Registration Dossier

Administrative data

Description of key information

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.

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 to 07 May 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Deviations from current test protocols: exposure period only 18 months and only 2 concentrations were tested.
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Principles of method if other than guideline:
Groups of Sprague-Dawley rats (Spartan substrain, 99-100 of each sex), were exposed to vapor atmosphere of 0.5 ppm or 5 ppm HEA for 6 hours per day, 5 days per week over an 18 month period. Exposures were not carried out on Saturdays, Sundays, or holidays. A third group of 200 rats, equally divided in sex, were maintained under ambient conditions in an animal holding room as controls. Food and water were removed from all rats during each daily exposure period. The rats were group housed in stainless steel wire bottom cages, 3 to 4 rats per cage. The same cages were used in the exposure chamber and for holding during the 18 month exposure period so that daily transfer of rats from one cage to another was not needed. Body weights of all rats were recorded at intervals to remove dead or moribund animals. When recognized, rats in moribund condition were removed for pathologic examination so they could be examined before post-mortem autolysis became advanced. Mortality data were accumulated and analysed statistically once monthly. The study included 12-month interim sacrifices for pathologic and cytogenic examinations. Subsequently to the completion of the 18-month exposure period, male rats were held for a 5-month post-exposure observation and female rats were held for a 6-month post-exposure observation period. Male rats were terminated early because of high mortality.
Deviations from the OECD Guideline 453 were that exposure period was 18 months and only 2 concentrations were tested. The exposure duration, applicable to inhalation route, was according the Guideline OECD 453. Clinical Chemistry, Haematology, Body and organ weights, Necropsy, Pathology and Histopatholy examination were performed as proposed by the Guideline.
GLP compliance:
no
Remarks:
pre GLP study
Specific details on test material used for the study:
- Name of test material (as cited in study report): 2-Hydroxyethyl acrylate
- Analytical purity: 94 %
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:
air
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 were referred 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 to 0.5 ppm
No. of animals per sex per dose:
99 - 100
Control animals:
yes, concurrent vehicle
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:
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.

HISTOPATHOLOGY:
- 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
Description (incidence and severity):
Overall, the cumulative mortality data did not suggest any unequivocal exposure-related effects with the possible exception of initial increased mortality associated with the onset of chronic murine pneumonia in rats exposed to 5.0 ppm HEA.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
The onset of a chronic murine pneumonia affected initially the group of male rats exposed to 5.0 ppm HEA which resulted in statistically increased cumulative mortality for this group compared to control males in the 16th month of the study. During months 20-22, the males exposed to 5.0 ppm HEA had decreased cumulative mortality when compared to the male control group. The mortality of male rats exposed to 0.5 ppm HEA was comparable to the mortality of control males, except for a statistical increase in the 10th month and a statistical decrease in the 17th month of the study. The mortality of exposed female rats was comparable to mortality of control females except for a statistical increase in the 17th month for female exposed to 5.0 ppm HEA and a statistical increase in the 15th month for females exposed to 0.5 ppm HEA. Overall, the cumulative mortality data did not suggest any unequivocal exposure-related effects, with the possible exception of initial increased mortality associated with the onset of chronic murine pneumonia in rats exposed to 5.0 ppm HEA.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Body weight data are presented in the table below, please see section "Any other information on results incl. tables". Male rats assigned to groups exposed to 5.0 or 0.5 ppm HEA had statistically lower body weights than the controls prior to initiation of the exposure period. These lower body weights were also noted during the exposure period, but the rate of body weight gain was comparable for all groups of male rats. Body weights of female rats in the HEA exposure groups were also slightly lower than control rats at the onset of the study. These differencies disappeared by the fifth day of the study. In female rats, sporadic differences in body weight between HEA exposed and control rats occured throughout the study. Overall, there were no alterations of body weights of either sex that could be attributed to the exposure to either level of HEA.
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
Description (incidence and severity):
Mean haematological values for the male rats exposed to HEA showed no differences from the values of control males. Haematologic data for female rats exposed to 5.0 ppm HEA were statistically higher in hemoglobin concentration and statistically lower in total white blood cell count than the similar values for control females. These statistical differences, which were not noted in female exposed to 0.5 ppm HEA, may or may not have been related to exposure to 5.0 ppm HEA.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no significant differences between control and exposed groups.
Urinalysis findings:
no effects observed
Description (incidence and severity):
- 12-months interim examination:
Examination of the data on the male rats 4 days prior to the 12-month interim kill suggested a possible increase in occult blood from one rat in each exposed group. Subsequently the urinalysis was repeated at the time of the interim kill and showed no evidence of occult blood in any of the rats tested. All other parameters measured on urine of male rats showed no difference from the control group. The urine of female rats tested 4 days prior to the interim kill showed a slight decrease in specific gravity when compared to that of the control group. Repetition of the urinanalysis at the time of the interim kill showed no apparent decrease of specific gravity when compared to control. All other parameters measured on urine of male rats showed no difference when compared to the control group.

