Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Based on results of the analogue 2-hydroxyethyl acrylate, hydroxypropyl acrylate is not anticipated to be carcinogenic in rats via inhalation at doses up to 5 ppm (0.024 mg/L air/day). Following chronic exposure by the inhalation route (5 d/w, 6 h/d), the NOAEC for general toxicity of HEA in Sprague-Dawley rats was 0.0024 mg/L air (nominal) based on an increased incidence, increased severity, and earlier onset of the lesions associated with the chronic murine pneumonia. Gross and histopathological examination of tissues from rats exposed to concentrations of 0.024 and 0.0024 mg/L HEA showed no indication of a carcinogenic effect.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 May 1974 - 07 May 1976 (experimental)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study report, acceptable for assessment with restrictions; deviations from current test protocols: exposure period only 18 months and only 2 concentrations were tested.
Reason / purpose:
reference to same study
Principles of method if other than guideline:
Groups of 99-100 male and female rats were erposed to atmospheres containing 0 ppm (controls), 5.0 ppm (24 mg/m3) or 0.5 ppm (2.4 mg/m3) 2-hydroxyethyl acrylate (HEA) for 6 hours/day, 5 days/week over an 18 month period, and subsequently held for a post-exposure period of 5 months (males) and 6 months (females).
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Spartan substrain
- Source: Spartan Research Animals, Michigan
- Housing: 3-4 animals/cage
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): ambient
- Humidity (%): ambient
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 3.7 cubic meters stainless steel chambers under dynamic airflov- conditions
- System of generating vapours: The exposure atmosphere in each chamber was generated by metering liquid HEA at a calculated rate into the top of
a 15 inch glass column ( 2" diameter) that was heated to a temperature (ca. 80°C) hot enough to vaporize the HEA. Dry compressed air was introduced at the bottom of the glass column to sweep the vapours into the chamber where they were diluted with room air at a rate calculated to provide the desired HEA Concentration.


TEST ATMOSPHERE
- The nominal concentration of HEA in the chamber was calculated from the ratio of the amount of liquid HEA used to the rate of total chamber airflow.
- Brief description of analytical method used:
The concentration of HEA in each chamber was determined three or more times daily.
Analytical concentrations for the first 6 1/2 months of exposure were obtained by drawing 10 liters of air from the chamber at a rate of 1 liter/min through a charcoal tube. The HEA absorbed on the charcoal was extracted into 2 mL of carbon disulfide. The quantity of HEA in a 2 µL sample of carbon disulfide extract was analysed by gas chromatography (detector: FID).
For the last 11 1/2 months of the study HEA samples were collected by bubbling chamber air through water instead of charcoal. Improved reproducibility of sample analysis and convenience were the primary reasons for using water instead of charcoal. Fifty liters of air from the chamber were drawn through 20 mL of distilled water in a fritted glass bubbler at a rate of 1 liter/min. The quantity of HEA in a 2 µL sample of the trapping solution was analyzed by gas chromatography using the same conditions as before.
- Samples taken from breathing zone: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Sixty per cent of the total exposure days for the low exposure level and 73 % of the total exposure days of the high exposure level were within 50 % of the an analytical concentrations. The high nominal concentration values and variability in analytical concentrations reflect the fact that HEA, having a relatively low vapour pressure, was difficult to vaporize. Much of the HEA dispensed into the vaporization apparatus was not vaporized, but that not vaporized was not subtracted from the amount dispensed in calculation of the nominal concentration. Although the analytical concentrations were not identical to the target concentrations, especially for the higher exposure level, the target concentrations of 0.5 and 5.0 ppm werereferred to throughout the study report.
Duration of treatment / exposure:
18 months
Frequency of treatment:
6 hours per day, 5 days per week
Post exposure period:
Males: 5 months; females: 6 months
Dose / conc.:
0.024 mg/L air (nominal)
Remarks:
corresponding to 5 ppm
Dose / conc.:
0.002 mg/L air (nominal)
Remarks:
corresponding 0.5 ppm
No. of animals per sex per dose:
99 - 100
Control animals:
yes, concurrent no treatment
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no details given


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no details given


BODY WEIGHT: Yes
- Time schedule for examinations: no details given


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to the scheduled 12-month interim sacrifice, and again after 5 months of the post-exposure observation period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 rats/sex/exposure group
- Parameters were examined: packed cell volume (PVC), red blood cell count (RBC), hemoglobin concentration (Hgb), total white blood cell count (WBC) and differential white blood cell count.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of serum: prior to the scheduled 12-month interim sacrifice, and again after 5 months of the post-exposure observation period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 and 9 or 10 rats/sex/exposure group, respectively
- Parameters were examined: blood urea nitrogen (DUN) concentration, serum alkaline phosphatase (AP) activity, and serum glutamic pyruvic transaminase (SGPT) activity



URINALYSIS: Yes
- Time schedule for collection of blood: prior to the scheduled 12-month interim sacrifice, and again after 5 months of the post-exposure observation period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 and 10 rats/sex/exposure group, respectively
- Parameters were examined: Urinary specific gravity, pH, and the presence or absence of glucose, protein, ketones, bilirubin and occult blood were evaluated at both time intervals. Urinary urobilinogen was evaluated at the preterminal sampling interval only.



