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Carcinogenicity

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Description of key information

n-Butyl acrylate showed no evidence of carcinogenicity in a 2-year vapour inhalation study in Sprague-Dawley rats up to the highest tested dose (135 ppm = 0.773 mg/L) and in a lifetime skin painting study in C3H/HeJ mice at approx. 8 mg/kg bw.

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:
28 Oct 1977 - 07 May 1980 (experimental start and termination)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with GLP
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Experimental Animal Breeding Institute, Sulzfeld
- Age at study initiation: 50 days
- Weight at study initiation: 183 grams (Males) and 157 grams (Females).
- Housing: 2 rats per cage
- Diet (e.g. ad libitum): Autoclaved standard pelletted feed (Eggersmann K.G., Rinteln)
- Water (e.g. ad libitum): tap water
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±10
- Air changes (per hr): 10-15 times
- Photoperiod (hrs dark / hrs light): 12/12


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
The liquid test substance was dosed continuously in an evaparator separately for each treatment group, evaporated from the surface of a high-grade steel element the hat end of which was maintained at about 120°C, and channeled into the inhalation chambers with a continuous stream of fresh air (0.3 to 3 m3/h) in high-grade steel pipes. Before entering the inhalation chamber, the test substance vapor was combined with the fresh air in the
chamber.



TEST ATMOSPHERE
- Brief description of analytical method used: Gas samples were obtained continuously from all inhalation chambers, and test substance concentration was measured in an approximately 60-min cycle either by a gas infrared photometer (Miran IA, CT, USA, wavelength 8.3 um, 2.25 m length cuvette) or by a total hydrocarbon flame ionization detector.
- Samples taken from breathing zone: yes


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The relative standard deviation of the daily mean test substance concentration was 3.2 to 7.4 % of the theoretical concentrations.
Duration of treatment / exposure:
2 years
Frequency of treatment:
6 hr/day, 5 days/week, for 24 months.
Post exposure period:
6 months
Remarks:
Doses / Concentrations:
0, 15, 45 and 135 ppm (corresponding to. 0; 0.0859; 0.258; 0.773 mg/L) from study month 4 to 24; 0, 5 and 45 ppm within the first 3 months of the study
Basis:
analytical conc.
No. of animals per sex per dose:
86
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS/ DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice on all exposure days and once weekly with special attention to grossly visible tumors (palpation with quantitative data collection). General condition, behavior, spontaneous activity, reactivity, reflexes, excrement, and body temperature were carefully evaluated. Survival was checked daily.


BODY WEIGHT: Yes
- Time schedule for examinations: once per week by individual weighing.


FOOD CONSUMPTION:
Food consumption of 2 rats each in a double cage was determined weekly for all rats.



OPHTHALMOSCOPIC EXAMINATION: Yes
Eye examinations were performed before all dissection times in all rats selected for dissection. The eye examinations consisted of an external evaluation, testing pupillary reflex to light, a comprehensive slit lamp examination of the anterior portion of the eye, and examination of the fundus with an eye mirror.


HAEMATOLOGY: Yes
Red and white cell counts were obtained in all rats terminated on schedule and in rats terminated when moribund. Further determinations of red and white cell counts were limited to rats in the control and high-dose groups. The following parameters were determined specifically:
red cell count, reticulocyte count, normoblast count, number of Heinz bodies, hematocrit, hemoglobin concentration, red cell volume, hemoglobin content and hemoglobin concentration in red cells, white cell count, and differential count.



URINALYSIS: Yes
The urine of all rats selected for dissection was analyzed before all dissection times. Urine was collected overnight (about 16 h) in metabolism cages with food and water available. The following were determined specifically: urine volume, color, and transparency, pH, protein concentration, glucose concentration, bilirubin concentration, urobilinogen concentration, ketone body concentration, occult blood, and other organized and unorganized sediments.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
After 12, 18, and 24 months of treatment, 10, 15 or 10 male and female rats per treatment group and after the subsequent 6-month follow-up period all surviving rats were terminated and dissected. Rats were terminated without preceding food deprivation. Body weight was determined after dissection by exsanguination from a retroorbital venous plexus under diethyl ether anesthesia.
All rats were thoroughly dissected under the guidance of the pathologist. 12 organs were weighed in male rats and 11 organs in female rats. 41 tissues from male rats were fixed in a 4 % neutralized formaldehyde solution and 42 tissues from female rats; testes were fixed in Bouin's solution. In addition, all grossly remarkable tissues were fixed in formalin.
Preparations of the nasal cavity, larynx, trachea, lungs, and liver were examined in all rats. After 12 and 18 months of treatment, an additional 26 or 27 different tissue samples were examined in at least 10 randomly selected male and female rats in the control and high-dose groups. In all rats dissected after 24 months of treatment, about 50 rats per dose and sex, 22 different tissue samples were examined in male rats and 25 in female rats. An additional 15 or 13 tissue samples were examined in at least 10 randomly selected male and female rats in the control and high-dose groups.
37 tissue samples were examined in male rats and 38 in female rats in all rats terminated when moribund or dying spontaneously. In addition, at least 1 preparation of each grossly remarkable tissue was evaluated.
All preparations were evaluated semiquantitatively by a pathologist. All tumors were classified and summarized by localization, biological behavior, histogenesis, degree of differentiation, and type of tumor.
Statistics:
The significance of differences between dosed and control group means was assessed using two-sided fiducial limit = 0.05 as the level of significance. No correction for multiple testing was performed. Mortality was analyzed using life-table method of Armitage (1971), after accounting for non-spontaneous deaths. The Student's t-test was used to analyze body weight gain, food consumption, organ weights, and all hematological parameters. Moribund rats were excluded from routine statistics. Histological observatiosn were analyzed using contingency tables of Sokal and Rohlf (1969). Tumors were classifed as "incidental" or "fatal" and then analyzed using the two-sided chi-square method of Peto (1980). Non-parametric tests were examined using Mann-Whitney (1947) or Pfanzagl (1978).
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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no compound related effects on general behavior or appearance; no overt signs of toxicity and no effects on mortality. All rats demonstrated a 20 % cumulative mortality rate at 24 months.