- 5-months post-exposure examination:
None of the parameters measured showed differences between exposed and control groups for either sex.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
There were significantly decreased terminal body weights for male rats exposed to 5 ppm or 0.5 ppm HEA. In addition, there was a significant increase in the brain/body weight ratio and in the testes/body weight ratio for male rats exposed to 0.5 ppm. These relative weight changes are considered secondary to the difference in total body weights. There were no significant differencies in body weight or weights of brain, heart, liver or kidney for female rats exposed to HEA.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Gross and histopathologic examination of rats exposed to 5.0 ppm HEA revealed a characteristic yellow staining of the haircoat, as well as an increased incidence, increased severity and earlier onset of the lesions associated with chronic murine pneumonia. These exposure-related effects were not observed in rats exposed to 0.5 ppm HEA. (see Histopathological findings: non-neoplastic).
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
- Gross and histopathologic examination of rats exposed to 5.0 ppm HEA revealed a characteristic yellow staining of the haircoat, as well as an increased incidence, increased severity and earlier onset of the lesions associated with chronic murine pneumonia. These exposure-related effects were not observed in rats exposed to 0.5 ppm HEA.


- Integument:
A statistically significant number of male and female rats exposed to 5.0 ppm HEA had a distinctive grossly-visible yellow staining of the haircoat that persisted into the post-exposure period of the study. This was considered to be the result of the contact of HEA with the haircoat. The yellow staining was not observed grossly on rats from the lower exposure level of HEA (0.5 ppm). Microscopic examination of sections of the stained haircoat revealed no histologic alterations.
 
- Respiratory System:
Chronic murine pneumonia occurred in the groups of rats used in this study. This was indicated by pulmonary consolidation, atelectasis, bronchiectasis or tenacious mucopurulent inflammation along the tracheobronchial system. Historically, the organism Mycoplasma has been cultured from lung-lesions of this type occurring in the testing laboratory. These cases of chronic murine pneumonia sometimes included abscess formation, pleuritis, pericarditis, rhinitis and/or tracheitis. In addition to the lesions of chronic murine pneumonia, all groups had rats with varying degrees of pulmonary inflammatory reactions or aggregates of alveolar macrophages, hematogenous pigment, cholesterol clefts or red blood cells.
Statistical evaluation:
An increase in the incidence of numerous gross or microscopically visible lesions occurring as part of or secondary to the chronic murine pneumonia in male and/or female rats exposed to 5.0 ppm HEA. This included pulmonary consolidation, congestion, bronchiectasis, peribronchiolar lymphoid hyperplasia, peribronchiolar fibrosis, focal purulent inflammation and epithelial hyperplasia of bronchi/bronchioles, diffuse epithelial hyperplasia of the trachea, pulmonary aggregates of haematogenous pigment, focal pulmonary atelectasis, and focal hypercellularity of alveolar walls secondary to aggregates of red blood cells within alveoli.
An increase in the incidence of pulmonary aggregates of haematogenous pigment and focal hypercellularity of alveolar walls secondary to aggregates of red blood cells within alveoli in lungs of female rats exposed to 0.5 ppm HEA.
An increase in the incidence of diffuse pulmonary congestion of female rats exposed to 0.5 ppm HEA.
Overall assessment of these data suggests exposure to 5.0 ppm HEA increased the severity of lesions occurring as part of chronic murine pneumonia. However, this appeared not to be the case with exposure of rats to 0.5 ppm HEA.
 
