further 2 animals. In this test, the control eyes were as expected, i.e., without any findings, and thus, this test was considered suitable for assessment of the irritant potential of the test item. The results provided below refer to this test.

SCORING SYSTEM: The findings were re-evaluated according to the Draize scoring system, as recommended by the OECD.

TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: 24, 48 hours

Score:

0.75

Max. score:

3

Reversibility:

fully reversible within: 8 days

Remarks on result:

other: 72 h reading is missing

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 24, 48 hours

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Remarks on result:

other: 72 h reading is missing

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 24, 48 hours

Score:

0

Max. score:

2

Reversibility:

other: reversibility: not applicable

Remarks on result:

other: 72 h reading is missing

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: 24, 48 hours

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Remarks on result:

other: 72 h reading is missing

Other effects:

After 10 min at one animal eye secretion was noted.

Findings (animal 1):

Time	Erythema	Chemosis	Corneal Opacity	Iritis
1h	1	0	0	0
24h	1	0	0	0
48h	0	0	0	0
72h	-	-	-	-
8d	0	0	0	0

Findings (animal 2):

Time	Erythema	Chemosis	Corneal Opacity	Iritis
1h	1	0	0	0
24h	1	0	0	0
48h	1	0	0	0
72h	-	-	-	-
8d	0	0	0	0

Mean values over 24h and 48h (72h reading is missing):

Animal 1: Opacity: 0; Chemosis: 0; Erythema: 0.5

Animal 2: Opacity: 0; Chemosis: 0; Erythema: 1

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Mean conjunctivae score for both animals at 24-h and 48-h reading time points is 0.75. The erythema was fully reversible within 8 days. For cornea and iris, all scores were 0.0 at all reading time points. According to this study result, tripropylamine is likely not irritating to eyes.

Executive summary:

The eye irritation potential of tripropylamine was determined in a test conducted to an internal BASF method. 50 µL of the test substance were applied to the conjunctival sac of one eye in 2 animals (Vienna White rabbits). The animals were observed after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The eyes were not washed out after 24 hours as specified in OECD Guideline 405. The mean conjunctivae scores for erythema were 0.5 and 1.0 in animal 1 and in animal 2 after 24 -h and 48 -h reading points, respectively (72 -h reading is missing). The mean conjunctivae score for both animals at 24 -h and 48 -h is 0.75. The erythema was fully reversible within 8 days. For cornea and iris, all scores were 0.0 at all reading time points. According to this study result, tripropylamine is likely not irritating to eyes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

To assess irritation potential of tripropylamine the following irritation studies have been used:

Skin Irritation

BASF-method: Skin irritation study (tripropylamine)

In a key study, the skin irritation potential of tripropylamine was determined in a test according to an internal BASF method (BASF, 1977; Report No. XXVI/207). Two animals (Vienna White rabbits) were treated with the test substance for 1, 5, 15 min or 20 h using occlusive conditions. An application site of 2.5 x 2.5 cm was covered with the liquid test substance. After the application time the skin was washed with Lutrol (conc.) and Lutrol/water (1:1). The animals were observed for 8 days and skin changes were recorded daily. The report describes findings after 24 and 48 hours and at the end of the observation period (8 days). The 1 -min and 5 -min exposure of the animal skin to tripropylamine resulted in skin reactions which were fully reversible within 8 days. Exposure to the substance for 15 minutes resulted in one animal in a leathery necrosis which was not reversible within 8 days. A 20-hour exposure resulted in both tested animals in leathery necrosis which was not reversible within 8 days.

Range-finding toxicity study (tripropylamine)

In a supporting study, tripropylamine was tested in a range-finding toxicity study in albino New Zealand rabbits (Smyth et al., 1969). Primary skin irritation was recorded in a 10 -grade ordinal series and was based upon the severest reaction that develops on the clipped skin of each of five animals within 24 hours of the uncovered application of 0.01 mL of undiluted test material. Grade 4 had been assigned for tripropylamine. According to the description the 10 -grade ordinal series, grade 4 corresponds likely to "highly irritating" since "...grade 1indicates no irritation and grade 2 the least visible capillary injection from the undiluted chemical. Grade 6 indicates necrosis when undiluted...".

