Frequently asked questions (FAQ)

The NOAEL-project is a fee for service. All the money are used to form and pay specialized personnel whose job is to add toxicological data to the database.
You can join the project by visiting this address

There is only one type of annual subscription:

  • Access to the database without NOAEL request
    With this profile, the user will see every toxicological datasheet present in the database (both in the electronic and pdf version) from the moment of subscription to the next year.
    The user with this profile will be able to download the excel file for the MOS and SED calculation but not to commit a toxicological datasheet for a substance of personal interest

In the case we have funds to pay a person in order to search and insert NOAELs, registered users may send an excel file with maximum 20 ingredients of interest to infoATnoaelproject.it. We don't ensure we will be able to find all the NOAELs listed, however this is our way to improve the users' experience.
The excel file must have two columns showing INCI name and CAS number.

The only scope of this database is to provide in the simpliest and fastest way the NOAELs from toxicological studies regarding cosmetic ingredients.
NOAEL-project staff doesn't assume the legal responsibility for the consequent MOS calculation or PIF compilation.

Endpoints to inspect and substance’s classification

The NOAEL-project follows SCCS guidelines.
To fully characterize the toxicological profile of the substance of interest 10 endpoints should be inspected:

  • Irritation and corrosivity
  • Sensitization
  • Dermic/percutaneous absorption
  • Repeated dose toxicity
  • Mutagenicity/Genotoxicity
  • Carcinogenicity
  • Reproductive toxicity
  • Toxicokinetic
  • Photo-toxicity
  • Human data

If one or more of the principal endpoints (underlined in the list above) are missing, the substance’s profile will be classified as “Incomplete”. In this way we will be able to further look for missing endpoints, completing the profile.
It’s important to remember that a substance classified as “Incomplete” will always have at least one NOAEL: one should consider “Incomplete” as “It does not have all the required NOAEL”.
If all the enpoinds are inspected, the substance will be classified as “NOAEL”.
If the NOAEL is derived from a read-across study (meaning that is retrieved from a very similar ingredient), the substance will be classified as “NOAEL from read-across”.
Occasionally dermal absorption could be available in the datasheet, the classifications as “NOAEL + SED” is no longer in use, so the user should carefully inspect the “Chemo-physical” section of the datasheet.

In some cases, the cosmetic ingredient is listed in the Annexes; in this situation we decided to use the same classification and restriction of SCCS, but we also decided to include the NOAEL (if available): the reason is that some restrictions are strictly related to some cosmetic product, therefore a NOAEL could be useful if the user employs the same ingredient in other types of cosmetics. This substance will be classified as “In the Annexes”.
If we weren’t able to find a NOAEL, the substance will be classified as “No test available” and will be excluded from the excel file listing all the ingredients in the database.

To sum up, according to our classification each substance can have the following states:

Status

Meaning

NOAEL

All the endpoints requested from SCCS are covered

NOAEL from LOAEL

The NOAEL was derived from a LOAEL and divided by 3

NOAEL from read-across

The NOAEL refers is the same of another ingredient with very similar chemo-physical properties

No test available

We weren’t able to find a single NOAEL

Incomplete

One ore more NOAEL are reported, but all the endpoints are not covered

CIR

There is no NOAEL but some toxicological info from CIR

In Annexes

The substance is listed in the Annexes, however a NOAEl could have been found

Only in the red cases a NOAEL is missing from the datasheet.

A NOAEl can be retrieved only from certain studies: repeated dose toxicity, cancerogenicity, teratogenicity and reproductive toxicity. Results from other endpoints are reported in the datasheet for completeness.
According to the SCCS, a NOAEl from a subacute study must be divided for a factor of 3 because the standard minimal duration is 90 days. In all the NOAEL-project datasheets the NOAEL is already divided by this factor if necessary.

 

Criteria for choosing a NOAEL

The final NOAEL has to be the lowest regardless of the animal species used or the toxicity test employed. In the “Notes” section of each datasheet all the considerations that drove us to our conclusion are summarized. If the interpretation of the source is very easy to understand, there will not be a detailed discussion but only a link pointing to the source’s details.

Toxicity type

NOAEL

Repeated dose toxicity (oral)

1500 mg/kg * bw/d

Inhalation

1200 mg/kg * bw/d

Reproductive toxicity

600 mg/kg * bw/d

In the case we have three NOAEL as showed in the table above, a common mistake is to consider the NOAAEL from inhalation if the cosmetic ingredient is part of a spray formulation. The right NAOEL to choose is the lowest among the three, that is the one from the reproductive toxicity test.
Being a database based on single substances, their toxicity evaluation will be totally unrelated from the final cosmetic product: for example, if a given ingredient is employed in a spray, we should take into account all the subministration routes, not only the inhalation one (oral, gavage etc...).
The final cosmetic product only affects the SED (and therefore MOS) calculation.

Single dose experiments

To get a NOAEL is mandatory to test several doses of one chemical. This way it will be possible to identify a toxicity threshold defining LOAEL and/or NOAEL.
Test using a single dose for testing a given toxicity endpoint are unable to identify thresholds. The lack of toxic effects following a single administration is not so informative, especially if the dose is very low. Even in the case some adverse effects would be observed, the single dose does not allow to consider that value as a LOAEL (meaning that there could be also smaller doses causing adverse effects).
By giving these values the same importance of a NOAEL/LOAEL retrieved from multiple dose test, it is possible to largely over/underestimate the real NOAEL/LOAEL. For this reason we decided not to consider these values unless no other test has been found. Even in this case in the “Notes” section it will be reported that this data come from a single dose experiment and that more reliable data will replace it when found.
In the case only a LOAEL from a single dose experiment is available, we don’t calculate the corresponding NOAEL unless the authors of the study or the commission approve it.

Experiments’ reliability

NOAELs from a more recent study doesn’t necessarily mean that this must be preferred to older ones. A very important parameter is represented by the range of dose tested.
Ideally the substance is administered for 14 days at dose very large and spanning from each other: the scope of this test is indeed to explore the dose range that will be used in the repeated dose tests (subacute, subchronic and chronic). Range with extremes very distant from each other and regularly spanned allow the identification of a NOAEL way more precise rather than range with doses spanned less regularly.

Example: A very recent study on Sorbic acid employing a very big dose range showed a NOAEL of 1.5% and 1% in rats and mice respectively. An older study with a shorter range of doses employed showed a NOAEL of 5% in both the animals. The first study tested the substance at 1.5% and then at a concentration bigger than 5%, which in turn showed clear adverse effects. In this case we didn’t considered the older study as replaced by the newer one since they used the same animal models and the dose range didn’t overlap1.

Bigliography

1 Reports of the Scientific Committee for Food (Thirty-fifth series) pag. 19 (1996) 

Consistency with OECD guidelines and GLP

According to SCCS all the studies taken into consideration should follow Good Laboratory Practice (GLP) and OECD guidelines. Unfortunately great part of the sources doesn’t have such detailed information. A study that follows these guidelines represents undoubtedly a very reliable source of data. Each NOAEL-project’s datasheet have a field relative to this guideline.

Weight of evidence (Woe) for choosing a NOAEL

SCCS states that for correctly choosing a NOAEL a “weight of evidence” approach should be used. In few words that means to evaluate all the studies and to consider their details in order to create the most complete toxicological profile. We can summarize three different cases accordingly to ECHA:

  • Case 1: No reliable study regarding substance’s toxicity. Use of studies not fully reliable with detailed description of employed methodologies.
  • Case 2: One reliable study. The study is considered as a key-studyLo studio è considerato chiave; detailed description of employed methodologies is mandatory
  • Case 3: More than one reliable study. If there is one key-study and other support informations, a detalied description of the key-study and a generic one of the additional documents are needed.

In the case wen have more than one reliable informations distributed in different studies (for example toxicological data retrieved from different animal models or from different tests) or in the case there is some conflict between them, a detailed description of all these studies is required.

In order to calculate the MOS, the NOAEL must have an unit of measure (um) expressed as mg/kg * bw/d.
This is due to the fact that MOS does not have a um and therefore, since SED is expressed as mg/kg * bw/d, NOAEL must show the same um.
The problem arises when sources show NOAELs expressed as part per milions (ppm), percentage of diet (% feed) etc and the user need a way to convert them into mg/kg * bw/d.
To do that, standardized and universally accepted (at least from European Commission) values of weight and diet intake for different animals are needed.
We have managed to find these data in order to perform all the conversion we needed.
To further facilitate and speed up the compilation of the PIF we inserted the already converted vlaue into our datasheets.

All the sources employed to find a NOAEL for any given substance can be divided into two categories:

  1. Specialized academic journals
  2. Toxicological databases of international bodies/committees

We analyze the reliability of the source (both scientific journals and databases) and the studies that report NOAELs. If important requirements as OECD guidelines or Good Laboratory Practice (GLP) are missing or not specified, we report this lack in the toxicological sheet in order to refine it in the future.
SCCS opinions are obviously considered the best sources, but we always check for more updated reports.

A crucial parameter, essential to inspect the reliability of an academic journal over time is the impact factor (IF), that is is a measure reflecting the average number of citations to recent articles published in the journal.