- Lvmphoreticular System:
Inflammatory or hyperplastic changes occurred in some lymph nodes of some rats for all groups. Some lymph nodes contained increased amounts of haematogenous pigment, oedema, abscess formation or pooling of red blood cells. There were inflammatory reactions in thoracic lymph nodes secondary to chronic murine pneumonia.
Statistical evaluation:
Increases in the incidence of oedema, inflammation and reactive lymphoid hyperplasia of the thoracic lymph nodes of female rats exposed to 5.0 ppm HEA. Female rats exposed to 0.5 ppm HEA also had increased incidence of oedema and reactive lymphoid hyperplasia of thoracic lymph nodes. These inflammatory responses were considered to be associated with chronic murine pneumonia that occurred in these rats.
An increase in the incidence of oedema of mesenteric lymph nodes of female rats exposed to 5.0 ppm
 
- Spleen:
Increased hemopoietic activity and haematogenous pigment was commonly observed in the spleen of some rats from both control and exposed groups. Reticuloendothelial hyperplasia and also splenic atrophy were noted in the spleens of some control and exposed rats.
 
- Liver:
All groups, exposed and control, had rats with variable degrees of focal inflammation, necrosis, fatty metamorphosis, cytoplasmic vacuolization, swollen hepatocytes, bile duct hyperplasia, pericholangiolar inflammation, sinusoidal distention, aggregates of reticuloendothelial cells adjacent to degenerate hepatocytes, biliary cyst formation, and foci or areas of atypical hepatocytes. Extramedullary hematopoiesis or vascular distention also occurred in livers of rats from all groups.
Statistical analysis:
Decreased incidence of mottling and also congestion of the liver in male rats exposed to 5.0 ppm HEA.
Increased incidence of focal areas of swollen hepatocytes and focal aggregates of mononuclear cells in liver of male rats exposed to 5.0 ppm HEA.
An increase in the incidence of focal bile duct proliferation in livers of female rats exposed to 5.0 ppm HEA.
 
- Thyroid and parathvroid glands:
Thyroid hyperplasia or adenoma formation was observed in rats of all control and exposed groups. This usually involved the interfollicular cells of the thyroid. The most frequent alteration in the parathyroid glands was hyperplasia occurring secondary to the age-related progressive chronic nephropathy.
 
- Pancreas:
Focal atrophy of pancreatic acinar tissue and focal fibrosis was noted in both control and exposed groups of rats. Hyperplastic nodules and neoplasms of the pancreatic acini were also noted in both control and exposed groups. Some control and exposed rats had pancreatic islets that were enlarged, or neoplastic. A few rats had pancreatic islets showing slight cytoplasmic vacuolation.
 
- Female Reproductive Svstem:
An age-related occurrence of uterine endometrial hyperplasia, polyp formation and ovarian cyst formation was observed. Various forms of uterine inflammation also occurred in rats of all groups. A few cases of uterine abscessation or cyst formation were noted. Neoplasm occurred in a few cases.
Statistical analysis:
An increase in the incidence of inflammation of the uterus in female rats exposed to 5.0 ppm HEA.
 
- Male Reproductive System:
An age-related decrease in testicular spermatogenic activity was noted in rats of both control and exposed groups. This was sometimes accompanied by decreased content of spermatogenic cells in the epididymis. Also, the accessory sex glands were sometimes found to have a decreased content of secretory material.
Other infrequent observations included inflammation of the accessory sex glands, abscessation of preputial glands, or neoplasia.
Statistical evaluation:
An increased incidence of vascular fibrinoid degeneration in testes of male rats exposed to 5.0 ppm HEA.
 
- Stomach:
All exposed and control groups had some rats with focal gastric erosions/ulcers, gastric hemorrhage or hyperemia. Dilatation of gastric pits was also noted upon microscopic examination of some rats from each of the exposed and control groups. Gastric mucosal hyperplasia or hyperkeratosis also occurred in a few control and exposed rats. Mineralization of the gastric wall was noted in some rats from each control and exposed group. These rats usually had chronic progressive nephropathy and uremia.
Statistical evaluation:
Increase in the incidence of microscopically visible dilatation of gastric pits in male rats exposed to 5.0 ppm HEA.
 
- Small and large intestines:
Various inflammatory processes were noted in segments of the intestinal tract of some rats from all control and exposed groups. Isolated cases of diverticulum formation, focal ulceration, reactive lymphoid hyperplasia and neoplasia were also noted. Intestinal nematodiasis was also noted in some rats from all groups. Focal inflammation and/or necrosis of the mesenteric fat was noted in a few rats scattered amongst all exposed and control groups of rats.
 
- Eyes:
All groups had rats with various inflammatory changes of the cornea or other components of the eye. Some rats had eyes with focal hyperplasia of the cornea epithelium.
 
- Nervous System:
The most common lesions were hyperplastic or neoplastic proliferations of the pituitary gland; some of these were associated with haematogenous pigment aggregates, hemangiectasis, or compression of the adjacent portion of the brain. Some rats had vacuolar degeneration of the peripheral nerves, and other rats had neoplasms originating from the Schwann cells of the peripheral nerves.
 