Skin Irritation Study in Rabbits (triethylamine, CAS No. 121-44-8)

The BASF test was used to assess irritating potential of triethylamine (BASF AG, 1960; Report No. VI/389). The conduction of the study was similar to the OECD Guideline 404. Two animals were treated for 1, 5, 15 min and 20 hours using occlusive conditions. An application site of 2.5x2.5 cm was covered with the liquid test substance. After the application time (1, 5, 15 min) the skin was washed with Lutrol (50%). The animals were observed for 8 days and skin changes were recorded daily. 1 min application caused marked oedema and haemorrhagic areas on the day of application which remained almost unchanged for 1 week. At the end of observation period of 26 days scar formation was observed. 5 min and 15 min application resulted in red-brown necrosis of leather-like consistency on the day of application which developed to hard crusts on day 8. After 3 weeks scar formation was observed. A 20% preparation in olive oil was also tested. The skin effects were less pronounced. The test material is considered to be corrosive to skin of rabbits.

Dermal Corrosivity Study in Rabbits (triethylamine, CAS No. 121-44-8)

Springborn Laboratiories performed an experiment to test the skin irritation / corrosion properties of triethylamine on rabbits (US EPA TSCA, 1989). A semiocclusive coverage of the test substance was done for 3 min and 1 hour, respectively. For both application times the active substance triethylamine showed corrosive properties.

Screening of skin irritancy/corrosivity (publication)

Triethylamine was tested in a range-finding skin irritation series test for amines (Meyers and Ballantyne, 1997). The test methods placed emphasis on limited number of animals and limited dosages. Two groups of five male rabbits were treated with small volume (0.01 mL) on uncovered skin or large volume (0.5 mL) occlusively. In case on unoccluded treatment, the test material was 30 min in contact with the skin of animals until it appeared to be completely absorbed or evaporated. Thereafter, residues of test material were removed. After 18 -24 hours the test site was inspected for signs of local injury and inflammation. The undiluted test material was also tested on occluded rabbit skin. For this procedure 0.5 mL of test material was applied to the skin of animals and covered with a gauze patch. Polyethylene sheeting was loosely wrapped around the animal's trunk and secured. During a 4-h contact period, the animal was restrained to avoid disturbing the dose site. Excess test material was carefully removed with cleansing tissue. Reactions were recorded at the end of the contact period and at 24 and 48 h following contact.

Triethylamine produced moderate erythema without necrosis if applied to the uncovered rabbit skin in small volume. However, when the test material was studied with large volume by a 4 -hour occluded contact it produced necrosis.

Skin irritating study (tributylamine, CAS 102 -82 -9)

In a reliable study (Kirsch and Grundler, 1989, Report No. 81/160) conducted with tributylamine, four rabbits were exposed dermally to single doses of 0.5 mL of undiluted test substance (purity not mentioned, skin was carefully clipped at least 15 hours prior to dosing, test item was soaked into gauze patch (2.54 x 2.54 cm = 0.5 mL fluid) for 3 minutes). The residual test item was wiped with lutrol and lutrol/water (1:1) and grading was performed according to Draize, 1959. Examinations for dermal reactions were carried out at 24, 48 hours, as well as after 7 days and 14 respectively 15 days following initiation of the exposure. After 3-min exposure 3/4 animals showed slight to well defined erythema (1x score 1 and 2x score 2) and 2/4 had slight oedemas (with score 1 each) after 24 h, which subsided over time. 3/4 animals exhibited eschar by the end of the observation period.