Example: Paper about safety assessment of Cocos Nucifera Oil toxicity
This study was published in the Malaysian Journal of Pharmaceutical Sciences1.
The authors state they have followed OECD guidelines and GLP, finding a NOAEL from a repeated dose toxicity study that lasted 28 days (subacute).
This article is not indexed in Pubmed Central (the most important/used search engine for references and abstracts on life sciences and biomedical topics). Looking for the impact factor, we found that the volume 9 (containing the article of interest) has been cited only once in the last few years, obtaining an IF around 0,028 (source, update 2012).

We weren't able to find other repeated dose toxicity tests carried out in the same animals, so we decided to use this data, pointing out the limitations deriving from citing an acadamic journal with a very low impact on the scientific community.

Bibliography

1A. M. S. Abdul Majid et al;  Malaysian Journal of Pharmaceutical Sciences Vol. 9, No. 1, (2011)

 

All these acronyms are parameters employed in toxicology to determine the potential hazard of substances; they are the result of repeated dose toxicity studies carried on animal model systems and are fundamental to understand potential risks to humans exposed to the substance investigated.
Still today there are no consistent standard definitions for the terms NOEL, or NOAEL or the corresponding LOEL and LOAEL. 
The most complete and clear definition for NOAEL is “The highest exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control. Some effects may be produced at this level, but they are not considered to be adverse or precursors to adverse effects.”
The highest exposure level at which no effects (adverse or nonadverse) are observed in the exposed population is the NOEL. 
The LOAEL corresponds to the lowest exposure level at which there are statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control.
 
It is obvious that, in order to distinguish NOAEL from NOEL, there is a need for definitions of “adverse” and “biologically significant”, especially considering that many organizations will actually be employing NOAELs in their regulatory process even though they may refer to them as a NOELs.
  • An adverse effect is defined as a biochemical, morphological or physiological change (in response to a stimulus) that either singly or in combination adversely affects the performance of the whole organism or reduces the organism’s ability to respond to an additional environmental challenge. 
  • A biologically significant effect is a response (to a stimulus) in an organism or other biological system that is considered to have substantial or noteworthy effect (positive or negative) on the well-being of the biological system. The concept is to be distinguished from statistically significant effects or changes, which may or may not be meaningful to the general state of health of the system.
 
Bibliography
 
Carpanini et al TOXICOLOGIC PATHOLOGY, vol 30, no 1, pp 66–74, 2002
 
Although some articles report that it is possible to extrapolate from LD50 to NOAEL1, this approach is totally wrong because of several reasons:
  • LD50 value is related to lethality (an endpoint that can't be classified as an adverse effect)
  • LD50 is calculated from acute exposure studies, whereas the NOAEL is extrapolated from longer term ones.
LD50 is used to classify toxic agents and a threshold for non-adverse effect is totally missing from the experimental design of employed tests.
In a typical LD50 protocol, a large amount of test-substance is used within 24 hour period, on the other hand repeated dose toxicity tests employ lower dose-range (which, in turn, are calculated from the outcome of 14-days repeated dose toxicity test and LD50).

 
Bibliography
 
1Pieters et al. Regulatory Toxicology and Pharmacology, Volume 23, Issue 3, June 1996, Pages 249–255

The Acceptable Daily Intake (ADI) indicates the amount of substance that can be ingested (orally) on a daily basis over a lifetime without an appreciable health risk. This parameter is obtained dividing a NOAEL for a factor equal to 10. Since many ingredients such as preservatives are used both in food and cosmetics, toxicological data used to calculate the ADI are accepted for safety evaluation of cosmetics. However we can't derive a NOAEL simply dividing an ADI by a factor of 10 because crucial informations would be missing (e.g. animal model used to investigate toxicity, time and route of subministration etc...).

The NOAEC is a parameter identical to the NOAEL except for the fact that a concentration is used instead of a dose (the most common case is when a gaseous substance is administered to the animal).
Most frequently, NOAECs are expressed as mg/m3, mg/L or ppm. Two parameters are needed in order to provide a conversion for the unit of measure:

  • The mean respiratory volume of the animal used for the test
  • The value of absorption of the inhaled substance
The latter parameter is fundamental, as the assumption of an absorption equal to 100% would lead to a big underestimation of the real toxicity (in case for example all the symptoms are caused by the 10% of the administered substance).
The NOAEL-project is capable of converting the NOAEC to NOAEL only if the dermal absorption is available; otherwise the substance will be classified as "No NOAEL found".
 
