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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
03 Dec 1986 - 03 Mar 1987 (experimental)
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Referenceopen allclose all

Reference Type:
study report
Report date:
Reference Type:
Comparison of the Maximum Tolerated Dose (MTD) Dermal Response in Three Strains of Mice Following Repeated Exposure to Acrylic Acid.
McLaughlin JE et al.
Bibliographic source:
Fd. Chem. Toxicol. 33: 507-513
Reference Type:
Tegeris AS et al.
Bibliographic source:
The Toxicologist 8: 127, Abstr. 504

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Principles of method if other than guideline:
13-week dermal irritation study conducted in three strains of mice to assess the MTD.
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Acrylic acid
EC Number:
EC Name:
Acrylic acid
Cas Number:
Molecular formula:
prop-2-enoic acid
Specific details on test material used for the study:
- Name of test material (as cited in study report): acrylic acid
- Source: Celanese
- Analytical purity: 99.5 %
- Impurities (identity and concentrations): 220 ppm of the inhibitor monomethyl ether of hydroquinone (maximum concentration)

Test animals

other: ICR, C3H, B6C3F1
Details on test animals or test system and environmental conditions:
- Source: Hilltop Lab Animals, Inc. Scottdale, Pennsylvania
- Age at study initiation: 42 days old
- Weight at study initiation:
- female ICR mice: 18.8 - 27.2 g,
- male C3H: 22.0 - 26.5 g,
- female B6C3F1: 18.4 - 24.2 g
- Housing: singly
- Diet (ad libitum): Purina Rodent Chow #5002, Purina Company, Richmond, Indiana
- Water (ad libitum): tap water
- Acclimation period: 1 week

- Temperature (°C): 22 ± 3 °C
- Humidity (%): 40 to 70 %
- Air changes (per hr): 8-10
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Type of coverage:
Details on exposure:
Route of Administration: dermal
At weekly intervals for each dose, dosing solutions were prepared from a pre-calculated volume of test article mixed with a predetermined set volume of acetone.

- Area of exposure: shaved dorsal area (dorsal mid-line midway between the caudal margin of the scapulae and the last rib); approx. 1 cm2
- Time intervals for shavings or clipplings: more than 20 hours before treatment

- Washing: no

- Amount(s) applied (volume or weight with unit): 100 µL
- Concentration (if solution): 1 and 4 %
- Constant volume or concentration used: yes

Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Samples were taken for analysis weekly, but only week 1, 4, 8 and 12 samples were analyzed for acrylic acid and dimer content. The 1 % solution varied from 95 to 134 % of target with an average of 108 %. The 4 % solutions varied from 97 to 121 % of target with an average of 103 %. The dimer content of the test article varied from 0.81 to 1.91 %. Dimer content in the dosing solutions did not vary over the one week dosing period.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
3 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
52 mg/kg bw/day
Dose / conc.:
208 mg/kg bw/day
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no
Positive control:


Observations and examinations performed and frequency:
- Time schedule: twice daily during dosing period

- Time schedule: twice daily during dosing period

- Time schedule for examinations: daily
All animals were observed daily for grading of skin reaction. The six parameters observed were erythema, edema, desquamation, fissuring, eschar and exfoliation.

- Time schedule for examinations: two days prior to dosing, on the first day of dosing, at weekly intervals thereafter for the duration of dosing and at terminal necropsy.

Sacrifice and pathology:

