Magnesium acrylate

Carcinogenicity

Description of key information

Oral route:
In a carcinogenicity study with acrylic acid, Wistar rats were treated with dosages up to
78 mg/kg body weight via drinking water for 26 (males) and 28 weeks (females).
- marginal reduction in water consumption in both sexes in the highest dose group
- no further toxic changes attributable to the test substance
- Under the experimental conditions chosen, acrylic acid was not oncogenic in Wistar rats.
This conclusion is in line with the European Union Risk Assessment Report Acrylic Acid, Volume 28ISBN 92-894-1272-0 (EU, 2002).
Inhalative route: no study available.
Dermal route:
Acrylic acid was applied to the skin of  40 C3H/HeJ male mice (approx. 11 mg/kg body weight / application, 3 times per week for the lifetime).
Histopathology revealed epidermal hyperplasia at the treatment site (one male). No signs of skin irritation were observed. The incidence of tumors was not increased. Acrylic acid was jugded as not oncogenic according to the results of this study. This is in line with the European Union Risk Assessment Report Acrylic Acid, Volume 28ISBN 92-894-1272-0 (EU, 2002).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study conducted in compliance with GLP regulations. Justification for read-across: similar chemical structure (see Cemical Safety Report)

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

yes

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: 177 (156 - 198) g
- female animals: 141 (122 - 157) 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

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration control analyses of the aqueous solutions of the test substances were carried out at the beginning of the study and at 3, 6, 12, 18, 24 and 28 months. The determinations were carried out by gas chromatography.The actual concentrations in the test solutions were in the ranges 96 to 106, 94 to 103 and 92 to 102 % of the target concentrations of 120, 400 and 1200 ppm, respectively.

Duration of treatment / exposure:

26 (males) -28 (females) months

Frequency of treatment:

continuously

Post exposure period:

no

Remarks:

Doses / Concentrations:
120, 400, and 1200 ppm (corresponding to approx. 8, 27, and 78 mg/kg bw/d)
Basis:
analytical conc.

No. of animals per sex per dose:

50

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale:
The doses were established on the basis of a subchronic toxicity study in which Fischer 344 rats received acrylic acid in doses of about 83, 250 or 750 mg/kg body weight for a period of 3 months in the drinking water (Bushy Run Research Center, 1980).

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: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: The blood samplings and the subsequent analysis of the blood samples were carried out approx. 12, 18, 24 and 26 or 28 months after the beginning of administration.
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: in the first 10 surviving animals per test group and sex; only control and highest dose were examined
- Parameters examined:
hemoglobin, erythrocytes, hematocrit, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, thrombocytes, leukocytes


CLINICAL CHEMISTRY: No


URINALYSIS: No


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, bone marrow (femur), vagina, coagulation gland, mandibular lymph node.

Statistics:

Clinical examinations: The statistical significance of the clinical data (drinking water consumption and body weight) was determined using an analysis of variance (ANOVA) with subsequent DUNNETT's test.
Blood examinations: For statistical evaluation the t-test was used to compare the individual dose groups with the control group.

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):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
The 3 doses (120, 400 and 1200 ppm) administered as addition to the drinking water did not lead in any of the animals participating in the study to clinical signs that could be associated with the test substance administered.
There were no mortalities attributable to an influence of the test substance during the period of time for which acrylic acid was administered.


BODY WEIGHT AND WEIGHT GAIN
The sporadically significant values which were observed in the males of the 400-ppm group (max. 6 %) were unrelated to the dose and within the biological range of variation. Although the initial weights were almost identical, the mean body weights of the female rats of the 120, 400 and 1200 ppm
groups were higher than those of the control group throughout the study period. These increased values were even sporadically significant in the female rats of the 120- and 400-ppm groups; however, since these increases often varied at different time intervals and were not clearly dose-related, in many cases a substance-induced relevance cannot be attributed to this finding.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
The drinking water consumption of the male and female rats of the 120, 400 and 1200 ppm groups showed no clearly substance-induced adverse effects in comparison to the control group. The amount of water consumed by the male and female animals of the 120 and 400 ppm groups was somewhat higher than that of the relevant control group for the most part of the study. By contrast, the drinking water consumption of the male and female rats of the 1200 ppm group was slightly reduced for the most part of the study from day 42 onward. The differences found were mainly slight and independent of the dose and are therefore assessed as being incidental in nature.


HAEMATOLOGY
The erythrocyte, leukocyte and platelet counts as well as the determination of hemoglobin and the erythrocyte indices calculated from these parameters resulted in no variations to be associated with the test substance. Due to the plausibility criteria applied the individual significant variations are not regarded as being substance-related.
The 26 or 28-month administration period of 1200 ppm acrylic acid to rats via the drinking water did not result in any variations of the white blood cells both in the males and in the females that were attributable to the test substance administered. The morphological variations of the white blood cells are equally distributed among the control and the highest dose group. Thus, it is certain that the changes found in the 1200-ppm group are not substance-related. The morphological features that were noteworthy are probably incidental or due to age.
During the 26- or 28-month administration period, there were no variation in the red blood cells both of the male and female that were sustance-related. The pathognomic changes to red blood cells found in individual animals of the control and highest dose groups are probably incidental or due to age.


ORGAN WEIGHTS
no data


GROSS PATHOLOGY
A number of necropsy findings were noted in rats that died or were killed in extremis and in rats sacrificed at the termination of the study. The type,
incidence, and severity of these findings were similar in treated rats and controls.


HISTOPATHOLOGY: NON-NEOPLASTIC
A number of non-neoptastic lesions were observed. Except for a slightly increased incidence of hepatoceIlular fatty change in males of the high dose, the type, incidence, and severity of these lesions were not considered to distinguish treated rats from controls.


HISTOPATHOLOGY: NEOPLASTIC
A total of 970 primary neoplasms were observed: 249 in group 0, 267 in group 1, 212 in group 2, 242 in group 3. From the 970 primary neoplasms seen in this study, 769 were benign (204, 214, 162, 189 in groups 0, 1, 2, and 3, respectively) and 201 wene malignant (45, 53, 50, 53 in groups 0,1, 2, and 3, respectively). The total number of rats with neoplasm was 388 (97, 98, 94, 99 in groups 0, 1, 2 and 3, respectivety). The number of rats with more than one primary neoplasm was 287 (77, 72, 60, 73 in groups 0, 1, 2, and 3, respectively). The number of treated rats with metastases was considered to be similar to that of control rats. (group 0, 1, 2, 3: 0, 120, 400, and 1200 ppm)
Neoplastic lesions were primarily seen in endocrine and reproductive organs, skin, hemolymphoreticular system, mesenteric lymph nodes.
The most frequently observed neoplastic lesions were adenomas of the anterior pituitary gland, benign and malignant pheochromocytoma of the
adrenal medulla, leydig cell tumours of the testes, fibroadenomas of the mammary glands, islet celI adenomas and carcinomas of the pancreas, theca granulosa cell tumours and luteomas of the ovaries, stromal polyps of the uterus, malignant lymphomas and fibrous histiocytomas of the hemolymphoreticular system, hemangiomas of the mesenteric lymph nodes, C-cell and follicular neoplasms of the thyroid glands, and various epithelial and
mesenchymal neoplasms of the skin.
The incidence and organ distribution of the tumours found in the groups treated with acrylic acid for 26 or 28 months did not differ from those of the controls, and the authours consider the observed neoplastic changes spontaneous.

Dose descriptor:

NOAEL

Effect level:

>= 78 mg/kg bw/day (actual dose received)

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

>= 78 mg/kg bw/day (actual dose received)

Sex:

male/female

Remarks on result:

other: Effect type: toxicity (migrated information)

Besides the marginal reduction in water consumption in both sexes of the highest dose group the administration of acrylic acid via the drinking water over a period of 26- or 28-months did not lead to any toxic changes attributable to the test substance administration. Furthermore it can be stated that, under the experimental conditions chosen, acrylic acid was not oncogenic in Wistar rats.

The extensive histopathological examination of the preserved tissues revealed that in all three treatment groups, the non-neoplastic tissue changes did not differ from those of the controls. In the males in the highest dose group (1200 ppm) there was a slightly increased incidence in hepatocellular fatty deposits in comparison with the other treatment groups and the controls, and a connection between this

effect and the administration of acrylic acid cannot be ruled out. All the other non-neoplastic tissue changes found were primarily of an inflammatory or degenerative nature, and were classified as spontaneous changes. The tumours observed were mainly located in the endocrinal and reproductive organs, the skin, the haemolymphoreticular system, and in the mesenterial lymph nodes. The most frequently observed neoplastic changes were anterior pituitary lobe adenomas, benign and malignant phaeochromocytomas of the medulla of the adrenal gland, testicular tumours originating from Leydig's cells, fibroadenomas of the mammary glands, islet cell adenomas and carcinomas of the pancreas, theca (granulosa) cell tumours and luteomas of the ovaries, polyps of the stroma of the uterus, malignant lymphomas and fibrous histiocytomas of the haemolymphoreticular system, haemangiosarcomas of the mesenterial lymph nodes, C-cell and follicular thyroid neoplasmas, and various neoplasmas of the dermal epithelia and mesenchyma. The incidence and organ distribution of the tumours found in the groups treated with acrylic acid for 26 or 28 months did not differ from those of the controls, and the authours consider that the neoplastic changes observed were spontaneous. Overall, no clear toxic or oncogenic effects were revealed by the histopathological examination of Wistar rats that had been administered acrylic acid at the maximum tolerable dose in the drinking water for 26 (males) or 28 (females) months.

Conclusions:

Acrylic acid was not oncogenic to the rat when given in drinking water up to and including concentrations of 1200 pp for 26 weeks to male and 28 weeks to female animals.

Executive summary:

Groups of 50 Wistar rats each were treated with concentrations of 0, 120, 400 and 1200 ppm in drinking water (approx. 0, 8, 27 and 78 mg/kg body weight) The male animals were treated for 26 weeks the females for 28 weeks. According to a preceeding study 1200 ppm acrylic acid in drinking water is the maximum tolerated dose.

Besides a marginal reduction in water consumption in both sexes of the highest dose group the administration of acrylic acid via the drinking water over a period of 26- or 28-months did not lead to any toxic changes attributable to the test substance administration. Furthermore it can be stated that, under the experimental conditions chosen, acrylic acid was not oncogenic in Wistar rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

88 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The data are taken from a fully reliable study with acrylic acid - the corresponding organic acid of Magnesium acrylate. In contrast to the free acid Magnesium acrylate has nearly no irritating properties. As the effect levels of acrylic acid are mainly determined by its irritating properties a read across to Magnsium acrylate will overestimate the toxicity. That means the effect levels of Magnesium acrylate should be considerably higher. Therefore the results of the studies with acrylic acid can be taken as a worst case to evaluate Magnesium acrylate. In summary the study is sufficient for evaluation of carcinogenicity after oral administration.

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: dermal

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: Well documented, acceptable study report conducted in compliance with GLP regulations. Justification for read-across: similar chemical structure (see Cemical Safety Report)

Principles of method if other than guideline:

A group of 40 C3H/HeJ male mice received 25 microliter (µL) applications of acrylic acid as 1.0 % dilutions in acetone. A negative control group received acetone only. The substances were applied to the skin of the back three times weekly for the lifetime of the animals.

GLP compliance:

yes

Species:

mouse

Strain:

other: C3H/HeJ

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Jackson Laboratories, Bar Harbor, ME
- Age at study initiation: 74 to 79 days of age
- Weight at study initiation: test group: 19.3 to 27.9 g, control group: 20.1 to 27.7 g
- Housing: 5/cage
- Diet (ad libitum): Zeigler block feed
- Water (ad libitum): tap water

Route of administration:

dermal

Vehicle:

acetone

Details on exposure:

TEST SITE
- Area of exposure: back of each mouse from which the fur was clipped once weekly.


