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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

No experimental data on the test substance is available. Data on the structural analogue acrylic acid which has been extensively studied, is included for assessment.

 

Repeated dose toxicity - oral:

NOAEL (rat, chronic) = 40 mg/kg bw/d (similar to OECD TG 452; study with the structural analogue acrylic acid CAS 79-10-7)

 

Repeated dose toxicity - inhalation:

Systemic effects: NOAEC (mouse, subchronic) = 15 mg/m³ air

Local effects: LOAEC (mouse, subchronic) = 15 mg/m³ air

(similar to OECD TG 413; study with the structural analogue acrylic acid CAS 79-10-7)

 

Repeated dose toxicity - dermal:

Systemic effects: no adverse effects observed

Local effects: adverse effects observed, no NOAEL identified

(similar to OECD TG 411; study with the structural analogue acrylic acid CAS 79-10-7)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
22 Aug 1983 - 24 Aug 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
Principles of method if other than guideline:
Acrylic acid was administered in 4 different doses (120, 800, 2000 and 5000 ppm corresponding to about 9, 61, 140 and 331 mg/kg body weight/day, respectively) in the drinking water to male and female Wistar rats for 3 (satellite groups) or 12 (main groups) months.
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid, pure
- Analytical purity: > 99 %
- Impurities (identity and concentrations): stabilized with 200 ppm MEHQ
- Test Substance No.: 82/380
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Wistar (Chbb = THOM (SPF))
- Source: Karl THOMAE, Biberach an der Riss, Germany
- Age at study initiation: 42 days old
- Weight at study initiation:
- male animals (main groups): 181.3 (155-202) g
- male animals (sat. groups): 180 .9 (163-199) g
- female animals (main groups): 145.3 (127-177) g
- female animals (sat. groups): 146.9 ( 131-169) g
- Fasting period before study: no
- Housing: singly in Type DK III stainless steel wire cages
- Diet (ad libitum): ground Kliba 343 rat/mouse/hamster "A" food supplied by KLINGENTALMUHLE AG, CH-4303, Kaiseraugst, Switzerland
- Water (ad libitum): tap water
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12 hours/ 12 hours
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DRINKING WATER PREPARATION
- Rate of preparation of diet (frequency): 3 times a week
- Mixing appropriate amounts with (Type of food): The test substance was weighed out for each test group and added to the appropriate amount of drinking water. The drinking water was agitated with a magnetic stirrer until the test substance had completely dissolved, which took about 3 minutes.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses to check the concentrations were carried out on each dose at the start of the study and after 3, 6 and 12 months. The determinations were carried out by gas chromatography.
The actual concentrations in the test solutions were found to be in the ranges 95 to 107, 90 to 96, 95 to 100 and 94 to 100 % of the target concentrations of 120, 800, 2000 and 5000 ppm, respectively.
Duration of treatment / exposure:
3 (satellite groups) and 12 months (main groups)
Frequency of treatment:
continuously
Dose / conc.:
120 ppm
Remarks:
nominal in water
Dose / conc.:
800 ppm
Remarks:
nominal in water
Dose / conc.:
2 000 ppm
Remarks:
nominal in water
Dose / conc.:
5 000 ppm
Remarks:
nominal in water
No. of animals per sex per dose:
10 (satellite groups) or 20 (main groups) animals
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: none
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day (Monday to Friday) or once a day (Saturdays, Sundays and public holidays)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the first three months, then every 4 weeks

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly during the first three months, at intervals of 3 months after the third month of the study

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: about 4, 12, 26 and 51 weeks after the start of administration
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: 10
- Parameters examined: Hemoglobin, Erythrocytes, Hematocrit, Mean hemoglobin content per erythrocyte, Mean cell volume, Mean corpuscular hemoglobin concentration, Platelets, Leukocytes, Prothrombin time (Hepato Quick's Test)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: about 4, 12, 26 and 51 weeks after the start of administration
- Animals fasted: No
- How many animals: 10
- Parameters examined:
Blood chemistry: Total bilirubin, Creatinine, Urea, Sodium, Potassium, Total protein, Glucose, Inorganic phosphate, Calcium, Chloride, Triglycerides, Cholesterol, Albumin
Enzyme activities: Glutamic-pyruvic transaminase, Alkaline phosphatase, Glutamic-oxalacetic transaminase

URINALYSIS: Yes
- Time schedule for collection of urine: about 3, 11, 25 and 50 weeks after the start of treatment
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters were examined: pH, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, sediment

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
The animals were exsanguinated, dissected and the gross pathology was assessed. The exsanguinated animals, and the liver, kidneys, testes/ovaries, spleen, brain and adrenals were weighed and the relative organ weights were determined.

HISTOPATHOLOGY: Yes
The following organs/tissues were fixed in 4% formaldehyde solution:
- liver, kidneys, adrenals, heart, lungs, thymus, esophagus, jejunum, colon, urinary, bladder, salivary glands, aorta, eyes, brain, thyroids/parathyroids, stomach, ileum, rectum, uterus, representative lymph nodes, accessory genital organs, skin, femur with articular surface, buccal mucosa, cervical/ thoracic/ lumbar cord, nasal mucosa, spleen, testes/epididymides, ovaries, pituitary, trachea, duodenum, cecum, pancreas, sternum with marrow, peripheral nerve, skeletal muscles, female mammary gland, tongue, all gross lesions

