Registration Dossier

Administrative data

Endpoint:
carcinogenicity
Remarks:
implantation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1969
Report Date:
1969

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
In dogs, a wound was created in the liver, kidney, femoral artery or small bowel. Hemostasis or anastomosis was accomplished by cyanoacrylate monomer spray using nitrogen or Freon as a propellant.
In rats and mice, under general anesthesia a 3 cm incision was made at the upper abdomen, and the peritoneum was entered. In some animals 0.5 cc. of cyanoacrylate monomer was sprayed into the abdominal cavity on the surface of the liver.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
dog
Strain:
other: mongrel
Sex:
not specified
Details on test animals and environmental conditions:
weight of the dogs: 11 to 28 kg
They also used rats:
Strain: Walter Reed
Weight: 180 -210 g
Age: 10 months
And they used mice:
Strain Wlater Reed
Weight: 19-20 g
Age: 10 months

Administration / exposure

Route of administration:
implantation
Vehicle:
other: nitrogen and Freon
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
single exposure
Post exposure period:
All animals were examined and autopsied when they died.
20 dogs were sacrified and auotopsied at 12 to 18 months.
All rats of the first generation were sacrified and autopsied at hte end of one year.
All mice were autopsied at the end of 12 months.
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5 ml
Basis:
other: implanted
No. of animals per sex per dose:
50 dogs per dose, 100 rats per dose, 100 mice per dose
Details on study design:
In dogs, a wound was created in the liver, kidney, femoral artery or small bowel. Hemostasis or anastomosis was accomplished by cyanoacrylate monomer spray using nitrogen or Freon as a propellant.
In the rat, under general anesthesia with ether the abdomen was prepared with merthiolate. A 3 cm incision was made at the upper abdomen, and the peritoneum was entered. In some animals 0.5 cc. of cyanoacrylate monomer was sprayed into the abdominal cavity on the surface of the liver using nitrogen spray gun or by means of aerosol spray. The abdominal wound was closed with metal clips. Essentially the same procedures were followed in mice.
The animals were divided into three groups:
Group I = 50 dogs
Group II = 100 rats
Group III = 100 mice
Group I was further diveded into 3 subgroups according to the monomer used:
Subgroub 1 = n-butyl cyanoacrylate with spray gun (20 dogs)
Subgroup 2 = isobutyl cyanoacrylate with spray gun (20 dogs)
Subgroup 3 = aerosol n-butyl spray (10 dogs)

Each of Group II and III further divided into seven subgroups:
Subgroup 1 = n-butyl cyanoacrylate with spray gun ( 10 animals)
subgroup 2 = isobutyl cyanoacrylate with spray gun (10 animals)
Subgroup 3 = aerosol n-butyl spray (20 animals)
Subgroup 4 = aerosol isobutyl spray (20 animals)
Subgroup 5 = Freon (10 animals)
Subgroup 6 = Freon 114 (10 animals)
Subgroup 7 = Mixture of Freon 12 and 114 (20 animals)

At six months after surgery 16 pairs of male and female rats in subgroup 3 and 4 were kept in 16 individual cages and 5 rats of second generation born to each of 16 pairs (total of 80 rats) were kept and observed for possible abnormal development.

Examinations

Observations and examinations performed and frequency:
All animals were routinely examined and autopsied when they died. Twenty dogs were sacrifired and auutopsied at 12 to 18 months. All rats of the first generation were sacrified and autopsied at the end of one year after surgery and abdominal cavity was examined. A piece of liver was obtained for microscopic study.
Half of the total number of rats in the second generation were autopsied and the same examiantions were performed at 6 months.
All mice were autopsied at the end of 12 months after surgery.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)

Results and discussion

Results of examinations

Details on results:
Dogs:
In the 50 dogs studied, three were eliminated from the study in the acute phase. At autopsy, gross and microscopy findings were similar at each site of adhesive application. Adhesives, often very dense, were noted. On the surface of the organs, particulary the liver or the kidney, polymer fragments were seen. some polymer had been extruded from the depths of the organs. In blood vessels and kidney specimens, some material was occasionally seen in the lumens. On microscopic examination small particles of polymer, 10 to 50 u, were seen implanted in the tissue. These particles were surrounded by a granulomatous reaction with giant cells. No changes suggestive of neoplasm were seen. No tumor foramtion or mitotic change of cells was noted in any of the animals. 27 dogs are being kept for a longer period.
Rats:
Six rats in the first generation died in 10 to 12 months after surgery. These rats appeared to be very old and senile. Four rats died with pneumonia and two died without pathological findings.
No death was noted and no evidence of tumor formation was found due to the monomer or Freon in all rats sacrified at the age of 22 months.
No pathologic development was found in 80 rats of the second generation.
Mice:
No mice died spontanously. Autopsy finding of these animals and others sacrified one year after surgery revealed no evidence of tumor formation exept scattered adhesions of omentum and liver in which easily removable small amounts of polymer fragments were seen.
Microscopic findings of examined liver revealed no pathologic findings.
Relevance of carcinogenic effects / potential:
The test substances have no carcinogenic potential.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks on result:
not determinable
Remarks:
no NOAEC identified
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
T25
Remarks on result:
not determinable
Remarks:
no T25 identified

Applicant's summary and conclusion

Conclusions:
In this study n-butyl cyanoacrylate and isobutyl cyanoacrylate was tested.
No tumor formation, either gross or microscopic, was seen in a series of dogs studied up to 2 years.
Similar results were found in rats and mice, as well as in the following generation of rats born to treated animals.
27 dogs still alive show no symptoms or evidence of tumor formation at that time.
Executive summary:

Aim of study

The aim of this study was to investigate possible carcinogenic effects by the test substances following a implantation.

Administration of the test substance

In dogs, a wound was created in the liver, kidney, femoral artery or small bowel. Hemostasis or anastomosis was accomplished by cyanoacrylate monomer spray using nitrogen or Freon as a propellant. In rats and mice, under general anesthesia a 3 cm incision was made at the upper abdomen, and the peritoneum was entered. In some animals 0.5 cc. of cyanoacrylate monomer was sprayed into the abdominal cavity on the surface of the liver.

Investigations:

The animals were investigated up to 2 years.

Results

No tumor formation, either gross or microscopic, was seen in a series of dogs studied up to 2 years. Similar results were found in rats and mice, as well as in the following generation of rats born to treated animals. 27 dogs still alive show no symptoms or evidence of tumor formation at that time.

The test substances n-butyl cyanoacrylate and isobutyl cyanoacrylate have no carcinogenic potential.