NOAEL-project toxicological datasheet (see an example at this link) is articulated in the following sections:
 
Substance identification
 
INCI name: the INCI name of the substance employed in toxicological studies that were used to identify the NOAEL reported
CAS number: all the CAS number for all the substance to which the chosen NOAEL can be extended
Substances with same NOAEL: the corresponding list of INCI name for the CAS numbers reported previously
Missing tests: list of missing endpoints required by SCCS to achieve a complete toxicological profile
Extract: indicates wheter a substance is an extract or not
Extraction source: the source from which the extract is obtained (fruit, leaves, flower...)
Extraction solvent: the solvent used to obtain the extract
Active ingredients: the list of active ingredients present in the extract with a link redirecting to their toxicological datasheet

Substance of reference for read-across: list of substances already present in the database employed to retrieve the NOAEL for the substance of interest
 
Optional fields

Annex number: if the substance is included in an Annex, this field show the Annex number, otherwise it shows the "Not in Annexes" label
Restrictionsif the substance is included in an Annex, this field shows the restrictions as reported by the SCCS

 

Chemo-physical properties section

INCI name: INCI name of the substance for which the info below refer
Log P: Partition coefficient of a substance in a mixture of 1-octanol/water
Molecular weight: Moleular weight of the substance
Dermal absorption: This value is always expressed as % and can be found in toxicological studies (specifically, in the pharmacokinetics section) or estimated following SCCS assumption that, if the molecular weight is equal or greater than 500 da and the Log P is <-1 or >4, the substance has a dermal absorption of 10%.
Dermal absorption 
(μg/cm2): dermal absoprtion expressed as μg/cm2, a parametere required in order to calculate the SED if dermal absorption (%) is missing
 

Toxicological profile of the substance

NOAEL: The NOAEL value expressed as mg/kg * bw/d
Test duration: Time of application of the substance expressed as days (d) or months (m)
Test type: Type of toxicological assay from which the NOAEL reported was retrieved
Animal model: the animal employed in the test from which the lowest NOAEL was chosen
Route of subministration: The route of subministration used in the toxicological assay

 
Quality system: This field indicates if the test employed to assess the NOAEL were conducted following OECD Principles of Good Laboratory Practice (GLP), OECD guidelines or other reliable but not GLP-compliant guidelines
Source: The source from which the reported NOAEL was retrieved, it can be an online toxicological database or a scientific journal
Notes: A field where additional toxicological endpoints such as mutgenicity and genotoxicity are described ando/or where the choise for the NOAEL reported is discussed in details.

There are two way to visualize toxicological datasheets of interest:

  • By clicking the Menù item "NOAEL-search". The search-panel will open and the user will fill the box named INCI name with the desired INCI or, in alternative, the box named Substances with same NOAEL or CAS number with the CAS number or the INCI of the substance of interest. The autocomplete function is only available in the first box: if you don't see any suggestment after typing a name, please click the Apply button anyway; results will be shown below.

After this step, if records are found, you will see a table with all the ingredients meeting the search criteria (depending on the search words, results could be very redundant). All the entry are visible as links to the relative datasheet.

  • By clicking the Menù item "Substances list" and browsing the alphabetically ordered list to spot the desired ingredient. The link is visible only for the substance for which a NOAEL was found, the other INCIs listed below inherit the same tixicological evaluation.

NOAEl-project provides an excel template where is possible to calculate the SED value in two diffrerent ways.

In any case you need the dermal absorption value (expressed as % or as μg/cm2) to calculate the SED; if this parameter is missing, a SED equal to 100 must be used.
In the first sheet the "Calculated relative dayly exposure" will be automatically filled after the user has selected the cosmetic category of interest (body lotion, shampoo ...). In order to calculate the SED, the user has to manually insert the concentration in the cosmetic product (this value must be a number between 0 and 100, where 100 corresponds to 100%) and the dermal absorption expressed as %.

In the second sheet of the same excel file, the user can calculate the SED only if the dermal absorption value (espressed as μg/cm2) is available; all the other values needed for calculation are automatically retrieved from the table on the right.

The user should keep in mind that the MOS value has to be calculated for every substance employed in the cosmetic formulation.
To calculate the MOS, the NOAEL should be divided by the SED (see FAQ section for more info).

In the "Downloads" section of the website the registered user can download an excel file already filled with example values in order to set the calculation on hiw substance of interest.

Last Tweets

06/06/2016 - 11:11
Nuovo componente inserito: Simmondsia Chinensis (Jojoba) Seed Oil https://t.co/mGvGLRQ05k
29/05/2016 - 10:04
Nuovo componente inserito: Linum Usitatissimum seed oil Error
27/05/2016 - 16:38
Nuovo componente inserito: Soybean oil https://t.co/9prxB7xyiu

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To get more info about the NOAEL project, go to FAQ section or contact Roberto Narducci at this address:
 
infoATnoaelproject.it
 
For info about subscription costs click the following link or contact Federica Cambiganu:
 
federica.cambiganuATpin.unifi.it
+390574602511
PIN s.c.r.l. - Piazza Giovanni Ciardi 25, 59100 - Prato