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Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 Aug 1983 - 24 Aug 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study conducted in compliance with GLP regulations

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987
Reference Type:
publication
Title:
SUBCHRONIC AND CHRONIC STUDIES OF THE EFFECTS OF ORAL ADMINISTRATION OF ACRYLIC ACID TO RATS.
Author:
Hellwig J et al.
Year:
1993
Bibliographic source:
Fd. Chem. Toxicol. 31: 1-18

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Acrylic acid
EC Number:
201-177-9
EC Name:
Acrylic acid
Cas Number:
79-10-7
Molecular formula:
C3H4O2
IUPAC Name:
acrylic acid
Details on test material:
- 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

Test animals

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

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
The test substance preparations were freshly prepared 3 times a week. 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
Doses / concentrations
Remarks:
Doses / Concentrations:
120, 800, 2000 und 5000 ppm (corresponding to approx. 6/10, 40/66, 100/150, 200/375 mg/kg body weight/day for males/females)
Basis:
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

Examinations

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.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
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:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
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.
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 GAIN
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
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.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
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.


HAEMATOLOGY
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 CHEMISTRY
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.


URINALYSIS
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.

ORGAN WEIGHTS
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 PATHOLOGY
None of the individual findings from the grosspathological assessment showed any relevant connection with the administration of the test substance.

HISTOPATHOLOGY: NON-NEOPLASTIC/NEOPLASTIC
None of the individual findings from the histopathological assessment showed any relevant connection with the administration of the test substance.




Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: body weight; water consumption and compound intake
Dose descriptor:
NOAEL
Effect level:
375 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: body weight; water consumption and compound intake
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: body weight; water consumption and compound intake

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

Conclusions:
Following repeated oral administration of acrylic acid in drinking water to Wistar rats at the dose levels of 0, 120, 800, 2000 or 5000 ppm (equivalent to 0, 6, 40, 100 or 200 mg/kg and 0, 10, 66, 150 or 375 mg/kg, for males and females respectively) for 12 months, the dose of 800 ppm in males (equivalent to 40 mg/kg) was identified as a NOAEL based on decreased water intake and body weight at higher dose levels. No target organs were identified.