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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
methaemoglobinaemia
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Old study, but correctly discribed and important in MetHb induction comparing animals and human, and isomers for induction. Publication in french, only summary in english.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Action Methemoglobinisante de Dérivés Trifluorométhyles de la Phenyl-3 Oxazolidinone-2.
Author:
Sergant M, Gouret C, Raynaud G, Delatte G
Year:
1969
Bibliographic source:
Proc. Eur. Soc. Study Drug Toxicity Vol. 11, pp. 212-221.
Reference Type:
secondary source
Title:
SIDS Initial Assessment Report for SIAM 13 (o-nitroaniline) November 6-9, 2001 Bern, Final July 2003.
Author:
OECD SIDS
Year:
2003
Bibliographic source:
UNEP Publications

Materials and methods

Principles of method if other than guideline:
The production of methemoglobin was studied in dogs with aniline, and p-,m-, and o-trifluoromethylaniline. The products were administered twice at 24-hour intervals. The levels of methemoglobin and sulfhemoglobin were measured 24 hours after the second administration.
GLP compliance:
no
Type of method:
in vivo
Endpoint addressed:
repeated dose toxicity: oral

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
no data

Test animals

Species:
dog
Strain:
other: bastard
Sex:
male/female

Administration / exposure

Route of administration:
oral: capsule
Vehicle:
not specified
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 oral administrations at 24 h intervals
Frequency of treatment:
two times
Post exposure period:
72 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
27.5, 55, and 110 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
no data
Control animals:
yes

Examinations

Examinations:
Blood was taken by punction of the cephalic vein adding heparin before administration of the products and 24 hr after the last administration.
MetHemoglobin (MetHb) and SulfHemoglobin (SHb) determination was conducted according to described methods (Evelyn & Malloy 1938, De Traverse et al 1961). MetHb was transformed in CyanHb and optical density difference was measured by suppressing the characteristic absorption of Hb at 635 μm. SulfHb was measured by residual optical density at 620 μm after conversion of Hb and MetHb in CyanHb. Total Hb was measured with Rabkin reagent following the method described by Crosby et al. (1957).

Evelyn & Malloy (1938). J. biol. Chem. 126: 655
De Traverse et al. (1961). Ann. Biol. Clin. 3-4: 303
Crosby et al. (1957). Blood 12: 1132

Results and discussion

Any other information on results incl. tables

The trifluoromethyl-aniline isomers (o-m-p TFMA) were used at 110, 55 or 27.5 mg/kg bw and aniline at doses of 15, 30, and 100 mg/kg bw in dogs, respectively.

After the first administration of para-TFMA, a rapid rise in MehHB (50% at 1h30) was observed in the test animal and the animal died within hours. Then the other isomers were only administered at 2 x 55 mg/kg bw. At this dose MetHb was: para-TFMA: 50%; meta-TFMA: 30%; ortho-TFMA: 1%.

Administration of aniline at 2 x 100 mg/kg bw resulted in 50% MetHb.

 

Thus, para-TFMA was a more potent MetHb inducer than aniline, while meta-TFMA was a weaker inducer and ortho-TFMA not inducing.

Applicant's summary and conclusion