IGF-1 LR3 — identity, handling and published literature

IGF-1 LR3 is a recombinant 83-residue analogue of human insulin-like growth factor 1, supplied as a sterile-filtered lyophilised powder for laboratory use.

Presentation and physical properties

IGF-1 LR3 is a single-chain, non-glycosylated polypeptide of 83 amino acid residues. It consists of the complete 70-residue mature human IGF-1 sequence carrying an arginine-for-glutamate substitution at position 3, preceded by a 13-residue N-terminal extension. The extension is derived from the first thirteen residues of porcine somatotropin, with methionine at position 1 and valine at position 12. The FDA Substance Registration System records the molecule systematically as 1-13-somatotropin (swine reduced), 1-L-methionine-12-L-valine-, (13→1′)-protein with 3-L-arginine insulin-like growth factor I (human), which is the most precise published statement of its construction.

Both modifications sit in the region of IGF-1 that contacts the insulin-like growth factor binding proteins (IGFBPs). Reduced IGFBP affinity relative to native IGF-1 is the property the analogue was designed around and the property the founding characterisation paper set out to measure [1].

The molecule retains the disulfide architecture of native IGF-1: three intramolecular bonds, reported in IGF-1 residue numbering as Cys6–Cys48, Cys18–Cys61 and Cys47–Cys52. In the 83-residue numbering of the analogue each of those positions is shifted by thirteen. The disulfide folding pathway of the IGF-1 scaffold has itself been studied as a protein-chemistry problem [6], which is relevant to any laboratory assessing whether a given lot is correctly folded rather than merely the correct mass.

The published single-letter sequence is:

MFPAMPLSSLFVNGPRTLCGAELVDALQFVCGDRGFYFNKPTGYGSSSRRAPQTGIVDECCFRSCDLRRLEMYCAPLKPAKSA

Two distinct commercial supply routes exist for this molecule and they are not the same material. It is sold as a laboratory research reagent, and separately as a cell-culture-grade supplement for serum-free and low-serum mammalian cell culture, where manufacturers document use with CHO, HEK 293, Vero and MDCK lines. The cell-culture-grade formulations are buffered and stabilised differently from the plain lyophilisate and carry different storage claims. Do not read handling data across from one to the other.

Reconstitution arithmetic

What follows is arithmetic on a 1 mg vial and nothing more. Concentration is mass divided by volume; the figures below are that division carried out, with no statement about what quantity is appropriate for any purpose.

A 1 mg vial contains 1,000 µg of peptide. Adding a volume V of diluent gives a nominal concentration of 1,000 ÷ V µg per mL, before any correction for the small volume displaced by the solid itself.

Two arithmetical cautions. First, the figures assume the full labelled mass is present and fully dissolved; a peptide that has adsorbed to the vial wall or has not gone fully into solution will give a lower real concentration than the calculation states. Second, at the low concentrations that follow from large diluent volumes, adsorptive loss to glass and plastic is proportionally larger, which is why supplier documentation for this molecule recommends a carrier protein for dilute stocks.

Supplier reconstitution documentation for the plain lyophilisate specifies sterile 18 MΩ·cm water, with further dilution into other aqueous solutions afterwards.

Storage and stability

Manufacturer and supplier documentation for the research-grade lyophilisate is consistent on the following points:

• Lyophilised powder. Stored desiccated below −18 °C for long-term storage. One major catalogue supplier specifies −20 °C. The dry powder tolerates short periods at ambient temperature, which is why it ships without a cold chain, but that tolerance is not a storage condition.
• Reconstituted solution. 2–8 °C for a working period of the order of two to seven days; below −18 °C for longer.
• Carrier protein. Addition of 0.1% HSA or BSA is recommended for long-term storage of solutions, to limit adsorptive loss.
• Freeze-thaw. Repeated freeze-thaw cycles are to be avoided. Aliquot before freezing.

The three disulfide bonds are the structural feature most at risk in handling. Reducing agents, strongly alkaline conditions and prolonged storage in solution all act against correct pairing, and a reduced or scrambled molecule will still return approximately the right intact mass on a crude measurement while being a different substance. Where folding matters, it has to be assessed directly.

Cell-culture-grade preparations of the same molecule are formulated for 2–8 °C stability and ambient shipping. That claim belongs to those formulations and does not transfer to plain lyophilised research material.

