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Additional information

In the AMES test, no increase in mutant frequency was observed in either standard plate or preincubation test in the absence or presence of metabolic activation. Hence, under the conditions of the study, phenoxypropanol was not considered to be mutagenic in bacteria.

In an in vitro mouse lymphoma assay test no statistically significant increases in mutant frequency were observed following treatment with the test substance at any dose level tested in the absence or presence of S-9 in Experiment 1 or 2. It is concluded that, under the conditions employed in this study, the test substance is not mutagenic to mammalian cells in this test system when tested up to a maximum concentration of 10 mM in the absence and presence of S-9.

In an in vitro chromosome aberration assay in CHO cells, frequencies of cells with structural aberrations observed in the absence and presence of S-9 (all experiments) were similar to those observed in concurrent vehicle controls. The aberrant cell frequency of all test substance treated cultures fell within historical negative control (normal) ranges. Hence, phenxoypropanol is not considered to be a clastogenic agent in mammalian cells.

In an in vivo micronucleus test, groups of 6 male mice were administered 0, 500, 1000, or 2000 mg PPh/kg body weight by gavage on 2 consecutive days by oral intubation. Because hypothermia resulted from treatment in this Phase 1 study, particularly in the high dose subjects, the experiment was repeated with both sexes (Phase 2) with 6 additional animals in the high dose group to serve as replacements in the event of mortality. In Phase 1, 1 of 6 males died from treatment in the high dose group (2000 mg/kg/day). Autopsy did not reveal a cause for death. Three males from this group (including the one that died) showed clinical signs of shallow breathing, decreased to absent activity, and hypothermia. The two surviving animals showing hypothermia were placed in a warm environment. No deaths, clinical signs, or hypothermia occurred in the lower dose groups or in the cyclophosphamide control groups. The high dose group showed an average increased frequency of micronuclei. The %MN-PCE (% micronuclei) values from two animals with hypothermia accounted for the increased average of this group and the authors of the study attributed the increase to hypothermia. These values were 18.0 % and 11.5% while the values in the three other survivors were 1.0%, 4.5%, and 3.0%, similar to the corn oil control group values. In Phase 2, the effects seen in Phase 1 were observed again in the 2000 mg/kg/day group. Although not statistically significant, the %MN-PCE was elevated once more. Marked hypothermia was observed yet again at this dose level only in both sexes. As in Phase 1, the ratio of polychromatic (PCE) to normo-chromatic erythrocytes (NCE) was decreased in the high dose group. Only males (6/dose level) were used in phase 1 while male and females (6/sex/dose level) were used in phase two. The authors of this study concluded that, most likely, the increased incidence of micronuclei seen at 2000 mg/kg/day was attributable to the hypothermia induced by PPh and not as a direct clastogenic effect from PPh. The authors cited papers by Asanami et al. (Asanami, S., Shimono, K., (1997). High body temperature induces micronuclei in mouse bone marrow. Mutation Research, 390:70-83 and Asanami, S., Shimono, K., Kaneda, S., (1998). Transient hypothermia induces micronuclei in mice. Mutation Research, 413:7-14) showing that agents such as reserpine and chlorpromazine, which induce hypothermia, cause increased micronuclei as an indirect result of this physiological change. Asanami et al. hypothesize that hypothermia may cause clastogenic injury by interfering with microtubule assembly and spindle function. Since a separate, additional group at the high dose level was not placed in a warmed environment after treatment to directly test the hypothesis of hypothermia causing the increased micronuclei, the possibility that the increased incidence of micronuclei at the high dose was directly attributable to PPh cannot be excluded. On the other hand, it is relevant to note that the next lower dose (still a very large dose of 1000 mg/kg) did not cause hypothermia or an increase in micronuclei. If the increase was directly attributable to PPh and not hypothermia, it is significant that only a marginal effect resulted (not statistically significant when repeated in a second experiment), which required a very large dose of 2000 mg/kg.

Short description of key information:
GLP studies according to OECD guidelines 471, 473, 476 and 474 are available for phenoxpropanol.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Phenoxypropanol was not mutagenic in bacteria (Salmonella typhimurium TA 1535, TA 1537, TA 1538, TA 98, and TA 100) and in mammalian cells in vitro. Phenoxypropanol was also not considered to be clastogenic in vitro and in vivo. Hence, the data available indicates that phenoxypropanol is not genotoxic and no classification is required according to EU criteria.