2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine

Endpoint summary

Description of key information

The substance was tested in an OECD 404 guideline study (Walker 1991). A single 3-minute, semi-occluded application of the test material to three rabbits produced dermal necrosis, severe haemorrhage of the dermal capillaries and the formation of an undulating, hardened dark brown/black coloured scab. Other adverse dermal reactions noted were moderate to well-defined erythema surrounding the treatment site, slight to serve oedema and oedema dropping ventrally below the treatment site. The reactions also extended beyond the treatment site.These reactions were considered to be indicative of corrosion.

Two skin irritation/corrosion studies (both Klimisch 4) showed that corrosivity of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine in rats, rabbits and mice is probably. Lack of documentation limits the value of these two studies, but the results are in reasonable agreement with the pH of the substance (pH >= 11.5) and its classification as corrosive.
Furthermore regarding to the eye irritation study with one rabbit 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is considered to be corrosive to the eyes of rabbits when tested according to OECD 405.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

no data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment

Principles of method if other than guideline:

Method: see Test Conditions

GLP compliance:

no

Species:

mouse

Strain:

other: homogeneous, not identified

Details on test animals or test system and environmental conditions:

TEST ANIMALS: 
- Strain: homogeneous, not identified
- Age: adult

Type of coverage:

open

Preparation of test site:

other: clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

undiluted

Duration of treatment / exposure:

no data

Observation period:

postexposure period: 2-5 months

Number of animals:

10

Details on study design:

Controls: no controls; 
reference substances: 1,2-diaminoethane (CAS No.  107-15-3) and 3,3'-dimethyl-4,4'-diaminodicyclohexylmethane (CAS No. 6864-37-5)

ADMINISTRATION/EXPOSURE 
- Area of exposure: 4-5 cm2 on clipped right flank
- Total volume applied: approx. 50 mg
- Postexposure period: 2-5 months
- Removal of test substance: no
EXAMINATIONS
- Examination time points: not reported
- Scoring system: no scoring

Remarks on result:

other: - Mortality: 3/10 animals treated with test item died (within 48 hours). In a second test, 1/10 mice died. (8/10 animals treated with the reference substance 3,3'-dimethyl-4,4'-diaminodicyclohexylmethane died within 48 hours, test not repeated.)

Remarks on result:

other: - Skin effects: Necroses of the epidermis and ulcus formation were observed.

Remarks on result:

other: - Reversibility: Scar formation and healing of all skin damages within 2 months was observed in the surviving animals.

Irritant / corrosive response data:

no data

Other effects:

no other effects

no remarks

Conclusions:

Under the conditions of this study, 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is corrosive to the skin of mice.

Executive summary:

The acute skin irritation properties of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were estimated in an open test. A dose of approx. 50 mg test item per animal was applied to the clipped skin of the right flank of each of 20 mice (2 experiments). There was no removal of test substance. 3/10 animals treated with the test substance died within 48 hours after treatment. In the second test, 1/10 mice died. (8/10 animals treated with the reference substance 3,3'-dimethyl-4,4'-diaminodicyclohexylmethane died within 48 hours.) Treatment resulted in necroses of the epidermis and ulcus formation. Scar formation and healing of all skin damages was observed within 2 months in the surviving animals.

Therefore, under the conditions of this study, 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is corrosive to skin of mice.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991-02-27 to 1991-03-15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS: 
- Strain: New Zealand white
- Sex: male/female
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, U.K.
- Weight at study initiation: 2.14 - 2.77 kg
- Age: approx. 12 - 16 weeks
- Acclimatisation: five days
HOUSING CONDITIONS:
- Room temperature: 18 - 22°C
- Humidity: 50 - 59%
- Light: 12 hours/day
- Air exchange: 15-fold/h
- Access to drinking water: ad libitum
- Diet: diet for rabbits (Spillers Rabbit Diet)

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

undiluted

Duration of treatment / exposure:

1.5 hours and 3 minutes

Observation period:

1.5 hours treatment: after 1 hour; following the 1-hour observation all animals were killed for humane reasons
3 minutes treatment: after 1 hour, 24 and 48 hours; following the 48-hour observation all animals were killed for humane reasons

Number of animals:

6 (3 per sex)

Details on study design:

ADMINISTRATION/EXPOSURE 
- Area of exposure: ca. 6 cm2
- Total volume applied: 0.5 ml
- Postexposure period: 
1.25 hours treatment: after 1 hour
3 minutes treatment: after 1 hour, 24 and 48 hours
- Removal of test substance: with gentle swabbing with cotton wool soaked in diethyl ether
EXAMINATIONS
- Scoring system: Draize scale
- Examination time points: 
1.5 hours treatment: after 1 hour
3 minutes treatment: after 1 hour, 24 and 48 hours

Irritation parameter:

primary dermal irritation index (PDII)

Remarks:

modified, 3 minutes exposure

Basis:

mean

Time point:

other: 24 hours observation

Score:

8

Max. score:

8

Reversibility:

not reversible

Irritant / corrosive response data:

Modified primary irritation index: 8.0 based on erythema values at 24 hour observation only, 3 minutes exposure
Classification: corrosive

Other effects:

no

no further remarks

Conclusions:

A study was performed to examine skin irritating effects of the test item ccording to OECD TG 404 in rabbits. In the study three rabbits per sex were
exposed occlusively for 3 minutes and 1.5 hours. The reactions were considered to be indicative of corrosion. The test material also produced a
modified primary irritation index of 8.0 (based on erythema values at the 24-hour observation only).
Air Products

Executive summary:

A study was performed to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. The method used followed that described in the DECO Guidelines for Testing of Chemicals ( 1981) No. 404 "Acute Derma 1 Irritation/Corrosion" referenced as Method B4 in Commission Directive 84/449/EEC {which constitutes Annex V of

Council Directive 67/548/EEC).

A single 1.5 hour, semi-occluded application of the test material to the intact skin of three rabbits produced severe dermal necrosis,

haemorrhage of the dermal capillaries and loss of skin elasticity and flexibility. These reactions also extended beyond the treatment site.

A single 3-minute, semi-occluded application of the test material to an additional group of three rabbits produced dermal necrosis, severe haemorrhage of the dermal capillaries and the formation of an undulating, hardened dark brown/black coloured scab. Other adverse dermal reactions noted were moderate to well-defined erythema surrounding the treatment site, slight to serve oedema and oedema dropping ventrally below the treatment site. The reactions also extended beyond the treatment site.

These reactions were considered to be indicative of corrosion.

Reference 4

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1965-03-04 to 1965-06-10

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment, particularly the duration of exposure is not reported.

Principles of method if other than guideline:

Method: other: The undiluted substance was applied to the depilated back skin, massaged into the skin by means of a glass rod and covered with gauze and adhesive tape ("Leukoplast") (duration of the occluded exposure not reported).

GLP compliance:

no

Species:

other: rabbit and rat

Strain:

not specified

Details on test animals or test system and environmental conditions:

no data

Type of coverage:

occlusive

Preparation of test site:

other: depilated

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

undiluted

Duration of treatment / exposure:

no data

Observation period:

no data

Number of animals:

no data

Details on study design:

ADMINISTRATION/EXPOSURE 
- Occlusion: covered with gauze and leukoplast
- Total volume applied:  rats: 50 µl; rabbits: 100-200 µl
- The undiluted substance was applied to the depilated back skin, massaged into the skin by means of a glass rod and covered with gauze and
adhesive tape ("Leukoplast") (duration of the occluded exposure not reported).

Remarks on result:

other: The substance penetrated the skin well and caused swelling. Treatment resulted in irritation and inflammatory effects. Repeated application led to severe effects on the skin with formation of crusts and necroses.

Irritant / corrosive response data:

no data

Other effects:

The effects were more  intensive with rabbits than with rats. 

no remarks

Conclusions:

After application of 50 µl (rats), respectively 100-200 µl (rabbits) undiluted test substance (2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine) to the depliated skin of rats and rabbits irritation and inflammatory effects were observed. Repeated application led to severe effects on the skin with formation of crusts and necroses. Therefore, under the conditions of this study, 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is corrosive to the skin.

Executive summary:

The acute skin irritation properties of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were estimated in an occlusive test (duration of the occluded exposure not reported). The undiluted substance (rats: 50 µl, rabbits: 100-200 µl) was applied to the depliated back skin of rats and rabbits, massaged into the skin by means of a glass rod and covered with gauze and adhesive tape.

The test item penetrated the skin well and caused swelling. Treatment resulted in irritation and inflammatory effects. The effects were more intensive with rabbits than with rats. Repeated application led to severe effects on the skin with formation of crusts and necroses. Therefore, under the conditions of this test, 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is corrosive to the skin.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983-11-24 to 1983-11-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

no

Species:

rabbit

Strain:

other: Small white Russian, Chbb-SPF

Details on test animals or tissues and environmental conditions:

TEST ANIMALS: 
- Strain: Small white Russian, Chbb-SPF
- Sex: male
- Source: Dr. Karl Thomae GmbH, Biberach (Germany)
- Weight at study initiation: 2.3 kg
- Number of animals: 1
- Diet: ad libitum Ssniff K4
- Water: ad libitum, tab water
- Controls: untreated eye
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1 °C
- Humidity (%): 60 % +/-5 %
- Air changes (per hr): 15 times per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/light

Vehicle:

unchanged (no vehicle)

Controls:

other: identical animal, untreated right eye

Amount / concentration applied:

undiluted
Amount applied: 0.1 ml

Duration of treatment / exposure:

not rinsed; no removal of test substance

Observation period (in vivo):

1 , 24 hours
- Postexposure observation period: 24 hours

Number of animals or in vitro replicates:

1

Details on study design:

Comment: not rinsed
EXAMINATIONS
- Ophtalmoscopic examination: 1 and 24 hours after treatment
- Scoring system: Draize (1959); evaluation: VCI notes on safety data  sheet

Irritation parameter:

other:

Basis:

animal #1

Time point:

other: 1 and 24 hours

Reversibility:

not reversible

Remarks on result:

other: The undiluted substance produced serious injury immediately (corrosive  effects, opalescence). 24 hours after treatment conjunctiva showed necrosis and test was interrupted.