Analytical identity

Identity for this molecule is a harder problem than for a short synthetic peptide, because it is a recombinant protein with a native-sequence core, and because the analytical question is usually not “is this a peptide” but “is this the analogue rather than native IGF-1, and what else is in the vial”.

• Mass spectrometry is the method that resolves the substitution and the extension. Intact-mass measurement separates the 83-residue analogue from the 70-residue native sequence by roughly 1.5 kDa; peptide mapping after digestion resolves the Arg-for-Glu substitution and the composition of the N-terminal extension.
• Immunoassay is not a sufficient identity test. Manufacturers of ELISA kits raised against this analogue state limited reactivity to native or recombinant IGF-1, which is a design feature of those particular kits, not a general property of anti-IGF-1 antibodies. A generic IGF-1 immunoassay cannot be relied upon to distinguish the two molecules in either direction.
• Purity is reported by suppliers by SDS-PAGE, typically at >98% for research-grade material, with RP-HPLC used alongside it. Neither method addresses disulfide isomers, which co-migrate and co-elute closely.
• Expression-system residues. Because the molecule is produced in E. coli, endotoxin, residual host cell protein and affinity-tag remnants are the realistic contaminants. This is not theoretical: Kohler and colleagues, analysing a black-market injection vial by immunoaffinity purification and mass spectrometry, identified the contents as Long-R³-IGF-I carrying a His-tag, and concluded that the material was most likely a by-product of biochemical research rather than something manufactured for injection [20]. A tagged construct is a different molecule from the untagged one and will not be flagged by a purity figure.

What the published literature investigated

In vitro and receptor-level studies

The founding characterisation is Francis and colleagues, 1992, who produced a series of recombinant fusion-protein analogues of IGF-1 — Long R³ among them — and compared them with authentic IGF-1 in rat L6 myoblasts. They reported that all the analogues were more potent than authentic IGF-1 in stimulating protein and DNA synthesis, and that the relative potency of a given variant depended substantially on its interaction with IGF-binding proteins, being most pronounced in cultures that secrete IGFBPs into the medium [1]. The paper’s stated purpose was to separate the contribution of binding-protein interaction from that of receptor binding, and that framing has governed the literature since.

Later in vitro work qualified the picture. Devi and colleagues examined the effect of IGFBP-3 on the initial steps of IGF-1 receptor signalling and reported that IGFBP-3 inhibited IGF-1-, IGF-II-, Des(1-3)IGF-I- and Long(R³)IGF-I-induced receptor phosphorylation in a dose-dependent manner over a similar concentration range. They concluded that the effect was attributable to sequestration of the ligand rather than to any direct interaction between IGFBP-3 and the receptor [2]. Reduced binding-protein affinity is therefore not the same as immunity to binding-protein regulation, at least in that system.

Comparable studies in myogenic cell culture examined recombinant porcine IGFBP-3 [3] and IGFBP-5 [4] against both IGF-1 and Long-R³-IGF-I. Separately, Bryant and colleagues used site-directed mutagenesis to produce long-R³-IGF-I muteins resistant to pepsin digestion, identifying five susceptible cleavage sites and reporting that a Phe16Ala variant showed marked improvement in stability across a range of pepsin-to-substrate ratios while retaining growth-promoting activity in their assay [5].

Rodent studies

The rodent literature is concentrated in the 1990s and comes largely from a small group of Australian laboratories. Two catabolic models dominate. In dexamethasone-treated rats, Tomas and colleagues reported that IGF-1 partially reversed the induced catabolic state, and that two IGF-1 analogues with reduced IGFBP binding were approximately 2.5 times as potent as IGF-1 on their endpoints [7]; Read and colleagues reported marked gut growth in the same model with N-terminally modified analogues [8]. In streptozotocin-induced diabetic rats, the same group reported that IGF-1 and its variants increased growth rate and nitrogen balance dose-dependently, with the variants 2.5 to 3 times as potent as IGF-1 at restoring growth, while not reproducing insulin’s effects on glucose excretion or muscle breakdown markers [9]. A further study examined protein and energy metabolism in tumour-bearing rats [10].

