Registration Dossier

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication.
Principles of method if other than guideline:
Modified Maguire Method
GLP compliance:
no
Type of study:
split adjuvant test
Justification for non-LLNA method:
A reliable in vivo test was available before the implementation of the OECD 429 method.
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: no data
Species:
guinea pig
Strain:
Hartley
Sex:
male
Route:
epicutaneous, occlusive
Vehicle:
no data
Concentration / amount:
Induction: 0.1 ml aliquot of the test substance
Challenge: not specified
Route:
epicutaneous, occlusive
Vehicle:
no data
Concentration / amount:
Induction: 0.1 ml aliquot of the test substance
Challenge: not specified
No. of animals per dose:
10
Details on study design:
- Positive control:
For induction, 10 guinea pigs were routinely subjected to the same dosing regimen with the diglycidyl ether of 2,2-di-(p,p'-hydroxyphenyl)propane (DER* 331 Epoxy Resin -- Dow Chemical U .S .A .), a known sensitizer to serve as a positive control . Challenge was performed two weeks after the lastinjection of the induction series.
Positive control substance(s):
yes
Remarks:
2,2-Di-(p,p'-hydroxyphenyl)propane didlycidyl ether (DER* 331 Epoxy Resin -- Dow Chemical U .S .A .)
Positive control results:
The positive reference substance ( DER* 331 Epoxy Resin) induced moderate skin sensitization.
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
0.1 ml
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0.1 ml. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
no data
No. with + reactions:
7
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: no data. No with. + reactions: 7.0. Total no. in groups: 10.0.

Preliminary study:

Prior to conducting the sensitization test, the test material was applied as received to the clipped flanks of animals to determine if primary irritation would occur. If significant irritation was observed, dilutions of the test material were made in a suitable solvent. The highest concentration which did not cause primary irritation was used for the sensitization test.

Test group:

Substance

animals tested

animals sensitized

Acrylic acid (0.1 ml aliquot)

10

0

Sensitization with the test substance was not observed in this test.

Interpretation of results:
GHS criteria not met
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication, basic data given.
Principles of method if other than guideline:
The study was conducted according to the method described by Klecak (1977) and Klecak and Geleick (1977).
GLP compliance:
no
Type of study:
Freund's complete adjuvant test
Justification for non-LLNA method:
A reliable in vivo test was available before the implementation of the OECD 429 method.
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 55% (gas chromatigraphy) / >98% after destillation procedure.
- Impurities (concentrations): 45% (gas chromatography) / < 2% after destillation procedure.
Species:
guinea pig
Strain:
other: Himalayan white and Dunkin-Hartley (two strains due to the shortage of animals)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Himalayan white (Inst. for Biomedical Research, Füllinsdorf, Switzerland) / Dunkin-Hartley (Olac Ltd., Bicester, England)
- Weight at study initiation: 350-450 g
- Housing: in pairs
- Diet (ad libitum): Pellet
- Water (ad libitum): water containing vitamin C


Route:
intradermal
Vehicle:
other: Refer to Details on study design (Traditional tests)
Concentration / amount:
Induction: 0.5 M
Challenge: no concentration given
Route:
epicutaneous, open
Vehicle:
other: Refer to Details on study design (Traditional tests)
Concentration / amount:
Induction: 0.5 M
Challenge: no concentration given
No. of animals per dose:
8
Details on study design:
RANGE FINDING TESTS:
Skin irritation caused by a single open application was determined for Acrylic acid in FCA pretreated animals (not participating in the sensitization procedure). On the clipped flank of 8 animals 0.025 ml of the test substance was applied with a pipette in progressively diluted (one third) concentrations, each in areas of 2 cm2 marked with a circular stamp. A mixture of 2 parts methyl ethyl ketone and 1 part of peanut oil by volume (Aramek) was used as a solvent. The reactions were read after 24 and 48 h. The maximum nonirritating concentration (m.n.i.c.) was determined, which is the highest concentration not causing a macroscopic reaction in any of the animals.


MAIN STUDY
A. INDUCTION EXPOSURE
After the acid was emulsified in FCA, an equal volume of distilled water was added. On days 0, 2, 4, 7 and 9 intradermal injections with 0.1 ml of this emulsion were given in the shoulder area from the left to the right paw. Control animals were similarly treated with FCA, blended with an equal volume of distilled water.

