2-Propenoic acid, reaction products with dipentaerythritol

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From September 16, 1996 to December 18, 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted by using method equivalent to standard guidelines in compliance with GLP. Pentaerythritol triacrylate is a constituent of PETIA.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2005

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-Propenoic acid, reaction products with pentaerythritol

EC Number:

629-850-6

Cas Number:

1245638-61-2

Molecular formula:

Not available for this UVCB.

IUPAC Name:

2-Propenoic acid, reaction products with pentaerythritol

Test material form:

other: Colorless or light amber nonvolatile liquid

Details on test material:

- Name of test material: Pentaerythritol triacrylate
- Molecular formula (if other than submission substance): C14H18O7
- Molecular weight (if other than submission substance): 298.3
- Physical state: Liquid (also occurs as a semisolid or crystalline solid at temperatures up to 40°C)
- Analytical purity: 45% (for lot HCC0340)
- Impurities: HPLC indicated a major peak, seven impurity components with areas greater than 1% of the major peak area, and nine impurity components with relative areas between 0.5% and 1%. The impurities were tentatively identified as structurally related adducts, dimers, and acrylates as well as trimethylolpropane triacrylate and its related esters and adducts.
- Lot/batch No.: HCC0340
- Stability under test conditions: No degradation of the bulk chemical was detected
- Storage condition of test material: Stored at room temperature, protected from light in amber glass bottles with Teflon®-lined lids.

Test animals

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
- 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

Administration / exposure

Type of coverage:

not specified

Vehicle:

acetone

Details on exposure:

TEST MATERIAL
- Amount(s) applied: 0.5 mL/kg

VEHICLE
- Lot/batch no.: KP206 and LS0051
- Purity: Greater than 99%

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The dose formulations were analysed at the beginning, midpoint, and end of the study; animal room samples of these dose formulations were also analysed. Of the dose formulations analyzed, all 15 were within 10% of the target concentration, with no value greater than 104% of the target concentration; 10 of 15 animal room samples were within 10% of the target concentration.

Duration of treatment / exposure:

3 months

Frequency of treatment:

5 days per week for 14 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.75, 1.5, 3, 6, or 12 mg/kg bw
Basis:
analytical per unit body weight

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Animals were observed twice daily and were weighed initially, weekly, and at the end of the studies. Clinical findings were recorded weekly and at the end of the studies for core study animals. Blood was collected from the retroorbital sinus on Days 4 and 23 and at the end of the studies for hematology and clinical chemistry.
Hematology: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte morphology; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials
Clinical chemistry: urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids

Sacrifice and pathology:

Necropsies were performed on all animals. Organs weighed were the heart, right kidney, liver, lung, right testis, and thymus. Complete histopathologic examinations were performed on vehicle control and 12 mg/kg bw rats. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, heart with aorta, large intestine (cecum, colon, and rectum), small intestine (duodenum, jejunum, and ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin (site of application), spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus. The skin at the site of application was also examined.

Other examinations:

At the end of the studies, sperm samples were collected from male animals in the vehicle control and 3, 6, and 12 mg/kg bw groups for sperm count and motility evaluations. The following parameters were evaluated: spermatid heads per testis or cauda and per gram testis or cauda and epididymal spermatozoal motility. The left cauda, left epididymis, and left testis were weighed. Vaginal samples were collected for up to 12 consecutive days prior to the end of the studies from females in the vehicle control and 3, 6, and 12 mg/kg bw groups for vaginal cytology evaluations. The percentage of time spent in the various estrous cycle stages and estrous cycle length were evaluated.

Results and discussion

Results of examinations

Dermal irritation:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Details on results:

All rats survived to the end of the study. Final mean body weights and body weight gains of 12 mg/kg bw males were significantly less than those of the vehicle controls. Irritation at the site of application occurred in 12 mg/kg bw rats.

