2-Propenoic acid, reaction products with pentaerythritol

Carcinogenicity

Description of key information

The substance is not carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1986

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short abstract available

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 50 male C3H/HeJ mice were given dermal applications of the test substance twice weekly for up to 80 weeks.

GLP compliance:

not specified

Species:

mouse

Strain:

C3H

Sex:

male

Route of administration:

dermal

Vehicle:

other: Mineral oil

Duration of treatment / exposure:

80 weeks

Frequency of treatment:

twice weekly

Remarks:

Doses / Concentrations:
100 mg/kg bw
Basis:
no data

No. of animals per sex per dose:

50 males

The test substance showed some potential for carcinogenicity when administered at doses of 100 mg/kg bw in mineral oil. Slightly epilated and crusted skin with acanthosis and fibrosis was noted, but no papillomas were induced. Six of 50 mice treated with the test substance were reported to have lymphomas. These effects were not verified on subsequent reexamination.

Conclusions:

Under the study conditions, the test substance showed some potential for carcinogenicity when administered at doses of 100 mg/kg bw in mineral oil. Slightly epilated and crusted skin with acanthosis and fibrosis was noted, but no papillomas were induced. Six of 50 mice treated with the test substance were reported to have lymphomas. These effects were not verified on subsequent reexamination.

Executive summary:

Groups of 50 male C3H/HeJ mice were given dermal applications of the test substance twice weekly for up to 80 weeks.

The test substance showed some potential for carcinogenicity when administered at doses of 100 mg/kg bw in mineral oil. Slightly epilated and crusted skin with acanthosis and fibrosis was noted, but no papillomas were induced. Six of 50 mice treated with the test substance were reported to have lymphomas. These effects were not verified on subsequent reexamination.

Reference 2

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1985

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short abstract available

Qualifier:

no guideline followed

Principles of method if other than guideline:

Test substance was studied for dermal tumorigenic activity by repeated application to the skin of mice. Groups of 40 male C3H/HeJ mice were given dermal applications of 3 mg (approximately 120 mg/kg bw) of test substance in acetone three times weekly for the life of the animals.

GLP compliance:

not specified

Species:

mouse

Strain:

C3H

Sex:

male

Route of administration:

dermal

Vehicle:

acetone

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Lifetime

Frequency of treatment:

3 times weekly

Remarks:

Doses / Concentrations:
120 mg/kg bw
Basis:
no data

No. of animals per sex per dose:

40 males

Control animals:

yes, concurrent vehicle

Positive control:

methylcholanthrene

No skin neoplasms were observed in the test substance treated mice.

Conclusions:

Under the study conditions, no skin neoplasms were observed in pentaerythritol triacrylate treated mice.

Executive summary:

A study was conducted to study dermal tumorigenic activity of the test substance by repeated application to the skin of mice. Groups of 40 male C3H/HeJ mice were given dermal applications of 3 mg (approximately 120 mg/kg bw) of test substance in acetone three times weekly for the life of the animals. Under the study conditions, no skin neoplasms were observed in pentaerythritol triacrylate-treated mice.

Reference 3

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

From July 20, 1998 to January 27, 1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report which meets basic scientific principles. However, the study was conducted in genetically modified mice.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The solutions of the test substance in acetone were painted on the backs of male and female Tg.AC mice 5 times per week for 6 months. The daily doses of test substance were 0.75, 1.5, 3, 6, or 12 mg/kg bw. Animals painted with acetone alone served as control groups. Tissues from 15 sites of every animal were examined for cancerous lesions.

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Taconic Laboratory Animals and Services (Germantown, NY).
- Age at study initiation: 6 weeks
- Housing: Polycarbonate (Lab Products, Inc., Maywood, NJ), changed at least once per week, rotated every 2 weeks
- Bedding: Sani-Chip® hardwood chips (P.J. Murphy Forest Products Corp., Montville, NJ), changed at least once per week. Bedding was irradiated
- Diet: NTP-2000 pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly. Irradiated
- Water: Tap water (Columbus municipal supply) via automatic watering system (Edstrom Industries, Waterford, WI), available ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature: 72±3°F
- Humidity: 50±15%
- Air changes: 10/h
- Photoperiod: 12 h light/dark cycle

Route of administration:

dermal

Vehicle:

acetone

Details on exposure:

TEST MATERIAL
- Amount(s) applied: 3.3 mL/kg
VEHICLE
- Lot/batch no.: MI0172 and NE0173
- Purity: Greater than 99%

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The dose formulations were analyzed every 8 or 9 weeks. Of the dose formulations analyzed, 14 of 15 were within 10% of the target concentration, with no value greater than 103% of the target concentration; all five animal room samples were also within 10% of the target concentration. The single dose formulation that was not within 10% of the target concentration was remixed and reanalyzed and was found to be within 10% of the target concentration.

Duration of treatment / exposure:

6 month

Frequency of treatment:

5 days per week for 27 weeks

Remarks:

Doses / Concentrations:
0, 0.75, 1.5, 3, 6, or 12 mg/kg bw
Basis:
analytical conc.

No. of animals per sex per dose:

15

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

Animals were observed twice daily and were weighed initially, weekly, and at the end of the study. Clinical findings were recorded weekly and at the end of the study. No clinical pathology was performed.

Sacrifice and pathology:

Necropsies were performed on core study mice. Organs weighed were the heart, right kidney, liver, lung, right testis, and thymus. Histopathologic examinations were performed on all core study mice. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, heart, kidney, liver, lung, lymph nodes (mandibular, mediastinal, and mesenteric), ovary, pituitary gland, skin (site of application and inguinal), spleen, stomach (forestomach), testis with epididymis, thymus, thyroid gland, and uterus.

Other examinations:

None

Dose descriptor:

NOAEL

Effect level:

1.5 mg/kg bw/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Survival of all dosed groups of mice was similar to that of the vehicle controls. With the exception of the 3 mg/kg bw group, body weights of male mice were less than those of the vehicle controls during the last 3 to 6 weeks of the study. Females administered 3 mg/kg bw had generally reduced body weights during the last month of the study. Treatment-related clinical findings included masses on the torso of males and females administered 3 mg/kg or greater; a single 0.75 mg/kg male and two 1.5 mg/kg males were also affected. Papilloma occurred at the site of application in the 3 mg/kg or greater male and female groups. Papillomas were observed earlier in the 6 and 12 mg/kg groups than in the 3 mg/kg groups. One vehicle control male, two 1.5 mg/kg males, and one 1.5 mg/kg female also had in-life papillomas.

Heart and liver weights of 12 mg/kg bw males were significantly greater than those of the vehicle controls. Lung weights of 6 and 12 mg/kg males and females were significantly decreased, as were thymus weights of 6 and 12 mg/kg females.

Histologic evaluation revealed that squamous cell papillomas at the site of application were present at the end of the study in all 3 and 6 mg/kg males, most females administered 3 or 6 mg/kg, and most 12 mg/kg males and females. Two 3 mg/kg and three 12 mg/kg males and one 12 mg/kg female had squamous cell carcinomas at the site of application. Significantly increased incidences of nonneoplastic lesions occurred at the site of application, including hyperkeratosis in 3 mg/kg or greater males and females, chronic active inflammation in 6 and 12 mg/kg males and females and 3 mg/kg females, and epidermal hyperplasia in males and females administered 3 mg/kg or greater; the incidence of epidermal hyperplasia was also significantly increased in 1.5 mg/kg females. The severity of epidermal hyperplasia increased with increasing dose.

Males administered 0.75, 3, or 6 mg/kg had significantly increased incidences of chronic active inflammation of the liver. The incidences of hematopoietic cell proliferation of the liver in 12 mg/kg females and of the spleen in 6 and 12 mg/kg males and females were significantly increased. Females administered 12 mg/kg had significantly increased incidences of hematopoietic cell proliferation of the mandibular lymph node and thymocyte necrosis.

Florid lesions, diagnosed as myelodysplasia, were identified in five 12 mg/kg males, while milder lesions, diagnosed as cell, infiltration, nonspecified site, were identified in several animals. The change was characterized predominantly by myeloid infiltration/proliferation that tended to be perivascular in the liver and lungs. Infiltrating cells were predominantly mature and immature granulocytes (eosinophils and neutrophils), with lesser numbers of admixed mononuclear cells. In severely affected livers, there was bridging between portal tracts and accumulations of brightly eosinophilic crystalline material in the lumen of bile ductules. The change was commonly observed in the mediastinal, mandibular, axillary, and mesenteric lymph nodes, and often included a pronounced plasma cell population in the medullary sinuses. The epididymis and spleen were also often involved.

Conclusions:

Under the study conditions, male and female Tg.AC hemizygous mice dosed with the test substance for 6 months had significantly increased incidences of squamous cell papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in male mice.

Executive summary:

A study was conducted with a genetically modified strain of mouse with sensitive skin to test if the test substance might cause skin cancer.

The solutions of the test substance in acetone were painted on the backs of male and female Tg.AC mice 5 times per week for 6 months. The daily doses of test substance were 0.75, 1.5, 3, 6, or 12 mg/kg bw. Animals painted with acetone alone served as control groups. Tissues from 15 sites of every animal were examined for cancerous.

The increased incidences of squamous cell papilloma at the site of application were dose related in males and females. The incidences of papilloma were significantly increased in 3, 6, and 12 mg/kg bw males and females. Squamous cell carcinomas at the site of application occurred in two 3 mg/kg bw males, three 12 mg/kg bw males, and one 12 mg/kg bw female.

Under the study conditions, male and female Tg.AC hemizygous mice dosed with the test substance for 6 months had significantly increased incidences of squamous cell papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in male mice. A NOAEL for carcinogenicity was considered to be 1.5 mg/kg bw for the test substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

A wide body of evidence supports the conclusion that PETIA does not pose in vivo mutagenic risk. In several studies involving dermal application, PETIA did not prove to have carcinogenic activity. This was confirmed in work conducted by the US EPA/ Acrylates and Methacrylates (SAM) industry panel using a representative acrylate under carefully controlled conditions based on which the US EPA no longer controls acrylates as a category with human health concerns.

Additional information

A study was conducted with a genetically modified strain of mouse with sensitive skin to test if PETIA might cause skin cancer. The solutions of the test substance in acetone were painted on the backs of male and female Tg.AC mice 5 times per week for 6 months. The daily doses of test substance were 0.75, 1.5, 3, 6 or 12 mg/kg bw. Animals painted with acetone alone served as control groups. Tissues from 15 sites of every animal were examined for cancerous effects. The increased incidences of squamous cell papilloma at the site of application were dose related in males and females. The incidences of papilloma were significantly increased in 3, 6, and 12 mg/kg bw animals. Squamous cell carcinomas at the site of application occurred in two 3 mg/kg bw males, three 12 mg/kg bw males, and one 12 mg/kg bw female. Under the study conditions, male and female Tg.AC hemizygous mice dosed with the test substance for 6 months had significantly increased incidences of squamous cell papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in male mice. The NOAEL for carcinogenicity was considered to be 1.5 mg/kg bw.

The results of unpublished skin painting studies conducted on a number of acrylates, including PETIA, have been summarised by Andrews and Clary (1986). The substance was administered to mice at 2.5 mg twice weekly for a total duration of 80 weeks. A low but increased incidence of lymphomas in the spleen and/or lymph nodes was observed but a subsequent pathological review determined that these lesions were non-neoplastic (unpublished information) (Van Miller et al., 2002). Another dermal application study by DePass et al. (1985) found no skin tumours with PETIA.

In the 1980’s, The United States Environmental Protection Agency (US EPA) and an industry Specialty Acrylates and Methacrylates (SAM) panel collaborated to evaluate the potential effects, in particular carcinogenesis, of this family of chemicals (Van Miller et al., 2002). In this context, a study was conducted with a selected representative acrylate, triethylene glycol diacrylate (TREGDA) using unoccluded skin application to male mice as follows: Study 1, evaluation of skin irritation compared to cell proliferation in the basal epithelium following 7 or 14 day application; Study 2, 14 day range-finder; Study 3: 90 day subchronic toxicity study and Study 4: chronic dermal bioassay according to US EPA guidelines. Organ weight changes (Studies 3 and 4) and increased mortality (Study 4) were observed for the highest dose rate. However, there was no related histopathology. The substance induced cell proliferation (7 days through 78 weeks) that correlated with acute and chronic inflammation of the skin. No skin tumours were observed following 78 weeks of exposure and, therefore, no correlation of skin irritation and/or cell proliferation with neoplasia was confirmed. In this study, in contrast to earlier work, a careful examination of skin effects was conducted and doses were selected to limit, although not exclude, skin irritation and cell proliferation. Under the conditions of the test, TREGDA was considered to be non-carcinogenic.