Why is 1 hexane wrong

26. n-hexane
(CAS No .: 110-54-3)

(BArbBl. 11/97 p. 58)

Reproductive toxicity / fertility:

To assess a possible impairment of fertility, more recent studies are available that include the mating period; In addition, studies are also used in which tests were carried out with regard to testicular toxicity:

In a 1-generation study (1986; [1]) on Sprague-Dawley rats premating with 100, 500, 1,500 ppm commercial hexane (n-hexane content 52%) with 6 h / d over 7 d / w for 100 days or 15 days mating period, the NOAEC was given by the authors as 1,500 ppm (5.3 mg / l). Neither an impairment of fertility nor of the reproductive organs were found.

In a new 2-generation study (1994; [3]) that meets today's requirements, rats were exposed to 900, 3,000 and 9,000 ppm commercial hexane (n-hexane content 52%). In addition to the first signs of toxic effects (reduction in body weight) in the highest dose group (3 1.7 mg / l), neither impairment of the reproductive parameters nor of the reproductive organs were found.

Compared with this test, which was carried out and fully reported according to the methods currently in force, the tests by Nylén et al. 1989 [4] published studies because of considerable methodological deficiencies and incomprehensible reporting practically worthless: Groups of 12 or 18 male Sprague-Dawley rats weighing 250 to 300 g (consequently too heavy and thus too old) were 21 or 18 hours per Exposure to concentrations of 986 ± 55 or 999 ± 29 ppm n-hexane for day 28 or 61 days. The exposure time is far too high compared to the norm of 6-8 hours per day because it does not allow a detoxification phase. No rats were examined at the end of exposure, but incomprehensible sub-populations of the originally exposed rats were, as far as understood, killed 2 weeks, 10 months and 1 year later and examined macroscopically, microscopically, immunohistochemically and endocrinologically. Both normal findings and various types of testicular damage were found. The various types of damage did not result in a plausible damage pattern, nor is it clear how the controls that were supposedly examined looked like. Since the rat testes are known to have a high residual capacity and regenerative capacity, acceptable statements can only be made if the incidences are compared in sufficiently large populations of exposed and control animals. Just like the description of the damage, the information that 2 out of 3 rats exposed to n-hexane were tested for fertility and found to be fertile cannot be used for a well-founded assessment because the number of rats is far too low. The findings of this frequently and, above all, frequently incorrectly cited work are therefore irrelevant in comparison to the generation experiments described above.

In a dominant lethal test on CD-1 mice, no impairment of male or female fertility was found after exposure to 100 and 400 ppm (0.35 or 1.4 mg / l) for 6 h / d, 5 d / w observed over 8 weeks with a mating period of 2 weeks (1980; [2]).

Studies with repeated application with a view to assessing testicular toxicity are listed below. In some cases, testicular damage was only observed under extreme exposure conditions with regard to the daily exposure time or the amount administered:

De Martino et al. (1987; [5]) report severe testicular and epididymal damage in Sprague-Dawley rats after exposure to 5,000 ppm (17.6 mg / l) for 16 hours / day, 6 days / week up to

6 weeks; the daily intake would be 11,260 mg / kg with 100% absorption (calculated for respiratory volume 0.2 l / min and 300 g body weight). In terms of general toxicity, significant growth impairment (... "average reduction in body weight ranging from 20 to 30% from the first to the sixth week of treatment") and a 30% reduction in feed consumption, and clinical symptoms of polyneuropathy were described. hourly exposure to 5,000 ppm also had a spermatotoxic effect; however, this effect was reversible after 30 days.

Howd et al. (1983; [6]) exposed Fischer-344 rats (21 or 80 days old) for 24 hours, initially for 4 weeks continuously, then for a further 7 weeks 24 hours a day over 6 days a week to 1,000 ppm (3.52 mg / l). In addition to significantly reduced testis weights (without histopathological findings), polyneuropathy, mortality (up to 50% in the older animals) and reduced body weight gain (46 and 67% of the body weight of the controls); in addition, reduced absolute liver and kidney weights were recorded. The observed effect on the testes was related to severe effects of general toxicity.

In the study by Nylen ([4]; see above), significant testicular atrophy and effects on the heads of the spermatozoa and the epididymis (occasionally hypertrophic epithelium) were found in 18 or 21 h / d over 61 days compared to animals exposed to 1,000 ppm after 10) and 14 months and no or few spermatozoa).

In a comparative neurotoxicity study (1980; [11]) in CD rats with n-hexane metabolites, after 90 days of administration (gavage) over 5 days / week of 1,140 mg / kg both with n-hexane and with "practical grade "-hexane (n-hexane content 40%) in the histological testicular examination no effects were found. While no damage was observed with “practical grade hexane even at 4,000 mg / kg (1,600 mg / kg pure hexane), atrophy of the germinative epithelium occurred at 4,000 mg / kg pure hexane -Hexane administration had a lesser effect on the germinal epithelium than did the other compounds; It was also stated: "comparisons of the severity of this effect were not made in this study because this change was time-dependent and a time to onset of atrophy was not controlled". In addition to neuropathy, reduced body weight gains from the 3rd week onwards were described with the two doses mentioned.

