Health and Safety
Executive / Commission
RIA: Chemicals
Issue and Objectives
1. Piperazine is a white or transparent crystalline compound with a boiling point of 148 C at 100 Kpa and vapour pressure of 0.28 KPa at 20 C.
2. Piperazine is included in the First Indicative Occupational Exposure Limit Values (IOELV) Directive. The IOELVs are 0.1 mg.m-3 as an 8-hour TWA, and 0.3 mg.m-3 as a 15-minute STEL. Member states are required to have set national occupational exposure limits for piperazine that take into account the IOELVs by 31 December 2001.
3. There is currently no Occupational Exposure Limit (OEL) for piperazine. However, there is an occupational exposure standard (OES) for piperazine dihydrochloride of 5 mg.m-3 8-hour TWA (but no STEL). Given that the risk management conclusions reached for piperazine may also have implication for piperazine dihydrochloride, the ultimate objective is to replace this OES with a Maximum Exposure Limit (MEL) for piperazine and piperazine dihydrochloride. Proposals to this effect are due to be included in a consultative document which will be placed on the HSE website in March 2001.
4. This RIA document will inform ACTS as to the financial consequences of this proposed procedure.
5. From the limited toxicology data available, the potential to cause asthma is identified as the key health effect for piperazine. In HSE's opinion, it is not possible to determine the threshold exposure level for piperazine-induced asthma. Thus, HSE feels that indicative criterion 1 for an OES is not met.
6. Following on from this position, in HSE's opinion the ability to induce asthma is sufficiently serious to warrant consideration of a MEL. Because both an 8hr TWA IOELV and a STEL IOELV have been set, British OELs for both 8hr TWA and 15-minute STEL reference periods must be established in order to meet the terms of the First IOELV Directive.
7. Considering other toxicology endpoints, piperazine appears to be of low systemic toxicity following short and long term exposure. However, it is corrosive and causes sensitisation by skin contact. The available evidence suggests that piperazine is not genotoxic. There is very little information on carcinogenicity and reproductive toxicity, but what is available does not raise concerns.
8. In relation to other risk management measures, there are no experimental data on the dermal absorption of piperazine. A consideration of the physico-chemical properties (Log P= -0.17, water solubility=150 g.L-1) indicate that there is some potential for uptake via this route. However, in view of the low systemic toxicity of this substance it is considered unlikely that dermally absorbed piperazine has the potential to contribute to systemic toxicity. Consequently, HSE's view is that a "Sk" notation is not required. Piperazine causes occupational asthma, so a "Sen" notation is required.
9. Regarding the toxicity of piperazine dihydrochloride, very little information is available and a read-across from the piperazine data must be considered. Although there are likely to be quantitative differences between the toxicities of piperazine and the dihydrochloride because of toxicokinetic differences, nevertheless it is reasonable to assume, in the absence of information to the contrary, that their effects will be qualitatively similar. Therefore, it is assumed that the dihydrochloride salt will also have the potential to cause asthma. For the dihydrochloride, there are no data available from which to attempt to explore a no-effect level for this presumed hazard.
Production and Use
10. There is no production of piperazine in the UK. Currently, about 100 to 150 Te/yr of piperazine are imported for use by the UK chemical process industry. There are less than five importers/distributors and less than ten user plants in the UK. The total number of workers at these sites who may be exposed to piperazine is estimated to be less than 50.
11. There is no production of piperazine dihydrochloride in the UK. About 1 Te/yr of piperazine dihydrochloride is imported to the UK. There is one importer/distributor and one repackager in the UK. The total number of workers at these sites who may be exposed is estimated to be less than 5. There are, however, numerous veterinary practices that will administer the dihydrochloride salt to animals.
12. Piperazine is currently used in the UK in the manufacture of: anthelminitics (dewormers) in veterinary and human medicine; the manufacture of polyamide hot melt adhesives; and, the manufacture of an amine derivative for use as a corrosion inhibitor in the offshore oil industry.
13. Piperazine is delivered to user plants in either 25, 50 or 100 kg kegs and stored in a designated storage area until needed. When required, a sealed keg is withdrawn from the storage area and taken to either: (1) a weighing room where small batch dry chemical mixes incorporating piperazine are made up for onward dispatch to a reactor vessel; or (2) a reactor vessel into which the entire piperazine content of the keg is poured either manually or remotely.
