Hexamethylene diisocyanate

Toxicological Summary

Workers - Hazard via inhalation 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:

DNEL (Derived No Effect Level)

Value:

0.035 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German MAK commission (national OEL Germany)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.07 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German MAK commission (national OEL Germany)

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Inhalation exposure is typically the most relevant route for assessing occupational risk in humans. Effects from repeated exposure of animals to hexamethylene diisocyanate (HDI) are limited to effects on the respiratory tract caused by local irritation. In a 2-year chronic toxicity and carcinogenicity study with vapour exposure of HDI to rats a NOAEC of 0.035 mg/m3 (0.005 ppm) was determined (Shiotsuka, 1989). Neither indications of systemic toxicity nor evidence of a carcinogenic potential were found in rats. Tests assessing the mutagenic potential of HDI in vitro and in vivo provide no evidence of mutagenic or genotoxic activity.

According to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008) a national occupational exposure limit (OEL) was used as a surrogate for a DNEL. For HDI the German MAK Commission established an OEL (MAK value) of 0.005 ppm (0.035 mg/m3) referring to an 8-hour exposure period. This OEL is used as a surrogate DNEL for long-term exposure. A ceiling limit value of 0.01 ppm (0.07 mg/m3) was settled. This ceiling limit is used as a surrogate DNEL for short-term exposure. The justification of these OELs is given in the published HDI evaluation of the German MAK Commission (DFG, 1996) with the following statements:

Both in humans and in animals, the main effects of hexamethylene diisocyanate (HDI) are irritation and sensitization of the respiratory tract . The available results with humans are however not suitable for the derivation of a MAK value, as practically always exposures to a mixture of substances with HDI prepolymers, other diisocyanates and solvents are involved and the real exposure levels have, for the most part, not been recorded quantitatively. For rats, the NOEC is 0.005 ml/m3 (0.035 mg/m3) in a subacute inhalation study. Concentrations above 0.15 ml/m3 (1.05 mg/m3) resulted in marked changes in the nasal mucosa (squamous cell metaplasia). In an investigation lasting 13 weeks, the same changes as well as first clinical signs of an irritant effect to the eyes were already observed at the lowest tested concentration of 0.011 ml/m3 (0.08 mg/m3). In a study lasting 2 years, concentrations of 0.005 ml/m3 and above produced metaplasia and/or hyperplasia with a hyaline degeneration of the respiratory epithelium and the mucus-secreting glands. At 0.025 ml/m3 (0.175 mg/m3) and above, hyperkeratosis of the respiratory epithelium and degeneration of the olfactory epithelium were additionally found. As the findings described at the concentration of 0.005 ml/m3 only increased as regards incidence but not severity, and comparable changes also occurred spontaneously, they were evaluated as an adaptive response (Foureman et al., 1994). Adaptive  reactions of this kind are frequently observed in rodents after exposure to gaseous irritants (Monticello et al., 1990). Thus, for the long-term inhalation study in the rat, a NOAEC of 0.005 ml/m3 is obtained. The MAK value for HDI is thus reduced to 0.005 ml/m3 (0.035 mg/m3). Even according to the findings with humans, which must still only be interpreted with caution, irritant effects are no longer to be expected at this concentration. However, this does not apply for persons with non-specific bronchial hyperreactivity or allergic HDI hypersensitivity, as minimal HDI concentrations are already able to provoke bronchospastic conditions in these persons.

The German OEL for HDI is in agreement with the threshold limit value (TLV-TWA: 0.005 ppm (0.034 mg/m3)) recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 2001) and no additional information became available in the meantime that would influence the respective assessment.

No comparative DNELs for systemic effects (short-term and long-term exposure) are calculated since no indications of systemic toxicity were observed in the repeated dose toxicity studies by the inhalation route. The toxicological database for inhaled HDI demonstrates consistently that toxicity is associated only with the portal of entry (respiratory tract).  Whereas the observed effects in the repeated inhalation studies are very consistent the concentrations do not directly fit together. This might be explained by a methodological bias in the early studies to underestimate actual exposure concentrations in the presence of overestimation of portal-of-entry-related toxicity due to re-breathing in the studies using whole body exposure. These methodological issues were overcome in a recent 1-week inhalation study by Kopf (2015b), in which no evidence of pulmonary or thoracic airways irritation was found after nose-only exposure to rats in concentrations up to 13.8 mg HDI/m3. In this study, the borderline NOAEC based on effects observed in the upper respiratory tract (nasal cavity) was 0.7 mg/m3. The comparison of this NOAEC with the MAK value (DNEL) of 0.035 mg/m3 shows that there is a sufficient safety margin of 20 for the inhalation route of HDI exposure.

