Registration Dossier

Administrative data

Description of key information

Skin:

- Fluhr (2005): 1 % DMA in distilled water on human skin (paravertebral mid back). No significant irritation, but barrier disruption of the stratum corneum.

Skin and eyes:

- BASF, Gewebetoxikologische Grundprüfung, 1980, 40 % DMA in aqueous solution, in this concentration: corrovive to the skin and the eyes.

Respiratory tract:

- DMA is an essentially irritant for the upper airways of rodents. (Gagnaire, 1989)


Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

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: Comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
Method: other: BASF-Test: Four animals were treated for 3 min and two animals were treated for 4 hour using occlusive conditions. An application site of 2 x 2 cm was covered with the liquid test substance. After the application the skin was washed with Lutrol (50 %). The report describes findings after 24 hours and at the end of the observation period (8 days).
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Duration of treatment / exposure:
3 min and 4 h
Observation period:
8 days
Number of animals:
3 min exposure: 2
4 h exposure: 4
Details on study design:
TEST SITE
- Area of exposure: 2 x 2 cm
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Lutrol and Lutrol/water (1:1)
- Time after start of exposure: 3 min and 4 h
Irritation parameter:
erythema score
Remarks:
Exposure time: 3 min
Basis:
animal #1
Remarks:
Animal No. 1 of a total of 2
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 2 animals
Irritation parameter:
erythema score
Remarks:
Exposure time: 3 min
Basis:
animal #2
Remarks:
Animal No. 2 of a total of 2
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 2 animals
Irritation parameter:
edema score
Remarks:
Exposure time: 3 min
Basis:
animal #1
Remarks:
Animal No. 1 or a total of 2
Time point:
24 h
Score:
0.5
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
positive indication of irritation
Remarks:
The score given above is the mean value reported for the 2 animals
Irritation parameter:
edema score
Remarks:
Exposure time 3 min
Basis:
animal #2
Remarks:
Animal No. 2 of a total of 2
Time point:
24 h
Score:
0.5
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 2 animals
Irritation parameter:
erythema score
Remarks:
Exposure time 4h
Basis:
animal #1
Remarks:
Animal No. 1 of a total of 4
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 4 animals
Irritation parameter:
erythema score
Remarks:
Exposure time 4 h
Basis:
animal #2
Remarks:
Animal No. 2 of a total of 4 animals
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 4 animals
Irritation parameter:
erythema score
Remarks:
Exposure time 4 h
Basis:
animal #3
Remarks:
Animal No. 3 of a total of 4
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 4 animals
Irritation parameter:
erythema score
Remarks:
Exposure time 4 h
Basis:
animal #4
Remarks:
Animal No. 4 of a total of 4
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 4 animals
Irritation parameter:
edema score
Remarks:
Exposure time 4 h
Basis:
animal #1
Remarks:
Animal No. 1 of a total of 4
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 4 animals
Irritation parameter:
edema score
Remarks:
Exposure time 4 h
Basis:
animal #2
Remarks:
Animal No. 2 of a total of 4
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 4 animals
Irritation parameter:
edema score
Remarks:
Exposure time 4 h
Basis:
animal #3
Remarks:
Animal No. 3 of a total of 4
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 4 animals
Irritation parameter:
edema score
Remarks:
Exposure time 4 h
Basis:
animal #4
Remarks:
ANimal No. 4 of a total of 4
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
Observation period 8 days
Remarks on result:
probability of severe irritation
Remarks:
The score given above is the mean value reported for the 4 animals
Irritation parameter:
erythema score
Remarks:
Exposure time 3 min and Exposure time 4 h
Basis:
animal #1
Time point:
48 h
Reversibility:
other: As no value has been reported:
Remarks:
not applicable
Remarks on result:
other: The time points reported were 24 hours and 8 days
Remarks:
not stated
Irritation parameter:
erythema score
Remarks:
Exposure time 3 min and Exposure time 4 h
Basis:
animal #2
Time point:
48 h
Reversibility:
other: As no value has been reported:
Remarks:
not applicable
Remarks on result:
other: The time points reported were 24 hours and 8 days
Remarks:
not stated
Irritation parameter:
erythema score
Remarks:
Exposure time 3 min and Exposure time 4 h
Basis:
animal #1
Time point:
72 h
Reversibility:
other: As no value has been reported:
Remarks:
not applicable
Remarks on result:
other: The time points reported were 24 hours and 8 days
Remarks:
not stated
Irritation parameter:
edema score
Remarks:
Exposure time 3 min and Exposure time 4 h
Basis:
animal #2
Time point:
72 h
Reversibility:
other: As no value has been reported:
Remarks:
not applicable
Remarks on result:
other: The time points reported were 24 hours and 8 days
Remarks:
not stated
Irritation parameter:
erythema score
Remarks:
Exposure time 4 h
Basis:
animal #3
Time point:
48 h
Reversibility:
other: As no value has been reported:
Remarks:
not applicable
Remarks on result:
other: The time points reported were 24 hours and 8 days
Remarks:
not stated
Irritation parameter:
erythema score
Remarks:
Exposure time 4 h
Basis:
animal #4
Time point:
48 h
Reversibility:
other: As no value has been reported:
Remarks:
not applicable
Remarks on result:
other: The time points reported were 24 hours and 8 days
Remarks:
not stated
Irritation parameter:
edema score
Remarks:
Exposure time 4 h
Basis:
animal #3
Time point:
72 h
Reversibility:
other: As no value has been reported:
Remarks:
not applicable
Remarks on result:
other: The time points reported were 24 hours and 8 days
Remarks:
not stated
Irritation parameter:
edema score
Remarks:
Exposure time 4 h
Basis:
animal #4
Time point:
72 h
Reversibility:
other: As no value has been repoted:
Remarks:
not applicable
Remarks on result:
other: The time points reported were 24 hours and 8 days
Remarks:
not stated
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Interpretation of results:
Category 1B (corrosive) based on GHS criteria
Conclusions:
Classification: corrosive (causes burns)
Executive summary:

A BASF AG internal procedure for skin irritation was used as in following described: two animals were treated with a 40 % DMA solution for 3 min and 4 animals for 4 hours using occlusive conditions. An application site of 2 x 2 cm was covered with the liquid test substance. After the application the skin was washed with Lutrol (50%). The animals were observed for 8 days and skin changes were recorded daily. On days 1 to 8 the exposure sites were examined and scored for erythema and edema on a graded scale of 0 to 2 or 4 respectively. The test substance was corrosive to the skin of rabbits. The report describes findings after 24 hours and at the end of the observation period (8 days). The 3 min exposure caused in every animal severe erythema and slight edema. The 4 h exposure caused severe erythema and severe edema.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable, well-documented publication, which meets basic scientific principles
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
other: Frosch PJ, Kligman AM: The soap chamber test: A new method for assessing the irritancy of soaps. J Am Acad Dermatol 1979;1:35–41.
Qualifier:
according to guideline
Guideline:
other: Pinnagoda J, Tupker RA, Agner T, Serup J: Guidelines for transepidermal water loss (TEWL) measurement: A report from the Standardization Group of the European Society of Contact Dermatitis. Contact Dermatitis 1990; 22:164–178.
Qualifier:
according to guideline
Guideline:
other: Rogiers V: EEMCO guidance for the assessment of transepidermal water loss in cosmetic sciences. Skin Pharmacol Appl Skin Physiol 2001;14:117–128
Qualifier:
according to guideline
Guideline:
other: Fullerton A, Fischer T, Lahti A, Wilhelm KP, Takiwaki H, Serup J: Guidelines for measurement of skin colour and erythema: A report from the Standardization Group of the European Society of Contact Dermatitis. Contact Dermatitis 1996;35:1–10
Qualifier:
according to guideline
Guideline:
other: Parra JL, Paye M: EEMCO Guidance for the in vivo assessment of skin surface pH. Skin Pharmacol Appl Skin Physiol 2003;16:188–202
GLP compliance:
no
Species:
human
Strain:
other: not applicable
Details on test animals or test system and environmental conditions:
20 healthy, non-preselected Caucasian volunteers (11 males and 9 females; aged 19–46 years, median age 28.3 years) without any skin or other systemic diseases were included. During the study period, the subjects were allowed to shower as usual, but they were instructed to avoid any application of detergents, emollients and moisturizers on their backs as well as natural or artificial UV exposure.
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
not specified
Remarks:
destilled water
Controls:
other: not applicable, humans
Amount / concentration applied:
(0.01, 0.1, 1, 1.5 and 2% in pilot study)
1 % in this study
Duration of treatment / exposure:
30 min, then 3 hours later again 30 min exposure, this treatment was performed on 4 consecutive days
Observation period:
5 days
Number of animals:
not applicable, 5 humans
Details on study design:
The application areas were located on the clinically normal skin of the paravertebral mid back. According to the number of different treatment options (see below), 14 test areas with a space of 3 cm between each test chamber were marked with a permanent marker, resulting in 4 vertical rows.

The test areas were randomized among the volunteers in order to avoid an anatomical selection bias. Aliquots of 50 ml of the freshly prepared aqueous irritants were applied to each test area by an occlusive epicutaneous patch test system (Large Finn Chambers® on Scanpor®, 12 mm diameter with filter discs, Epitest Ltd., Hyrlä, Finland). Patches were removed after 30 min. The exposed areas were rinsed with 10 ml of tap water and carefully dried with a paper tissue without rubbing. After a 3-hour interval, a second exposure with one of the irritants, according to the different treatment options, was performed. Using this scheme of application, each test site was repeatedly treated for 4 days.
Irritation parameter:
other: biogenic amines cause disruption of the permeability barrier
Basis:
mean
Time point:
72 h
Remarks on result:
no indication of irritation
Remarks:
The biogenic amines without the combination with SLS (AA/ AA, DMA/DMA, TMA/TMA) did not induce a significant irritation measured by Chromameter a* values
Irritant / corrosive response data:
at a concentration of 1 % not irritant
Other effects:
barrier disruption of the Stratum corneum

One day of treatment with detergents or biogenic amines did not result in irritation in any of the test sites.

All biogenic amines tested caused barrier disruption. The ranking order was TMA/TMA > DMA/DMA > AM/AM. The sequential irritation of the biogenic amines with SLS (AM/SLS, DMA/SLS and TMA/SLS) resulted in an increase in the barrier disruption starting for all three groups already on day 3, but this barrier disruption was less prominent than SLS/SLS alone.

The irritation was assessed measuring the redness.

The biogenic amines without the combination with SLS (AA/ AA, DMA/DMA, TMA/TMA) did not induce a significant irritation measured by Chromameter a* values. However, the combination with SLS depicted a significant increase in redness values for AM/SLS (only for day 5) and TMA/SLS (from day 3 on), while such an increase in the combination with DMA/SLS was not detectable

The biogenic amines in combination with SLS showed all an increase of the stratum corneum pH, e.g. AM/SLS on day 5, DMA/ SLS and TMA/SLS already on day 4.

The values assessed with the visual score were overall very low.

Interpretation of results:
study cannot be used for classification
Remarks:
Criteria used for interpretation of results: other: Frosch PJ, Kligman AM: The soap chamber test: A new method for assessing the irritancy of soaps. J Am Acad Dermatol 1979;1:35–41.
Conclusions:
The highest irritative potential could be detected, as expected, by the double application of SLS/SLS followed by NaOH/SLS. Next we ranked TMA/SLS, followed by AA/SLS > AM/SLS > DMA/SLS.
Biogenic amines induce a permeability barrier disruption after 3 days of application in a tandem repeated irritation test model. This effect was paralleled with the onset of inflammatory signs and an increase in pH. The sequential application of SLS further increased these effects, and the initiation of both barrier disruption and inflammation occurred earlier.
Executive summary:

In the study performed by Fluhr et al, 2005, it was shown that biogenic amines cause disruption of the permeability barrier. The biogenic amines without the combination with SLS (AA/ AA, DMA/DMA, TMA/TMA) did not induce a significant irritation measured by Chromameter a* values. The values assessed with the visual score were overall very low. However, the application of each of the three biogenic amines did not reveal a significant irritation or increase in SC pH. Sequential application of SLS further enhanced the barrier disruption induced by the biogenic amines. The only exception was the irritation parameter Chroma a*, where no significant increase of redness could be observed. The TMA/SLS irritation and barrier disruption was slightly more prominent than those induced by AM/SLS and DMA/SLS, which can be explained by the higher concentration (1.5 vs. 1.0%). Since these results are detectable in all analyzed parameters, we assume that the described features may be consistent properties of biogenic amines. This dichotomy of usually related parameters of barrier disruption and induction of irritation might be based on the fact that the amines disturbed the intercellular barrier-lipid processing but did not induce a pH change and a subsequent increase in pH.

They assume that the mechanism by which the biogenic amines induce a barrier disruption and inflammatory reaction are different from that of SLS. The contact with both classes of irritants however did not show over additive effects.

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: Comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Principles of method if other than guideline:
Method: Draize Test
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3.17 kg (mean)
- Diet (e.g. ad libitum): SNIFF
Vehicle:
unchanged (no vehicle)
Controls:
other: the adjacent eye served as untreated control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100µL
Duration of treatment / exposure:
single application
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
3
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: corrosive
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
not specified
Remarks on result:
other: reading not possible
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: corrosive
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Reversibility:
not specified
Remarks on result:
not measured/tested

No further details available.

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
Classification: risk of serious damage to eyes
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin corrosion

A BASF AG internal procedure for skin irritation was used as in following described: two animals were treated with a 40 % DMA solution for 3 min and 4 animals for 4 hours using occlusive conditions. An application site of 2x2 cm was covered with the liquid test substance. After the application the skin was washed with Lutrol (50%). The animals were observed for 8 days and skin changes were recorded daily. On days 1 to 8 the exposure sites were examined and scored for erythema and edema on a graded scale of 0 to 2 or 4 respectively. The test substance was corrosive to the skin of rabbits. The report describes findings after 24 hours and at the end of the observation period (8 days). The 3 min exposure caused in every animal severe erythema and slight edema. The 4 h exposure caused severe erythema and severe edema.

