How Much? 2-Ethylhexanoic Acid Limits

March 14th, 2014 Leave a reply »

Salts of 2-ethylhexanoic acid, inexpensive carriers of the sodium or potassium ion, have been used to make salts of carboxylic acids, such as fosinopril sodium and sodium clavulanate. Limits should be set for residual impurities such as 2-ethylhexanoic acid in APIs. The toxicity of 2-ethylhexanoic acid must be reviewed in order to set realistic limits, especially since developing highly sensitive assays can consume considerable effort [1].

CAUTION: 2-ETHYLHEXANOIC ACID IS A TERATOGEN AND REPRODUCTIVE TOXIN. WOMEN ESPECIALLY MUST TAKE SUITABLE PRECAUTIONS TO MINIMIZE CONTACT WITH THIS COMPOUND AND ITS SALTS. This SAFETY information should be made available to everyone, including chemists, QA, QC, and operators, who handles 2-ethylhexanoic acid and its salts.

Some people have avoided using 2-ethylhexanoic acid because of a reputation for being highly toxic. The question is: How Much? How toxic is it? BG Chemie has manufactured 2-ethylhexanoic acid, and stated in 2000 that it has “low acute oral toxicity (LD50 rat oral 2043 to 3640 mg/kg body weight)” [2]. An EPA report in 2001 [3] described toxicity to rat embryos and fetuses with high dosing, referencing a 1987 report. The latter stated that valproic acid (2-propylpentanoic acid, isomeric to 2-ethylhexanoic acid) was about twice as potent to rat embryos and fetuses as 2-ethylhexanoic acid [4]. (Valproic acid is marketed generically as an anticonvulsant and mood stabilizer. The starting dosage for sodium valproate is 600 mg/day, increasing up to 1000 – 2000 mg/day. Contraindications are listed for women taking this drug [5].) The EPA report also cited a 1993 report that mentioned that effects on reproduction and post-natal development in rats were seen with high doses [6]. 2-Ethylhexanoic acid was examined on a cellular level in 2005 and found to increase the incidence of sister chromatid exchange [7]. In a 1998 study 2-ethylhexanoic acid was shown to be a weak embryotoxic compound in male rats and mice, and the NOEL (no observable effects limit) was 60 mg/kg [8]. A 2005 study showed that 2-ethylhexanoic acid was toxic to pregnant rabbits, and the NOEL was determined to be 25 mg/kg [9]. 2-Ethylhexanoic acid has no functional groups alerting for mutagenicity, and tested negative in vitro for mutagenicity [9]. Female mice developed some liver cancers when exposed to 2-ethylhexanol, which can be oxidized in vivo to 2- ethylhexanoic acid, and the TD50 was calculated at 1650 mg/kg/day [10]. In a study with rats in which 2-ethylhexanoic acid was administered orally, 7 – 12% of 14C-labelled 2-ethylhexanoic acid was detected in the feces, indicating that about 90% of 2-ethylhexanoic acid was orally absorbed [11].

Several approaches could be taken to set permissible daily exposure (PDE) limits for residual 2-ethylhexanoic acid in drug candidates. One could propose that the PDE limit should be the same as for residual 2-ethylhexanoic acid in clavulanate, thus minimizing discussions with regulatory authorities. Another, sound approach is to calculate a limit for 2-ethylhexanoic acid based on toxicology data and applying the calculations discussed in ICH Q3C (R5) [12]. Using those calculations, the PDE limits for a 50 kg patient are calculated at 12 mg/day from the study in rats and mice (F1, F2, F3, F4, F5 = 5, 10, 5, 1, 1), and 50 mg/day from the study in rabbits (F1, F2, F3, F4, F5 = 2.5, 10, 1, 1, 1). The more conservative approach would be to propose the lower limit, a PDE of 12 mg/day for a 50 kg patient, for a drug substance administered orally. For other means of administration a limit could be proposed at 90% of the oral dosing, or 10.8 mg/day.

The toxicity of residual 2-ethylhexanoic acid and its salts should of course be acknowledged in reviews with the FDA and other regulatory authorities. Dionex has developed a procedure to quantitate residual 2-ethylhexanoic acid, which may be better than the USP assay for 2-ethylhexanoic acid in clavulanate [13].

Many thanks to Dr David Snodin for his helpful comments.

1. Snodin, D. J. Org. Process Res. Dev. 2014, 18, XXXX (doi.org/10.1021/op5000368)
2. http://www.bgrci.de/fileadmin/BGRCI/Downloads/DL_Praevention/Fachwissen/Gefahrstoffe/TOXIKOLOGISCHE_BEWERTUNGEN/Bewertungen/ToxBew275-E.pdf (2000)
3. http://www.epa.gov/hpv/pubs/summaries/metalcarb/c14172rr12.pdf
4. E. J. Ritter, E. J.; W. J. Scott, W. L., Jr., Randall, J. L.; Ritter, J. M. Teratology 35(1), 46 (February 1987).
5. http://www.medicines.org.uk/emcmobile/medicine/26115/spc
6. Pennanen, S.; Tuovinen, K.; Huuskonen, H.; Kosma, V. M.; Komulainen, H. Fundam Appl Toxicol. 1993 Aug;21(2), 204.
7. Song, J.-Y. ; Cho, Y.-H. ; Kim, Y.-J. ; Chung, H.-W. Environmental Mutagens and Carcinogens 2005, 25(3), 110.
8. Juberg, D. R., et al., 1998; see http://www.contactalimentaire.com/fileadmin/ImageFichier_Archive/contact_alimentaire/Fichiers_Documents/Avis_de_AESA/cef_ej959-963-966-968_22list_op_en.pdf
9. http://www.vkm.no/dav/c067aa526e.pdf (Norwegian Scientific Committee for Food Safety)
10. http://toxnet.nlm.nih.gov/cpdb/chempages/2-ETHYLHEXANOL.html
11. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@DOCNO+5649
12. http://www.gmp-compliance.org/guidemgr/files/Q3C_R5_STEP4.PDF
13. http://www.dionex.com/en-us/webdocs/88443-AN262-IC-2EthylhexanoicAcid-Clavulanate-01Oct2010-LPN2608-R2.pdf

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