B. CHALLENGE EXPOSURE
All the animals were tested epicutaneously on day 21 (right flank) and day 35 (left flank). On day 21 right flank and on day 35 left flank of both groups were shaved. The test substance and the vehicle was applied in an amount of 0.025 ml with a pipette on an area of 2 cm2, marked with a circular stamp. The test sites were left uncovered and read at 24 h and 48 h.
Reading:
1st reading
Hours after challenge:
24
Group:
other: Test group (Acrylic acid containing an unidentified impurity of 45%)
Dose level:
no data
No. with + reactions:
8
Total no. in group:
8
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: Test group (Acrylic acid containing an unidentified impurity of 45%). Dose level: no data. No with. + reactions: 8.0. Total no. in groups: 8.0.
Reading:
1st reading
Hours after challenge:
24
Group:
other: Test group (Acrylic acid (destillate, >98%)
Dose level:
no data
No. with + reactions:
0
Total no. in group:
8
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: Test group (Acrylic acid (destillate, >98%). Dose level: no data. No with. + reactions: 0.0. Total no. in groups: 8.0.
Interpretation of results:
GHS criteria not met
Conclusions:
Classification: not sensitizing
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1984
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 was conducted according to the method described by Klecak (1977) and Van der Walle (1983).
GLP compliance:
no
Type of study:
other: modified Freund's complete adjuvant test
Justification for non-LLNA method:
At the time of the study there was only the maximization test available and was recommended by regulatory authorities.
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid from Merck Schuchardt, impure
- Analytical purity: < 93% (GC)
- Impurities (identity and concentrations): alpha, beta-Diacryloxypropionic acid, 7% (analytically determined), 5-hexenoic acid (identified but not quantified)

Species:
guinea pig
Strain:
Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Hartley outbred
- Source: Broekman Institute, Netherlands
- Weight at study initiation: 400 g
- Housing: in pairs in steel cages.
- Diet (ad libitum): Pellet food (Hope Farms, Netherlands)
- Water (ad libitum): yes
Route:
intradermal
Vehicle:
water
Remarks:
distilled
Concentration / amount:
1.2% / 0.1 ml
Day(s)/duration:
Day 0, 5, and 9
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
No.:
#1
Route:
epicutaneous, open
Vehicle:
methyl ethyl ketone
Remarks:
2 parts methyl ethyl ketone and one part of peanut oil by volume
Concentration / amount:
0.3 M / 0.025 ml
Day(s)/duration:
Day 21. Readings were performed after 24 and 48 h of administration.
Adequacy of challenge:
highest non-irritant concentration
No.:
#2
Route:
epicutaneous, open
Vehicle:
methyl ethyl ketone
Remarks:
2 parts methyl ethyl ketone and one part of peanut oil by volume
Concentration / amount:
0.3 M / 0.025 ml
Day(s)/duration:
Day 35. Readings were performed after 24 and 48 h of administration.
Adequacy of challenge:
highest non-irritant concentration
No.:
#3
Route:
epicutaneous, open
Vehicle:
methyl ethyl ketone
Remarks:
2 parts methyl ethyl ketone and one part of peanut oil by volume
Concentration / amount:
0.3 M / 0.025 ml
Day(s)/duration:
Day 49. Readings were performed after 24 and 48 h of administration.
Adequacy of challenge:
highest non-irritant concentration
No.:
#1
Route:
epicutaneous, open
Vehicle:
methyl ethyl ketone
Remarks:
2 parts methyl ethyl ketone and one part of peanut oil by volume
Concentration / amount:
1 M / 0.025 ml
Day(s)/duration:
Day 21. Readings were performed after 24 and 48 h of administration
Adequacy of challenge:
highest non-irritant concentration
No.:
#2
Route:
epicutaneous, open
Vehicle:
methyl ethyl ketone
Remarks:
2 parts methyl ethyl ketone and one part of peanut oil by volume
Concentration / amount:
1 M / 0.025 ml
Day(s)/duration:
Day 35. Readings were performed after 24 and 48 h of administration
Adequacy of challenge:
highest non-irritant concentration
No.:
#3
Route:
epicutaneous, open
Vehicle:
methyl ethyl ketone
Remarks:
2 parts methyl ethyl ketone and one part of peanut oil by volume
Concentration / amount:
1 M / 0.025 ml
Day(s)/duration:
Day 49. Readings were performed after 24 and 48 h of administration.
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
8
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: Three
- Exposure period: day 0, 5, and 9
- Test groups: impure acrylic acid, 5-hexenoic acid, a,b-diacryloxypropionic acid
- Control group: no substance was added
- Site: in the shaved nuchal area
- Frequency of applications: not specified
- Duration: 9 days
- Concentrations: 0.17 M for all test substances

B. CHALLENGE EXPOSURE
- No. of exposures: Three
- Day(s) of challenge: Day 21, 35, and 49
- Exposure period: 28 days
- Test groups: impure acrylic acid, 5-hexenoic acid, a,b-diacryloxypropionic acid (DAPA)
- Control group: all test compounds
- Site: shaved contralateral flank
- Concentrations: impure acrylic acid (0.3 M, 1 M), DAPA (0.01 M, 0.03 M), 5-hexenoic acid (1 M, 3 M)
- Evaluation (hr after challenge): 24 h and 48 h
Challenge controls:
Challenge controls received all tested compounds, i.e. impure acrylic acid, DAPA (a,b-diacryloxypropionic acid), and 5-hexenoic acid. Concentrations of the challenge for the control group are not specified.
Reading:
other: Day 21
Group:
other: impure acrylic acid
Dose level:
1 M
No. with + reactions:
8
Total no. in group:
8
Clinical observations:
not specified
Remarks on result:
positive indication of skin sensitisation
Reading:
other: Day 35
Group:
other: impure acrylic acid
Dose level:
1 M
No. with + reactions:
8
Total no. in group:
8
Clinical observations:
not specified
Remarks on result:
positive indication of skin sensitisation
Reading:
other: Day 21
Group:
other: impure acrylic acid
Dose level:
0.3 M
No. with + reactions:
1
Total no. in group:
8
Clinical observations:
not specified
Remarks on result:
positive indication of skin sensitisation
Reading:
other: Day 49
Group:
other: impure acrylic acid
Dose level:
0.3 M
No. with + reactions:
7
Total no. in group:
8
Clinical observations:
not specified
Remarks on result:
positive indication of skin sensitisation