After 1 -h exposure 4/4 animals showed well defined erythema (score 2 each) and 4/4 and 3/4 animals slight oedema (score 1 each) after 24 and 48 h, respectively, which subsided over time. Erythemas were still present after 8 d (3/4 score 1, 1/4 score 2), yet not fully reversible until the end of the observation period (2/4 score 1 after 14/15 d). All animals exhibited eschar by the end of the observation period. Based on the given results the test item was considered to be irritating to skin under the test conditions.

Eye Irritation

Eye irritation (BASF Test): tripropylamine

In a key study, the eye irritation potential of tripropylamine was determined in a test conducted to an internal BASF method (BASF, 1977, Report No. XXVI/207). 50 µL of the test substance were applied to the conjunctival sac of one eye in 2 animals (Vienna White rabbits). The animals were observed after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The eyes were not washed out after 24 hours as specified in OECD Guideline 405. The mean conjunctivae scores for erythema were 0.5 and 1.0 in animal 1 and in animal 2 after 24 -h and 48 -h reading points, respectively (72 -h reading is missing). The mean conjunctivae score for both animals at 24 -h and 48 -h is 0.75. The erythema was fully reversible within 8 days. For cornea and iris, all scores were 0.0 at all reading time points. According to this study result, tripropylamine is not irritating to eyes.

Range-finding toxicity study: tripropylamine

In a supporting study, tripropylamine was tested in a range-finding toxicity study in albino New Zealand rabbits (Smyth et al., 1969). Eye injury in rabbits was recorded in a 10-grade ordinal series and was based upon the degree of corneal necrosis that resulted from instillation of 0.5 mL of undiluted test material in the eyes of animals. Grade 1 established for tripropylamine indicates a very small area of necrosis.

Eye irritation (BASF Test): triethylamine (CAS 121 -44 -8)

The BASF study design was similar to that in the OECD Guideline 405 (BASF AG, 1985; Report No. VI/389). The duration of the study was sufficient to evaluate reversibility of the effects. Triethylamine was applied to the conjunctival sac of one rabbit eye to assess eye irritation potential. The application of the test substance caused after 10 minutes severe corneal opacity, bleeding of the nictating membrane, conjunctival oedema, chemosis and redness. The symptoms were persisting for the next 2 weeks. The corneal opacity was not regarded to be reversible.

Eye irritation (US EPA, 1976): triethylamine (CAS 121 -44 -8)

0.1 mL of triethylamine was placed in the conjunctival sac of both eyes of each of three albino rabbits (US EPA, 1976). One eye of each animal was washed with flowing water initiated fifteen seconds after instillation and continued of one minute; the contralateral eye remained unwashed. The test substance is reported to be corrosive without washing and irritating with washing.

Screening of eye irritancy/corrosivity (publication)

Triethylamine was tested in a range-finding eye irritation series test for amines (Meyers and Ballantyne, 1997). The test methods placed emphasis on limited number of animals and limited dosages. The eyes of five male rabbits were examined following application of fluorescein stain to ensure that no corneal lesions were present prior to testing. The small volume of 0.005 mL was placed directly on the cornea with a pipette. After 18 -24 hours, the treated eye was rinsed with water and again stained with fluorescein. Eyes were examined for ocular and periocular injury and/or inflammation. The test material produced severe corneal opacity , iritis, necrosis and haemorrhage of the eyelids, and chemosis.

Eye irritating study (tributylamine, CAS 102 -82 -9)

The eye irritation potential of tributylamine was analysed in a reliable (OECD 405) experimental study in rabbits (BASF AG, 1985; Report No. 82/197 -1). No corneal opacity was observed. Scores for iris lesions were all 0.0 for all treated eyes. Mean of conjunctiva score of 0.9 (mean of all animals; 24 -48 -72 h) was reported and the observed effects were fully reversible within 72 h, thus the test item was not irritating to the eyes.