14. Piperazine is processed in reactor vessels at atmospheric pressure and at temperatures varying from ambient (typically 20 oC) to 60 oC to produce a chemical intermediate. Typically, the piperazine is fully reacted in the process and no residual piperazine remains so there is usually no risk of exposure to piperazine from the final product.
15. Piperazine dihydrochloride is imported in 25 kg kegs and repackaged into 1 kg packs for use by veterinary practices as an anthelminitic medicine.
(i) Use of piperazine in small batch processes
16. Small batch processes do not require the addition of a complete 25 kg keg of piperazine. In such cases, the required amount of piperazine is weighed out in a dedicated weighing and mixing room together with other additives to form a dry chemical mix.
17. For example, one company consulted adds it to sugar and other additives before adding the mix to water in an open topped mixer vessel at ambient temperature (typically 20 oC) to produce an anthelminitic (dewormer) medicine for humans. Typically, one batch is produced every three months. LEV is provided in the weighing and mixing room and the employees wear overalls and particulate respirators.
(ii) Use of piperazine in large batch processes
18. Large batch processes undertaken using piperazine as an intermediate all require the addition of several kegs of piperazine directly into a chemical reactor vessel, which is maintained typically at a temperature of about 60 0C.
19. For example, one company consulted add 1 Te (twenty 50 kg kegs) of piperazine to an acidic solution to produce a polyamide hot melt resin and run two batches per week. Two men are employed for about one hour per batch charging the reactor with piperazine. By comparison, a second company consulted add 600 kg (twelve 50 kg kegs) of piperazine to a chemical solution to produce an amine derivative but produce only three batches per year. The charging of the reactor takes about thirty minutes.
20. In both examples, the kegs are transferred by forklift truck from the storage area directly to the vessel charge port where the workers open the kegs and empty the piperazine into the vessel. LEV is provided at this point and the workers wear overalls, PVC gloves and air-fed rpe.
(iii) Repackaging of piperazine dihydrochloride
21. Piperazine dihydrochloride is delivered in 25 kg kegs to one UK company who repackage it into 1 kg packs for use by veterinary practices. The required amount of piperazine dihydrochloride is weighed out in a dedicated weighing and packing room. LEV is provided in the weighing and packing room and the employees wear overalls and particulate respirators.
(iv) Dispensing of piperazine dihydrochloride
22. Typically, workers at veterinary practices can pour and dissolve a 1 kg pack of the dihydrochloride salt into water in thirty seconds. No LEV is provided and workers do not wear RPE.
Exposure to hazard and methods of control
23. Validated methods for sampling and analysis of concentrations of piperazine or piperazine dihydrochloride in air are not yet available. As a consequence, there are no published occupational exposure data for either chemical as used in the UK.
24. In the absence of any real data, the EASE model was used to predict exposure to piperazine and piperazine dihydrochloride.
(i) Piperazine
25. The most likely activities where exposure may occur during the use of piperazine are: (i) weighing and mixing small amounts of piperazine with other additives and adding the dry mix to a mixer vessel at 20 oC; and, (ii) emptying large amounts of piperazine from full kegs into a reactor vessel at 60 oC. The former will be undertaken typically once every three months and takes about fifteen minutes. The exposure scenario is best represented as a dry manipulation use pattern with LEV as the pattern of control.
26. Exposures are expected to range between 0.5 to 1 ppm (1.8 to 3.6 mg.m-3) of piperazine vapour and between 2 to 5 mg.m-3 of piperazine dust, both at 20 oC. These exposures occur at the same time so it is appropriate to add them together to calculate the worker's total exposure to piperazine. The modelled exposures will equate, therefore, to an exposure range of 3.8 to 8.6 mg.m-3. As it typically takes 15 minutes to carry out this work, then these exposures equate to a range of 3.8 to 8.6 mg.m-3 when expressed as a 15 minute reference period short term exposure. If no other exposures occur during an eight hour shift, these exposures equate to a range of 0.1 to 0.3 mg.m-3 when expressed as 8 hour TWAs.
27. The most likely activity where exposure may occur during the use of piperazine in large batch processes at 60 oC will be in emptying the piperazine from the keg into the reactor vessel. The kegs of piperazine will be opened manually in the area immediately adjacent to the reactor at 20 oC and then emptied into the reactor which is maintained typically at about 60 oC. The exposure scenario is best represented as a dry manipulation use pattern with LEV as the pattern of control.
28. Exposures are expected to range between 10 to 20 ppm (35.8 to 71.6 mg.m-3) of piperazine vapour at 60 oC and between 2 to 5 mg.m-3 of piperazine dust at 20 oC. These exposures occur at the same time so it is appropriate to add them together to calculate the worker's total exposure to piperazine. The modelled exposures will equate, therefore, to an exposure range of 37.8 to 76.6 mg.m-3. These exposures equate to a range of 37.8 to 76.6 mg/m3 when expressed as a 15 minute reference period short term exposure. Assuming the work is carried out in one hour and no other exposure occurs during an eight hour shift, these exposures equate to a range of 4.7 to 8.9 mg.m-3 when expressed as 8 hour TWAs.
29. The EASE predictions for personal exposures to workers employed in these activities are summarised at Table 1. EASE predicts that 8 hour TWA exposures can be controlled to less than 8.9 mg.m-3 whilst short term exposures will lie in the range of 3.8 to 76.6 mg.m-3.
| Data Source | Process | Piperazine | |
|---|---|---|---|
| 8 hour TWA (mg.m-3) | Short Term (mg.m-3) | ||
| EASE prediction | Weighing, mixing and blending small amounts of piperazine at 20 0C | 0.1 to 0.3 | 3.8 to 8.6 |
| Charging reactor with large amounts of piperazine at 60 0C | 4.7 to 8.9 | 37.8 to 76.6 | |
Table 1: EASE predictions for personal exposures to Piperazine
(ii) Piperazine dihydrochloride
30. The most likely activities where exposure may occur during the use of piperazine dihydrochloride are:
(i) weighing the dihydrochloride salt into 1 kg amounts during repackaging; and,
(ii) dissolving the dihydrochloride salt in water during dispensing.
31. Repackaging a 25 kg keg of the dihydrochloride salt into 1 kg packs takes about one hour. The exposure scenario is best represented as a dry manipulation use pattern with LEV as the pattern of control.
32. Exposures are expected to range between 2 to 5 mg.m-3. As it typically takes one hour to carry out repackaging and this is carried out only once in a shift, these exposures equate to a range of 0.2 to 0.6 mg.m-3 when expressed as 8 hour TWAs. When expressed as a 15 minute reference period short term exposure, these exposures equate to a range of 2 to 5 mg.m-3 .
33. Typically, it takes only thirty seconds to pour and dissolve a 1 kg pack of the dihydrochloride salt into water. It is unlikely that steady state conditions could be established in that time. The EASE model cannot therefore be used to predict these exposures as it assumes steady state conditions apply.
34. Inhalation exposures are expected to be very low however because the dihydrochloride salt is poured in small quantity directly into water.
35. The following options have been chosen for comparison:
36. Information for this RIA was collected via a survey of the companies affected. Questionnaires, asking for information on processes, exposure patterns and potential costings were sent to the following:
Technical assumptions
38. All costs are calculated in 2000/2001 prices over a ten year period1. The base year for appraisal is year 2000/2001. Details of the actual costings are described below.
Health and safety benefits
(i) Occupational Asthma
39. The use of piperazine has been associated with the development of asthma in the workplace.
40. The exact mechanism is unclear but the available data suggests an immunological basis for the asthma. Data linking the induction of occupational asthma to exposure levels is lacking, and therefore a no-effect level has not been determined. There is little correlation between symptoms and exposure levels, and therefore, the nature of the dose-response also cannot be determined.
41. Regarding piperazine dihydrochloride, very little information is available and a read-across from the piperazine data must be considered. Although there are likely to be quantitative differences between the toxicities of piperazine and the dihydrochloride toxicities because of toxicokinetic differences, nevertheless it is reasonable to assume, in the absence of information to the contrary, that their effects will be qualitatively similar. Therefore, it is assumed that the dihydrochloride salt will also have the potential to cause asthma. For the dihydrochloride, there are no data available from which to attempt to explore a no-effect level for this presumed hazard and dose-response cannot be determined.
42. In the UK, no data on the prevalence of asthma cases attributed to piperazine or piperazine dihydrochloride are available.
43. Any reduction in exposure which may arise from the introduction of MELs (8-hour TWA) for piperazine and piperazine dihydrochloride would be predicted to reduce the occurrence of induction of asthma. Due to uncertaintiy regarding the dose-response relationship for the induction of asthma and the absence of information on prevalence it is not possible to quantify the reduction in prevalence of asthma which may arise from a reduction in exposure to piperazine.
(ii) Corrosivity and skin sensitisation
44. Any reduction in exposure arising from the introduction of the short-term MEL would be predicted to reduce the occurrence of skin effects due to corrosion, irritation or sensitisation. Due to uncertainty regarding the dose-response relationship for effects on the skin and the absence of information on prevalence it is not possible to quantify the reduction in prevalence of skin effects which may arise from a reduction in exposure to piperazine.
Compliance costs to business
Policy Costs
(i) Use of piperazine in small batch processes
45. EASE predicts that for this activity, 8 hour TWA exposures will lie in the range of 0.1 to 0.3 mg/m3 whilst short term exposures will lie in the range of 3.8 to 8.6 mg/m3.
46. Typically, this activity is carried out only once every three months and LEV is already provided. Continued reliance will be placed on the use of particulate respirators to further mitigate exposures than those predicted by EASE and no additional cost implications are anticipated for this activity if the proposed 8 hour TWA ILV of 0.1 mg.m-3 and short term exposure limit of 0.3 mg.m-3 is adopted as a MEL .
(ii) Use of piperazine in large batch processes
47. EASE predicts that for this activity, 8 hour TWA exposures will lie in the range of 4.7 to 8.9 mg.m-3 whilst short term exposures will lie in the range of 37.8 to 76.6 mg.m-3.
48. Although LEV is provided, industry contacts already describe the manual loading of hundreds of kgs of piperazine into reactors as 'very dusty' and automated loading methods are currently being developed for the industry. Typically such systems cost about £3,000 to purchase, install and set to work. Operational and running costs are intermittent only and will be absorbed as overheads, as they are for the associated LEV system.Maintenance costs are estimated to be approximately two hours per month. This is approximately £276 per year per plant22. Training costs, if they were incurred, would be negligible.This is equal to a ten year net present value of up to £21,800.
49. There are no more than ten user plants in the UK so as a worst case therefore, a maximum total one-off, additional cost to industry of £32,755 may be anticipated for this activity if the proposed 8 hour TWA IOELV of 0.1 mg.m-3 and short term exposure limit of 0.3 mg.m-3 is adopted as a MEL.
(iii) Piperazine user plants - Additional monitoring
50. Validated methods for sampling and analysis of concentrations of piperazine or piperazine dihydrochloride in air are not yet available. HSE is currently developing a cheap and simple measurement method which is appropriate for industry to use. HSE estimates that this method will result in a one-off cost of £2,000 per piperazine user plant (representing the cost of employing commercial laboratory staff to undertake a one-off monitoring and measurement study in the workplace). Assuming that all 10 plants adopt this measurement method, there will be a maximum total one-off cost to industry of £20,000. No ongoing additional costs for monitoring are anticipated by HSE.
(iv) Repackaging of piperazine dihydrochloride
51. EASE predicts that for this activity, 8 hour TWA exposures will lie in the range of 0.2 to 0.6 mg.m-3 whilst short term exposures will lie in the range of 2 to 5 mg.m-3.
52. Typically, this activity is carried out for one hour per shift and LEV is already provided. Continued reliance will be placed on the use of particulate respirators to further mitigate exposures than those predicted by EASE and no additional cost implications are anticipated for this activity if the proposed 8 hour TWA IOELV of 0.1 mg.m-3 and short term exposure limit of 0.3 mg.m-3 is adopted as a MEL .
(v) Dispensing of piperazine dihydrochloride
53. Inhalation exposures are expected to be very low however because the dihydrochloride salt is poured in small quantity directly into water and no additional cost implications are anticipated for this activity if the proposed 8 hour TWA IOELV of 0.1 mg.m-3 and short term exposure limit of 0.3 mg.m-3 is adopted as a MEL .
Implementation Costs
54. There are no implementation costs
Total compliance costs
55. The information provided by piperazine users in the UK is quite limited. The maximum quantifiable total costs to industry equal up around £73,100 over 10 years, in present value terms, and do not change whether the MEL includes or excludes piperazine dihydrochloride. The annual costs over ten years are represented in Table 2. The total costs for all the affected users of piperazine and piperazine dihydrochloride are summarised in Table 3.
