Mecrilate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

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

Materials and methods

Objective of study:

other: absorption and degradation

Test guideline

Qualifier:

no guideline followed

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Mecrilate

EC Number:

205-275-2

EC Name:

Mecrilate

Cas Number:

137-05-3

Molecular formula:

C5H5NO2

IUPAC Name:

methyl 2-cyanoprop-2-enoate

Test material form:

other: liquid (Part 1) or polymerized powder (Part 2)

Details on test material:

- Part 1: radioactive methyl α-cyanoacrylate (MCA, 18.4 x 10E6 dpm/mL) or n-butyl α-cyanoacrylate (BCA, 14.9 x 10E6 dpm/mL)
- Part 2: radioactive methyl α-cyanoacrylate polymer powder (21.8 x 10E6 dpm/g) or n-butyl α-cyanoacrylate polymer powder (18.3 x 10E6 dpm/g)

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

not specified

Details on test animals or test system and environmental conditions:

- Part 1: Rats weighing approx. 375g were placed singly in limited-motion metabolic cages. Hydration was maintained, during the period of the study, with subcutaneous and intraperitoneal injections of sterile normal saline solution (no feeding).
- Part 2: Rats weighing approx. 425g were placed singly in limited-motion metabolic cages and allowed to eat and drink ad libitum.

Administration / exposure

Route of administration:

other: Part 1: oral mucosa / Part 2: oral feeding tube

Vehicle:

other: Part 1: unchanged (no vehicle) / Part 2: vegetable oil

Details on exposure:

- Part 1: liquid application of test material on intact oral mucosa of the cheeks (ligated esophagus)
- Part 2: placement of polymer powder with vegetable oil as a vehicle in the stomach using a size 8 French feeding tube

Duration and frequency of treatment / exposure:

- Part 1: 2 days, single application
- Part 2: 4 days, single application

Doses / concentrations

Remarks:

Doses / Concentrations:
- Part 1: 0.05 mL of methyl α-cyanoacrylate-ß-14C or n-butyl α-cyanoacrylate-ß-14C
- Part 2: 100 mg of polimerized powder of methyl α-cyanoacrylate-ß-14C or n-butyl α-cyanoacrylate-ß-14C

No. of animals per sex per dose / concentration:

- Part 1: total 4, 2 for each substance
- Part 2: total 4, 2 for each substance

Control animals:

no

Positive control reference chemical:

no

Details on study design:

see "any other information on materials and methods"

Details on dosing and sampling:

see "any other information on materials and methods"

Statistics:

no data

Results and discussion

Preliminary studies:

not applicable

Main ADME results

Main ADME results 1

Type:

absorption

Results:

MCA / intact oral mucosa: approx. 1 % per day (urine)

Main ADME results 2

Type:

absorption

Results:

BCA / intact oral mucosa: max. 0.1 % per day (urine)

Main ADME results 3

Type:

other: degradation

Results:

MCA polymer powder / stomach: approx. 15.9 % total (urine)

Main ADME results 4

Type:

other: degradation

Results:

BCA polymer powder / stomach: approx. 2.2 % total (urine)

Main ADME results 5

Type:

excretion

Results:

MCA polymer powder / stomach: approx. 17.8 % total (stool)

Main ADME results 6

Type:

excretion

Results:

BCA polymer powder / stomach: approx. 73.1 % total (stool)

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The mechanism of absorption of cyanoacrylate applied to intact oral mucosa (Part 1) is not known.

Details on distribution in tissues:

Not in the scope of the study.

Details on excretion:

see "any other information on results"

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

The hydrolytic degradation of cyanoacrylate has been reported (J. Appl. Polym. Sc. 10, 259-272, 1966). During hydrolytic degradation, water molecules are randomly added to the polymer chain at the beta carbon atoms, which then degrades to a polymer fraction (ultimately alkyl cyanoacetate) and formaldehyde. If the monomer has carbon-14 in the beta position, much of the carbon-14 is ultimately found in urine as urea-14C, a product of formaldehyde metabolism.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

not applicable

Any other information on results incl. tables

PART 1

The radioactivity of urine, representing carbon-14 oral absorption from MCA or BCA monomer polymerized on intact oral mucosa, was determined as shown in Table 1.

TABLE 1: % of original radioactivity counted in urine

rat no. / test material	day 1	day 2	total
1 / MCA	1.1	1.1	2.2
2 / MCA	1.0	0.4	1.4
average / MCA	1.1	0.8	1.8
3 / BCA	0.1	0.1	0.2
4 / BCA	no	no	no
average / BCA	0.1	0.1	0.1

PART 2

MCA or BCA polymer powder was placed in the rat's stomach and the carbon-14 radioactivity of urine and stool was determined. The urine radioactivity represents polymer degradation, while the stool carbon-14 activity probably represents primarily undegraded polymer.

The data from this portion of the study are shown in Table 2.

The hydrolytic degradation rate of MCA is relatively fast when compared to BCA, therefore only a small percentage of radioactivity from MCA has been found in the stool, compared to BCA, while a large percentage of radioactivity from MCA has been obtained in the urine, compared to BCA.

The 4 days of stool collection seem to be adequate in view of the lack of low level of radioactivity in the stools and urine on the fourth day of collection and the report that the gastrointestinal clearance time in the rat is approximately 3 days.

TABLE 2: % of original radioactivity delivered to stomach

rat no. / test material / sample	day 1	day 2	day 3	day 4	total
5 / MCA / urine	5.7	2.8	0.6	0.1	9.2
6 / MCA / urine	9.4	11.5	1.7	no	22.6
average / MCA / urine	7.6	7.2	1.2	0.1	15.9
7 / BCA / urine	1.8	no	no	no	1.8
8 / BCA / urine	2.1	0.3	0.1	no	2.5
average / BCA / urine	2.0	0.2	0.1	no	2.2
5 / MCA / stool	2.5	8.0	0.4	no	10.9
6 / MCA / stool	0.6	20.2	3.6	0.2	24.6
average / MCA / stool	1.6	14.1	2.0	0.1	17.8
7 / BCA / stool	80.4	7.5	0.7	0.4	89.0
8 / BCA / stool	28.3	21.7	5.1	2.1	57.2
average / BCA / stool	54.4	14.6	2.9	1.3	73.1

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: Because of limited oral absorption and fast degradation, a low bioaccumulation potential is assumed.
When MCA monomer was applied to the oral mucosa of rats, the absorption rate of 1%/day corresponded to the rate of degradation that is known for implanted MCA. After application of MCA polymer via gavage, degradation occured, and 33.7% of the original radioactivity was found in the urine and the stool within four days.

Executive summary:

Absorption and assimilation of methyl- and n-butyl α-cyanoacrylate-ß-¹⁴C was evaluated in the digestive tract of the rat. By evaluating the urine for carbon-14, it was demonstrated that there is absorption of monomer and/or polymer degradation products of cyanoacrylate when applied as a monomer and allowed to polymerize on the oral mucosa.

It was also demonstrated that if these materials in polymer form were to be inadvertently swallowed, degradation and assimilation of a significant percentage of the polymer would occur.