A second cluster concerns the gastrointestinal tract. Steeb and colleagues reported that three days of administration stimulated proliferation of the small intestinal epithelium in rats [11], and that systemic infusion of IGF-1 or LR³IGF-I stimulated visceral organ growth and proliferation of gut tissues in suckling rats [12]. A subsequent paper is explicit about route: intestinal disaccharidase activity was stimulated by systemically but not orogastrically delivered IGF-1 and long[Arg³]IGF-I [13].

In guinea pigs, Conlon and colleagues reported that infusion stimulated organ growth but reduced circulating IGF-1, IGF-II and IGF binding protein concentrations [14]. In lactating mice, Hadsell and colleagues reported that Long-R³-IGF-I increased mammary phospho-Akt and SOCS3 gene expression and had what they described as a modest ability to increase lactation capacity, with murine growth hormone producing the larger effect on that endpoint [15].

Large-animal studies, and a direct species contradiction

The pig literature does not agree with the rat literature, and the disagreement is stated in the primary sources rather than inferred. Dunaiski and colleagues open their 1997 paper by noting that analogues of IGF-1 which bind poorly to IGFBPs stimulate growth in the rat but, in contrast, inhibit growth in the pig. Their four-day infusion of Long[R³]IGF-I in finisher pigs decreased average daily gain, food intake, and plasma IGFBP-3, IGF-1 and insulin concentrations; mean plasma growth hormone concentration fell by 23% and the area under the growth hormone peaks by 60%. Co-administration of porcine growth hormone did not restore growth performance [16].

Dunshea and colleagues reached a mixed result in a different pig model. Across two infusion experiments in artificially reared neonatal pigs, there was no overall effect on daily weight gain or slaughter weight in the first experiment; in the second, over the later nine days of an eighteen-day protocol, daily weight gain was higher in LR³IGF-I-infused pigs (457 versus 386 g/day) but not in those infused with IGF-1. The authors conclude that the growth factors increased growth rate and milk intake in pigs fed ad libitum but not in limit-fed piglets [17], which makes the result conditional on feeding regime.

Two further studies sit outside these models: a report on the response of isolated ruminant mammary arteries to the analogue [18], and a study of clearance of IGFs and insulin from wounds in an animal wound model, examining the effect of binding-protein interactions on clearance rate [19].

Human studies

There are none. See the following section.

Sport and anti-doping literature

Guha and colleagues, reviewing IGF-1 misuse in athletes, record that a variety of IGF-1 compounds and IGF-1 analogues are advertised on the internet and have been available on the black market for several years, and that at the time of writing no test was in place for detecting IGF-1 misuse, with marker-based and mass-spectrometric approaches under development by the GH-2004 research group [21]. A later review covers growth hormone and IGF-1 together in the same context [22]. The Kohler analytical case discussed above [20] is the documented instance of a Long-R³-IGF-I product being recovered from that market and characterised.

Evidence gaps and limitations

These are absences, not uncertainties, and they should be read literally.

• No human clinical trial has ever administered IGF-1 LR3 to human subjects. A PubMed search restricted to human and clinical-trial publication types returns no study in which this molecule was given to people. There is consequently no human pharmacokinetic data, no human dose-response relationship, no human safety database, no adverse event profile, and no established maximum recommended dose. Nothing published permits any statement about what this substance does in a human being.
• The animal literature does not converge. Rats and pigs give opposite directional results on growth, and the primary sources say so. That contradiction has not been resolved; it has simply been left standing since 1997.
• The evidence base is old and narrow. The bulk of the in vivo work was published between 1992 and 2002 by a small number of connected laboratories, using continuous-infusion designs in catabolic, diabetic, neonatal or lactating animals. The endpoints are organ mass, gut mucosal growth, nitrogen balance and feed intake. No published study examines athletic performance, body composition in healthy adults, or anything resembling the uses for which the molecule is traded.
• The mechanistic premise is contested in its own literature. Reduced IGFBP affinity is the design rationale, but Devi and colleagues reported IGFBP-3 inhibiting Long(R³)IGF-I-induced receptor phosphorylation over the same concentration range as native IGF-1 [2].
• No carcinogenicity, genotoxicity or reproductive toxicology data exist for this molecule. The relationship between the IGF-1 axis and neoplasia is an active question in the wider literature, and none of that work is about IGF-1 LR3.
• There is no pharmacopoeial monograph. No European Pharmacopoeia, British Pharmacopoeia or USP monograph exists, so there is no compendial identity, purity or assay standard against which a lot can be judged. Specifications are set by individual suppliers.
• Material circulating outside the research-reagent supply chain has been shown to be something other than what it was sold as — a His-tagged construct, in the one published characterisation [20].
• Nothing establishes equivalence with mecasermin. The authorised recombinant human IGF-1 medicine is the native 70-residue sequence. It is a different molecule, and its clinical trial base says nothing about this one.