Table 2: Summary of annual costs to comply with a MEL of 0.1 mg.m-3 (8-hour TWA) and 0.3 mg.m-3 (STEL).
| Total Annual Costs | Yr1 | Yr2 | Yr3 | Yr4 | Yr5 | Yr6 | Yr7 | Yr8 | Yr9 | Yr10 | 10 Yr NPV |
|---|---|---|---|---|---|---|---|---|---|---|---|
| MAX | 52,755 | 2,805 | 2,855 | 2,906 | 2,959 | 3,012 | 3,066 | 3,121 | 3,178 | 3,235 | 73,123 |
Table 3: Summary of costs to comply with a MEL of 0.1 mg.m-3 (8-hour TWA) and 0.3 mg.m-3 (STEL),
present values over ten years (£).
| Pattern of use | Cost for a MEL for piperazine (£) | Cost for a MEL for piperazine and piperazine dihydrochloride (£) |
|---|---|---|
| Use of piperazine in small batch processes | 0 | 0 |
| Use of piperazine in large batch processes | 53,123 | 53,123 |
| Additional monitoring at piperazine user plants3. | 20,000 | 20,000 |
| Repackaging of piperazine dihydrochloride | - | 0 |
| Dispensing of piperazine dihydrochloride | - | 0 |
| Total present value (ten years, £) | 73,123 | 73,123 |
3 These figures assume a total of 10 piperazine user plants in the UK - see para 10 above.
Costs to HSE
56. Because of the proposed change to a MEL, there will be an increased emphasis on piperazine exposure at all premises during inspection visits. However, since there are only a few companies handling piperazine any increased workload for inspectors, and therefore any additional costs, are likely to be minimal.
Total costs to society
57. The vast majority of the societal cost is borne by industry. This is detailed above.
Impact on small businesses, charities and voluntary organisations
58. As part of a regulatory impact assessment small-sized businesses are normally contacted to determine the impact for this sector. This was not applicable in the case of piperazine as it is not used by small businesses. The main small business users of piperazine dihydrochloride are veterinary practices. As outlined in paragraph 49 above, HSE does not anticipate additional cost implications for them arising from the proposed MEL. There are no anticipated costs for charities and voluntary organisations.
59. There are no environmental impacts other than the health effects already discussed. The external environmental effects of diffusing piperazine using local exhaust ventilation are negligible.
Balance of costs and benefits
60. Since benefits are unquantifiable, it is not possible to compare total costs and total benefits. We know, though, that there might be up to 50 workers exposed to piperazine, and that the maximum total quantifiable costs add up to £73,100 over a period of ten years, in present value terms.
61. It is useful to consider what the cost per worker exposed are from setting a MEL for piperazine, and how these costs compare with past MELs. Given the total compliance costs and that the number of workers exposed is up to 50, the minimum cost per employee exposed with setting a MEL at 0.1 mg.m-3 (8-hour TWA) and 0.3 mg.m-3 (STEL) is approximately around £1,500.
Uncertainties
62. The information received from industry is rather scarce, thus many of the assumptions are based on limited replies to our questionnaire and HSE's best judgement.
63. The proposed MEL will be enforced by HSE at the premises where they are the enforcing agency and by the Local Authority at premises where they are the enforcing authority. Because of the proposed change to a MEL, there will be an increase in the emphasis inspectors attach to piperazine exposure. However, since there are only a few companies handling piperazine any increased workload for HSE inspectors is likely to be minimal. The MEL will be revised if significant new information becomes available which places doubt on the current assessment of the health risks.
Summary and Recommendations
64. On the basis of the information obtained from industry, costs associated with the proposed MEL for piperazine and piperazine dihydrochloride are likely to be quite low. In view of the information collected to date, HSE recommends a MEL for piperazine and piperazine dihydrochloride of 0.1mg.m-3 (8-hour TWA) and 0.3 mg.m-3 (STEL).
Contact
Paul McCormack, HD C
E mail paul.mccormack@hse.gsi.gov.uk
January 2001
1In arriving at ten year cost figures, two adjustments are made. Firstly, earnings are assumed to rise by 1.8% per year in real terms - the observed increase for the whole economy over the past twenty-five years or so. Secondly, costs are discounted to present value using the Treasury recommended 6% discount rate.
2This assumes an hourly wage rate of £8.83 adjusted by 30% for non-wage labour costs.