By Little Pro on 2016-07-20 Views: Update:2018-02-09
Chemical intermediates are a common necessity during the synthesis of many products such as pesticides, pharmaceuticals and cosmetic ingredients. Under chemical control regulations (i.e, REACH), an intermediate is defined as a substance that is manufactured for and consumed in or used for chemical processing in order to be transformed into another substance or product. In this article, we will summarize the exposure characteristics of intermediates and registration requirements for intermediates in EU, USA, Japan, China and Korea.
Unlike regular chemical substances, intermediates are consumed in subsequent chemical reactions after they have been manufactured and they are usually not present in a final substance or product (unless as residue impurities). During the life-cycle stage of an intermediate (from production to consumption), only workers may be exposed to it (no exposure to the general public). Intentional release to various environmental compartments (water, air, soil) is unlikely and the quantity released is also very low. Compared to a regular substance, an intermediate poses very low risk if its exposure to workers and unintentional release to environment is properly managed, which would justify for reduced data requirement for registration.
There are 3 types of intermediates. Their regulatory requirements may be different in each country. Their definitions are listed as follows:
|Non isolated intermediates||An intermediate that during synthesis is not intentionally removed/separated (except for sampling) from the equipment in which the synthesis takes place.||Usually out of scope|
|No-site isolated intermediates||An intermediate not meeting the criteria of a non isolated intermediate and where the manufacture of the intermediate and the synthesis of (an)other substance(s) from that intermediate take place on the same site.|
|Transported isolated intermediates||An intermediate not meeting the criteria of a non isolated intermediate and transported between or supplied to other sites.|
It should be pointed out that monomers/reactants used to produce polymers are not regarded as intermediates in Europe.
|On-site /transported isolated intermediates manufactured or used under strictly controlled conditions (SCC*)||<1t/y: exempt;
1-1,000t/y: providing available data;
1,000t/y: providing standard 1-10t/y registration data.
|Reduced data requirement. Manufacturer or/and downstream user needs to provide SCC confirmation letter.|
|Isolated intermediates not manufactured or used under strictly controlled conditions (SCC*)||<1t/y: exempt;
>1t/y: standard REACH registration data requirement.
|Data requirement increases with tonnage bands. Qsar accepted.Testing proposal accepted for high tier studies.|
To assess if an isolated intermediate qualifies for reduced data requirements, a registrant shall assess if the intermediate meets the following strictly controlled conditions (SCC*) :
According to ECHA's 2013 registration statistics, among 9,099 registrations received before May 2013, about 1,867 registrations are reduced intermediate registrations.
|On-site /transported isolated intermediates with low environmental releases and human exposures.||Low Releases and Low Exposures (LoREX) Exemption||Must meet low release and exposure criteria (*)|
|Other isolated intermediates||Submit specialintermediate pre-manufacture notice (PMN) or regular PMN||Provide available data only. Lower fee for intermediate PMN than regular PMN.|
It should be noted that TSCA only requires pre-market approval of new chemical substances. When applying for LoREX exemption for isolated intermediate under TSCA, the submitter must show that there are no exposures to consumers and low or no exposures to the general public inherent in the proposed manufacturing, processing, or uses of the substance, and that any worker exposure which is likely to occur will be adequately controlled through use of engineering controls, work practices, and/or personal protective equipment.
If an isolated intermediate does not qualify for LoREX exemption, applicants can submit special type of intermediate PMNs and provide available data only. The fee for intermediate notification is lower than regular PMN.
Reference 1: EPA LoREX for New Chemicals Review under TSCA
Reference 2: EPA FAQs on New Chemicals Review
|On-site /transported isolated intermediates||Application of confirmation on exemption||Provide detailed info showing that protective measures have been taken to prevent the substance from being released to the environment.|
It should be noted that Japan CSCL only requires registration of new chemical substances. If an isolated intermediate does not meet the criteria for exemption, a standard new substance notification needs to be submitted. Data requirement for new substance notification in Japan can be found here.
Reference 1: METI summary of new substance notification in Japan.
|On-site isolated intermediates||Exempt from notification||Treated the same as non isolated intermediates.|
|Transported Isolated intermediates||<1t/y: simplified notification
>1t/y: regular notification
|Data requirement increases with tonnage band. Testing proposals not accepted.|
It should be noted that China only requires notification of new chemical substances. Unlike EU, US and Japan, China MEP order 7 does not distinguish transported isolated intermediates from regular substances.
|On-site isolated intermediates||Application of prior confirmation on exemption|
|Transported isolated intermediates (*)||<1t/y: simplified notification
>1t/y: standard registration
|Data requirement increases with tonnage band. QSAR and testing proposals accepted.|
Under K-REACH presidential decree, there is only definition for isolated intermediate. It is generally regarded that the isolated intermediate in K-REACH refers to "on-site isolated intermediate". Like China, Korea does not differentiate transported isolated intermediates from regular chemical substances either. The difference is that Korea accepts testing proposals for high-tier studies and QSARs. Companies can submit testing proposals first, gain registrations, engage in production or import and provide higher tier studies later.
Reference 1: K-REACH Presidential Decree
In conclusion, EU, USA and Japan's intermediate registration requirements have all taken into account of the intermediate's low exposure characteristics. China's registration requirement is the highest due to the fact that it does not differentiate transported isolated intermediate from regular substances and it does not accept QAR or testing proposals. Compared to EU, USA and Japan, Korea's registration requirement for transported isolated intermediate is also high.