- Adrenal Glands:
Hyperplastic or neoplastic changes were observed in the adrenal cortex or medulla of rats from all groups. Hematocyst formation and vascular sinusoidal distention and cytoplasmic vacuolization of the adrenal cortical cells also occurred in all groups.
 
- Cardiovascular System:
All groups, exposed and control, had rats with age-related myocardial degenerative changes, aortic and thoracic vessel mineralization, periarteritis of the mesenteric and other vessels (testes, liver, etc.). Thrombosis and hematoma formation were occasional complications of the mesenteric periarteritis. Thrombosis of the left atrium caused the death of some rats.
Statistical evaluation:
An increase in the incidence of a grossly-visible flaccidity of the myocardium of males exposed to 0.5 ppm HEA.
An increase in the incidence of a microscopically-visible degeneration of myocardial blood vessels in female rats exposed to 5.0 ppm HEA.
 
- Urinary System:
An age-related progressive chronic nephropathy occurred in rats (especially males) from all groups of rats. This was sometimes accompanied by secondary parathyroid hyperplasia and mineralization of certain tissues, such as the gastric wall. Other incidental lesions in kidneys included inflammation or hyperplasia of renal pelvic epithelium, mineralized deposits, focal purulent inflammation, focal fibrosis, cyst formation, calculus formation or neoplasia. A few rats had diffuse or focal urocystitis, inflammation or hyperplasia of the urinary bladder mucosa.
 
- Subcutaneous Tissues and Mammary Glands:
A substantial number of control and exposed females had evidence of mammary gland hyperplasia, neoplasia and/or galactocele formation. Epidermal inclusion cysts or subcutaneous or integumentary neoplasms were also noted in a few control and exposed rats.
Statistical evaluation:
Increase in the incidence of female rats having a total of 3 grossly-visible subcutaneous masses (suggestive of mammary tissue origin) in the groups exposed to 5.0 or 0.5 ppm HEA. However, this was not the case with female rats of either exposure group that had 1, 2, 4 or 5 subcutaneous masses suggestive of mammary tissue origin.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
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 adenomas, 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.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 0.024 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: neoplastic
Key result
Critical effects observed:
no

Table 1a-b: Mean body weights of male and female rats exposed to vapors of 2 -Hydroxyethyl acrylate for up to 23 months (males) and 24 months (females)

 

1a: Days 0 -251

Days on Test

0

5

7

12

19

26

33

40

54

68

96

131

159

194

223

251

Males

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0.0

ppm

299.8

(100)

314.4

(100)

322.2

(100)

343.4

(100)

375.3

(100)

393.3

(100)

416.1

(100)

437.6

(100)

466.9

(100)

488.0

(99)

522.6

(99)

548.3

(99)

569.0

(99)

594.6

(98)

557.3

(98)

608.2

(98)

5.0

ppm

*290.3

(99)

*308.7

(99)

320.4

(99)

*334.6

(99)

*364.1

(99)

392.5

(99)

*406.8

(99)

*422.4

(99)

*453.3

(99)

*473.4

(99)

*501.0

(99)

*528.0

(99)

*532.8

(99)

*546.4

(99)

555.6

(99)

*553.5

(99)

0.5

ppm

*287.0

(100)

*301.7

(100)

*309.3

(100)

*334.2

(100)

*357.0

(100)

379.7*

(100)

*391.9

(100)

*410.2

(100)

*437.6

(99)

*455.4

(99)

*495.3

(99)

*514.4

(97)

*519.9

(96)

*536.8

(95)

*541.5

(95)

*546.7

(94)

Females

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0.0

ppm

224.1

(100)

221.0

(100)

222.7

(100)

232.8

(100)

241.8

(100)

247.3

(100)

259.3

(100)

266.7

(100)

277.6

(100)

287.2

(100)

302.6

(100)

293.7

(99)

309.3

(99)

331.2

(99)

337.0

(98)

336.9

(97)

5.0

ppm

*216.9

(100)

224.2

(100)

*230.6

(100)

235.0

(100)

243.7

(100)

*260.7

(100)

265.8

(100)

266.3

(100)

*287.0

(100)

*299.7

(100)

*312.1

(99)

*318.8

(99)

325.2

(99)

327.6

(98)

336.8

(98)

337.0

(98)

0.5

ppm

*219.2

(99)

222.2

(99)

220.0

(99)

