Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
117 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
117 mg/m³
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - workers

Carbon monoxide – Rationale for determining DNELs

Regulatory animal toxicology data for carbon monoxide are limited and current occupational exposure limits (OEL) appear to have been established using human data. There is extensive information in the literature on epidemiological studies and human volunteer studies at occupationally relevant carbon monoxide (CO) concentrations (e.g. EPA, 2010 and EHC, 1999). These studies have provided a wealth of data from which OELs have been derived. A search of the literature has revealed that most animal toxicity studies have been conducted at high doses to characterise adverse effects of CO exposure and in some cases to investigate mechanisms of CO toxicity. Few studies have been designed to define NOAELs for risk assessment purposes. DNELs could be derived from toxicology studies submitted in this dossier; however, these would ignore the extensive human data upon which OELs are set. For example, the lowest dose level in developmental toxicity studies in mice (section 7.8) was 65 ppm which was a LOAEC for teratogenic effects. According to the guidance in Chapter R.8 the following assessment factors (AFs) would be appropriate:

Interspecies factor = 2.5 (no correction required for allometric scaling)

Intraspecies factor = 5 for workers

Exposure duration = 1 (23 hours exposure/day during days 8-18 of gestation, therefore no correction required)

Dose-response = 10 (extrapolation from LOAEC to NOAEC and severity of effects at LOAEC)

Quality of whole database = 1 (this factor could arguably be higher based on quality of the animal toxicity data)

Total AF = 125

DNEL = 65/125 = 0.52 ppm

This DNEL is almost 2 orders of magnitude lower than current occupational health limits (see below) and also lower than most background levels in the environment. A decade ago the CO levels inside motor vehicles were generally around 9-25 ppm and street workers could be exposed to 10-50 ppm (EHC, 1999). More recent data from the USA indicate a gradual downward trend in CO emissions, including those from motor vehicles (EPA, 2010). Typical ambient neighbourhood 8-hour daily maximum values averaged 0.6 ppm and ranged from 0 to 2.7 ppm (99thpercentile) in the period 2005 – 2007. CO levels in vehicles were reported to be 2 and 5 times higher than ambient concentrations. Lowering the occupational limit to 0.52 ppm based on a DNEL from animal toxicity data would clearly give an exposure which is much lower than that to which a significant proportion of the human population is already exposed and that would be illogical.

Occupational Exposure Limits

Elevated concentrations of CO occur in numerous settings, including those at work, at home or in the street. Acute effects related to production of anoxia from exposures to CO have historically been a basis for concern. In recent years, however, this concern has grown to include concerns for potential effects from chronic exposure as well. Three kinds of occupational exposure limits are currently utilized in a number of countries. The most common are: average permissible concentrations for a typical 8 hour working day (time-weighted average, TWA); concentrations for short-term exposures, generally of 15-min duration (short-term exposure limit, STEL); and maximum permissible concentrations not to be exceeded (ceiling limit). This discussion will centre round the justification for a common OEL (TWA and STEL) to take forward for DNEL setting and risk characterisation for the CO chemical safety report.

Discussion of OELs below has been summarised from authoritative reviews of extensive, relevant current published literature (EPA, 2010 and EHC, 1999), with a summary of available OELs (Table 15) taken directly from the IFA website.

Occupational Exposure Limits

Europe

Country

Limit value – 8 hours

Limit value – Short term

ppm

mg/m3

ppm

mg/m3

France

50

55

 

 

Sweden

35

40

 

 

Austria

30

33

60

66

UK

30

35

200

232

Switzerland

30

35

30

35

Germany

30

35

30

35

Denmark

25

29

50

58

Spain

25

29

 

 

Belgium

25

29

 

 

EU (IOELV)a

20

23

100

117

 

 

 

 

 

North America and US

Canada

35

40

200

230

US – NIOSH

35

40

200

229

USA – OSHA

50

55

 

 

a    IOELVs are non-binding values, derived from the most recent scientific data available, taking into account the availability of measurement techniques. Once established, Member States must establish a national OEL in accordance with national legislation and practices. The national OEL can be higher or lower than the IOELV, with variations in national OEL resulting from practicability of monitoring and maintaining levels, and interpretation of data at a national level as a level where no adverse effects occur / are identified. The EU IOELV for carbon monoxide is currently a proposed limit.