REMOVAL OF TEST SUBSTANCE
- Washing: no


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 25 µl

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The samples were analyzed for stability as the undiluted liquid using a titration procedure and as a 1 % (by volume) dilution in acetone using a gas chromatographic procedure. In addition, the concentration of acrylic acid in the dilutions (prepared weekly) was measured monthly during the study.
The solutions were shown by these analyses to be quite close to the target concentration of 1 %.

Duration of treatment / exposure:

entire lifetime

Frequency of treatment:

3 days/week

Post exposure period:

no

Remarks:

Doses / Concentrations:
25 µl 1% solution (v/v) in acetone (corresponding to approx. 0.26 mg acrylic acid/application, corresponding to approx. 11 mg/kg bw/application) (mean body weight = 23 g)
Basis:
nominal conc.

No. of animals per sex per dose:

40

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
- Rationale for animal assignment: C3H/HeJ mice were used because of their low incidence of spontaneous skin tumours.

Positive control:

Positive control group consisting of 40 mice received 0.1 % 3-methylcholanthrene (MC).

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: The mice were carefully examined for lesions of the skin once per month.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Necropsy consisted of a careful examination of the skin and body cavities. All observations were recorded. The skin and any suspect internal tumours from all non-autolyzed mice were fixed in 10 % neutral buffered formalin. Sections were prepared and stained and were examined histologically.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

not specified

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 examined

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
In the group that received 25 µL acrylic acid as 1 % v/v dilutions in acetone, the mean survival time was 515 days, while the mean survival time for the acetone control group was 484 days. The difference was not statistically significant.


HISTOPATHOLOGY: NEOPLASTIC (if applicable)
While one mouse in the acrylic acid group had evidence of epidermal hyperplasia, no neoplasms were found in the skin or subcutis of the acrylic
acid-treated mice or in the negative controls. No signs of skin irritation were observed during the study.

Dose descriptor:

NOAEL

Effect level:

> 10 mg/kg bw/day (nominal)

Sex:

male

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

No tumors of the skin or subcutis were observed in male mice treated for their lifetime with acrylic acid as a 1.0 % v/v dilution in acetone. In contrast, 39 tumour-bearing rnice were seen in the positive control group. Furthermore, mortality was not affected by treatment. Therefore, acrylic acid was not oncogenic by this testing method.

Conclusions:

Acrylic acid was jugded as not oncogenic according the results of this study

Executive summary:

A group of 40 C3H/HeJ male mice received 25 microliter (µL) applications of acrylic acid as 1.0 % dilutions in acetone. A negative control group received acetone only. The substances were applied to the skin of the back three times weekly for the lifetime of the animals.

25 µl 1% solution (v/v) of acrylic acid in acetone (corresponding to approx. 0.26 mg acrylic acid/application, corresponging to approx. 11 mg/kg body weight / application) (mean body weight of mice: 23 g).

In the group that received 25 µL acrylic acid as 1 % v/v dilutions in acetone, the mean survival time was 515 days, while the mean survival time for the acetone control group was 484 days. The difference was not statistically significant.

Although no clinical effects were seen, histopathology revealed with 1/40 animals epidermal hyperplasia at the treatment site. The incidence of tumors was not increased.

Acrylic acid was jugded as not oncogenic according to the results of this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LOAEL

11 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

The data are taken from a fully reliable study with acrylic acid - the corresponding organic acid of Magnesium acrylate. In contrast to the free acid Magnesium acrylate has nearly no irritating properties. As the effect levels of acrylic acid are mainly determined by its irritating properties a read across to Magnsium acrylate will overestimate the toxicity. That means the effect levels of Magnesium acrylate should be considerably higher. Therefore the results of the studies with acrylic acid can be taken as a worst case to evaluate Magnesium acrylate. In summary the study is sufficient for evaluation of carcinogenicity after dermal application.

Justification for classification or non-classification

There is no evidence that Acrylic acid administered orally to rats or applied dermally to mice is carcinogenic ( European Union Risk Assessment Report Acrylic Acid, Volume 28ISBN 92-894-1272-0). The same is true for Magnesium acrylate.

Additional information

Justification for selection of carcinogenicity via oral route endpoint:
key study

Justification for selection of carcinogenicity via dermal route endpoint:
key study