230.3

(99)

241.7

(99)

*255.1

(98)

258.4

(98)

266.0

(98)

281.3

(98)

290.4

(98)

307.8

(98)

*320.7

(98)

309.5

(98)

327.4

(98)

332.2

(98)

336.4

(98)

1b: Days 286- 723

Days on Test

286

314

342

377

405

433

468

496

532

552

585

620

648

675

702

723

Males

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0.0

ppm

632.7

(98)

642.8

(98)

648.9

(97)

654.3

(86)

658.0

(85)

661.4

(83)

664.1

(83)

628.3

(83)

593.0

(43)

604.0

(38)

577.2

(31)

587.1

(24)

558.3

(20)

521.8

(16)

518.8

(14)

 

5.0

ppm

*578.8

(99)

*583.4

(99)

*607.7

(98)

*615.2

(87)

*621.0

(86)

*621.0

(84)

*602.0

(78)

*543.4

(60)

589.2

(48)

589.3

(47)

599.0

(43)

587.0

(40)

557.7

(34)

507.2

(29)

535.3

(19)

 

0.5

ppm

*570.6

(93)

*575.5

(93)

*589.2

(93)

*596.0

(84)

637.8

(83)

*625.1

(84)

*627.7

(81)

611.4

(77)

587.3

(60)

573.9

(47)

558.7

(36)

559.4

(24)

520.5

(17)

549.1

(10)

518.9

(09)

 

Females

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0.0

ppm

349.8

(97)

348.8

(95)

356.3

(96)

363.5

(86)

372.2

(86)

387.6

(85)

395.2

(85)

395.8

(85)

393.6

(73)

401.4

(67)

401.2

(61)

410.7

(52)

430.9

(48)

437.3

(38)

456.5

(29)

442.2

(20)

5.0

ppm

349.4

(95)

350.9

(95)

369.7

(93)

376.1

(83)

373.3

(83)

385.9

(82)

395.4

(81)

*359.7

(74)

387.6

(63)

395.8

(57)

417.7

(52)

413.3

(46)

421.9

(41)

404.3

(35)

406.9

(30)

411.0

(27)

0.5

ppm

351.9

(96)

351.6

(94)

351.6

(92)

367.2

(81)

*400.2

(81)

389.2

(78)

400.9

(76)

397.1

(73)

396.8

(73)

409.6

(63)

405.6

(55)

405.8

(47)

412.0

(41)

418.3

(31)

425.0

(23)

422.9

(20)

* : Significant difference from control data using analysis of variance and Dunnett's test p < 0.05.

( ) : Indicates numbers of rats weighed.

Day 0: Pre-exposure data

Table 2a-b: Body weights, and organ/body weight ratios for male (a) and female (b) rats exposed to vapors of 2 -Hydroxyethyl acrylate 5 days / week for 12 months

(a) males:

Exposure level (ppm)

Sex

Body weight g

Organ Weights (g and g/100 g Body Weight)

Brain

Heart

Liver

Kidneys

Testes

g

g/100g

g

g/100g

g

g/100g

g

g/100g

g

g/100g

0

M

633

1.94

0.31

1.60

0.25

17.83

2.82

4.40

0.70

4.35

0.69

M

584

2.02

0.35

1.54

0.26

12.76

2.18

3.48

0.60

4.36

0.75

M

670

1.97

0.29

1.68

0.25

17.46

2.61

4.60

0.69

4.18

0.62

M

635

1.96

0.31

1.73

0.27

15.89

2.50

4.12

0.65

3.88

0.61

M

583

1.95

0.33

1.66

0.28

11.75

2.02

3.13

0.54

2.55

0.44

Mean

± S.D.

621 ± 37

1.97 ± 0.03

0.32 ± 0.02

1.64 ± 0.07

0.26 ± 0.01

15.14 ± 2.75

2.42 ± 0.32

3.95 ± 0.62

0.63 ± 0.07

3.87 ± 0.76

0.62 ± 0.12

5.0

M

582

1.97

0.34

1.58

0.27

15.29

2.63

3.72

0.64

4.27

0.73

M

550

1.87

0.34

1.60

0.29

13.41

2.44

3.24

0.59

3.98

0.72

M

566

1.84

0.33

1.50

0.26

13.34

2.36

3.54

0.63

4.19

0.74

M

533

1.90

0.36

1.49

0.28

12.51

2.35

3.20

0.60

3.81

0.72

M

592

2.04

0.34

1.79

0.30

20.34

3.44

5.13

0.87

4.14

0.70

Mean

± S.D.

