PMID- 29860528
OWN - NLM
STAT- MEDLINE
DCOM- 20190902
LR  - 20190902
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 165
IP  - 1
DP  - 2018 Sep 1
TI  - Deriving a No Expected Sensitization Induction Level for Fragrance Ingredients 
      Without Animal Testing: An Integrated Approach Applied to Specific Case Studies.
PG  - 170-185
LID - 10.1093/toxsci/kfy135 [doi]
AB  - Cosmetic regulations prohibit animal testing for the purpose of safety assessment 
      and recent registration, evaluation and authorization of chemicals guidance 
      states that the local lymph node assay (LLNA) in mice shall only be conducted if 
      in vitro data cannot give sufficient information for classification and labeling. 
      However, Quantitative Risk Assessment for fragrance ingredients requires an NESIL 
      (no expected sensitization induction level), a dose not expected to cause 
      induction of skin sensitization in humans. In absence of human data, this is 
      derived from the LLNA and it remains a key challenge for risk assessors to derive 
      this value from nonanimal data. Here we present a workflow using structural 
      information, reactivity data and KeratinoSens results to predict an LLNA result 
      as a point of departure. Specific additional tests (metabolic activation, 
      complementary reactivity tests) are applied in selected cases depending on the 
      chemical domain of a molecule. Finally, in vitro and in vivo data on close 
      analogues are used to estimate uncertainty of the prediction in the specific 
      chemical domain. This approach was applied to three molecules which were 
      subsequently tested in the LLNA and 22 molecules with available and sometimes 
      discordant human and LLNA data. Four additional case studies illustrate how this 
      approach is being applied to recently developed molecules in the absence of 
      animal data. Estimation of uncertainty and how this can be applied to determine a 
      final NESIL for risk assessment is discussed. We conclude that, in the data-rich 
      domain of fragrance ingredients, sensitization risk assessment without animal 
      testing is possible in most cases by this integrated approach.
FAU - Natsch, Andreas
AU  - Natsch A
AD  - Fragrances S&T, in vitro molecular screening, Ingredients Research, Givaudan 
      Schweiz AG, CH-8600 Duebendorf, Switzerland.
FAU - Emter, Roger
AU  - Emter R
AD  - Fragrances S&T, in vitro molecular screening, Ingredients Research, Givaudan 
      Schweiz AG, CH-8600 Duebendorf, Switzerland.
FAU - Haupt, Tina
AU  - Haupt T
AD  - Fragrances S&T, in vitro molecular screening, Ingredients Research, Givaudan 
      Schweiz AG, CH-8600 Duebendorf, Switzerland.
FAU - Ellis, Graham
AU  - Ellis G
AD  - Regulatory Affairs and Product Safety, global toxicology Givaudan International 
      SA, CH-1214 Vernier, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Perfume)
SB  - IM
MH  - Animal Testing Alternatives/*methods
MH  - Animals
MH  - Dermatitis, Allergic Contact/*etiology
MH  - Humans
MH  - Local Lymph Node Assay
MH  - No-Observed-Adverse-Effect Level
MH  - *Perfume/administration & dosage/chemistry/toxicity
MH  - Risk Assessment
EDAT- 2018/06/04 06:00
MHDA- 2019/09/03 06:00
CRDT- 2018/06/04 06:00
PHST- 2018/06/04 06:00 [pubmed]
PHST- 2019/09/03 06:00 [medline]
PHST- 2018/06/04 06:00 [entrez]
AID - 5026503 [pii]
AID - 10.1093/toxsci/kfy135 [doi]
PST - ppublish
SO  - Toxicol Sci. 2018 Sep 1;165(1):170-185. doi: 10.1093/toxsci/kfy135.