Regulatory and standards position

Marketing authorisation

IGF-1 LR3 holds no marketing authorisation in the United Kingdom, the European Union, the United States or, so far as can be determined, any other jurisdiction. It has never been the subject of an approved application to any medicines regulator. It is not an authorised medicine, an unlicensed medicinal product with a named-patient route, or an investigational medicinal product with an open trial.

The authorised IGF-1 product is a different substance. Mecasermin — recombinant human IGF-1, the native 70-residue sequence — is authorised as Increlex for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. It holds an EU centralised marketing authorisation granted on 2 August 2007, currently held by Esteve Pharmaceuticals, S.A.; it holds a Great Britain marketing authorisation with a Summary of Product Characteristics published on the electronic Medicines Compendium; and it is approved in the United States under NDA 021839. None of that authorisation extends to IGF-1 LR3, which differs from mecasermin by a 13-residue N-terminal extension and a substitution at position 3.

Controlled-drug status in the United Kingdom

IGF-1 LR3 is not a controlled drug in the United Kingdom. Neither insulin-like growth factor 1 nor any IGF-1 analogue appears in Schedule 2 to the Misuse of Drugs Act 1971.

This is worth stating precisely, because the compound sits in the growth-hormone axis and the two are frequently conflated. Somatotropin, somatrem and somatropin are listed, as Class C drugs in Part III of Schedule 2 to the Act, and somatropin sits in Schedule 4 Part II of the Misuse of Drugs Regulations 2001. IGF-1 and its analogues are not in either instrument. The absence of controlled-drug status says nothing about medicines law, which applies independently.

Anti-doping

IGF-1 LR3 is prohibited in sport as an analogue of IGF-1. The 2026 World Anti-Doping Code Prohibited List, in force from 1 January 2026, lists under S2.3 Growth Factors and Growth Factor Modulators, “including, but not limited to”:

Insulin-like growth factor 1 (IGF-1, mecasermin) and its analogues

S2.3 falls within class S2, Peptide Hormones, Growth Factors, Related Substances, and Mimetics, of which the List states: “All prohibited substances in this class are prohibited at all times (in- and out-of-competition). All prohibited substances in this class are non-Specified Substances.” Prohibition at all times means in-competition and out-of-competition alike; non-Specified status carries the stricter sanctioning consequences under Article 10 of the Code.

The category is closed by a catch-all covering “other growth factors or growth factor modulators affecting muscle, tendon or ligament protein synthesis/degradation, vascularisation, energy utilization, regenerative capacity or fibre type switching”, so a novel analogue is not outside the List merely by being novel.

Presentation and medicines law

Under the Human Medicines Regulations 2012 and MHRA Guidance Note 8, a product may become a medicinal product by presentation on the strength of the claims made for it, independently of its composition — the principle applied in Ter Voort (C-219/91). A substance with no authorisation, no human data and no pharmacopoeial standard cannot lawfully be presented as having any effect on the human body. That constraint is a function of what is said about the material, not of what the material is.

Documented enforcement and market analysis

The published record of enforcement activity specific to this molecule is thin. The clearest documented instance is the Kohler analysis of a seized black-market injection vial containing His-tagged Long-R³-IGF-I, published in the anti-doping analytical literature [20]. Contemporary review literature records IGF-1 analogues as established black-market commodities [21].

Laboratory handling and safety

IGF-1 LR3 is a research reagent. It is not supplied sterile for injection, has no assigned occupational exposure limit, and has no harmonised CLP classification. A COSHH assessment is required before use in a UK laboratory, and it should be written against the fact that toxicological data on this specific molecule are absent rather than reassuring.