565*

±24

1.93 ± 0.08

0.34 ± 0.01

1.59 ± 0.12

0.28 ± 0.02

14.98 ± 3.17

2.64 ± 0.46

3.77 ± 0.79

0.66 ± 0.12

4.08 ± 0.18

0.72 ± 0.02

0.5

M

596

1.98

0.33

1.66

0.28

13.45

2.26

3.10

0.52

4.73

0.79

M

542

1.93

0.36

1.55

0.29

12.72

2.35

3.38

0.62

4.36

0.81

M

581

1.98

0.34

1.75

0.30

14.92

2.57

3.38

0.58

4.36

0.75

M

498

1.92

0.39

1.29

0.26

11.79

2.37

3.18

0.64

4.06

0.81

M

526

2.08

0.40

1.50

0.29

11.74

2.23

3.47

0.66

4.37

0.83

Mean

± S.D.

549*

±40

1.98 ± 0.06

0.36* ± 0.03

1.55 ± 0.17

0.28 ± 0.02

12.92 ± 1.32

2.35 ± 0.13

3.30 ± 0.15

0.60 ± 0.06

4.38 ± 0.24

0.80* ± 0.03

*: Statistically significant difference from control mean by analysis of variance and Dunnett's test p < 0.05.

(b) females:

Exposure level (ppm)

Sex

Body Body

weight g

Organ Weights (g and g/100 g Body Weight)

Brain

Heart

Liver

Kidneys

g

g/100g

g

g/100g

g

g/100g

g

g/100g

0

F

300

1.83

0.61

1.03

0.34

7.30

2.43

1.91

0.64

F

328

1.82

0.56

1.03

0.31

7.72

2.35

2.06

0.63

F

309

1.91

0.62

1.05

0.34

6.89

2.23

2.35

0.76

F

310

1.89

0.61

1.09

0.35

7.83

2.53

2.41

0.78

F

339

1.81

0.53

1.03

0.30

7.04

2.08

2.08

0.61

Mean

± S.D.

317 ± 16

1.85 ± 0.05

0.59 ± 0.04

1.05 ± 0.02

0.33 ± 0.02

7.36 ± 0.41

2.32 ± 0.18

2.16 ± 0.21

0.68 ± 0.08

5.0

F

359

1.83

0.51

1.17

0.33

7.50

2.09

2.47

0.69

F

332

1.83

0.55

0.12

0.34

7.69

2.32

2.43

0.73

F

337

1.69

0.50

1.04

0.31

7.98

2.37

2.27

0.67

F

376

1.85

0.49

1.22

0.32

8.90

2.37

2.53

0.67

F

307

1.83

0.60

1.09

0.36

7.29

2.38

1.87

0.61

Mean

± S.D.

342 ± 26

1.80 ± 0.07

0.53 ± 0.04

1.13 ± 0.07

0.33 ± 0.02

7.87 ± 0.63

2.30 ± 0.12

2.31 ± 0.27

0.68 ± 0.04

0.5

F

340

1.90

0.56

0.92

0.27

7.76

2.28

2.05

0.60

F

336

1.81

0.54

1.07

0.32

7.98

2.38

2.21

0.66

F

373

1.89

0.51

1.27

0.34

12.77

3.42

2.38

0.64

F

338

1.90

0.56

1.11

0.33

8.88

2.63

2.03

0.60

F

347

1.86

0.54

1.17

0.34

8.52

2.46

2.21

0.64

Mean

± S.D.

347 ± 15

1.87 ± 0.04

0.54 ± 0.02

1.11 ± 0.13

0.32 ± 0.03

9.18 ± 2.05

2.63 ± 0.46

2.17 ± 0.14

0.63 ± 0.02

for more details see attachment: Carcinogenicity study - tables

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
24 mg/m³
Study duration:
chronic
Species:
rat

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a chronic inhalation study (Dow Chemical Co., 1979), 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) test substance 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.

Evaluation of urinalyses, clinical chemistry tests, body weights, terminal organ weights, and cumulative mortality revealed no alterations that could be unequivocally related to exposure to 5.0 or 0.5 ppm of test substance. 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 test substance-exposed rats compared to control rats. Statistical analyses also revealed no differences between the temporal or total incidence of substance-exposed rats bearing benign neoplasms, malignant neoplasms, or all types of neoplasms combined compared to control rats.

Overall chronic inhalation exposure to test substance 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.

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).

Justification for classification or non-classification

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