Table adapted from IFA Institut fur Arbeitsschutz der Deutschen Gesetzlichen (website details included under references)

Whilst it is recognised that OEL limits within Europe and the US vary (with the exception of France and the US – OSHA), actual variation in absolute 8 hour TWA values is minimal (varying from 25 to 35 ppm). It would appear that OEL limits are not set at a ‘ppm’ level for CO, but rather at what level of carboxyhaemoglobin (COHb) the individual country has concluded that no adverse health effects occur.

The World Health Organisation (WHO) has recommended that COHb levels should not exceed 2.5%. At this level, the WHO stated that susceptible populations (i.e. non-smoking, middle-aged and elderly population groups with documented or latent coronary artery disease from acute ischaemic heart attacks and to protect the foetus of non-smoking pregnant women) were taken into account and deemed protected at such levels. This level of COHb equates to 10 ppm CO for 8 hours and 87 ppm for 15 minutes. However, this level of CO has been set to provide protection to all populations (i. e. workers and susceptible populations).

OELs are set on the assumption that the sensitive/susceptible population are not occupationally exposed (osha-europa website), being protected by the air quality standards. European countries have appeared to set/align their OELs based on either recommendations of the American Conference of Governmental Industrial Hygienists (ACGIH) or National Institute for Occupational Safety and Health (NIOSH).

ACIGH have set an 8 hour TWA for CO at 25 ppm. This was based on a normal 8 hour workday, 40hr/week to which nearly all workers may be repeatedly exposed day after day without adverse effects. This level is intended to maintain blood levels of COHb below 3.5% to minimise potential adverse neurobehavioural changes and to maintain cardiovascular work and exercise capabilities. This level was derived from the Coburn Foster Kane exponential equation.

NIOSH set a CO level of 35ppm (defined as per ACIGH TWA). Of note, NIOSH concluded that subtle aberrations in the nervous system with exposures producing COHb concentrations in blood up to 5% did not demonstrate significant impairments that would cause concern for the health and safety of workers.

Germany – defined as per ACIGH TWA, however it is based on COHb levels of 5% and CO levels = 30 ppm.

UK – CO = 30 ppm. It is unknown what the basis this level was set on or what level of COHb this equates to. The OEL for CO was revisited by the Health and Safety Executive in 2005. It would however be reasonable to assume that this is closely related to the ACIGH-TWA.

EU - CO = 20 ppm (IFA, GESTIS International Limit Values). No information on the rationale for a value of 20 ppm for the EU was found. It is most likely a conservative level that encompass the diverse range of values present within the EU (Spain/Belgium/Denmark = 25ppm through to Sweden = 35ppm). It is understtod that this value is at this stage still only a proposal and is being evaluated by the advisory committe and no official harmonised value has been published.The EU directive which documents the Indicative occupational exposure limit values (IOELV) states that ‘IOELVs should be regarded as an important part of the overall approach to ensuring that the health of workers is protected against the risks arising from hazardous chemicals’ (i. e. protecting against the worker, but not including susceptible populations).

Conclusions on DNEL setting

The use of animal toxicity data on CO is not appropriate for deriving DNELs. The use of occupational exposure limits from which to derive DNELs for CO is considered to be scientifically justified since OELs have been set based on extensive human data. Reviews of animal toxicity data indicate a general concordance with human data (EHC, 1999; EPA, 2010).

Therefore under guidance from ECHA (2010), as IOELVs have already been proposed by the EU for daily inhalation exposure over 8 hours/working day and for acute / short term exposure (15 minutes); relevant DNELs will be derived from these.

The proposed EU IOELVs are considered to be appropriate. Therefore the 8-hour working limit of 20 ppm (23 mg/m3) and the short term 15 minute value of 100 ppm (117 mg/m3) are selected as the DNELs for occupational exposure. These values equate to COHb levels of approximately 3% and following a review of the latest available data there are no new studies which would negatively impact upon the position that these values are protective with regard to occupational exposure.

References:

ECHA, 2010. DNEL/DMEL Derivation from Human Data. Draft Rev 2.0

http://guidance.echa.europa.eu/docs/draft_documents/R8_DNEL_HD_Draft_Rev2%200_after%20RAC.pdf

EHC, 1999. Environmental Health Criteria, 213, International Programme for Chemical Safety, WHO.

EPA, 2010. Integrated Science Assessment for Carbon Monoxide. EPA/600/R-09/019F. January 2010.

IFA - Institut fur Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung GESTIS International Limit Values:

http://www.dguv.de/ifa/en/gestis/limit_values/index.jsp

http://osha.europa.eu/en/faq/dangerous-substances/are-oels-made-for-everybody

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

As the general population will not be exposed, DNEL considered unnecessary