BODY WEIGHT AND WEIGHT GAIN: Body weight gain was normal in all groups, with only a slight decrease in food consumption in treated males and females.


FOOD CONSUMPTION: No compound related effect was observed.


OPHTHALMOSCOPIC EXAMINATION: Ophthalmology examinations demonstrated localized or diffuse stippling of the corneal epithelium, cloudiness of the cornea and various degrees of vascularization that increased with dose and duration of exposure. An increase in parenchymal damage with length of test substance exposure was demonstrated in rats in the high dose group. After 24 months of treatment, these changes occurred in about 30% of male and female rats in the high-dose group. The difference is statistically significant versus control. The frequency of findings in the low- and mid-dose groups was approximately similar to control. There was clear regression of parenchymal findings during the 6-month observation period. These changes appeared above all as reversible epithelial changes. Under the given conditions, 45 ppm was considered as the "no-effect level" for irreversible changes in the corneal parenchyma caused by n-butyl acrylate. The changes were attributed to the irritating properties of the test substance.


HAEMATOLOGY: There were no compound related effects on hematological measurement.


URINALYSIS: There were no compound related effects on urinalysis.


ORGAN WEIGHTS: Organ weights were generally uneffected by treatment, except for slightly lower relative heart, kidney, liver and thyroid weights at the highest dose.


GROSS PATHOLOGY: Apart from gross changes in eyes, no other compound related effects were observed.


HISTOPATHOLOGY: NON-NEOPLASTIC: A dose-related reserve cell hyperplasia in the transitional region between the respiratory and olfactory nasal epithelium, in part with loss of the functional epithelial component, occurred in all dose groups. Findings of very mild atrophy predominated in the low-dose group; atrophy and reserve cell hyperplasia with loss of olfactory and ciliated cells occurred in the mid-dose group, and reserve cell hyperplasia predominated in the high-dose group. Corneal opacification and vascularization occurred in addition at the highest dosage. These lesions were attributed to the irritating properties of the test substance. The changes in the nasal mucosa and cornea proved to be reversible up to a point in the follow-up period.


HISTOPATHOLOGY: NEOPLASTIC: No compound related neoplastic lesions were observed. The statistical evaluation of all neoplasms produced a significantly inhomogeneous frequency distribution in female rats with benign and malignant mesenchymal tumors and in male rats with sarcomas in the chest cavity and in female rats with soft-tissue fibrosarcomas. Since a dose relationship was not discernible in any case, these inhomogeneous frequency distributions are regarded as incidental.

Dose descriptor:
NOAEC
Effect level:
>= 0.773 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: No tumors were observed in rats receiving 135 ppm (0.773 mg/L) butyl acrylate via inhalation for 24 months.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
LOAEC
Effect level:
0.086 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Histological changes of the nasal mucosa
Remarks on result:
other: Effect type: toxicity (migrated information)

Butyl acrylate has an irritating effect in the area of transition between respiratory and olfactory epithelium in the nasal cavity and in the cornea. There were no indications of systemic toxicity of the test substance. No tumorigenic activity was determined for the test substance.

Based upon an examination of the histopathological findings, it was concluded that n-Butyl Acrylate was not carcinogenic to Sprague-Dawley rats when administered via inhalation in concentrations up to 135 ppm for 24 months.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
80 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
Study performed equivalent to OECD 453 and under GLP conditions

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable study report which meets basic scientific principles.
Principles of method if other than guideline:
Male C3H/HeJ mice (40 per group) were treated with 25 µl of 1% butyl acrylate (0.2 mg/animal/application) (corresponding to 8 mg/kg bw)* on the dorsal skin 3 times weekly for their lifetime
GLP compliance:
yes
Remarks:
(only QAU statement available)
Species:
mouse
Strain:
other: C3H/HeJ
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Jackson Laboratories, Bar Harbor, Maine
- Age at study initiation: 74-79 day
- Weight at study initiation: n-BA group: 21.7 - 27.6 g; vehicle control group: 20.1 - 27.7 g
- Housing: Groups of five in stainless-steel cages with wire-mesh floors. Because of an increase in early mortality, the mice were housed individually after 13 months of study.
- Diet: Zeigler Bros . pellets (Gardners Pa.), ad libitum
- Water: ad libitum