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

An interim necropsy of 5 rats/sex/exposure group was conducted after 12 months exposure. Terminal necropsy was conducted after completion of
23 months (18 months exposure + 5 months post-exposure) for male rats, and after completion of 24 months (18 months exposure + 6 months post-exposure) for female rats.

The eyes of 5 rats/sex/exposure group were placed in Zenker's fixative. The trachea and lungs were removed as a unit and distended with formalin
fixative. The weights of the brain, heart, liver, kidneys and testes (males) were recorded for 5 rats/sex/group sacrificed after 12 months and also for 9-19 rats/sex/exposure group sacrificed at termination.

Gross examination:
Representative portions of the major organs and tissues, including brain, heart, liver, kidneys, testes, lungs, thoracic and/or mesenteric lymph nodes, salivary glands, pancreas, adrenals, spleen, thymus, aorta, skeletal muscle, small intestine, large intestine, thyroid gland, parathyroid glands, eyes (those not fixed in Zenker's fixative), esophagus, trachea, spinal cord, peripheral nerve, pituitary gland, epididymides, urinary bladder, accessory sex glands, adipose tissue, ovaries, uterus, nasal turbinates, and any gross lesion suggestive of an unexpected pathologic process or with a tumour formation was preserved in buffered 10 % formalin fixative. The eyes were examined with a glass slide technique and the data were entered with the gross data.

Microscopic examination:
- Control and high (5.0 ppm) Exposure Group: All available tissues from all rats were examined.
- Low (0.5 ppm) Exposure Group: In the absence of any discernible exposure-related lesions in the tissues from rats exposed to 5.0 ppm, the 12-month interim examination of rats of the 0.5 ppm exposure group was limited to grossly visible lesions suggestive of tumour formation. From the terminal necropsy, all available lungs, livers, kidneys, lymph nodes, tracheas, plus grossly visible lesions suggestive of an unexpected pathologic process
or tumour formation were examined from all rats.
Statistics:
Significance of differences between control and test values for hematology, clinical chemistry, body weights, organ weights, and organ/body weight ratio data was statistically determined by an analysis of variance and Dunnett's Test (Steel and Torrie, 1960). A significance level of p<0.05 was used. Cumulative mortality data were analysed using Fisher's Exact Probability Test, p<0.05 (Siegel, 1956). The pathologic data were statistically analysed using Fisher's Exact Probability Test and the Mantel-Haenzel Test (Siegel, 1956). A significance level of p<0.05 was used.
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:
effects observed, treatment-related
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
HISTOPATHOLOGY: NEOPLASTIC
A variety of neoplasms considered spontaneous in origin occurred in a number of tissues or organs of control and exposed groups of rats. As
expected, mammary fibroadenomas and pituitary adenomas were the most frequently occurring neoplasms in female rats of all groups. Adrenal pheochromocytomas, pancreatic acinar adenomoas, pituitary adenomas and subcutaneous fibromas were the most common neoplasms in the male rats of all groups.
Neoplasms, all of which were considered spontaneous in origin, occurred in the following organs and tissues: liver, lung, pancreas, kidney, testes, preputial gland, stomach, small and large intestine, spinal cord and peripheral nerves, pituitary gland, subcutaneous tissue, mammary tissue, integument, ear canal, oral cavity, adrenal gland, lymph nodes, spleen, brain, adipose tissue, thyroid, ovary, uterus, clitoral gland and vagina.
Statistical analyses revealed no exposure-related increases in the incidence of any of these neoplasms in HEA exposed rats compared to control rats. Statistical analyses also revealed no differences between the temporal or total incidence of HEA-exposed rats bearing benign neoplasms, malignant
neoplasms, or all types of neoplasms combined compared to control rats.

Dose descriptor:
NOAEC
Remarks:
carcinogenicity
Effect level:
ca. 0.024 mg/L air (nominal)
Sex:
male/female
Remarks on result:
other: no carcinogenicity indicating effects observed up to and including the highest tested dose
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
ca. 0.002 mg/L air (nominal)
Sex:
male/female
Basis for effect level:
other: tracheobronchial system (inflammatory effects)

Chronic exposure of rats to 5.0 or 0.5 ppm HEA did not increase the incidence of any type of neoplasm.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rat

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No adequate animal data are available and no epidemiological studies investigating the carcinogenicity of hydroxypropyl acrylate were identified. However, data from the structural analogue 2-hydroxyethyl acrylate are available.

