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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
other: Experimental study with acrylic acid (structural analogue) which is used for read-across (see attached read across justification document in IUCLID section 13)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions. Justification for read-across: similar chemical structure (see Cemical Safety Report)

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979
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 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 Type:
other company data
Title:
Unnamed
Year:
1979
Reference Type:
other company data
Title:
Unnamed
Year:
1981

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 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

Test material

Constituent 1
Reference substance name:
Acrylic acid
EC Number:
201-177-9
EC Name:
Acrylic acid
Cas Number:
79-10-7
IUPAC Name:
acrylic acid
Details on test material:
- 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:
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

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 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
Remarks:
Doses / Concentrations:
0, 5, 25, or 75 ppm (0, 0.015, 0.074, 0.221 mg/L)
Basis:
analytical conc.
No. of animals per sex per dose:
15
Control animals:
yes, sham-exposed
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: 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.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Animal observations revealed no discernible effects on appearance or demeanor of rats which were related to exposure. There were no spontaneous deaths of rats during the study.

BODY WEIGHT AND WEIGHT GAIN
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.


HAEMATOLOGY
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 CHEMISTRY
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
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.


ORGAN WEIGHTS
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 PATHOLOGY
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.


HISTOPATHOLOGY: NON-NEOPLASTIC
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.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
0.074 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects
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
Dose descriptor:
NOAEC
Effect level:
0.221 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Systemic toxicity

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The results of this study with acrylic acid can be extrapolated to magnesium acrylate.
Please refer to the justification for read across in the Chemical Safety Report.