Skin irritation

In the study performed by Fluhr et al, 2005, it was shown that biogenic amines (1 %) cause disruption of the permeability barrier. The biogenic amines without the combination with SLS (AA/ AA, DMA/DMA, TMA/TMA) did not induce a significant irritation measured by Chromameter a* values. The values assessed with the visual score were overall very low. However, the application of each of the three biogenic amines did not reveal a significant irritation or increase in SC pH. Sequential application of SLS further enhanced the barrier disruption induced by the biogenic amines. The only exception was the irritation parameter Chroma a*, where no significant increase of redness could be observed. The TMA/SLS irritation and barrier disruption was slightly more prominent than those induced by AM/SLS and DMA/SLS, which can be explained by the higher concentration (1.5 vs. 1.0%). Since these results are detectable in all analyzed parameters, they assume that the described features may be consistent properties of biogenic amines. This dichotomy of usually related parameters of barrier disruption and induction of irritation might be based on the fact that the amines disturbed the intercellular barrier-lipid processing but did not induce a pH change and a subsequent increase in pH.

They assume that the mechanism by which the biogenic amines induce a barrier disruption and inflammatory reaction are different from that of SLS. The contact with both classes of irritants however did not show over additive effects. So the skin represents a better barrier for DMA induced alterations than all the mucosal membrane investigated.

Eye corrosion

For eye irritation a Draize test was performed on 3 rabbits (Vienna White) by BASF (1980). One single application was done with 100 µL, the eyes were not washed out afterwards. The untreated eye served as control. The test duration was 14 days. Scoring of ocular lesions was done according to the method of Draize et al. (1944). The application of the test substance caused an irreversible cornea and conjunctivae disturbance of a score of 4 of 4 and the animals did not recover within 8 days after treatment.

According to the authors, the test substance was classified as (severely) irritating to the rabbit eyes when applied without rinsing.

Respiratory irritation

In nasal irritation and pulmonary toxicity study of 20 aliphatic amines in mice, Gagnaire et al. exposed mice to airborne DMA to determine the RD50 value (Gagnaire et al., 1989). This value indicates 50 % decrease in the respiratory rate and considered to be successfully used to predict safe industrial exposure. The onset of action of DMA was very rapid, ca. 30 sec. to 1 min. 70 ppm of DMA was determined as RD50 in mice. 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, dimethylamine is considered to be moderately irritating to the upper respiratory and lower respiratory tract. This indictaes that DMA is more irritating as MMA and less irritating than TMA. The predicted safe levels to prevent upper airway irritation should not exceed 15 ppm for DMA. The effects of DMA were reversible in non-cannulated mice, but irreversible in tracheally cannulated mice (effects on the lower airways, can culminate in pulmonary congestion).

Conclusions:

Irritation/Corrosivity

The test substance was corrosive to the skin of rabbits (BASF, 1980). Every animal showed severe erythema and slight to severe edema of the skin. Dimethylamine was also highly irritating/corrosive to the eyes of rabbits (BASF, 1980) and the animals did not recover within 8 days after treatment. Additionally Gagnaire et al, 1989 proved that DMA is also highly irritating to the epithelium in the upper and lower respiratory tract. A concentration of 70 ppm DMA reduced the breathing frequency to 50 %. This indicates that DMA is more irritating as MMA and less irritating than TMA. The predicted safe levels to prevent upper airway irritation should not exceed 15 ppm for DMA. The effects of DMA were reversible in non-cannulated mice, but irreversible in tracheally cannulated mice (effects on the lower airways, can culminate in pulmonary congestion). Fluhr et al, 2005, showed that biogenic amines cause disruption of the permeability barrier. The biogenic amines without the combination with SLS (AA/ AA, DMA/DMA, TMA/TMA) did not induce a significant irritation measured by Chromameter a* values. The values assessed with the visual score were overall very low. So the skin represents a better barrier for DMA induced alterations than all the mucosal membrane investigated.

In the skin irritation studies, DMA was highly irritating - corrosive - to the skin. In the eye irritation study, DMA caused severe signs of irritation and they were not reversible within 8 days. So this substance is corrosive under the conditions used.


Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Classification is needed according to GHS:

DMA (aqueous solution) is classified according to GHS:

- Skin Corr. 1B. (H314: Causes severe skin burns and eye damage);

- Eye Damage 1 (H318: Causes serious eye damage)

DMA (gas) is classified according to GHS:

- Skin Irrit. 2 (H315: Causes skin irritation),

- Eye Damage 1 (H318: Causes serious eye damage.),

- STOT Single Exp. 3 (H335: May cause respiratory irritation)