A medial longitudinal section of the tongue (satellite groups) was examined.
The buccal mucosa ( satellite groups) was removed from the region of the molars and examined as a longitudinal section.
After the facial bones had been decalcified (satellite groups) a fragment at the level of the 2nd palatine ridge and of the 1st molar was removed. The side facing the molars was intended to be the cut surface. The section contains the ectoturbinates, endoturbinates with nasal septum, maxillary sinus, nasopharyngeal duct as well as, in some cases, parts of the molars.
Other examinations:
The mean amount of test substance consumed each day (in mg per kg body weight) was calculated by way of example for weeks 1, 13, 25, 37 and
52 of the study (main groups) and for the entire duration of the study (satellite groups) at weekly intervals.
Statistics:
Clinical examination and pathology: Statistical significance was determined by analysis of variance (ANOVA) followed by a Dunnett Test or a t-test generalized by WILLIAMS (pathology) for the simultaneous comparison of several dose groups with a control group.
Clinical chemistry/haematology: To test for significance, the t-test was used to compare the individual dose groups with the control group.
Urinanalysis: A chi2 test was carried out in appropriate 2 x 2 contingency tables to assess whether particular features differed between the control and test groups.
Clinical signs:
no effects observed
Description (incidence and severity):
The 4 doses administered by addition to the drinking water (120, 800, 2000 and 5000 ppm) resulted in no impairment of general wellbeing of any of the animals in this study.
Mortality:
no mortality observed
Description (incidence):
Apart from one male animal in main group (120 ppm) which, having previously attracted attention due to a marked increase in the consumption of drinking water and an anemic appearance, died after 326 days of the study, no animal in the main or satellite groups died prematurely. The gross-pathological findings of this animal indicated chronic progressive nephropathy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean body weights of the male rats in main and satellite groups (2000 and 5000 ppm) were up to about 9 % below those of the control animals from 1 week after the start of administration up to the end of the study. In contrast, the mean body weights of the other males and of all the females treated with acrylic acid corresponded to those of the relevant controls. The rather marginal effect on the body weights of the male rats in the 2000 and 5000 ppm groups has to be viewed in the context of the reduction in the consumption of food and/or drinking water by these animals and must be attributed to the administration of the test substance.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Only the male rats in the main and satellite group at the highest dose of 5000 ppm showed reduced food consumption throughout the study. In contrast, the food consumptions of the other animals treated with acrylic acid solutions were comparable with those of the relevant control groups. The reduction in food consumption by the male animals in highest dose group (5000 ppm; main and satellite groups), although slight, was seen throughout the study and must be regarded as connected with administration of the test substance.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
The consumption of drinking water by the male animals in the main and satellite groups receiving 120 and 800 ppm was the same or somewhat higher than that of the relevant control groups; in contrast, the corresponding figures for the animals in the 5000 ppm group were distinctly (up to about 20 %) lower, and for the rats in the 2000 ppm were less markedly lower (not more than about 13 %) than the figures for the controls.
The consumption of drinking water by the female rats in the main and satellite groups (120 and 800 ppm) showed nothing abnormal on comparison with the controls. The differences found, which were mainly slight and independent of the dose, are of an incidental nature. In contrast, the drinking water consumption by the animals in the highest dose main and satellite groups (5000 ppm) was reduced, although only slightly, throughout the study. At times, the female rats in the 2000 ppm group also showed a tendency to this.
The marked reduction in the drinking water consumed by the male animals in test group (5000 ppm) and the less pronounced reduction in the drinking water consumption of the male rats in test group (2000 ppm) and the female animals in test groups (2000 and 5000 ppm) are attributed to the test substance.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Administration of acrylic acid in doses of 120, 800, 2000 and 5000 ppm in the drinking water to rats for 12 months resulted in no changes in the haematology which were unambiguously attributable to the test substance administration.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Administration of acrylic acid in doses of 120, 800, 2000 and 5000 ppm in the drinking water to rats for 12 months resulted in no changes in the clinical chemistry which were unambiguously attributable to the test substance administration.
Endocrine findings:
not examined
Urinalysis findings:
no effects observed
Description (incidence and severity):
Administration of acrylic acid in doses of 120, 800, 2000 and 5000 ppm in the drinking water to rats for 12 months resulted in no changes in the urinanalysis which were unambiguously attributable to the test substance administration.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
At 5000 ppm in the male animals a fall in the absolute adrenal weight, and increased relative kidney, brain and testes weight were observed. In the female animals of the highest dose group (5000 ppm) a fall in the relative spleen weight was found. The changes are very slight and there is no similar change in the other sex. Furthermore, the computed increases in the relative weights are regarded as the consequence of the reduction in the body weight while the absolute weights of the relevant organs remained unchanged. Thus, the weight changes are not regarded as having pathognomonic relevance.
Gross pathological findings:
no effects observed
Description (incidence and severity):
None of the individual findings from the grosspathological assessment showed any relevant connection with the administration of the test substance.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
None of the individual findings from the histopathological assessment showed any relevant connection with the administration of the test substance.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
body weight and weight gain
water consumption and compound intake
Remarks on result:
other: Based on the reduced body weight gain in males and lower water consumption in both sexes, the NOAEL of this study was considered to be 800 ppm in male rats (corresponding to 40 mg/kg bw).
Key result
Dose descriptor:
NOAEL
Effect level:
375 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
water consumption and compound intake
Remarks on result:
other: In females the NOAEL was considered to be 5000 ppm (corresponding to 375 mg/kg bw) since reduced water consumption was not interpreted as a clear adverse health effect.
Key result
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
body weight and weight gain
water consumption and compound intake
Key result
Critical effects observed:
no

Conclusions:


The following findings were obtained and assessed as being related to the test substance:


 


5000 ppm group:


- reduced food consumption by the male rats (main and satellite groups)


- distinctly reduced drinking water consumption (main and satellite groups) by the males, and to a slight extent also by the female rats


- retarded body weight gain of the male rats (main and satellite groups)


 


2000 ppm group:


- slight reduction in drinking water consumption by both sexes (main and satellite groups)


- marginal effect on body weight gain of the male rats (main and satellite groups)


 


120 and 800 ppm groups:


- no changes which could be connected with the test substance administered.


 


In conclusion, it can be said that administration of various doses of acrylic acid in the drinking water for up to 12 months to male and female Wistar rats produced nothing in the clinical chemistry, haematology, urinanalysis or gross-pathological or histopathological findings, or changes in organ weights, which was unambiguously connected with administration of the test substance. Only at the two higher doses (2000 and 5000 ppm) did the animals show clinical signs (reduced consumption of drinking water and/or food, retarded body weight gain) which has to be regarded as related to the test substance. The reaction of the male animals was more sensitive than that of the females.


Acrylic acid at 2000 ppm (corresponding to 140 mg/kg bw) was unpalatable to rats. Thus, for the carcinogenicity study, a lower maximum dose of 1200 ppm was selected.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Principles of method if other than guideline:
Male and female 66C3F1 mice were exposed to 0, 5 , 25 or 75 ppm acrylic acid vapours (corresponding to 0, 0.015, 0.074, 0.221 mg/L) 6 hours per day, 5 days per week, for 13 weeks.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 99.7 %
- Impurities (identity and concentrations):
- water wt% 0.08,
- monomethyl ether of hydroquione 218 ppm
- Dimer wt% 0.23
- Acetic Acid wt% 0.12
- Propionic Acid wt% 0.15
- Acrolein ppm <25
- Ethyl Acrylate ppm <25
- Phenothiazine ppm 0.10
- Proto-anemonin ppm <20
- Furfural ppm <20
- Source: Celanese Chemical Company
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA
- Age at study initiation: 3 weeks
- Fasting period before study: no
- Housing: single
- Diet (ad libitum): standard laboratory diet (Purina Laboratory Chow, Ralston Purina Co., St. Louis, MO) except during exposure
- Water: ad libitum
- Acclimation period: 16 days

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: inhalation chambers (14500 liters) with stainless steel pyramidal-shaped ceilings and epoxy resin-coated walls and floors with dynamic airflow conditions
- Source and rate of air: Exposure levels of acrylic acid were generated by pumping liquid acrylic acid at calculated rates into glass vaporization flasks heated to approximately 130°C. Vapours from the flasks were swept into the chamber air supply duct with compressed air and mixed with incoming air by turbulence.
- Temperature, humidity, pressure in air chamber: 21 °C, 50 %, slight negative pressure
- Air flow rate: 2500 liters per minute
- Air change rate: 10 air changes per hour


TEST ATMOSPHERE
- Brief description of analytical method used: The actual concentration of acrylic acid in each chamber was measured 2-3 times per hour (12-15 times daily) by infrared spectrophotometry using a Miran I Infrared Analyzer at a wavelength of 8.9 µm. Prior to initiating exposures, distribution of acrylic acid vapours within the chambers was determined to be uniform within 10 % of the target concentrations.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Percent dimer in the liquid acrylic acid monomer varied between 0.4% and 3.7% during the exposure interval.
Analytical concentrations (mean ± SD): 5.0 ± 0.3 ppm; 25 ± 1 ppm; 75 ± 1 ppm
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day; 5 days/week
Dose / conc.:
5 ppm
Remarks:
analytical concentration
Dose / conc.:
25 ppm
Remarks:
analytical concentration
Dose / conc.:
75 ppm
Remarks:
analytical concentration
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: none
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: on the 1st day of exposure and weekly thereafter


OPHTHALMOSCOPIC EXAMINATION: YES


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1 week prior to sacrifice
- Anaesthetic used for blood collection: No
- Animals fasted: Yes / No / No data
- How many animals: 10/sex/dose group
- Parameters examined: Packed Cell Volume (PCV), Hemoglobin (Hgb), Erythrocyte count and morphology, Total and differential leukocyte counts


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to sacrifice
- Animals fasted: Yes
- How many animals: 10/sex/dose group
- Parameters examined: Glucose, Blood urea nitrogen (BUN), Alkaline Phosphatase (AP), Glutamic-pyruvic transaminase (SGPT)


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Approximately 18 hours after the final exposure, animals were sacrificed and submitted to necropsy. Animals were fasted overnight prior to sacrifice. Each animal was examined externally and internally for gross pathologic alterations. Immediately after decapitation, the eyes of each animal were examined by a glass slide technique with fluorescent illumination. Weights of brain, heart, liver, kidneys and testes were determined and recorded. Lungs and trachea were removed as a unit and the lungs were expanded to approximately their normal inspiratory volume with buffered 10 % formalin.
Animals which died spontaneously or which were sacrificed in a moribund condition during the course of the study were given a complete gross pathological examination. In general, representative portions of the organs and tissues listed below from each animal were preserved in buffered 10 % formalin.