No DNEL for skin sensitization is calculated as the relationship between skin dose and response is not clear. There is no validated method of DNEL calculation for skin sensitization. According to the potency categorisation approach HDI is classified as a moderate to strong skin sensitizer (Category 1) based on a guinea pig maximization test (GPMT: 10 % induction conc., ≥ 94 % incidence of sensitization; Schmidt and Bomhard, 1983) and a Buehler test (1 % induction conc., 70 % incidence of sensitization; Zissu et al., 1998), respectively. The results of a local lymph node assay with HDI (LLNA: calculated EC3 value of 0.03 %; Hilton et al., 1995) were not considered for the potency categorisation on skin sensitization since this test is also sensitive against respiratory sensitizers and irritants (De Jong et al., 2009) and does not allow differentiation of antigen-specific immune responses from non-specific inflammatory reactions (McGarry, 2007). Therefore, LLNA results with HDI are deemed to be over-predictive.

A lung sensitization test in guinea pigs (Pauluhn, 1996) as well as a modified LLNA in mice (Arts et al. 2008; De Jong et al., 2009) provides clear evidence that HDI is a respiratory sensitizer (Category 1). It is known, that a specific sensitization of the respiratory tract may be induced by the inhalation or dermal route. For diisocyanates a potential relevance of dermal contact for the induction can be derived from animal experiments, although this has not yet been conclusively demonstrated based on human occupational case reports. In general, current mechanistic understanding of allergic responses such as respiratory allergy and allergic contact dermatitis is such, that it can be assumed that the development of sensitization (induction) and also the elicitation are threshold phenomena. This is acknowledged in the ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.8 (Version 2.1, Nov 2012) where it is indicated that (skin) sensitization is generally regarded as a threshold effect. A common initiating step in the induction of respiratory allergy and allergic contact dermatitis is e.g. the activation of dendritic cells. Furthermore, the ECHA Guidance Chapter R8 is indicating that “…as for skins sensitization, there is evidence that for respiratory sensitization dose-response relationships exist, although these are frequently less well defined (Appendix R. 8-11).

For HDI the existence of a threshold for elicitation of respiratory sensitization following induction and subsequent multiple challenges was demonstrated in a BN rat asthma model (Kopf, 2015a). Based on the most sensitive endpoint PMNs in BAL showing a clear Cxt-dose-related increase in PMNs a NOAEL of 68 mg HDI/m3 x 13 min was derived in this study. Hence, based on this endpoint, approx. 900 mg HDI/m3 x min is considered to be the effect threshold for elicitation in sensitized, i.e. asthmatic rats. In addition, analysis of worker populations exposed to controlled HDI atmospheres of 2.9 ppb (0.02 mg/m3) did not identify any increase in the incidence of work-related respiratory symptoms (Hathaway et al., 1999). This assessment indicates that induction and elicitation of an HDI specific chemical respiratory allergy would be covered by the existing OEL of 0.035 mg/m3. Since there are currently no available methods to determine thresholds and DNELs for respiratory sensitizers, a quantitative risk assessment for this endpoint is not possible.

For HDI no repeated dose toxicity studies by the dermal route are available. As mentioned above exposure to HDI via the air does not lead to systemic toxicity, therefore systemic toxicity is covered by the respective DNELs for inhalation exposure. As there is no indication that dermal contact could lead to principally different and more severe systemic effects compared to inhalation exposure, a DNEL for systemic toxicity (short-term and long-term) after dermal contact is not required. Regarding local effects the corrosive potential as well as the sensitization potential needs to be considered in the selection of the respective risk management measures (RMMs) at the workplaces.

The DNEL for long-term exposure covers also reproductive toxicity, as HDI is not a reproductive toxicant and the local effects at the respiratory tract covered by the DNEL for long-term exposure are the most sensitive effects also in the reproduction/developmental toxicity screening test and the developmental toxicity study.

References

De Jong WH et al. (2009): Contact and respiratory sensitizers can be identified by cytokine profiles following inhalation exposure. Toxicology 261: 103-111

Deutsche Forschungsgemeinschaft (DFG, 1996): Hexamethylendiisocyanat. In: Gesundheitsschädliche Arbeitsstoffe - Toxikologisch-arbeitsmedizinische Begründung von MAK-Werten. DFG, Nachtrag 23. Lieferung 1996

(for English version see The MAK Collection for Occupational Health and Safety, DFG, 2013; http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb82206e2313/pdf )

Foureman GL et al. (1994): Evaluation of nasal tract lesions in derivation of the inhalation reference concentration for hexamethylene diisocyanate. Inhalation Toxicology 6 (Suppl.): 341-355

McGarry HF (2007): The murine local lymph node assay - Regulatory and potency considerations under REACH. Toxicology 238: 71-89

Monticello TM et al. (1990): Nonneoplastic nasal lesions in rats and mice. Environ. Health Perspect. 85: 249-274

General Population - Hazard via inhalation 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:

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:

no hazard identified

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:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified