Nitrogen trifluoride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29 mg/m³

DNEL related information

DNEL derivation method:

other: National OEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44 mg/m³

DNEL related information

DNEL derivation method:

other: National OEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29 mg/m³

DNEL related information

DNEL derivation method:

other: National OEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44 mg/m³

DNEL related information

DNEL derivation method:

other: National OEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Nitrogen trifluoride – Rationale for determining DNELs

 

Regulatory animal toxicology data for NF3 are limited and current occupational exposure limits (OEL) appear to have been established from limited, old experimental data. A search of the literature has revealed that most animal toxicity studies have been conducted at high doses to characterise adverse effects of NF3 exposure and in some cases to investigate mechanisms of NF3 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, this would result in a DNEL set several orders of magnitude below the current OEL already set. For example, the lowest dose level in repeat dose toxicity study in rats (section 7.5.2) was 5 pm [14.8 mg/m³], based on evidence of haemolytic anaemia at 10 ppm (the LOAEC). Before applying assessment factors, the inhalatory rat NOAEC needs to be corrected for differences between experimental and human exposure conditions:     

• Correction to the experimental exposure conditions (6 h/d), which do not equal the human exposure condition (i.e. 8h/d) need to be corrected.
• Correction to the human inhalatory volume for an 8 h exposure:

Therefore: inhalatory NOAEC x (6 h/d / 8 h/d) x (6.7 m³(8 h) / 10 m³(10 h)) = 14.8 mg/m³x (0.75) x (0.67) = 7.44 mg/m³

 

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 (default)
•  Dose-response = 1 (default) 
• Quality of whole database = 1 (default)
• Total AF = 12.5

DNEL = 7.44 mg/m³/ 12.5 = 0.59 mg/m³, equivalent to 0.2 ppm

 

This DNEL is almost 2 orders of magnitude lower than current occupational health limits (see below). Unfortunately relating human exposure to background levels of NF3 is problematic in the sense that environmental air monitoring of NF3 is limited, with only one study found in the literature which reports levels of 0.454 ppt detected in clean air, with no comparable measurements taken for built up / industrial areas. This measurement was taken back in 2008, with an increase of ~0.053 ppt/yr between 1978 – 2008 [taking this forward an equivalent to a level of ~0.666 ppt would be predict present day (2012)]. Weisset al. (2008)). It is highly likely that this background level is expected to increase exponentially in built up areas due to the potential emission sources of NF3.

 

The new data available whilst adding to the current data available for NF3 do not provide sufficient data for risk assessment purposes and would result in a DNEL which would not be enforceable.

 

The data for establishing the country specific OEL would suggest that theses have been established from the Torklesonet al(1962) study (see below). If this study is taken as the point of departure (LOAEC = 100 ppm [296 mg/m³]), the following DNEL would be obtained:

 

Correction of the starting dose descriptor:

• Correction to the experimental exposure conditions (6 h/d), which do not equal the human exposure condition (i.e. 8h/d) need to be corrected.
• Correction to the human inhalatory volume for an 8 h exposure:

Therefore: inhalatory NOAEC x (7 h/d / 8 h/d) x (6.7 m³(8 h) / 10 m³(10 h)) = 296 mg/m³x (0.875) x (0.67) = 173.5 mg/m³

 

Assessment factors:

• Interspecies factor = 2.5 (no correction required for allometric scaling)
• Intraspecies factor = 5 for workers
•  Exposure duration = 1 (default)
•  Dose-response = 10 (default AF increased in the absence of a NOAEC) 
•  Quality of whole database = 10 (default increased due to deficiencies recognised in the test methodology) 

• Total AF = 1250

DNEL = 173.5 mg/m³/ 1250 = 0.14 mg/m³, equivalent to 0.04 ppm

 

The derived DNEL is almost an order of magnitude below the DNEL calculated from GLP, test guideline compliant study and three orders of magnitude belwo the current OEL.

 

Conversion factors:

At 20°C, 101.3kPa: 1 mg/m³= 0.34 ppm; 1 ppm = 2.96 mg/m³(ref)

 

Occupational Exposure Limits

Elevated concentrations of NF3 occur in numerous environmental settings. Acute effects related to production of anoxia from exposures to NF3 have historically been a basis for concern, with OEL set 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 NF3 chemical safety report. A summary of available OELs (Table 7-1) has been taken directly from the IFA website.

 

Table 7-1: Occupational Exposure Limits

Country	Limit value – 8 hours		Limit value – Short term
	ppm	mg/m^3	ppm	mg/m^3
Australia	10	29
Austria
Belgium	10	29
Denmark	10	29	20	58
EU
France	10	30
Germany
Hungary
Italy
New Zealand
Poland
Singapore	10	29
Spain	10	30
Sweden
Switzerland	10	30
The Netherlands
United Kingdom	(10)	(30)	15	44
North America and US
Canada	10	29
US – NIOSH	10	29
USA – OSHA	10	29
USA – ACGIH	10	29

For the UK, The UK Advisory Committee on Toxic Substances has expressed concern that, for the OEL shown in parentheses, health may not be adequately protected because of doubts that the limit was not soundly-based; however there is a lack of sufficient data available to challenge this for risk assessment purposes.

 

Table adapted from IFA Institut fur Arbeitsschutz der Deutschen Gesetzlichen (website details included under references). The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value – time weighted average (TLV-TWA) of 10 ppm is in accordance with EU countries and is a 10-fold reduction of the 100 ppm value that resulted in mild to moderate hepatic and renal changes in rats (Torkelsonet al. 1962). In this study there are a number of deficiencies with which draw concerns from the point of departure for determining the OEL; this study was conducted using a single dose level, without any ability to determine a dose response; the haematology reported is inconsistent with the data generated from all of the GLP studies, where evidence of haemolytic anaemia was observed at lower doses (10 ppm) following both shorter daily exposures and experimental duration; the sensitivity of the assay could be questioned with limited numbers of animals used/gp; organ weight changes (particularly liver and spleen) were not observed in female rats; lack of any histopathological findings reported for the spleen.

 

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 NF3 at 10 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. With the TWA set at this level the level of MetHb is not expected to exceed 1.5%. In the absence of adverse data it is assumed that this OEL provides sufficient protection, which is enforceable by virtue of the fact that the majority of EU countries have adopted the same level.

The sub-chronic data generated for NF3 shows no evidence of skeletal fluorosis.

Conclusions on DNEL setting

The use of animal toxicity data on NF3 is not considered appropriate for deriving DNELs. The use of OELs from which to derive DNELs for NF3 is considered to be robust and based on the experience following implementation this OEL has provided a level of safety which is both enforcible and able to be monitored. Therefore under guidance from ECHA (2010), as national OELs have already been proposed by several EU countries 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 countries OELs are considered to be appropriate. Therefore the 8-hour working limit of 10 ppm (29 mg/m³) and the short term 15 minute value of 15 ppm (44 mg/m³) are selected as the DNELs for occupational exposure, however where possible these levels should be reduced. These values are assumed to equate to MetHb levels where no adverse effects are observed 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

 

European Agency for Safety and Health at Work

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

 

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

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

 

Weiss, R.F., Muhle, J., Salameh, P.K. & Harth, C.M. (2008). Nitrogen trifluoride in the global atmosphere. Geophysical

Research Letters, 35, L20821, doi:10.1929/2008GL035913

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

Additional information - General Population

As the general population will not be exposed there is no requirement to establish DNELs