HISTOPATHOLOGY: Yes
Slides (hematoxylin and eosin stained) were prepared and histopathologic examinations performed on tissues listed below for 10 animals of each
sex in the control and 75 ppm exposure groups. Similar histopathologic examinations were conducted on all animals that died spontaneously during the course of the study. Target organs identified in the 75 ppm exposure group were also examined for 10 animals in the 5 ppm and 25 ppm exposure groups.

Organs/Tissues:
adipose tissue, adrenals, aorta, brain, cecum, esophagus, eyes, gall bladder, gonads, gross lesions, heart, small intestine, large intestine, kidneys, lacrimal gland, larynx, liver, lungs, lymph nodes (mesenteric & thoracic), mammary gland, nasal turbinates, pancreas, peripheral nerve, pituitary, prostate, salivary gland, seminal vesicles & coagulating glands, skeletal muscle, skin, spinal cord, spleen, stomach, trachea, thymus, thyroid/parathyroid, urinary bladder, uterus, vertebrae with bone marrow
Statistics:
Variances of group body weight changes were analyzed for Bartlett's test for homogeneity of variances (Snedecor and Cochran, 1967). Body weight changes, organ weights, organ-to-body weight ratios, haematology values, clinical chemistry values and urinary specific gravity were evaluated by analysis of variance; differences between control and treatment groups were delineated by Dunnett's test (Steel and Torrie, 1960). The level of significance chosen in all cases was p<0.05.
Clinical signs:
no effects observed
Description (incidence and severity):
Animal observations revealed no discernible effects on appearance or demeanor of mice which were related to exposure.
Mortality:
no mortality observed
Description (incidence):
A female mouse in the 75 ppm group and a male mouse in the 25 ppm group died as a result of traumatic injury. An additional female mouse in the 75 ppm group was sent to pathology in a moribund condition after 5-6 weeks of exposure.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weight gains of male mice in the 5 ppm exposure group were in general significantly higher than for controls during the study. Likewise, mean body weight gains of male mice in the two higher exposure groups (25 and 75 ppm) were generally either higher than for controls or were not different from controls. The mean body weight gains of female mice in the 25 and 75 ppm groups were significantly lower than for controls after 12 weeks of exposure but not at any of the previous weekly weighings. These statistical differences may have resulted from the unusually high mean body weight gain of female mice in the control group (the mean body weight gain of female control mice was even higher than for male control mice). It was concluded that exposure to acrylic acid vapours had no adverse effect on growth of male mice, and a very slight effect, if any, on the growth of female mice.
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:
effects observed, treatment-related
Description (incidence and severity):
Mean hemoglobin values of male mice in the 25 and 75 ppm exposure groups and for female mice in the 75 ppm group were significantly lower than for controls; these effects on hemoglobin of mice were probably related to exposure to the test material, but they were considered to be of only minor toxicologic significance. The reduced white cell count for male mice in the 25 ppm group was considered to be a spontaneous statistical difference.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The mean alkaline phosphatase values of female mice in the 25 and 75 ppm exposure groups were significantly lower than for controls but decreases in alkaline phosphatase have no known toxicologic significance. All other differences in clinical chemistry parameters of mice (blood urea nitrogen values in male mice) were considered to be spontaneous statistical differences unrelated to exposure due to the absence of a dose-response relationship.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no effects on organ weights or organ-to-body weight ratios of male or female mice which were considered to be related to exposure. All statistical differences in absolute and relative organ weights between control and exposure groups of mice, including relative brain and kidney weights of female mice in the 25 pqm group, and relative heart weights of female mice in the 75 ppm group were considered spontaneous in nature and unrelated to exposure to the test material.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross pathologic alterations that were considered to be related to treatment with the test material. Alopecia of variable distribution was the only frequently occurring observation and was observed in nearly all groups including the male and female control groups. Two mice, one female in the 75 ppm exposure group and one male in the 25 ppm exposure group, died spontaneously as a result of traumatic injury incurred while handling. One additional female mouse in the 75 ppm group was sacrificed in a moribund condition. Gross pathological examination of this animal revealed depletion of the abdominal adipose tissue and absence of ingesta in the gastrointestinal tract, suggesting that possibly the animal did not have access to either food or water.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic lesions of the olfactory portion of the nasal mucosa were detected in all male and female mice in the 75 ppm exposure group, in all males and nine of ten females in the 25 ppm group, and in one of ten males and four of ten females in the 5 ppm group. These lesions of the nasal mucosa were considered to be a result of treatment with the test material. Similar lesions were not observed in any of the male or female mice in the control group. The nasal lesions of all affected mice were confined to the olfactory portion of the nasal mucosa on the dorsomedial aspect of the nasal passages. However, there was a clearcut dose-response relationship based upon the size of the affected area; the severity of the lesions within the affected area; and the numbers of animals affected. The lesions in mice in the 75 ppm exposure group consisted of: focal degeneration of the olfactory epithelium with partial replacement by an epithelium resembling respiratory epithelium; very slight focal infiltration of principally mononuclear inflammatory cells in the mucosa and submucosa of the affected regions; and very slight focal hyperplasia of the submucosal glands within some of the affected area. Overall, the lesions in these mice were graded as slight to moderate. The lesions of affected mice in the 25 ppm exposure group were limited to slight focal degeneration of the olfactory epithelium, usually without evidence of an inflammatory response. Only very slight focal degeneration of the olfactory mucosa was observed in affected mice in the 5 ppm exposure group. As noted previously, the nasal lesions observed in the mice in this study were confined to the olfactory portions of the nasal mucosa. This distribution of the lesions and their microscopic appearance indicated that the olfactory epithelium of the nasal mucosa is more vulnerable than the respiratory epithelium to the irritant properties of acrylic acid vapour. All other histopathologic observations were considered to be spontaneous in nature and unrelated to treatment with the test material.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
0.221 mg/L air (analytical)
Sex:
male
Basis for effect level:
other: Systemic toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
0.015 mg/L air (analytical)
Sex:
female
Basis for effect level:
other: Systemic toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
0.015 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects: focal degeneration of the olfactory epithelium
Critical effects observed:
not specified

For local effects no NOAEC was identified.

