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Endpoint:
basic toxicokinetics
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
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
Objective of study:
other: absorption and degradation
Qualifier:
no guideline followed
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
14C
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.
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
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
Preliminary studies:
not applicable
Type:
absorption
Results:
MCA / intact oral mucosa: approx. 1 % per day (urine)
Type:
absorption
Results:
BCA / intact oral mucosa: max. 0.1 % per day (urine)
Type:
other: degradation
Results:
MCA polymer powder / stomach: approx. 15.9 % total (urine)
Type:
other: degradation
Results:
BCA polymer powder / stomach: approx. 2.2 % total (urine)
Type:
excretion
Results:
MCA polymer powder / stomach: approx. 17.8 % total (stool)
Type:
excretion
Results:
BCA polymer powder / stomach: approx. 73.1 % total (stool)
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"
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) testing results:
not applicable

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

Conclusions:
Interpretation of results: 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.

Description of key information

Alkyl 2-cyanoacrylates such as ethyl 2-cyanoacrylate (ECA) are known to polymerize rapidly in the presence of water. Even the moisture in the surrounding, e. g. on the skin or in ambient air, is sufficient to start the polymerization process. As described by Krall et al., alkyl 2-cyanoacrylates "polymerize on and adhere to moist living tissues" (Krall, 1983). This effect triggered also the use of this substance class as tissue adhesives in medical applications.

Within seconds, a significant amount of the original ECA monomer forms a hardened mass. The speed of polymerization was analyzed by calorimetry measurements and ATR FT-IR spectroscopy, showing polymerization times of seconds to minutes, depending on the specific test condition. The formation of the polymer in the stomach after application via gavage was also described in the acute oral toxicity studies with ECA (see also chapter 'acute toxicity'). This intrinsic property to polymerize in the presence of water limits the absorption of cyanoacrylates via all three routes (oral, dermal, inhalation).

Nevertheless, absorption after oral or dermal application was shown for acryl 2-cyanoacrylates in animal studies (Nordic Expert Group, 1997). It seems that over time, a part of the polymerized acryl 2-cyanoacrylate is being absorbed, probably due to degradation of the polymer. The absorption rate of MCA applied to oral rat mucosa was similar to that known for implanted MCA, i. e. approximately 1% per day (Ousterhout et al, 1969). So far, no information is available regarding absorption after inhalation or via the dermal route.

In comparison to the butyl 2 -cyanoacrylate (BCA) polymer, the percentage excreted via urine was much higher for the MCA polymer, indicating a faster turnover for MCA. Ousterhout et al. concluded that hydrolytic degradation of alkyl 2-cyanoacrylates could be the underlying mechanism, resulting in alkyl 2-cyanoacetate and formaldehyde (Ousterhout et al., 1969).

Compared to other alkyl 2-cyanoacrylates, MCA seems to be eliminated most rapidly (Nordic Expert Group, 1997). After application of MCA polymer via gavage, 33.7% of the original radioactivity was excreted within four days (urine: 15.9%, stool: 17.8%). On day four, the lowest excretion rate (0.1% for urine, 0.1% for stool) was observed (Ousterhout et al., 1969). The WHO suggested that 'the detection of radiolabel in the stool samples may well reflect the passage of poly-MCA particles directly through the gastrointestinal tract rather than any absorption and metabolism' (WHO, 2001).

After implantation of14C-labelled acryl 2-cyanoacrylates under the skin of guinea pigs, radioactivity was detected in different organs, but decreased to base levels again. Other studies with rats did not detect radioactivity in organs, muscles or fat (Nordic Expert Group, 1997). Therefore, a bioaccumulation potential of ECA is not expected based on polymerization data and analogy to other cyanoacrylates.

References:

Krall R. E., Neuwirth R. S. and Richart R. M., Pharmacology and Toxicology of Methyl Cyanoacrylate, Fem. Transcervic Steril., Proc. Int. Workshop, 1983, pp175 -185

Nordic Expert Group, Scientific Basis for Swedish Occupational Standard XVIII - Consensus Report for Cyanoacrylates, Arbete och Hlsa, 25, 1997, pp. 17 -28

Osterhout D., Gladieux G. V., Wade C. W. R., Margetis P. M. and Leonard F., Digestive tract absorption of alkyl alpha-cyanoacrylate-beta-14C, O. S., O. M. & O. P., Vol. 27, No. 3, 1969, pp. 410-416

World Health Organization, Methyl Cyanoacrylate and Ethyl Cyanoacrylate, Concise International Chemical Assessment Document (CICAD) 36, Geneva, 2001; including corrigenda published by 12 April 2005

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information