In a Japanese study (Kurita. 1974; [12]), Wistar rats were exposed after 20 weeks. 6 d / w, compared to 2.99 mg / l n-hexane, "slight congestion in the testes" was described. Further details regarding purity of the substance. daily exposure time and other methodological details are not available, so that an assessment is not possible.

No testicular damage was observed in the following studies:

The 5 times administration of 10,000 mg / kg (daily 5,000 each morning and afternoon) to Sprague-Dawley rats gave no evidence of spermatotoxic effects or damage to the male reproductive organs after 3 and 13 days (1992; [7]).

In two studies (API, 1983; [8] and DeGroot and Kepner, 1984; [8]), Wistar and CD rats were exposed to a maximum of 900 ppm for 18 months. No effects on the testes were reported (further details are not available).

Fischer 344 rats showed no testicular damage in the macroscopic and histological examination after exposure for 6 h / d, 5 d / w for 13 weeks to 3,000 - 10,000 ppm (1984; [9]).

In more recent carcinogenicity studies, rats and mice were exposed to 900, 3,000 and 9,000 ppm commercial hexane (n-hexane content 52%) for 6 hours a day, 5 days a week (1995; [10]). In addition to the observed impairment of body weight gain, especially at the highest dose of 9,000 ppm (31.7 mg / l), no effects on the testes in rats and mice were found.

A comparative evaluation of the studies with regard to testicular toxicity suggests that, in addition to the absolute level of the dose / concentration, the duration of exposure per day plays a decisive role. Thus, an effect can only be seen in animals without the possibility of detoxification.


In one- and multi-generation studies with high concentrations (rats) and a DL test on mice, neither impairment of fertility nor of the male or female reproductive organs were found. Subchronic / chronic examinations with the exposure times specified in the test guidelines also showed no damage to the testes, even in very high concentrations up to lifetime exposure. The testicular damage observed in some studies with unusual exposure times at high concentrations did not occur "in a dose range without the presence of other toxic effects"; the equivalent for the daily intake in these studies was well above the limit dose of 1,000 mg / kg / day provided for the oral route of administration. According to the EU classification criteria, there is therefore no classification with regard to reproductive toxicity / fertility (RF.-).


EU dossier Hexanes, WO20, Danish Toxicology center, December 22nd, 1994

[1] American Petroleum Inst. Report 33-32864. A single generation inhalation reproduction / fertility study on commercial grade hexane; 1986.

[2] API (American Petroleum Institute): Mutagenicity evaluation of n-hexane in the mouse dominant lethal assay. Submitted by Litton Bionetics Inc., LBI Project No. 21 141-0l (1980)

[3] Daughtrey et al .: Twogeneration reproduction study on commercial hexane solvent.

[4] Journal of Applied Toxicology 14, 487-393 (1994)

[5] Nylen et al .: Testicular atrophy and loss of nerve growth factorimmunoreactive germ cell line in rats exposed to n-hexane and a protective effect of simultaneous exposure to toluene or xylene. Arch. Toxicol. 63: 296-307 (1989)

[6] de Martino et al .: Effects of respiratory treatment with n-hexane on rat testis morphology. Experimental and Molecular Pathology 46, 199-216 (1987)

[7] Howd et al .: A comparison of the rates of development of functional hexane neuropathy in weanling and young adult rats. Neurobehavioural Toxicology and Teratology 5, 63-68 (1983)

[8] Linder et al .: Endpoints of spermatotoxicity in the rat after short duration exposures to fourteen reproductive toxicants. Reproductive Toxicology 6, 491-505 (1992)

[9] API (1983) and DeGroot & Kepner (1984), cited in: International Program on Chemical Safety; Environmental Health Criteria 122: n-Hexanes. World Health Organization, Geneva, 1991, 53-54

[10] Cavender et al .: A 13-week vapor inhalation study of n-hexane in rats with emphasis on neurotoxic effects. Foundation. Appl. Toxicol. 4, 191-201 (1984)

[11] American Petroleum Institute: Reports 404 and 405. Inhalation oncogenicity study of commercial grade hexane in mice and rats. (1995)

[12] Krasavage et al .: The relative neurotoxicity of methyl-n-butyl ketone. n-hexanes and their metabolites. Toxicol. Appl. Pharmacol. 52, 433-441 (1980)

[13] Kurita. H .: Experimental studies on the effects of n-hexane in albino rats. Ind. Health 9 (8), 24-29 (1974; Japanese).