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Principles of method if other than guideline:
Male and female Fischer 344 rats were exposed to 0, 5 , 25 or 75 ppm acrylic acid vapours (corresponding to 0, 0.015, 0.074, 0.221 mg/L) 6 hours per day, 5 days per week, for 13 weeks.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 99.7 %
- Impurities (identity and concentrations):
- water wt% 0.08,
- monomethyl ether of hydroquione 218 ppm
- Dimer wt% 0.23
- Acetic Acid wt% 0.12
- Propionic Acid wt% 0.15
- Acrolein ppm <25
- Ethyl Acrylate ppm <25
- Phenothiazine ppm 0.10
- Proto-anemonin ppm <20
- Furfural ppm <20
- Source: Celanese Chemical Company
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA
- Age at study initiation: 3 weeks
- Fasting period before study: no
- Housing: 22-3/cage
- Diet (ad libitum): standard laboratory diet (Purina Laboratory Chow, Ralston Purina Co., St. Louis, MO) except during exposure
- Water: ad libitum
- Acclimation period: 16 days
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: inhalation chambers (14500 liters) with stainless steel pyramidal-shaped ceilings and epoxy resin-coated walls and floors dynamic airflow conditions
- Source and rate of air: Exposure levels of acrylic acid were generated by pumping liquid acrylic acid at calculated rates into glass vaporization flasks heated to approximately 130°C. Vapours from the flasks were swept into the chamber air supply duct with compressed air and mixed with incoming air by turbulence.
- Temperature, humidity, pressure in air chamber: 21 °C, 50 %, slight negative pressure
- Air flow rate: 2500 liters per minute
- Air change rate: 10 air changes per hour


TEST ATMOSPHERE
- Brief description of analytical method used: The actual concentration of acrylic acid in each chamber was measured 2-3 times per hour (12-15 times daily) by infrared spectrophotometry using a Miran I Infrared Analyzer at a wavelength of 8.9 µm. Prior to initiating exposures, distribution of acrylic acid vapours within the chambers was determined to be uniform within 10 % of the target concentrations.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Percent dimer in the liquid acrylic acid monomer varied between 0.4% and 3.7% during the exposure interval.
Analytical concentrations (mean ± SD): 5.0 ± 0.3 ppm; 25 ± 1 ppm; 75 ± 1 ppm
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day; 5 days/week
Dose / conc.:
5 ppm
Remarks:
analytical concentration
Dose / conc.:
25 ppm
Remarks:
analytical concentration
Dose / conc.:
75 ppm
Remarks:
analytical concentration
No. of animals per sex per dose:
15
Control animals:
yes, sham-exposed
Details on study design:
Post-exposure period: none
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: on the 1st day of exposure and weekly thereafter


OPHTHALMOSCOPIC EXAMINATION: YES


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1 week prior to sacrifice
- Anaesthetic used for blood collection: No
- Animals fasted: Yes / No / No data
- How many animals: 10/sex/dose group
- Parameters examined: Packed Cell Volume (PCV), Hemoglobin (Hgb), Erythrocyte count and morphology, Total and differential leukocyte counts


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the time of sacrifice
- Animals fasted: Yes
- How many animals: 10/sex/dose group
- Parameters examined: Glucose, Blood urea nitrogen (BUN), Alkaline Phosphatase (AP), Glutamic-pyruvic transaminase (SGPT), Total Protein, Albumin, Albumin/Globulin (A/G) Ratio


URINALYSIS: Yes
- Time schedule for collection of urine: 1 week prior to sacrifice
- Metabolism cages used for collection of urine: No
- Animals fasted: No
- Parameters examined: Bilirubin, pH, Glucose, Protein, Ketone, Urobilinogen, Occult Blood, Specific Gravity (refractive ìndex)


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Approximately 18 hours after the final exposure, animals were sacrificed and submitted to necropsy. Animals were fasted overnight prior to sacrifice. Each animal was examined externally and internally for gross pathologic alterations. Immediately after decapitation, the eyes of each animal were examined by a glass slide technique with fluorescent illumination. Weights of brain, heart, liver, kidneys and testes were determined and recorded. Lungs and trachea were removed as a unit and the lungs were expanded to approximately their normal inspiratory volume with buffered 10 % formalin.
Animals which died spontaneously or which were sacrificed in a moribund condition during the course of the study were given a complete gross pathological examination. In general, representative portions of the organs and tissues listed below from each animal were preserved in buffered 10 % formalin.


HISTOPATHOLOGY: Yes
Slides (hematoxylin and eosin stained) were prepared and histopathologic examinations performed on tissues listed below for 10 animals of each
sex in the control and 75 ppm exposure groups. Similar histopathologic examinations were conducted on all animals that died spontaneously during the course of the study. Target organs identified in the 75 ppm exposure group were also examined for 10 animals in the 5 ppm and 25 ppm exposure groups.

Organs/Tissues:
adipose tissue, adrenals, aorta, brain, cecum, esophagus, eyes, gonads, gross lesions, heart, small intestine, large intestine, kidneys, lacrimal gland, larynx, liver, lungs, lymph nodes (mesenteric & thoracic), mammary gland, nasal turbinates, pancreas, peripheral nerve, pituitary, prostate, salivary gland, seminal vesicles & coagulating glands, skeletal muscle, skin, spinal cord, spleen, stomach, tongue, trachea, thymus, thyroid/parathyroid, urinary bladder, uterus, vertebrae with bone marrow, zymbal gland
Statistics:
Variances of group body weight changes were analyzed for Bartlett's test for homogeneity of variances (Snedecor and Cochran, 1967). Body weight changes, organ weights, organ-to-body weight ratios, haematology values, clinical chemistry values and urinary specific gravity were evaluated by analysis of variance; differences between control and treatment groups were delineated by Dunnett's test (Steel and Torrie, 1960). The level of significance chosen in all cases was p<0.05.
Clinical signs:
no effects observed
Description (incidence and severity):
Animal observations revealed no discernible effects on appearance or demeanor of rats which were related to exposure.
Mortality:
no mortality observed
Description (incidence):
There were no spontaneous deaths of rats during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weight gains of male and female rats in the 5, 25 and 75 ppm exposure groups were not different from controls except during the first
two weeks of exposure when the body weight gains of female rats in the 5 and 25 ppm groups were statistically higher than for controls. Thus exposure to 5, 25 or 75 ppm acrylic acid vapors had no adverse effect on growth of male or female rats.
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:
no effects observed
Description (incidence and severity):
There were no statistical differences, in hematologic values of male rats or female rats exposed to acrylic acid vapours which were considered
to be related to exposure. The reduced white cell count for male rats in the 25 ppm group was considered to be a spontaneous statistical difference unrelated to exposure in view of the absence of any effect on white cell count for animals in the higher (75 ppm) exposure group.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Mean alkaline phosphatase values of female rats in the 75 ppm group were significantly higher than for controls; this effect may have been related to exposure but is of uncertain toxicologic significance. All other differences in clinical chemistry parameters of rats (glucose values) were considered to be spontaneous statistical differences unrelated to exposure due to the absence of a dose-response relationship.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no discernible effects on urinalysis parameters of male or female rats. Statistical analyses of urinary specific gravity values revealed no significant differences between control and exposure groups of rats.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no effects on organ weights or organ-to-body weight ratios of male or female rats which were considered to be related to exposure. All statistical differences in absolute and relative organ weights between control and exposure groups of rats, including absolute and relative liver weights of male rats in the 5 ppm group and relative liver weights of female rats in the 5 ppm group were considered spontaneous in nature and unrelated to exposure to the test material.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross pathologic observations which were considered to be related to treatment with the test material. All gross pathologic observations on the male and female rats in this study were considered to be spontaneous in nature and typical of those usually encountered in rats of this strain and age.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic lesions of the nasal mucosa were observed in 7/10 male and 10/10 female rats in the 75 ppm exposure group but not in rats in the 25 or 5 ppm exposure groups; these were the only lesions considered to be related to treatment. In affected rats in the 75 ppm exposure group, the nasal lesions consisted of slight focal degeneration of the olfactory epithelium on the dorsomedial aspect of the nasal passages. The nasal lesions in most affected rats were detected only in the most rostral of four cross sections obtained through the nasal. However, lesions were observed in the more caudal sections in a few cases. The lesions were characterized principally by disorganization of the normal arrangement of the nuclei of the olfactory epithelium and associated mild degenerative alterations of the epithelial cells in the affected regions. No lesions of the nasal mucosa were observed in 3/10 male rats in the 75 ppm group. Since it was possible that the original sections prepared for these rats were not through the proper portion of the nasal passages, additional sections were prepared. Examination of these additional sections also failed to reveal any discernible lesions. As indicated above, no lesions of the nasal mucosa were observed in either male or female rats in the groups exposed to 25 or 5 ppm acrylic acid. Slight subacute inflammatory lesions were observed in the nasal mucosa of one female rat in the control group. These lesions were unlike the lesions observed in the rats in the 75 ppm group. All other observations were considered to be spontaneous in nature and unrelated to treatment with the test material.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
0.074 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects
Key result
Dose descriptor:
NOAEC
Effect level:
0.221 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Systemic toxicity
Dose descriptor:
LOAEC
Effect level:
0.221 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects: focal degeneration of the olfactory epithelium
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
15 mg/m³
Study duration:
subchronic
Species:
mouse

