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資料３－３ ストラテラカプセル及びストラテラ内用液にて検出された新規ニトロソアミンの限度値について（企業見解）［7.8MB］ (5 ページ)
出典
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| 出典情報 | 薬事審議会 医薬品等安全対策部会安全対策調査会（令和6年度第5回 8／28）《厚生労働省》 |
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Regulatory Response
Page 3
3. Questions and Responses
3.1. Question 1
Please summarize the Lilly’s opinion including background information and discussion history
which assert that 4400 ng/day is safe, scientific, compound-specific and data-based limit for NNitroso-atomoxetine or a limit of 1500 ng/day is also reasonable.
3.1.1. Lilly Response to Question 1
Lilly used a weight of evidence method to determine that 4400 ng/day is a safe limit for Nnitroso-atomoxetine. This weight of evidence method used the following to determine the 4400
ng/day limit:
Known mechanism of action of nitrosamines
Read-across based on physicochemical properties (Jolly et al 2024)
In silico models, such as quantum mechanical models (De et al 2024) and QSARFlex
(Jolly et al 2024)
In vivo gene mutation assay (Jolly et al 2024).
For the convenience of the reviewer, the results of the gene mutation assay, which are the
primary data supporting a limit of 4400 ng/day, are described below. Results of other supporting
data for the limit of 4400 ng/day are provided by literature reference (Jolly et al 2024, De et al
2024).
Importantly, N-nitroso-atomoxetine is clearly differentiated from the more potent nitrosamines in
terms of its in vivo mutagenicity and as supported by the read-across analysis. Thus, N-nitrosoatomoxetine does not fall into the Cohort of Concern as identified in ICH M7R2 (2022), which is
based on the more potent nitrosamines. ICH M7(R2) has established that the threshold of
toxicological concern (TTC) for mutagens that lack carcinogenicity data and that are not in the
cohort of concern is 1.5 µg/day (1500 ng/day) chronically for a lifetime. At the TTC, the increase
in cancer risk is negligible, which is defined as an excess cancer risk of <1 in 100000 over a
lifetime of exposure. On that basis, a limit of 1500 ng/day is scientifically reasonable.
In vivo mutation assay results
N-nitroso-atomoxetine, which was Ames test positive, was tested in an in vivo study of
mutagenicity in transgenic rats according to OECD test guidelines and in compliance with GLP
requirements. The results demonstrated that N-nitroso-atomoxetine caused an increase in mutant
frequency at the cII gene in duodenal tissue at a dose level of 100 mg/kg/day and in the liver at
dose levels ≥30 mg/kg/day. Mutation frequency was not increased at the lower dose levels of
0.1, 0.537, and 5 mg/kg/day in liver and thus exhibited a “threshold” dose-response relationship.
The no-effect-level (NOEL) for in vivo mutagenicity was 5 mg/kg/day and the Benchmark Dose
Lower Confidence Limit (BMDL; based on the well-validated benchmark dose approach to data
analysis) was 4.4 mg/kg/day. The Acceptable Intake of 4400 ng/d was derived using principles in
the ICH M7R2 guidance where the BMDL value was conservatively used in lieu of the TD50
value, the dose associated with a 50% tumor incidence (ICH 2023; Note 4).
LY139603
VV-REG-326326
v1.0
Page 3 of 5
5 / 34 ページ
Eli Lilly Confidential
Page 3
3. Questions and Responses
3.1. Question 1
Please summarize the Lilly’s opinion including background information and discussion history
which assert that 4400 ng/day is safe, scientific, compound-specific and data-based limit for NNitroso-atomoxetine or a limit of 1500 ng/day is also reasonable.
3.1.1. Lilly Response to Question 1
Lilly used a weight of evidence method to determine that 4400 ng/day is a safe limit for Nnitroso-atomoxetine. This weight of evidence method used the following to determine the 4400
ng/day limit:
Known mechanism of action of nitrosamines
Read-across based on physicochemical properties (Jolly et al 2024)
In silico models, such as quantum mechanical models (De et al 2024) and QSARFlex
(Jolly et al 2024)
In vivo gene mutation assay (Jolly et al 2024).
For the convenience of the reviewer, the results of the gene mutation assay, which are the
primary data supporting a limit of 4400 ng/day, are described below. Results of other supporting
data for the limit of 4400 ng/day are provided by literature reference (Jolly et al 2024, De et al
2024).
Importantly, N-nitroso-atomoxetine is clearly differentiated from the more potent nitrosamines in
terms of its in vivo mutagenicity and as supported by the read-across analysis. Thus, N-nitrosoatomoxetine does not fall into the Cohort of Concern as identified in ICH M7R2 (2022), which is
based on the more potent nitrosamines. ICH M7(R2) has established that the threshold of
toxicological concern (TTC) for mutagens that lack carcinogenicity data and that are not in the
cohort of concern is 1.5 µg/day (1500 ng/day) chronically for a lifetime. At the TTC, the increase
in cancer risk is negligible, which is defined as an excess cancer risk of <1 in 100000 over a
lifetime of exposure. On that basis, a limit of 1500 ng/day is scientifically reasonable.
In vivo mutation assay results
N-nitroso-atomoxetine, which was Ames test positive, was tested in an in vivo study of
mutagenicity in transgenic rats according to OECD test guidelines and in compliance with GLP
requirements. The results demonstrated that N-nitroso-atomoxetine caused an increase in mutant
frequency at the cII gene in duodenal tissue at a dose level of 100 mg/kg/day and in the liver at
dose levels ≥30 mg/kg/day. Mutation frequency was not increased at the lower dose levels of
0.1, 0.537, and 5 mg/kg/day in liver and thus exhibited a “threshold” dose-response relationship.
The no-effect-level (NOEL) for in vivo mutagenicity was 5 mg/kg/day and the Benchmark Dose
Lower Confidence Limit (BMDL; based on the well-validated benchmark dose approach to data
analysis) was 4.4 mg/kg/day. The Acceptable Intake of 4400 ng/d was derived using principles in
the ICH M7R2 guidance where the BMDL value was conservatively used in lieu of the TD50
value, the dose associated with a 50% tumor incidence (ICH 2023; Note 4).
LY139603
VV-REG-326326
v1.0
Page 3 of 5
5 / 34 ページ
Eli Lilly Confidential