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Administrative data

Description of key information

7.5.1 Repeated dose toxicity: oral: 
KS - 90d rat. Whale & Christenson, 1997. KL.1. NOAEL M: 32.9, F: 38 mg/kg/day;
KS - 1yr rat. Wahle, 1999. KL.1. NOAEL M: 2.3 F: 2.7 mg/kg/.day;
SS - 90d dog. Sheets, 2001. KL.2. NOAEL M: 6.74 F: 6.28 mg/kg/day;
SS - 1yr dog. Wahle, 1999. KL.2. NOAEL M: 2.5 F: 2.3 mg/kg/day.
7.5.2 Repeated dose toxicity: dermal:
KS - 21d rat. Sheet & Gastner, 1998. KL.1. NOAEL 1000 mg/kg/day
7.5.3 Repeated dose toxicity: inhalation:
No available studies

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
2.3 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Repeat oral toxicity

In the sub-chronic key rat study (Wahle and Christenson, 1997) slight effects on the thyroid gland which included increases in T3 levels and follicular cell hyperplasia were observed. Mechanistic studies (refer to Section 7.9.3) in rats were performed to better characterise these effects. These studies showed that there were no treatment related effects on thyroid weight or microscopic changes in the thyroid at any dose. Thyroid to blood ratios of 125I in treated groups were comparable to negative controls, indicating that the increase in thyroid hormones was mostly likely not due to increased synthesis. It would appear that amicarbazone is conjugated by liver UDP-GT enzyme, which subsequently is the same enzyme used for both T3 and T4 conjugation. Amicarbazone appears to compete with T3 / T4 for this enzyme, therefore thyroid homeostasis is affected as T3 / T4 levels rise due to lack of conjugation in the liver. Increased liver weights were also observed in the sub-chronic rat study. As the liver is implicated as the extra-thyroidal site and also where UDP-glucuronosyltransferase activity is greatest, this provides an explanation for the increased liver weights observed (hence cytomegaly and enlarged cells with granular eosinophilic vacuolated cytoplasm). In this study NOAEL of 32.9 and 38 mg/kg/day were established for males and females respectively, based on the effects observed (discussed above at LOAEL of 67.2/77.7 mg/kg/day [M/F]). 

 

In the chronic key rat study (Wahle, 1999) similar effects as to those already discussed were observed. Due to the doses selected, the NOAEL was established at 2.3 and 2.7 mg/kg/day in males and females, respectively (the lowest dose tested), with LOAEL of 25 and 30 mg/kg/day for male and females, respectively. These data would suggest that the true NOAEL for the chronic study may lie closer to 25 mg/kg/day based on both the dose level intervals from the chronic and sub-chronic studies with similar effects reported, which did not progress over an extended period of testing.

 

The two supporting dog studies (Sheets, 2001 [sub-chronic] and Jones, 1999 [chronic]) reported similar effects to the rodent study. The 90-day study reported NOAEL of 6.74 and 6.28 mg/kg/day for males and females, respectively (LOAEL M: 27 and F: 25 mg/kg/day). The 1 year study reported NOAEL of 2.5 and 2.3 mg/kg/day for males and females, respectively (LOAEL M: 8.9 and F: 8.7 mg/kg/day).

 

Repeat dermal toxicity

In the key study (Sheet and Gastner, 1998) no systemic effects or treatment related signs of dermal irritation were observed when animals were exposed to a maximum recommended dose of 1000 mg/kg/day for 21 days. Whilst no dermal absorption data is available, both the acute and sub-acute dermal toxicity data suggest that dermal absorption is minimal with no evidence of local or systemic toxicity compared to the acute oral toxicity study where the NOEL was ~100 mg/kg. Irrespective of the duration of the study the available data suggest that local and systemic toxicity are not likely to markedly increase in severity.

 

Repeat inhalation toxicity

No toxicological studies have been submitted to support this toxicological endpoint. In accordance with the guidance from ECHA (2008) route to route extrapolation will be undertaken, extrapolating from the oral route to the inhalatory route to provide a repeat dose dermal systemic DNEL. Further testing is not justified and therefore a waiver is requested for this endpoint.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; glandular: thyroids

Justification for classification or non-classification

Amicarbazone is not genotoxic, and therefore classification is not required.