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Principles of method if other than guideline:
Male and female 66C3F1 mice were exposed to 0, 5 , 25 or 75 ppm acrylic acid vapours (corresponding to 0, 0.015, 0.074, 0.221 mg/L) 6 hours per day, 5 days per week, for 13 weeks.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 99.7 %
- Impurities (identity and concentrations):
- water wt% 0.08,
- monomethyl ether of hydroquione 218 ppm
- Dimer wt% 0.23
- Acetic Acid wt% 0.12
- Propionic Acid wt% 0.15
- Acrolein ppm <25
- Ethyl Acrylate ppm <25
- Phenothiazine ppm 0.10
- Proto-anemonin ppm <20
- Furfural ppm <20
- Source: Celanese Chemical Company
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA
- Age at study initiation: 3 weeks
- Fasting period before study: no
- Housing: single
- Diet (ad libitum): standard laboratory diet (Purina Laboratory Chow, Ralston Purina Co., St. Louis, MO) except during exposure
- Water: ad libitum
- Acclimation period: 16 days

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: inhalation chambers (14500 liters) with stainless steel pyramidal-shaped ceilings and epoxy resin-coated walls and floors with dynamic airflow conditions
- Source and rate of air: Exposure levels of acrylic acid were generated by pumping liquid acrylic acid at calculated rates into glass vaporization flasks heated to approximately 130°C. Vapours from the flasks were swept into the chamber air supply duct with compressed air and mixed with incoming air by turbulence.
- Temperature, humidity, pressure in air chamber: 21 °C, 50 %, slight negative pressure
- Air flow rate: 2500 liters per minute
- Air change rate: 10 air changes per hour


TEST ATMOSPHERE
- Brief description of analytical method used: The actual concentration of acrylic acid in each chamber was measured 2-3 times per hour (12-15 times daily) by infrared spectrophotometry using a Miran I Infrared Analyzer at a wavelength of 8.9 µm. Prior to initiating exposures, distribution of acrylic acid vapours within the chambers was determined to be uniform within 10 % of the target concentrations.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Percent dimer in the liquid acrylic acid monomer varied between 0.4% and 3.7% during the exposure interval.
Analytical concentrations (mean ± SD): 5.0 ± 0.3 ppm; 25 ± 1 ppm; 75 ± 1 ppm
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day; 5 days/week
Dose / conc.:
5 ppm
Remarks:
analytical concentration
Dose / conc.:
25 ppm
Remarks:
analytical concentration
Dose / conc.:
75 ppm
Remarks:
analytical concentration
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: none
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: on the 1st day of exposure and weekly thereafter


OPHTHALMOSCOPIC EXAMINATION: YES


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1 week prior to sacrifice
- Anaesthetic used for blood collection: No
- Animals fasted: Yes / No / No data
- How many animals: 10/sex/dose group
- Parameters examined: Packed Cell Volume (PCV), Hemoglobin (Hgb), Erythrocyte count and morphology, Total and differential leukocyte counts


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to sacrifice
- Animals fasted: Yes
- How many animals: 10/sex/dose group
- Parameters examined: Glucose, Blood urea nitrogen (BUN), Alkaline Phosphatase (AP), Glutamic-pyruvic transaminase (SGPT)


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Approximately 18 hours after the final exposure, animals were sacrificed and submitted to necropsy. Animals were fasted overnight prior to sacrifice. Each animal was examined externally and internally for gross pathologic alterations. Immediately after decapitation, the eyes of each animal were examined by a glass slide technique with fluorescent illumination. Weights of brain, heart, liver, kidneys and testes were determined and recorded. Lungs and trachea were removed as a unit and the lungs were expanded to approximately their normal inspiratory volume with buffered 10 % formalin.
Animals which died spontaneously or which were sacrificed in a moribund condition during the course of the study were given a complete gross pathological examination. In general, representative portions of the organs and tissues listed below from each animal were preserved in buffered 10 % formalin.


HISTOPATHOLOGY: Yes
Slides (hematoxylin and eosin stained) were prepared and histopathologic examinations performed on tissues listed below for 10 animals of each
sex in the control and 75 ppm exposure groups. Similar histopathologic examinations were conducted on all animals that died spontaneously during the course of the study. Target organs identified in the 75 ppm exposure group were also examined for 10 animals in the 5 ppm and 25 ppm exposure groups.

Organs/Tissues:
adipose tissue, adrenals, aorta, brain, cecum, esophagus, eyes, gall bladder, gonads, gross lesions, heart, small intestine, large intestine, kidneys, lacrimal gland, larynx, liver, lungs, lymph nodes (mesenteric & thoracic), mammary gland, nasal turbinates, pancreas, peripheral nerve, pituitary, prostate, salivary gland, seminal vesicles & coagulating glands, skeletal muscle, skin, spinal cord, spleen, stomach, trachea, thymus, thyroid/parathyroid, urinary bladder, uterus, vertebrae with bone marrow
Statistics:
Variances of group body weight changes were analyzed for Bartlett's test for homogeneity of variances (Snedecor and Cochran, 1967). Body weight changes, organ weights, organ-to-body weight ratios, haematology values, clinical chemistry values and urinary specific gravity were evaluated by analysis of variance; differences between control and treatment groups were delineated by Dunnett's test (Steel and Torrie, 1960). The level of significance chosen in all cases was p<0.05.
Clinical signs:
no effects observed
Description (incidence and severity):
Animal observations revealed no discernible effects on appearance or demeanor of mice which were related to exposure.
Mortality:
no mortality observed
Description (incidence):
A female mouse in the 75 ppm group and a male mouse in the 25 ppm group died as a result of traumatic injury. An additional female mouse in the 75 ppm group was sent to pathology in a moribund condition after 5-6 weeks of exposure.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weight gains of male mice in the 5 ppm exposure group were in general significantly higher than for controls during the study. Likewise, mean body weight gains of male mice in the two higher exposure groups (25 and 75 ppm) were generally either higher than for controls or were not different from controls. The mean body weight gains of female mice in the 25 and 75 ppm groups were significantly lower than for controls after 12 weeks of exposure but not at any of the previous weekly weighings. These statistical differences may have resulted from the unusually high mean body weight gain of female mice in the control group (the mean body weight gain of female control mice was even higher than for male control mice). It was concluded that exposure to acrylic acid vapours had no adverse effect on growth of male mice, and a very slight effect, if any, on the growth of female mice.
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:
effects observed, treatment-related
Description (incidence and severity):
Mean hemoglobin values of male mice in the 25 and 75 ppm exposure groups and for female mice in the 75 ppm group were significantly lower than for controls; these effects on hemoglobin of mice were probably related to exposure to the test material, but they were considered to be of only minor toxicologic significance. The reduced white cell count for male mice in the 25 ppm group was considered to be a spontaneous statistical difference.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The mean alkaline phosphatase values of female mice in the 25 and 75 ppm exposure groups were significantly lower than for controls but decreases in alkaline phosphatase have no known toxicologic significance. All other differences in clinical chemistry parameters of mice (blood urea nitrogen values in male mice) were considered to be spontaneous statistical differences unrelated to exposure due to the absence of a dose-response relationship.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no effects on organ weights or organ-to-body weight ratios of male or female mice which were considered to be related to exposure. All statistical differences in absolute and relative organ weights between control and exposure groups of mice, including relative brain and kidney weights of female mice in the 25 pqm group, and relative heart weights of female mice in the 75 ppm group were considered spontaneous in nature and unrelated to exposure to the test material.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross pathologic alterations that were considered to be related to treatment with the test material. Alopecia of variable distribution was the only frequently occurring observation and was observed in nearly all groups including the male and female control groups. Two mice, one female in the 75 ppm exposure group and one male in the 25 ppm exposure group, died spontaneously as a result of traumatic injury incurred while handling. One additional female mouse in the 75 ppm group was sacrificed in a moribund condition. Gross pathological examination of this animal revealed depletion of the abdominal adipose tissue and absence of ingesta in the gastrointestinal tract, suggesting that possibly the animal did not have access to either food or water.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic lesions of the olfactory portion of the nasal mucosa were detected in all male and female mice in the 75 ppm exposure group, in all males and nine of ten females in the 25 ppm group, and in one of ten males and four of ten females in the 5 ppm group. These lesions of the nasal mucosa were considered to be a result of treatment with the test material. Similar lesions were not observed in any of the male or female mice in the control group. The nasal lesions of all affected mice were confined to the olfactory portion of the nasal mucosa on the dorsomedial aspect of the nasal passages. However, there was a clearcut dose-response relationship based upon the size of the affected area; the severity of the lesions within the affected area; and the numbers of animals affected. The lesions in mice in the 75 ppm exposure group consisted of: focal degeneration of the olfactory epithelium with partial replacement by an epithelium resembling respiratory epithelium; very slight focal infiltration of principally mononuclear inflammatory cells in the mucosa and submucosa of the affected regions; and very slight focal hyperplasia of the submucosal glands within some of the affected area. Overall, the lesions in these mice were graded as slight to moderate. The lesions of affected mice in the 25 ppm exposure group were limited to slight focal degeneration of the olfactory epithelium, usually without evidence of an inflammatory response. Only very slight focal degeneration of the olfactory mucosa was observed in affected mice in the 5 ppm exposure group. As noted previously, the nasal lesions observed in the mice in this study were confined to the olfactory portions of the nasal mucosa. This distribution of the lesions and their microscopic appearance indicated that the olfactory epithelium of the nasal mucosa is more vulnerable than the respiratory epithelium to the irritant properties of acrylic acid vapour. All other histopathologic observations were considered to be spontaneous in nature and unrelated to treatment with the test material.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
0.221 mg/L air (analytical)
Sex:
male
Basis for effect level:
other: Systemic toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
0.015 mg/L air (analytical)
Sex:
female
Basis for effect level:
other: Systemic toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
0.015 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects: focal degeneration of the olfactory epithelium
Critical effects observed:
not specified