• Weighing and reconstitution. Lyophilised protein is a fine, readily airborne powder. Open vials in a biological safety cabinet or under local exhaust ventilation. Inhalation of aerosolised protein carries a respiratory sensitisation risk that is generic to protein handling and is not quantified for this substance.
• Personal protective equipment. Nitrile gloves, laboratory coat, eye protection. Avoid skin and mucosal contact.
• Bacterial expression residues. Material produced in E. coli may carry endotoxin, host cell protein and affinity-tag sequences. Treat any lot without a lot-specific endotoxin figure as endotoxin-unqualified.
• Solution handling. Use low-protein-binding tubes and tips. Aliquot before freezing. Add carrier protein where dilute stocks are to be stored. Avoid repeated freeze-thaw.
• Cross-contamination. A potent growth factor introduced into a shared cell-culture facility can confound unrelated experiments at very low carry-over. Dedicate consumables and decontaminate surfaces after use.
• Waste. Dispose of vials, solutions and contaminated consumables as laboratory chemical waste under local arrangements. Do not discharge to drain.
• Records. Retain the lot number, supplier specification and reconstitution date against every prepared solution. Where no compendial standard exists, provenance is the only identity record available.

References

1. Francis GL, Ross M, Ballard FJ, Milner SJ, Senn C, McNeil KA, Wallace JC, King R, Wells JR. Novel recombinant fusion protein analogues of insulin-like growth factor (IGF)-I indicate the relative importance of IGF-binding protein and receptor binding for enhanced biological potency. Journal of Molecular Endocrinology. 1992;8(3):213–23. In vitro (rat L6 myoblasts). PMID 1378742
2. Devi GR, Graham DL, Oh Y, Rosenfeld RG. Effect of IGFBP-3 on IGF- and IGF-analogue-induced insulin-like growth factor-I receptor (IGFIR) signalling. Growth Hormone & IGF Research. 2001;11(4):231–9. In vitro. PMID 11735239
3. Xi G, Kamanga-Sollo E, Pampusch MS, White ME, Hathaway MR, Dayton WR. Effect of recombinant porcine IGFBP-3 on IGF-I and long-R3-IGF-I-stimulated proliferation and differentiation of L6 myogenic cells. Journal of Cellular Physiology. 2004;200(3):387–94. In vitro. PMID 15254966
4. Pampusch MS, Xi G, Kamanga-Sollo E, Loseth KJ, Hathaway MR, Dayton WR, White ME. Production of recombinant porcine IGF-binding protein-5 and its effect on proliferation of porcine embryonic myoblast cultures in the presence and absence of IGF-I and Long-R3-IGF-I. Journal of Endocrinology. 2005;185(1):197–206. In vitro. PMID 15817840
5. Bryant KJ, Read LC, Forsberg G, Wallace JC. Design and characterisation of long-R3-insulin-like growth factor-I muteins which show resistance to pepsin digestion. Growth Factors. 1996;13(3–4):261–72. In vitro. PMID 8919033
6. Milner SJ, Carver JA, Ballard FJ, Francis GL. Probing the disulfide folding pathway of insulin-like growth factor-I. Biotechnology and Bioengineering. 1999;62(6):693–703. In vitro (protein chemistry). PMID 9951525
7. Tomas FM, Knowles SE, Owens PC, Chandler CS, Francis GL, Read LC, Ballard FJ. Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats. Biochemical Journal. 1992;282(Pt 1):91–7. Rodent (rat). PMID 1371669
8. Read LC, Tomas FM, Howarth GS, Martin AA, Edson KJ, Gillespie CM, Owens PC, Ballard FJ. Insulin-like growth factor-I and its N-terminal modified analogues induce marked gut growth in dexamethasone-treated rats. Journal of Endocrinology. 1992;133(3):421–31. Rodent (rat). PMID 1613443
9. Tomas FM, Knowles SE, Owens PC, Chandler CS, Francis GL, Ballard FJ. Insulin-like growth factor-I and more potent variants restore growth of diabetic rats without inducing all characteristic insulin effects. Biochemical Journal. 1993;291(Pt 3):781–6. Rodent (rat). PMID 7683875
10. Tomas FM, Chandler CS, Coyle P, Bourgeois CS, Burgoyne JL, Rofe AM. Effects of insulin and insulin-like growth factors on protein and energy metabolism in tumour-bearing rats. Biochemical Journal. 1994;301(Pt 3):769–75. Rodent (rat). PMID 8053901