In a chronic inhalation study male and female Sprague-Dawley rats (99 or 100 animals/ sex/dose group) were exposed to atmospheres containing 0 ppm (controls), 5.0 ppm (0.024 mg/L) or 0.5 ppm (0.0024 mg/L) 2-hydroxyethyl acrylate (HEA) for 6 hours/day, 5 days/week over an 18 month period, and subsequently held for a post-exposure period of 5 months (males) and 6 months (females). The study included 12-month interim sacrifices for pathologic and cytogenetic examinations. Haematology, blood chemistry and urine analysis were measured prior to the scheduled 12-month interim sacrifice, and again after 5 months of the post-exposure observation period. Histopathological examination was carried out for the following tissues of the control and 5 ppm groups, at interim and terminal sacrifice: brain, heart, liver, kidneys, testes, lungs, thoracic and/or mesenteric lymph nodes, salivary glands, pancreas, adrenals, spleen, thymus, aorta, skeletal muscle, small intestine, large intestine, thyroid gland, trachea, spinal cord, peripheral nerve, pituitary gland, epididymides, urinary bladder, accessory sex glands, adipose tissue, ovaries, uterus, nasal turbinates, and any gross lesion suggestive of a pathologic process or with tumor formation. At 0.5 ppm terminal sacrifice the following tissues were examined by light microscopy: lungs, liver, kidneys, lymph nodes, tracheas and all grossly visible lesions from all surviving animals; at interim sacrifice all grossly visible lesions or tissues where lesions had been seen at 5 ppm. Rats dying or culled during the course of the study, were subjected to complete necropsy and microscopic exam as described above (except when autolysis precluded evaluation) and the presence and absence of neoplasms was recorded.

Body weights, terminal organ weights and cumulative mortality, urinalysis, clinical chemistry and haematology did not appear to be altered by chronic HEA exposure. Overall treatment was not associated with adverse effects except that the rats in the 5 ppm treatment group developed yellow staining of the fur and a marginal increase in Mycoplasma-induced chronic murine pneumonia which was interpreted as being treatment-related. No treatment-related effects were seen in the 0.5 ppm group.

A variety of neoplasms considered spontaneous in origin occurred in a number of tissues or organs of control and exposed groups of rats. As expected, mammary fibroadenomas and pituitary adenomas were the most frequently occurring neoplasms in female rats of all groups. Adrenal pheochromocytomas, pancreatic acinar adenomoas, pituitary adenomas and subcutaneous fibromas were the most common neoplasms in the male rats of all groups. Neoplasms, all of which were considered spontaneous in origin, occurred in the following organs and tissues: liver, lung, pancreas, kidney, testes, preputial gland, stomach, small and large intestine, spinal cord and peripheral nerves, pituitary gland, subcutaneous tissue, mammary tissue, integument, ear canal, oral cavity, adrenal gland, lymph nodes, spleen, brain, adipose tissue, thyroid, ovary, uterus, clitoral gland and vagina. Statistical analyses revealed no exposure-related increases in the incidence of any of these neoplasms in HEA exposed rats compared to control rats. Statistical analyses also revealed no differences between the temporal or total incidence of HEA-exposed rats bearing benign neoplasms, malignant neoplasms, or all types of neoplasms combined compared to control rats.

Overall chronic inhalation exposure to HEA at a dose of 5 ppm caused only a minimal toxicological effect while no toxicity was seen at 0.5 ppm. Gross and histopathological examination of tissues showed no indication of significant chronic toxicity or a carcinogenic effect in either the 5 or 0.5 ppm treatment groups (Dow Chemical Co., 1979).

The NOAEC for general toxicity was set at 0.0024 mg/L (nominal) based on an increased incidence, increased severity, and earlier onset of the lesions associated with the chronic murine pneumonia observed at the high dose level. The NOAEC for carcinogenicity was equal to or greater than the high dose of 0.024 mg/L (nominal).

Summary:

Following chronic exposure by the inhalation route (5 d/w, 6 h/d), the NOAEC for general toxicity in Sprague-Dawley rats was 0.0024 mg/L (nominal) based on an increased incidence, increased severity, and earlier onset of the lesions associated with the chronic murine pneumonia. Gross and histopathological examination of tissues from rats exposed to concentrations of 0.024 and 0.0024 mg/L showed no indication of a carcinogenic effect.

Based on results of the analogue 2-hydroxyethyl acrylate, hydroxypropyl acrylate is not anticipated to be carcinogenic in rats via inhalation at doses up to 5 ppm (0.024 mg/L air/day).

Justification for classification or non-classification

Based on the available data, classification as a carcinogenic substance is not triggered according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.