For local effects no NOAEC was identified.

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Principles of method if other than guideline:
Male and female Fischer 344 rats were exposed to 0, 5 , 25 or 75 ppm acrylic acid vapours (corresponding to 0, 0.015, 0.074, 0.221 mg/L) 6 hours per day, 5 days per week, for 13 weeks.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 99.7 %
- Impurities (identity and concentrations):
- water wt% 0.08,
- monomethyl ether of hydroquione 218 ppm
- Dimer wt% 0.23
- Acetic Acid wt% 0.12
- Propionic Acid wt% 0.15
- Acrolein ppm <25
- Ethyl Acrylate ppm <25
- Phenothiazine ppm 0.10
- Proto-anemonin ppm <20
- Furfural ppm <20
- Source: Celanese Chemical Company
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA
- Age at study initiation: 3 weeks
- Fasting period before study: no
- Housing: 22-3/cage
- Diet (ad libitum): standard laboratory diet (Purina Laboratory Chow, Ralston Purina Co., St. Louis, MO) except during exposure
- Water: ad libitum
- Acclimation period: 16 days
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: inhalation chambers (14500 liters) with stainless steel pyramidal-shaped ceilings and epoxy resin-coated walls and floors dynamic airflow conditions
- Source and rate of air: Exposure levels of acrylic acid were generated by pumping liquid acrylic acid at calculated rates into glass vaporization flasks heated to approximately 130°C. Vapours from the flasks were swept into the chamber air supply duct with compressed air and mixed with incoming air by turbulence.
- Temperature, humidity, pressure in air chamber: 21 °C, 50 %, slight negative pressure
- Air flow rate: 2500 liters per minute
- Air change rate: 10 air changes per hour


TEST ATMOSPHERE
- Brief description of analytical method used: The actual concentration of acrylic acid in each chamber was measured 2-3 times per hour (12-15 times daily) by infrared spectrophotometry using a Miran I Infrared Analyzer at a wavelength of 8.9 µm. Prior to initiating exposures, distribution of acrylic acid vapours within the chambers was determined to be uniform within 10 % of the target concentrations.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Percent dimer in the liquid acrylic acid monomer varied between 0.4% and 3.7% during the exposure interval.
Analytical concentrations (mean ± SD): 5.0 ± 0.3 ppm; 25 ± 1 ppm; 75 ± 1 ppm
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day; 5 days/week
Dose / conc.:
5 ppm
Remarks:
analytical concentration
Dose / conc.:
25 ppm
Remarks:
analytical concentration
Dose / conc.:
75 ppm
Remarks:
analytical concentration
No. of animals per sex per dose:
15
Control animals:
yes, sham-exposed
Details on study design:
Post-exposure period: none
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: on the 1st day of exposure and weekly thereafter


OPHTHALMOSCOPIC EXAMINATION: YES


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1 week prior to sacrifice
- Anaesthetic used for blood collection: No
- Animals fasted: Yes / No / No data
- How many animals: 10/sex/dose group
- Parameters examined: Packed Cell Volume (PCV), Hemoglobin (Hgb), Erythrocyte count and morphology, Total and differential leukocyte counts


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the time of sacrifice
- Animals fasted: Yes
- How many animals: 10/sex/dose group
- Parameters examined: Glucose, Blood urea nitrogen (BUN), Alkaline Phosphatase (AP), Glutamic-pyruvic transaminase (SGPT), Total Protein, Albumin, Albumin/Globulin (A/G) Ratio


URINALYSIS: Yes
- Time schedule for collection of urine: 1 week prior to sacrifice
- Metabolism cages used for collection of urine: No
- Animals fasted: No
- Parameters examined: Bilirubin, pH, Glucose, Protein, Ketone, Urobilinogen, Occult Blood, Specific Gravity (refractive ìndex)


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Approximately 18 hours after the final exposure, animals were sacrificed and submitted to necropsy. Animals were fasted overnight prior to sacrifice. Each animal was examined externally and internally for gross pathologic alterations. Immediately after decapitation, the eyes of each animal were examined by a glass slide technique with fluorescent illumination. Weights of brain, heart, liver, kidneys and testes were determined and recorded. Lungs and trachea were removed as a unit and the lungs were expanded to approximately their normal inspiratory volume with buffered 10 % formalin.
Animals which died spontaneously or which were sacrificed in a moribund condition during the course of the study were given a complete gross pathological examination. In general, representative portions of the organs and tissues listed below from each animal were preserved in buffered 10 % formalin.


HISTOPATHOLOGY: Yes
Slides (hematoxylin and eosin stained) were prepared and histopathologic examinations performed on tissues listed below for 10 animals of each
sex in the control and 75 ppm exposure groups. Similar histopathologic examinations were conducted on all animals that died spontaneously during the course of the study. Target organs identified in the 75 ppm exposure group were also examined for 10 animals in the 5 ppm and 25 ppm exposure groups.