11. Steeb CB, Trahair JF, Read LC. Administration of insulin-like growth factor-I (IGF-I) peptides for three days stimulates proliferation of the small intestinal epithelium in rats. Gut. 1995;37(5):630–8. Rodent (rat). PMID 8549937
12. Steeb CB, Shoubridge CA, Tivey DR, Read LC. Systemic infusion of IGF-I or LR(3)IGF-I stimulates visceral organ growth and proliferation of gut tissues in suckling rats. American Journal of Physiology. 1997;272(3 Pt 1):G522–33. Rodent (rat). PMID 9124573
13. Steeb CB, Lamb J, Shoubridge CA, Tivey DR, Penttila I, Read LC. Systemically but not orogastrically delivered insulin-like growth factor (IGF)-I and long [Arg3]IGF-I stimulates intestinal disaccharidase activity in two age groups of suckling rats. Pediatric Research. 1998;44(5):663–72. Rodent (rat). PMID 9803447
14. Conlon MA, Tomas FM, Owens PC, Wallace JC, Howarth GS, Ballard FJ. Long R3 insulin-like growth factor-I (IGF-I) infusion stimulates organ growth but reduces plasma IGF-I, IGF-II and IGF binding protein concentrations in the guinea pig. Journal of Endocrinology. 1995;146(2):247–53. Rodent (guinea pig). PMID 7561636
15. Hadsell DL, Parlow AF, Torres D, George J, Olea W. Enhancement of maternal lactation performance during prolonged lactation in the mouse by mouse GH and long-R3-IGF-I is linked to changes in mammary signaling and gene expression. Journal of Endocrinology. 2008;198(1):61–70. Rodent (mouse). PMID 18577570
16. Dunaiski V, Dunshea FR, Walton PE, Goddard C. Long [R3] insulin-like growth factor-I reduces growth, plasma growth hormone, IGF binding protein-3 and endogenous IGF-I concentrations in pigs. Journal of Endocrinology. 1997;155(3):559–65. Large animal (pig). PMID 9488001
17. Dunshea FR, Chung CS, Owens PC, Ballard JF, Walton PE. Insulin-like growth factor-I and analogues increase growth in artificially-reared neonatal pigs. British Journal of Nutrition. 2002;87(6):587–93. Large animal (pig). PMID 12067429
18. Gow IF. Response of isolated ruminant mammary arteries to the long R3 analogue of insulin-like growth factor I. Experimental Physiology. 2000;85(3):275–9. Ex vivo (ruminant tissue). PMID 10825414
19. Robertson JG, Belford DA, Ballard FJ. Clearance of IGFs and insulin from wounds: effect of IGF-binding protein interactions. American Journal of Physiology. 1999;276(4):E663–71. In vivo (animal wound model). PMID 10198302
20. Kohler M, Thomas A, Walpurgis K, Terlouw K, Schänzer W, Thevis M. Detection of His-tagged Long-R³-IGF-I in a black market product. Growth Hormone & IGF Research. 2010;20(5):386–90. Analytical characterisation of a seized product. PMID 20675162
21. Guha N, Cowan DA, Sönksen PH, Holt RI. Insulin-like growth factor-I (IGF-I) misuse in athletes and potential methods for detection. Analytical and Bioanalytical Chemistry. 2013;405(30):9669–83. Review. PMID 23934394
22. Nicholls AR, Holt RI. Growth Hormone and Insulin-Like Growth Factor-1. Frontiers of Hormone Research. 2016;47:101–14. Review. PMID 27347885

Research use only

IGF-1 LR3 is supplied strictly as a laboratory chemical for research use only. It is not a medicinal product and holds no marketing authorisation in the United Kingdom or elsewhere. It is not authorised, licensed or approved for human or veterinary use, for administration to any person or animal, for diagnostic use, for household use, or for use as a food, food ingredient or dietary supplement.

Nothing on this page is a recommendation to administer this substance, a statement that it produces any effect in a human being, or guidance on quantity, route or frequency of administration. The reconstitution figures above are arithmetic on the contents of a vial and nothing more. This page reports what has been published about a substance; it makes no claim that the substance does anything.

Purchase and possession of research chemicals carry legal obligations that rest with the purchaser, including any institutional, COSHH and waste-disposal requirements applicable at the place of use.