SafePharm is foremost among European contract research organisations in experience with the notification of new chemicals in Japan, having conducted more studies for this notification scheme than any other non-Japanese laboratory. As such, SafePharm, with the assistance of our Japanese agents Media Services Ltd, are able to offer a complete service covering all of the testing which may be necessary, together with preparation and submission of the notification dossier to the Japanese authorities. It is our belief that this service is unique outside of Japan.

METI and MHLW jointly administer the "Law Concerning the Examination and Regulation of Manufacture of Chemical Substances etc", which is normally referred to as the Chemical Substances Control Law (CSCL). Full notification is needed for manufacture or import at greater than or equal to 1 metric tonne.

This notification scheme is complicated to deal with because in principle it is a stepwise process, beginning with a biodegradation study, and there is a possibility of having to consult METI part way through. Also, regulatory decisions regarding the test material description are often relevant.

Ideally, the biodegradation study is conducted first (using the METI Biodegradation guidelines) to determine whether the parent substance and/or environmental degradants are further evaluated. This is the stage at which METI advice may be need via our Japanese agent, Media Services Ltd.

If the substance undergoes a high degree of mineralisation in the METI (I) ready biodegradation test, it may be that METI require a METI (II) inherent biodegradation study to be conducted on the parent substance, before deciding what to test further.

The next stage will be to evaluate the bioaccumulation potential of either the parent substance or its environmental degradant(s). It is essential to consider the possibility of using "analogy", however, only Pow or fish bioaccumulation data conducted under the METI scheme is admissible. Media Services can arrange for a consultation about this at METI. If the chemical structures are not considered close enough for METI to agree to miss out the bioaccumulation study they may agree to a shortened version of the study.

If evaluation of bioacumulation by analogy is not applicable, the next option is to consider using Pow. This is considered a predictor of bioaccumulation only if the substance satisfies certain conditions, as specified in the CSCL. The flask-shake Pow method must be used. For substances with ionisable groups there are equations based on the measured pH of the aqueous phase in the Pow determination and the pKa to decide whether the substance is not ionised and hence whether Pow is a valid indicator of bioaccumulation.

If the two previous approaches fail, bioaccumulation has to be assessed be conducting a fish bioaccumulation study. There may be analytical difficulties in conducting such studies because the test material has to be measured at low concentrations in both water and fish.

If the measured bioconcentration factor (BCF) is less then ca. 500, the substance is not regarded as bioaccumulative. An elimination test is needed if the BCF is greater than 1000, and METI reach a decision on whether a substance is bioaccumulative based on all the measured parameters. Bioaccumulative substances require full safety toxicity testing and would not normally be progressed.

Assuming the substance (or its environmental metabolite) is not bioaccumulative the final step is to undertake the "screening" toxicity studies. These are the 28-day repeated dose oral toxicity, Ames test and in vitro chromosome aberration tests. These are conducted to MHLW methods.

It is essential that full compositional data is available. In particular, the impurity profile is needed. Any impurity present at above 1% is treated as a potentially notifiable component of a mixture. Hence, any such impurity has to be in the inventory or notified separately. MHLW may also require the screening toxicity studies for an existing substance present as as impurity at above 1%.

The outcome of the studies will either be that the substance is "safe" or "designation". Designation is based on either NOEL in the 28-day study or a points system from the combined mutagenicity studies.

The Industrial Safety and Health Law (ISHL) applies to chemicals used in the workplace. The scheme is administered by MHLW but commonly referred to as the ‘MoL’. scheme. It applies where a substance is manufactured or used in the workplace.

Mutagenicity and carcinogenicity are the main criteria of the ISHL notification. For a full ISHL notification normally only an Ames test is needed (done to meet the minimum Japanese requirements). If the test result is negative, or positive with <<1000 revertants/mg, notification will be approved by MHLW without further requirements. Only when the results are near or above 1000 revertants/mg is an additional mutagenicity test needed; i.e. an in vitro chromosome aberration test in CHL or CHO cells. Assuming this second in vitro test in negative, MoL will probably ask for further tests, bit if it is positive MoL will make a special "Administrative Guidance" and/or require in vivo testing.

The same comments apply to mutagenicity studies as for the METI / MHLW scheme.

This work is undertaken by our Japanese agents, Media Services Ltd. The Techno-Support Group of this company is staffed by highly experienced scientists dedicated specifically to SafePharm's business in Japan, and to work associated with the notification of new chemicals. They provide a full service covering preliminary discussions with METI / MHLW, translation of reports, preparation of the technical dossier, submission of the notification, and attendance at METI / MHLW hearings. MoL notification work is also undertaken.