Organs/Tissues:
adipose tissue, adrenals, aorta, brain, cecum, esophagus, eyes, gonads, gross lesions, heart, small intestine, large intestine, kidneys, lacrimal gland, larynx, liver, lungs, lymph nodes (mesenteric & thoracic), mammary gland, nasal turbinates, pancreas, peripheral nerve, pituitary, prostate, salivary gland, seminal vesicles & coagulating glands, skeletal muscle, skin, spinal cord, spleen, stomach, tongue, trachea, thymus, thyroid/parathyroid, urinary bladder, uterus, vertebrae with bone marrow, zymbal gland
Statistics:
Variances of group body weight changes were analyzed for Bartlett's test for homogeneity of variances (Snedecor and Cochran, 1967). Body weight changes, organ weights, organ-to-body weight ratios, haematology values, clinical chemistry values and urinary specific gravity were evaluated by analysis of variance; differences between control and treatment groups were delineated by Dunnett's test (Steel and Torrie, 1960). The level of significance chosen in all cases was p<0.05.
Clinical signs:
no effects observed
Description (incidence and severity):
Animal observations revealed no discernible effects on appearance or demeanor of rats which were related to exposure.
Mortality:
no mortality observed
Description (incidence):
There were no spontaneous deaths of rats during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weight gains of male and female rats in the 5, 25 and 75 ppm exposure groups were not different from controls except during the first
two weeks of exposure when the body weight gains of female rats in the 5 and 25 ppm groups were statistically higher than for controls. Thus exposure to 5, 25 or 75 ppm acrylic acid vapors had no adverse effect on growth of male or female rats.
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:
no effects observed
Description (incidence and severity):
There were no statistical differences, in hematologic values of male rats or female rats exposed to acrylic acid vapours which were considered
to be related to exposure. The reduced white cell count for male rats in the 25 ppm group was considered to be a spontaneous statistical difference unrelated to exposure in view of the absence of any effect on white cell count for animals in the higher (75 ppm) exposure group.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Mean alkaline phosphatase values of female rats in the 75 ppm group were significantly higher than for controls; this effect may have been related to exposure but is of uncertain toxicologic significance. All other differences in clinical chemistry parameters of rats (glucose values) were considered to be spontaneous statistical differences unrelated to exposure due to the absence of a dose-response relationship.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no discernible effects on urinalysis parameters of male or female rats. Statistical analyses of urinary specific gravity values revealed no significant differences between control and exposure groups of rats.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no effects on organ weights or organ-to-body weight ratios of male or female rats which were considered to be related to exposure. All statistical differences in absolute and relative organ weights between control and exposure groups of rats, including absolute and relative liver weights of male rats in the 5 ppm group and relative liver weights of female rats in the 5 ppm group were considered spontaneous in nature and unrelated to exposure to the test material.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross pathologic observations which were considered to be related to treatment with the test material. All gross pathologic observations on the male and female rats in this study were considered to be spontaneous in nature and typical of those usually encountered in rats of this strain and age.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic lesions of the nasal mucosa were observed in 7/10 male and 10/10 female rats in the 75 ppm exposure group but not in rats in the 25 or 5 ppm exposure groups; these were the only lesions considered to be related to treatment. In affected rats in the 75 ppm exposure group, the nasal lesions consisted of slight focal degeneration of the olfactory epithelium on the dorsomedial aspect of the nasal passages. The nasal lesions in most affected rats were detected only in the most rostral of four cross sections obtained through the nasal. However, lesions were observed in the more caudal sections in a few cases. The lesions were characterized principally by disorganization of the normal arrangement of the nuclei of the olfactory epithelium and associated mild degenerative alterations of the epithelial cells in the affected regions. No lesions of the nasal mucosa were observed in 3/10 male rats in the 75 ppm group. Since it was possible that the original sections prepared for these rats were not through the proper portion of the nasal passages, additional sections were prepared. Examination of these additional sections also failed to reveal any discernible lesions. As indicated above, no lesions of the nasal mucosa were observed in either male or female rats in the groups exposed to 25 or 5 ppm acrylic acid. Slight subacute inflammatory lesions were observed in the nasal mucosa of one female rat in the control group. These lesions were unlike the lesions observed in the rats in the 75 ppm group. All other observations were considered to be spontaneous in nature and unrelated to treatment with the test material.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
0.074 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects
Key result
Dose descriptor:
NOAEC
Effect level:
0.221 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Systemic toxicity
Dose descriptor:
LOAEC
Effect level:
0.221 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects: focal degeneration of the olfactory epithelium
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
15 mg/m³
Study duration:
subchronic
Species:
mouse

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
03 Dec 1986 - 03 Mar 1987 (experimental)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
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:
yes
Limit test:
no
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)
Species:
mouse
Strain:
other: ICR, C3H, B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- 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


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


IN-LIFE DATES: From: To:
Type of coverage:
open
Vehicle:
acetone
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.

TEST SITE
- 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

REMOVAL OF TEST SUBSTANCE
- Washing: no

TEST MATERIAL
- 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:
yes
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
Dose / conc.:
52 mg/kg bw/day
Dose / conc.:
208 mg/kg bw/day
No. of animals per sex per dose:
30
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during dosing period

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily during dosing period

DERMAL IRRITATION: Yes
- 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.

BODY WEIGHT: Yes
- 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 PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

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.
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.
Mortality:
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
Key result
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified

Summary

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
mouse

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
03 Dec 1986 - 03 Mar 1987 (experimental)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
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:
yes
Limit test:
no
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)
Species:
mouse
Strain:
other: ICR, C3H, B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- 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


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


IN-LIFE DATES: From: To:
Type of coverage:
open
Vehicle:
acetone
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.

TEST SITE
- 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

REMOVAL OF TEST SUBSTANCE
- Washing: no

TEST MATERIAL
- 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:
yes
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
Dose / conc.:
52 mg/kg bw/day
Dose / conc.:
208 mg/kg bw/day
No. of animals per sex per dose:
30
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during dosing period

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily during dosing period

DERMAL IRRITATION: Yes
- 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.

BODY WEIGHT: Yes
- 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 PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

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.
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.
Mortality:
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
Key result
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified

Summary

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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subchronic
Species:
mouse

Additional information

No experimental data on the test substance is available.

Sodium acrylate is the sodium salt of acrylic acid, only the proton of the hydroxy group has been replaced by a sodium ion in NaA. Both are equally charged ions.pH dependent sodium acrylate dissociates into acrylic acid and sodium hydroxid in aqueous media.

According to Henderson-Hasselbalch: pH = pKs + lg (c(NaAcrylate) / c(Acrylic acid))

With the pKa-value of acylic acid = 4.25.

The ratio c(NaAcrylate) / c(Acrylic acid) was caluclated according to the Henderson-Hasselbalch equation: c(NaAcrylate) / c(Acrylic acid)) = 10 pH - pKs

pH 1 : c(NaAcrylate) / c(Acrylic acid)) = 10 1 – 4,25 = 0,00056; ~ 99,94 % as acrylic acid

pH 3 : c(NaAcrylate) / c(Acrylic acid)) = 10 3 – 4,25 = 0,056; t ~ 94,7 % as acrylic acid

pH 5 : c(NaAcrylate) / c(Acrylic acid) = 10 5 – 4,25 = 5,62; ~ 15,1 % as acrylic acid

pH 7 : c(NaAcrylate) / c(Acrylic acid) = 10 7 – 4,25 = 562,3; ~ 0,2 % as acrylic acid

Especially after oral uptake in the acidic environment in the stomach sodium acrylate is nearly completely dissociated to acrylic acid. Therefore, it is appropriate to use the human health hazard data of acrylic acid for the assessment of sodium acrylate. In respect to the hazard data on ecotoxicity, using the acrylic acid data assuming a complete dissociation reflects the worst case.