Sensitizing potential in the modified Freund's Adjuvant Test

Test substance

Induction

Challenge concentration*)

Number of sensitized animals/number of tested animals

Day 21

Day 35

Day 49

Acrylic acid, from Merck Schuchardt

30.17 M

(= 1.2%)

1 M

0.3 M

8/8

1/8

8/8

N.T.

N.T.

7/8

DAPA

10.17 M**)

(= 3.6%)

0.03 M

0.01 M

8/8

7/8

N.T.

7/8

N.T.

7/8

5-hexenoic acid

30.17 M

(= 1.9%)

3 M

1 M

0/8

0/8

0/8

0/8

0/8

0/8

controls

3FCA dist. water

All the above compounds

0/8

0/8

0/8

N.T. = not tested

*) = In Aramek, 2 parts methyl ethyl ketone, one part peanut oil by volume

**) = Different induction procedure

Interpretation of results:
study cannot be used for classification
Conclusions:
In conclusion, acrylic acid containing 7% of a,b-diacryloxypropionic acid (DAPA) is sensitizing. Sensitization is caused by DAPA and not by acrylic acid.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Eight acrylates and methacrylates including acrylic acid and an additional 64 substances were tested in guinea pigs using a modified Split Adjuvant Test procedure. The purity of the test substances was not mentioned. The highest concentration which did not cause primary irritation was used but no data were given on the test concentrations. Ten animals per test received a 0.1 ml aliquot of the test material to the backs four times in 10 days. At the time of the third application, 0.2 ml Freund's adjuvant was injected at one point adjacent to the insult site. After a 2-week rest period, the guinea pigs were challenged with the test material on one flank and a solvent (if used) on the other flank. The challenge site was evaluated for erythema and oedema at 24 and 48 hours. Acrylic acid was negative (0/10) (Rao et al. 1981).

 

Van der Walle et al.(1982) reported a sample of commercial grade acrylic acid to be sensitizing in a Freund’s Complete Adjuvant test. 8/8 guinea pigs were sensitized. However, analysis by gas chromatography revealed an impurity of 45 % in this sample. The sample of acrylic acid was distilled in vacuo and the sensitized animals were tested with the distillate (containing >98% acrylic acid) and with the residue. None of the animals reacted to the distillate but all the animals reacted to the residue. The identity of the allergen in this residue was under investigation at the time of publication of this paper.

 

In a modified Freund's Complete Adjuvant test 8 guinea pigs/group received 3 intradermal injections during the induction phase on days 0, 5 and 9 (the test substance was mixed with FCA in a volume of 0.1 ml). Non-irritant test concentrations were used for challenge at day 21. The test concentrations for intradermal injections were 3 x 0,17 M (1.2%) in water and for challenge 1 and 0.3 M in Aramek, a mixture of 2 parts methyl ethyl ketone and 1 part of peanut oil. Distilled acrylic acid was negative but commercial acrylic acid proved to be a strong skin sensitizer. The skin reactions were due to the presence of varying quantities (up to 7%) of a,ß-diacryloxypropionic acid (DAPA). Positive skin reactions were still present after a third challenge on day 49 (Waegemakers and Van der Walle 1984).

Based on the presented data, acrylic acid does not have a skin sensitizing potential in animal studies. Positive test results obtained with commercial grade samples of the compound were caused by the presence of the impurity DAPA.

 

Recent investigations on the occurrence of DAPA in industrial acrylic acid have shown that DAPA is not present (at a detection limit of 20 ppm) in current commercial samples of acrylic acid (Elf Atochem 1998, EU Risk Assessment 2002). (see Chapter 7.12 Additional Toxicological Information)

 

 


Migrated from Short description of key information:
Acrylic acid does not cause skin sensitization in animals.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

There is no information available on the potential of acrylic acid to produce respiratory sensitisation in animals.

Respiratory sensitisation has not been observed in humans (EU RAR 2002).


Migrated from Short description of key information:
Respiratory sensitisation has not been observed in humans.

Justification for classification or non-classification

EU classification according to Annex I of Directive 67/548/EEC: no classification required

GHS classification (GHS UN rev.3, 2009): no classification required