Acrylic acid

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Reference 2

Reference Type:

publication

Title:

Inhalation Toxicity of Acrylic Acid.

Author:

Miller RR et al.

Year:

1981

Bibliographic source:

Fund. Appl. Toxicol. 1: 271-277

Reference 3

Reference Type:

publication

Title:

RESULTS OF A 90-DAY ACRYLIC ACID VAPOR INHALATION STUDY WITH RATS AND MICE.

Author:

Miller RR et al.

Year:

1981

Bibliographic source:

The Toxicologist 1: 83, Abstr.301

Reference 4

Reference Type:

secondary source

Title:

Intercompany Acrylate Study Group - Summary of Toxicological Research.

Author:

BASF Corp.

Year:

1979

Bibliographic source:

TSCATS/OTS 0520805, NEW DOC. I.D.: 86-890001301

Reference 5

Reference Type:

secondary source

Title:

Summary of Toxicology Studies.

Author:

BASF Corp.

Year:

1981

Bibliographic source:

TSCATS/OTS 0520806, NEW DOC. I.D.: 86-890001302

Reference 6

Reference Type:

secondary source

Title:

Acrylic Acid 10-Day Vapor Inhalation Study with Rats and Mice

Author:

Dow Chemicals Corp.

Year:

1979

Bibliographic source:

TSCATS/ OTS 0529492, New Doc. I.D.: 44-7929258

Reference 7

Reference Type:

secondary source

Title:

Acrylic Acid 90-Day Vapor Inhalation Study with Rats and Mice

Author:

Dow Chemicals Corp.

Year:

1979

Bibliographic source:

TSCATS/ OTS 0529493, New Doc. I.D.: 44-7929259

Reference 8

Reference Type:

secondary source

Title:

Review of the Toxicology of Acrylates

Author:

Hoechst Celanese Corp.

Year:

1981

Bibliographic source:

TSCATS/ OTS 0534626, New. Doc. I.D.: 88-920000176

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Acrylic acid

EC Number:

201-177-9

EC Name:

Acrylic acid

Cas Number:

79-10-7

Molecular formula:

C3H4O2

IUPAC Name:

prop-2-enoic acid

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

Test animals

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

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

5 ppm

Remarks:

analytical concentration

Doses / concentrations 2

Dose / conc.:

25 ppm

Remarks:

analytical concentration

Doses / concentrations 3

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

Examinations

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.

Results and discussion

Results of examinations

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

Effect levels

1

Key result

Dose descriptor:

NOAEC

Effect level:

0.221 mg/L air (analytical)

Sex:

male

Basis for effect level:

other: Systemic toxicity

2

Key result

Dose descriptor:

NOAEC

Effect level:

0.015 mg/L air (analytical)

Sex:

female

Basis for effect level:

other: Systemic toxicity

3

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

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

For local effects no NOAEC was identified.