On Day 23, an increase in segmented neutrophils occurred in 12 mg/kg bw males and females. At study termination, an increased neutrophil count occurred in 6 mg/kg bw males. The neutrophilia would be consistent with skin inflammation observed microscopically. No other hematology or clinical chemistry changes were considered to be toxicologically relevant.

Thymus weights of males administered 3 mg/kg bw or greater were significantly less than those of the vehicle controls. There were no significant differences in sperm motility or vaginal cytology parameters between dosed groups and the vehicle controls.

No treatment-related lesions were observed grossly in rats except irritation at the site of application in the 12 mg/kg bw groups. Microscopically, the primary changes at the site of application consisted of epidermal hyperplasia, hyperkeratosis, epidermal degeneration and necrosis, and chronic active inflammation. The incidence and severity of hyperplasia increased with increasing dose; most animals administered 3 mg/kg bw or greater were affected. Severity was minimal to mild and characterized by focally extensive to diffuse increased thickness of the epidermis, from the normal one to three cell layers thick to four to six layers thick. Hyperplasia was accompanied by minimal to mild increased thickness of the superficial keratin layer (hyperkeratosis). Minimal hyperkeratosis without accompanying hyperplasia was present in the 0.75 and 1.5 mg/kg bw groups. Degeneration was diagnosed in many animals treated with 1.5 mg/kg bw or greater.

Degeneration was a minimal focal change consisting of intraepidermal vacuolization, presumably due to intra or intercellular fluid accumulation. Vacuoles occasionally coalesced to form small vesicles that contained a few neutrophils. Epidermal necrosis was present in some males, although a dose-related response was not clear. Necrosis consisted of partial to full-thickness coagulative change of the epidermis and was likely a pathogenic sequela of degeneration. Intraepidermal infiltration of neutrophils (suppurative inflammation) often accompanied degeneration or necrosis of the epidermis. A mixed inflammatory cell infiltrate (chronic active inflammation) was present in the dermis of animals administered 1.5 mg/kg bw or greater, with dose dependent increases in incidences and severity. Sebaceous glands at the site of application were slightly enlarged and prominent in animals with the other changes described above.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

12 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

gross pathology

haematology

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

2

Dose descriptor:

NOAEL

Effect level:

0.75 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: Irritation

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

A study was conducted to assess the repeated dose dermal toxicity of the test substance in male and female rats.

Groups of 10 male and 10 female rats received dermal applications of 0, 0.75, 1.5, 3, 6, or 12 mg/kg bw of test substance in acetone, 5 days per week for 14 weeks; the dosing volume was 0.5 mL/kg bw. Animals were observed twice daily and were weighed initially, weekly, and at the end of the studies. Clinical findings were recorded weekly and at the end of the studies for core study animals. Necropsies were performed on all animals. Organs weighed were the heart, right kidney, liver, lung, right testis, and thymus. Blood was collected from the retroorbital sinus on Days 4, 23 and at the end of the studies for hematology and clinical chemistry.

All rats survived to the end of the study. Final mean body weights and body weight gains of 12 mg/kg bw males were significantly less than those of the vehicle controls. Irritation at the site of application occurred in 12 mg/kg bw rats. On Day 23, an increase in segmented neutrophils occurred in 12 mg/kg bw males and females. At study termination, an increased neutrophil count occurred in 6 mg/kg bw males. The neutrophilia would be consistent with skin inflammation observed microscopically. No other hematology or clinical chemistry changes were considered to be toxicologically relevant. Thymus weights of males administered 3 mg/kg bw or greater were significantly less than those of the vehicle controls. There were no significant differences in sperm motility or vaginal cytology parameters between dosed groups and the vehicle controls. No treatment-related lesions were observed grossly in rats except irritation at the site of application in the 12 mg/kg bw groups. Microscopically, the primary changes at the site of application consisted of epidermal hyperplasia, hyperkeratosis, epidermal degeneration and necrosis, and chronic active inflammation. The local NOAEL for this study could be considered to be 0.75 mg/kg bw/day.