Gross examinations were performed and a skin section of approximately 2 cm X 1.5 cm was taken from the test site and an untreated section of skin from the scored area as well as the carcass were placed in 10 % neutral buffered formalin. The treated skin section was divided into three sections
oriented transversely and embedded in glycol methacrylate (Pathology Associates, Inc. Durham, NC). These were stained with hematoxylin and eosin and examined microscopically by a veterinary pathologist.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
The only clinical signs observed other than shaving injuries were a swollen anus during week 7 in a control mouse, hunched posture and thinness prior to death of a control (0%) ICR mouse. All the above signs are considered incidental findings and unrelated to the test article.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
In the ICR mice receiving 1% solutions, dermal desquamation was observed in 2 of 25 mice on day 14 only. Erythema was noted in B6C3FI mice receiving control and 1% solutions during weeks 2, 3 or 4. No other reactions were seen in the control and 1% dose level groups. The predominant reactions observed occurred predominately in the mice receiving 4% solutions on the dorsal thorax.
Minimal erythema changes scored as a 1 (slight or barely perceptible) were observed predominantly in the B6C3F1 strain during the first five weeks. Erythema was first observed as early as day 4.
Edema was observed at the end of the first week but only in the C3H strain. The maximum score was 1.
The major reactions of the skin were desquamation, fissuring and eschar seen in all strains of mice at the 4% dose level.
Desquamation was observed during the first week. The onset of marked desquamation (score of 3) occurred with a higher frequency with the C3H strain. This was followed by the B6C3F1 strain. After peaking at 21 days, the C3H strain remained the more severely affected group until day 35. Using chi-square to determine if a strain difference existed, significances were noted on days 7, 11, 14, 18, 25, 28 and 32. No differences were noted on days 21, 35, 39 and 42. Therefore, it was observed that desquamation occurred in all strains and was at its peak approximately on day 21 but the onset varied.
Fissuring was first observed after the first week. On day 18 the frequency of slight fissuring (score of 1) was greater in the ICR strain yet on days 32 and 35 the range (0 to 3) and frequency was greater in the C3H strain. Using chi-square, strain differences existed on days 18, 32 and 35.
Eschar was observed during the first week initially in the C3H strain. During the second week the B6C3F1 strain displayed this reaction. At no time interval did the ICR strain mice show any eschar.
Exfoliation followed the same time course and strain difference as eschar.
Therefore, there were strain differences within the six parameters of skin reactions evaluated but there were no consistent strain differences across the six parameters.
no mortality observed
Description (incidence):
Five mice died during the study. Of these, three (4% ICR, 1% C3H and 0% B6C3F1) were accidental deaths due to animals getting caught in feeders, watering opening or cage openings. The cause of death of two mice were undetermined; one of these mice was a control (0%) ICR mouse and one was a 1% C3H mouse. All other animals survived to terminal necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weights of control and compound-treated mice were comparable throughout the 13-week dosing period.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
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 specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The gross lesions observed were in the lungs, kidneys, adrenals, ovary/uterus, lymph nodes and skin. In the lungs and kidneys, reddening or white-grey foci were noted in various dose groups. Darkened adrenals were observed in all dose groups of the C3H mice beginning at the 4-week interim necropsy. Enlarged or cystic ovary or uterus and enlarged lymph nodes were observed in the 1% groups of all strains. Alopecia in a 1 % mouse was noted on the abdomen of one B6C3F1 mouse at terminal necropsy.
All lesions except the skin reactions noted in the treated area did not appear to be related to compound treatment.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopic findings in the dermis and epidermis described as proliferative degenerative or inflammatory changes were seen predominantly in the 4% treatment level in all mouse strains; similar findings were seen occasionally in the 1% dose groups but rarely in the control groups. Dysplasia and hyperplasia were not seen in tissues from any of the groups.
The proliferative changes involving the epidermis and, to a lesser degree, the dermis were characterized as parakeratosis, granulosis and acanthosis of moderate degree and were consistent findings throughout all the 4% groups. Minimal to mild fibroplasia were almost entirely confined to the 4% groups. Sebaceous gland hyperplasia was recognized in the pilosebaceous apparatus of most of the animals in the 4% dose level. Necrosis was the most frequent degenerative change observed in the 4% level. This lesion was characterized by large eosinophilic changes resembling edema in the dermis; however, the squamous cells could be seen faintly as ghost cells. These areas could often be traced out to areas that were transformed into early parakeratosis. Crusts and ulcers were occasionally observed but with no constant feature. Inflammatory changes in the epidermis consisted of occasional pustules and exocytosis. Dermal infiltrates were almost entirely leukocytic predominantly with neutrophils and eosinophils. Macrophages and mast cells appeared to a minimal or lesser degree in most sections.
Histopathological findings: neoplastic:
no effects observed

Effect levels

Key result
Dose descriptor:
Remarks on result:
not determinable
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables


Results of the present study with three strains of mice receiving acrylic acid dermally at levels of 4, 1 and 0% for 13 weeks caused comparable skin irritation to ICR, C3H and B6C3F1 mice at the 4% dose level. Minimal skin reactions were observed in all strains at the 1% dose level. Gross lesions other than skin reactions were incidental to treatment. Microscopic findings characterized as proliferative, degenerative or inflammatory changes were seen predominantly at the 4% level in all strains, occasionally at the 1% level and only rarely in controls. Body weights of all strains at all dose levels were similar.

Current guidelines for dose selection in chronic dermal studies retrospectively were applied to this study to ascertain MTD. Using proposed MTD criteria established in the EPA Workshops on dermal carcinogenesis bioassays, microscopic and gross changes to the skin in subchronic studies can easily be used to classify skin response as exceeding the MTD, reaching the MTD, or tolerating the treatment dose. However, one must be aware of certain hazards to interpretation. The present work shows that microscopic examination alone at the end of 13 wk of treatment could adequately categorize tolerated doses from those exceeding the MTD. Similarily, gross examination of the skin throughout the whole course of exposure could be used to identify concentrations in excess of a tolerated dose. However, gross examination alone, performed only at final autopsy, would miss early skin lesions that would trigger 'exceeding MTD' classification. There appears to be a 'hardening' or accommodation of the skin to irritants such as acrylic acid with repeated insult, reflected by the apparent refractoriness to irritation that developed after 8 wk in this study. Data collected during visual examination prior to wk 8 indicate that the MTD had been reached or exceeded. Data collected by gross examination after 8 wk of exposure suggest that the 4% acrylic acid would be tolerated in a long-term exposure. However, microscopic examination after 13 wk showed that 4% acrylic acid clearly exceeds MTD. Thus, microscopic findings provided a more sensitive index for exceeding MTD than gross observations taken only at autopsy, but generally correlated well for MTD if gross observations were taken at regular intervals during treatment. Gross examination at study termination alone would be insufficient to predict doses for use in a chronic dermal study. Acrylic acid at 1% in acetone was fairly well tolerated by all mice in all strains, although signs suggest that the MTD was approached. Thus, 1% acrylic acid in acetone, one-quarter of that concentration in clear excess of MTD, would be the appropriate dose concentration for lifetime skin studies, based on MTD criteria.

Applicant's summary and conclusion