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): 25µl
- Concentration: 1% in acetone
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The weekly 1 % dilutions prepared for dosing were analyzed for content by gas liquid chromatography. The content of n-butyl acrylate ranged from 0.90 % to 1.29 % of n-butyl acrylate in acetone.
Duration of treatment / exposure:
entire lifetime
Frequency of treatment:
3 days/week
Post exposure period:
no post exposure
Remarks:
Doses / Concentrations:
0.2 mg/ animal per application (corresponding to approx. 8 mg/kg bw)
Basis:
nominal conc.
No. of animals per sex per dose:
40
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The concentrations were selected in preliminary 2-wk studies in which various concentrations of each substance were applied daily. The skin was closely observed for signs of irritation, and the mice were weighed so that their weight gain could be compared with that of acetone controls. At concentrations as low as 5.0%, n-butyl acrylate caused peeling and flaking of the skin. At 1.0% there were no adverse effects. Therefore, 1.0% was chosen as the "maximum tolerated concentration" for this study.

Positive control:
Positive control group consisting of 40 mice received 0.1 % 3-methylcholanthrene (MC).
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: Yes


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Mortality incidences were assessed by the product-limit method (Kaplan and Meier, 1958). The Mantel-Cox and Breslow statistics were used for testing the equality of the survival curves (Mantel, 1966; Breslow, 1970).
Kalpan and Meier, J. Amer. Statis. Assoc. 53: 457-481, 1958.
Mantel, N. Cancer Chemotherapy Reports, 50: 163-170, 1966.
Breslow, N. Biometrika, 57: 579-594, 1970.
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:
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: No significant difference in mortality rates was observed between the treated group and the acetone control group. The mean survival time of 503 days for butyl acrylate group did not differ significantly from that of the acetone control group (484 days).


BODY WEIGHT AND WEIGHT GAIN: No effects were observed.


GROSS PATHOLOGY: No skin tumors were observed in the groups treated  butyl acrylate or with acetone.


HISTOPATHOLOGY: NON-NEOPLASTIC: No histological lesions were observed except one animal had epidermal hyperplasia.

HISTOPATHOLOGY: NEOPLASTIC: No exposure related neoplastic changes were observed. One of the two masses observed grossly in the n-butyl acrylate treated group was diagnosed as a fibrosarcoma. While no skin tumors were observed in the acetone control group started concurrently with n-butyl acrylate, a similar acetone control group started approximately one month earlier was discovered to have a mouse bearing a fibrosarcome on the front leg. Consequently, the fibrosarcoma found in the n-butyl acrylate group cannot be attributed to the test compound.


Dose descriptor:
NOAEL
Effect level:
>= 8 mg/kg bw/day
Sex:
male
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Butyl acrylate was considered non-carcinogenic when applied to the skin of C3H/HeJ mice throughout their lifetime. In the positive control group, 39 tumor-bearing mice were observed.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
8 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
Acceptable study report which meets basic scientific principles and performed under GLP conditions.

Additional information

Inhalation:

In a 2-year inhalation study, Sprague-Dawley rats were exposed by whole body exposure 6 hours per day, 5 days a week to 0, 15, 45 or 135 ppm (corresponding to approx. 0, 0.086, 0.258, 0.773 mg/L/day) butyl acrylate. During the first 13 weeks of the study, the concentrations were lower: 0, 5, 15 or 45 ppm. The post observation period was 6 months. Results of the clinical, clinico-chemical, haematological, ophthalmological, gross pathological and histopathological examinations are described in section 7.5, Repeated dose toxicity. Butyl acrylate showed no carcinogenic effect up to the highest concentration tested of 135 ppm (0.773 mg/L/day) (BASF AG 1985).

Dermal application:

A lifetime dermal carcinogenesis study was conducted in mice (BASF AG 1982). The dermal carcinogenic potential of butyl acrylate was assessed by applying 25 µL of a 1% (v/v) dilution in acetone (corresponding to approx. 8 mg/kg bw) to the backs of 40 male C3H/HeJ mice. A negative control group receiving acetone was dosed simultaneously. Both applications were performed three times a week throughout the lifetime of the animals. No biologically significant skin tumours were observed in the group tested with acetone or in the butyl acrylate group. No signs of skin irritation were observed in this study. No significant difference in mortality rate was observed between the treated group and the acetone control group. Butyl acrylate was not carcinogenic when applied to the skin of C3H/HeJ mice throughout their lifetime.

Conclusion

Butyl acrylate was not carcinogenic in an adequately performed 2-year inhalation study in Sprague-Dawley rats up to the highest tested dose (135 ppm = 0.773 mg/L) and in a lifetime skin painting study in C3H/HeJ mice at approx. 8 mg/kg bw.

This conclusion is in line with the IARC evaluation. The expert committee concluded that Butyl acrylate is not classifiable with regards to carcinogenicity to humans (Group 3).

Justification for classification or non-classification

CLP classification (Regulation (EC) No 1272/2008):

no classification required