Respiratory Irritation

Tripropylamine induced clinical signs and deaths in the acute inhalation study in rats (Biosearch, 1975). At 12.8 mg/L, the animals exhibited initially an increased activity than normal but soon they exhibited decreased activity. Within 10 minutes they exhibited whole body tremors and after 20 minutes the rats were still twitching. By 35 minutes all 10 rats were dead. At 7.4 mg/L the rats exhibited within 20 minutes vigorous pawing and then tremors. By 30 minutes all rats exhibited tremors. By 40 minutes all 10 rats were dead. At 4.5 mg/L all rats exhibited body tremors within 30 minutes. By 40 minutes the rats were inactive. Within 60 minutes 2 rats were dead and the remaining rats were still exhibited tremors. Within 15 minutes after exposure 4 additional rats died. Tremors ceased within 24 hours and there were no additional deaths during the 14 day observation period. A total of 6 rats died during the 14 day observation period. No information is given on body weight changes or pathological examinations.The study thus shows that the test substance has high acute inhalation toxicity. The death of animals is probably due to the local effects (severe irritation effects of respiratory tract).

The nearest analogues TEA and TBA were also irritating to respiratory tract of animals tested in acute inhalation toxicity studies (International Research and Development, 1995; Jackson and Hardy, 1987). Treated animals showed laboured breathing, dyspnoea, nasal irritation, lacrimation and increased salivation (please refer to section 5.2.3 of the CSR or 7.2.2 of the IUCLID file).

In a nasal irritation and pulmonary toxicity study of 20 aliphatic amines in mice, Gagnaire et al. exposed mice to airborne TEA to determine the RD50 value (Gagnaire et al., 1989) (refer to section 7.9.3 of IUCLID file). This value indicates 50% decrease in the respiratory rate and is considered to be successfully used to predict safe industrial exposure. Mice were exposed nasal to a range of concentrations of Triethylamine. The breathing frequency was used as an index of upper respiratory tract irritation.The onset of action of TEA was very rapid, ca. 30 sec. to 1 min. 156 ppm of TEA was determined as RD50 in mice.The tested concentrations produced a range of effects, whose severity was concentration dependent.At the end of a 15 -min exposure period, the recovery of respiratory frequencies to the pre-exposure values was also rapid, ca.1 min. Due to the rapid recovery of respiratory frequency in mice, Triethylamine is considered to be moderately irritating to the upper respiratory and lower respiratory tract. The predicted safe levels to prevent upper airway irritation should not exceed 15 ppm for TEA. The effects of TEA were reversible in non-canulated mice, but irreversible in tracheally canulated mice (effects on the lower airways, can culminate in pulmonary congestion).

Justification for selection of skin irritation / corrosion endpoint:
Test result originates from a reliable well-documented skin irritation study conducted according to an internal BASF method.

Justification for selection of eye irritation endpoint:
Test result originates from a reliable well-documented eye irritation study conducted according to an internal BASF method.

Effects on skin irritation/corrosion: corrosive

Effects on respiratory irritation: highly irritating

Justification for classification or non-classification

In the available skin irrirtation studies conducted with tripropylamine and with the nearest structural analogue TEA, the test substance showed corrosive properties. Another structural analogue TBA was irritating to skin. In the eye irritation studies, exposure of rabbit's eyes to tripropylamine resulted in the average conjunctivae score of 0.75 in two animals at 24-h and at 48-h reading time points. The erythema was fully reversible within 8 days (BASF test). In a supporting study, tripropylamine produced very small area of necrosis in the eyes of rabbits. TEA was highly irritating/corrosive to eyes, while TBA was not irritating to eyes. Based on these data, TnPA is considered to be corrosive and according to Regulation (EC) No 1272/2008 should be classified as H314 Cat. 1B (causes severe skin burns and eye damage).

Irritation symptoms to respiratory tract in animals exposed to the vapours of tripropylamine were noted in the acute inhalation toxicity studies (Biosearch, 1975; Biosearch, 1976). In analogy to the nearest analoguesTEA, TnPA is considered to be irritating to respiratory tract and according to Regulation (EC) No 1272/2008 should be classified as H335 (STOT-SE) (may cause respiratory irritation).