Therefore, the evaluation of the endpoint repeated dose toxicity is based on a weight of evidence approach using the toxicological data of the structural analogue acrylic acid (CAS 79-10-7) (for WoE information, see chapter 13.2).

Repeated dose toxicity: Oral

 

Wistar rats which received acrylic acid in the drinking water at doses of 120, 800, 2000 or 5000 ppm (corresponding to approx. 6, 40, 100 or 200 mg/kg bw/d in males, and 10, 66, 150 or 375 mg/kg bw/d in females) for 3 months (10 rats/group/sex) and 12 months (20 rats/group/sex) showed reduced water consumption at 2000 ppm and 5000 ppm dosages (BASF, 1987). No treatment-related premature deaths occurred. Lower food consumption was seen in high dose males and reduced body weight gain was observed in males from 2000 ppm and 5000 ppm groups. No treatment-related effects on haematology, clinical chemistry, and urine parameters were found. No substance-related toxic effect could be microscopically demonstrated in a comprehensive list of organs examined in the two high doses. Obviously due to the bad palatability treated animals had lower drinking water uptake, which was considered to result in lower food consumption and body weight gain.

Based on the reduced body weight gain in males and lower water consumption in both sexes, the NOAEL of this study was considered to be 800 ppm in male rats (corresponding to 40 mg/kg bw). In females the NOAEL was considered to be 5000 ppm (corresponding to 375 mg/kg bw) since reduced water consumption was not interpreted as a clear adverse health effect.

 

Fischer 344 rats (15 animals/sex/group) in another 90-day drinking water study (Inter-Company Acrylate Study Group, 1980) were administered doses of 83, 250, or 750 mg/kg bw/d of acrylic acid. No deaths occurred during the treatment period. However, clear dose-related effects were observed. At the high-dose level there was reduced food and water consumption, reduced body weight gain, lower organ weights of liver, kidneys, spleen, heart, brain, and elevated testes weight and some altered clinical chemistry parameters (increased levels of serum urea nitrogen, glucose, alkaline phosphatase and aspartate transaminase). Furthermore, there was a statistically significant decrease in total serum cholesterol noted for the high level females. In both sexes increases of urinary protein and specific gravity and a decrease in urinary pH values were noted. No significant prevalence of microscopic lesions was found in any of the animals. At 250 mg/kg bw, a decrease in water consumption was noted for both sexes. Body weight gain was lower in females. Kidney weights were increased in both sexes and relative testes weights were increased in males. Effects on serum urea nitrogen, cholesterol and alkaline phosphatase in female rats and urinary specific gravity and protein in both sexes were similar, but less pronounced than those observed at the high dose level.

At 83 mg/kg bw the only effects noted were a reduction of water consumption by male rats and a slight increase in red blood cells in female rats. Both findings were not considered to be of toxicological relevance, therefore 83 mg/kg bw was the NOAEL of this study.

 

In an oral 90-day study (BASF, 1987) acrylic acid was administered by gavage in two dosages (150 and 375 mg/kg bw/d) to Wistar rats. Toxicological findings reported in this study were mainly related to local irritating and corrosive effects of acrylic acid at the port of entry due to gavage administration. Since sodium acrylate does not possess any irritating properties, this study was disregarded for the hazard assessment of the acrylic salt.

 

Repeated dose toxicity: Inhalation

 

A 90-day inhalation study on Fischer 344 rats and B6C3F1 mice (Industry Acrylate Testing Group, 1979) using 15 animals/sex/group exposed to doses of 5, 25 or 75 ppm (corresponding to approx. 0.015, 0.074 or 0.221 mg/L air) of acrylic acid vapour on 6 hours/day on 5 days/week had no adverse effect on the growth of male and female rats and male mice. However, the mean body weight gains of female mice in the 25 and 75 ppm exposure groups were statistically lower than for controls after 12 weeks of exposure. There were no effects on absolute or relative weights of brain, heart, liver, kidneys or testes for either rats or mice which were considered to be related to exposure. Hematologic values of male and female rats were unaffected by exposure to acrylic acid vapours except for slight, although statistically significant, reductions in mean hemoglobin values for male mice in the 25 and 75 ppm exposure groups as well as for female mice in the 75 ppm exposure groups. Although these reductions in hemoglobin of mice were probably related to exposure, they were considered of only minor toxicologic significance. Serum alkaline phosphatase values of female rats in the 75 ppm exposure group were higher than for controls; possibly as a result of exposure to the test material. Urinalysis parameters of male and female rats were not altered by the exposures. Gross pathologic examinations revealed no alterations in either rats or mice which were considered to be related to exposure to the test material. Histopathologic examination of an extensive list of tissues from 10 rats per sex in the 0 and 75 ppm exposure groups and of the nasal turbinates of 10 rats per sex in the 25 and 5 ppm groups revealed slight degenerative lesions of the nasal mucosa of 7/10 male and 10/10 female rats in the 75 ppm exposure group that were attributed to treatment with the test material. No histopathologic alterations that could be attributed to treatment were detected in any of the male or female rats in the 25 and 5 ppm exposure groups.

Histopathologic examination of an extensive list of tissues of 10 mice per sex from the control and 75 ppm groups and of the nasal turbinate tissue of 10 mice per sex from the 5 and 25 ppm groups revealed lesions of the nasal mucosa of some or all mice at each treatment level that were considered to be related to treatment. The nasal lesions observed at all exposure levels were limited to the olfactory portions of the nasal mucosa. Mice in the 75 ppm exposure group had slight to moderate focal degeneration of the olfactory epithelium which was accompanied by very slight inflammatory cell infiltration and very slight hyperplasia of the submucosal glands in the affected areas. In some of the affected regions, the olfactory epithelium had been replaced by an epithelium that resembled respiratory epithelium. Slight focal degeneration of the olfactory nasal mucosa was observed in ten of ten male and nine of ten female mice in the 25 ppm exposure group. Only very slight focal degeneration of the olfactory mucosa was detected in one of ten males and four of ten females in the 5 ppm group. Three mice, one male in the 25 ppm group and two females in the 75 ppm group, died during the course of the study. None of these early deaths appeared to be related to treatment with the test material.

It was concluded that the nasal lesions observed in the mice in this study were a result of the irritant properties of acrylic acid vapour and that the olfactory epithelium of the nasal passages was more susceptible than the respiratory epithelium to the irritant properties of this vapour. Results of the study indicate that mice are more susceptible than rats to acrylic acid vapours.

In this study, histopathology of four cross-sections were examined in 10 animals/sex/group at different levels of the nasal turbinates, being the target organ identified. For local effects, this study revealed a NOAEC of 25 ppm (corresponding to approx. 0.074 mg/L air) for rats. No local NOAEC was derived in mice, the LOAEC (local) was 5 ppm (corresponding to approx. 0.015 mg/L air). There was no systemic toxicity in rats and male mice and the systemic NOAEC was therefore 75 ppm (corresponding to approx. 0.221 mg/L air). Because of lower body weight gain, the NOAEC for female mice was 5 ppm (corresponding to approx. 0.015 mg/L air).

 

Repeated dose toxicity: Dermal

 

Skin irritation become prevalent with higher incidence and severity in mice treated with 4 % acrylic acid compared to 1 % acrylic acid or vehicle control (acetone) after 13 weeks of dermal application (3 d/wk) (BAMM, 1987).

 

Conclusions

 

The oral NOAEL for the test substance was derived from the NOAEL = 40 mg/kg bw/d determined in the chronic drinking water study in Wistar rats (BASF, 1987).

 

The inhalative NOAEC for the test substance was derived from the systemic NOAEC = 15 mg/m³ determined in the subchronic inhalation study in B6C3F1 mice (IATG, 1979).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result, the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the fourteenth time in Regulation (EC) No. 2020/217.