Irritant / corrosive response data:

The undiluted substance produced serious injury immediately (corrosive  effects, opalescence). 24 hours after treatment conjunctiva showed  
necrosis and test was interrupted.

Other effects:

No other effects.

no further remarks

Conclusions:

Under the conditions of this study, the test item 2,2,4(or 2,4,4) -trimethylhexane -1,6- diamine is considered to be corrosive to eyes of rabbits.

Executive summary:

The acute eye irritation properties of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were estimated in a Draize test according to OECD TG 405. An amount of 0.1 ml of the undiluted test substance was instilled into the left eye of one male albino rabbit, and the untreated right eye served as control. The eye remained unrinsed and there was no removal of test substance. The undiluted substance produced serious injury immediately (corrosive  effects, opalescence). 24 hours after treatment conjunctiva 

showed necrosis and the test was interrupted. Therefore, under the conditions of this test 2,2,4(or 2,4,4) -trimethyl hexane -1,6-

diamine is considered to be corrosive to eyes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

Studies in animals

The acute skin irritation properties of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were estimated in an occlusive test (duration of the occluded exposure not reported) (Klimmer, 1965). The undiluted substance (rats: 50 µl, rabbits: 100-200 µl) was applied to the depilated back skin of rats and rabbits, massaged into the skin by means of a glass rod and covered with gauze and adhesive tape.

The test item penetrated the skin well and caused swelling. Treatment resulted in irritation and inflammatory effects. The effects were more intensive with rabbits than with rats. Repeated application led to severe effects on the skin with formation of crusts and necroses. Therefore, under the conditions of this test, 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is corrosive to the skin.

 

In addition, the acute skin irritation properties of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were estimated in an open test (Schmid, 1968). A dose of approx. 50 mg test item per animal was applied to the clipped skin of the right flank of each of 20 mice (2 experiments). There was no removal of test substance. 3/10 animals treated with the test substance died within 48 hours after treatment. In the second test, 1/10 mice died. (8/10 animals treated with the reference substance 3,3'-dimethyl-4,4'-diaminodicyclohexylmethane died within 48 hours.) Treatment resulted in necroses of the epidermis and ulcus formation. Scar formation and healing of all skin damages was observed within 2 months in the surviving animals.

Therefore, under the conditions of this study, 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is corrosive to skin of mice.

 

Lack of documentation limits the value of the studies (both Klimisch 4), but the results are in reasonable agreement with the pH of the substance (pH >= 11.5) and its classification as corrosive.

A guideline study was performed to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. The method used followed that described in the DECO Guidelines for Testing of Chemicals ( 1981) No. 404 "Acute Derma 1 Irritation/Corrosion" referenced as Method B4 in Commission Directive 84/449/EEC {which constitutes Annex V of Council Directive 67/548/EEC) (Walker, 1991).

A single 1.5 hour, semi-occluded application of the test material to the intact skin of three rabbits produced severe dermal necrosis,

haemorrhage of the dermal capillaries and loss of skin elasticity and flexibility. These reactions also extended beyond the treatment site.

A single 3-minute, semi-occluded application of the test material to an additional group of three rabbits produced dermal necrosis, severe haemorrhage of the dermal capillaries and the formation of an undulating, hardened dark brown/black coloured scab. Other adverse dermal reactions noted were moderate to well-defined erythema surrounding the treatment site, slight to serve oedema and oedema dropping ventrally below the treatment site. The reactions also extended beyond the treatment site.

These reactions were considered to be indicative of corrosion (Cat 1 A).

 

Eye irritation

Studies in animals

The acute eye irritation properties of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were estimated in a Draize test according to OECD TG 405. An amount of 0.1 ml of the undiluted test substance was instilled into the left eye of one male albino rabbit, and the untreated right eye served as control. The eye remained unrinsed and there was no removal of test substance. The undiluted substance produced serious injury immediately (corrosive effects, opalescence). 24 hours after treatment conjunctiva showed necrosis and the test was interrupted. Therefore, under the conditions of this test 2,2,4(or 2,4,4) -trimethyl hexane -1,6- diamine is considered to be corrosive to eyes.

Justification for classification or non-classification

Because of the results of one guideline study according to OECD 404 and the high pH-value (pH >= 11.5) the substance 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine must be classified as Category 1A (Skin Corr., H314: Causes severe skin burns and eye damage) according EC Regulation 1272/2008. No further classification for "Serious eye damage/irritation" is necessary because of the aforementioned skin classification as "Corrosive".