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EC number: 239-556-6 | CAS number: 15520-10-2
Table 7.5.3/1: Incidence and Severity of Histopathologic lesions in F344/N rats
1n=10 for all groups. The average severity score ( ) was based on the number of animals with lesions from each group; 1=minimal, 2=mild, 3=moderate, 4=marked.
A 13-week study of the toxicity of the dihydrochloride salt of HMD (HDDC) was conducted in male and female Fischer 344/N rats using whole body inhalation exposure (NTP, 1993). The method followed was comparable to OECD 413 and was conducted according to the US-EPA GLP which were similar to the EU-GLP.
HDDC has the same organic backbone as HDA and its use would allow detection of any specific toxicity associated with that backbone while avoiding the causticity and the stability problems that would be encountered with the use of HDA. Therefore, the use of HDDC aerosol is relevant to study the toxicity of the HDA aerosol in a read-across strategy.
Animals were exposed to HDDC aerosol at concentrations of 0, 1.6, 5, 16, 50 and 160 mg HDDC/m3 for 6 hours plus T90 (30 minutes) per day, 5 days/week for 13 weeks corresponding to 0, 1.0, 3.1, 10, 31 and 100 mg HMD /m3. The aerosol mass median aerodynamic diameter values for each chamber ranged from 1.62 to 1.72 µm, with a geometric standard deviation of 1.52 to 1.53. All control chamber respirable mass concentration vaues were less than 0.005 mg/m3. Mortality, clinical signs, body weights, hematology, clinical chemistry, sperm morphology, vaginal cytology, organ weight, microscopic and macroscopic examinations were recorded.
No mortality was observed during the study. Nasal discharge occurred in male in the 5 and 16 mg/m3 exposure groups and in female in all exposure groups (including the control group) except those in the 160 mg/m3/d group. Similarly, rales occurred in female groups but not in exposed males. However, because these signs appeared late in the study and because the incidence was not dose related, these clinical signs were not considered to be the result of specific HDDC toxicity.
No treatment related changes in body weight.
The only consistent changes in organ weights seen in rats were significant decreases in absolutes and relative lung weights of HDDC-exposed rats by comparison with the lung weights of the study controls. However, the apparent reduction was considered to be an artefact resulting from the greater lung weights of the control due to inflammation. Hence, the lung weights of the exposed rats were well within the normal range (historical data of the NTP).
By day 94, a dose-related decrease in lymphocytes and leucocytes was observed in females at both highest doses while an increased hematocrit values were noted at both lowest dose. A statistically significative decrease in segmented neutrophil counts was also observed in females exposed from 16 mg HDDC/m3 (slight decrease) to 160 mg HDDC/m3/d(moderate decrease). A slight decrease in erythrocyte count was noted in males rats in the 16 mg HDDC/m3 exposure group while a minor increase in mean cell hemoglobin values occurred only in males exposed at 50 mg HDDC/m3. Hence, the hematological changes were minor and/or sporadic without any related histopathological finding. Moreover, the overall decrease in the leukocyte count, in the absence of evidence of bone marrow toxicity, was consistent with the inflammatory changes in the larynx and nasal passages inducing increased margination to tissues or the marginal pool, a decreased release to circulation or increased destruction. Therefore, these effects were considered as a secondary effect of the HMD related respiratory inflammation.
Some clinical chemistry changes in rats (such as urea nitrogen on day 18 in both sexes) were not considered as biologically significant since these effects were minor and/or sporadic and were not accompanied by any related histological finding and were probably related to causes such as dehydration, increased protein catabolism, diet.
Based on the results observed in the rat after subchronic inhalation of HDDC, the NOAEC for both males and females was 16 mg HDDC/m3 for local respiratory damage, corresponding to 10 mg HMD/mg3.
This subchronic study by inhalation is considered as acceptable. It does satisfy the guideline requirement for a 13-week repeated dose toxicity study for a OECD 413 guideline in the rat. Hence, this study can be considered as valide for classification.
Under the test conditions, no adverse effects were observed at HDDC concentrations up to 16 mg/m3 corresponding to 10 mg HDA/m3 .
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