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Description of key information

As toxicokinetic data are not available for ZMB2, the endpoint is addressed through consideration of the results of the acute oral, dermal and inhalation toxicity studies (see Section 7.2), the skin sensitization study (Section 7.4) and the 47 day dietary study (Sections 7.5 and 7.8).

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

As toxicokinetic data are not available for the test substance, the endpoint is addressed through consideration of the results of the acute oral, dermal and inhalation toxicity studies (see Section 7.2), the skin sensitization study (Section 7.4) and the 47 day dietary study (sections 7.5 and 7.8).

 

Absorption: The acute oral/inhalation and 47 day repeated dose diet studies results indicate that the test substance is absorbed following oral (gavage/dietary) and inhalation exposures. Acute lethality was observed in the acute oral study (Biosearch 1977, similar to OECD 401, male albino rats, LD50 = 800 mg/kg bw, clinical signs/gross pathology data not reported). In the acute inhalation study (Safepharm 2003, EPA OPPTS 870.1300, male/female Sprague-Dawley rats, LC50 > single concentration tested of 2120 mg/m3), no deaths occurred and there were no adverse gross pathology findings. However, clinical signs (increased respiratory rate, hunched posture, lethargy, and/or pilo-erection) were noted during exposure and post-exposure, with a return to normal by day three or four post-exposure. In the 47 day repeated dose dietary study (Safepharm 2006, OECD 422, male/female Sprague-Dawley rats, LOAEL = 60 mg/kg bw/day, lowest dose tested), multiple systemic effects and histopathology findings were observed in adult animals suggestive of absorption. At the lowest dose, these effects included decreased male body weight gain, reduced food consumption, changes in clinical chemistry, decreased relative organ weights for spleen, thymus, and female adrenals, and histopathology findings for male spleen, male pituitary, thyroid, salivary gland, and male bone marrow. Inclusive of higher dose effects, the primary systemic effect was described as altered metabolic state. No significant findings were seen during the behavioural or external/internal macroscopic exams.

 

The results of the acute dermal toxicity and sensitisation studies are less clear with respect to absorption. The acute dermal study suggests that the test substance may not be readily absorbed through intact skin (Safepharm 2002, OECD 402, male/female Sprague-Dawley rats, LD50 > single dose tested of 2000 mg/kg bw). Or, if absorbed, acute exposure up to 2000 mg/kg bw is not sufficient to cause effects (death, clinical signs, dermal irritation, or macroscopic abnormalities). The molecular weight and log Pow of the test substance (391.83 g/mol and 3.07, respectively) also may indicate a reduced potential for dermal absorption, >10% but <100%; low absorption (10%) may be assumed when molecular weight > 500 g/mol and log Pow <-1 or >4 (EU, 2004; WHO 2006)[1]. The skin sensitization study (Safepharm 2002, OECD 406, male Dunkin-Hartley guinea pigs, 50% sensitization rate upon challenge), however, indicates that some dermal absorption of the test substance does occur.

 

Distribution: The systemic findings in the acute inhalation study and 47 day dietary study (as noted under absorption above) support the conclusion that the test substance is distributed systemically following inhalation and oral dietary exposure. The target organs identified in the 47 day study were adrenals, pituitary gland, salivary gland, spleen, and thyroid. Distribution following oral exposure is expected based on the dietary study findings. Distribution following dermal contact is less well defined given the lack of effects in the acute dermal toxicity study but positive (skin, immune system) effects were observed in the skin sensitization study.

 

Metabolism: The liver effects noted in the 47 day repeated dose dietary study indicate metabolism may occur within the liver. At the high and intermediate doses, male liver weights relative to body weight were increased, although the histopathology findings were considered generally adaptive in nature (hepatocyte enlargement) or common in laboratory maintained rats (scattered mononuclear cell foci). 

 

Elimination: The results of the acute inhalation study indicate that fairly rapid clearance of the test substance may occur following acute exposure. While clinical signs were seen during and after exposure, a return to normal was observed by day three or four post-exposure. In the 47 day repeated dose dietary study, the effects on male absolute kidney weights (decreased for all three dose groups) indicate the test substance may be at least partially cleared through the kidneys. Male kidney weights relative to body weight and female kidney weights were not affected. Aside from renal histopathology typically seen in laboratory maintained rats, the renal histopathology was negative. No gross intestinal (duodenum through colon) abnormalities were noted during the internal macroscopic exam of decedents or sacrificed animals.

 


[1]EU, 2004, Guidance on dermal absorption; World Health Organization (WHO), 2006, Environmental Health Criteria 235:Dermal absorption