Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.035 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
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)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Most sensitive endpoint:
sensitisation (respiratory tract)
Acute/short term exposure
Most sensitive endpoint:
sensitisation (respiratory tract)
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
sensitisation (respiratory tract)
Acute/short term exposure
Most sensitive endpoint:
sensitisation (respiratory tract)

Workers - Hazard for the eyes

Additional information - workers

For the risk assessment of the substance the DNELs derived for 2,4-/2,6-TDI (TDI; CAS No. 26471-62-5) were used. This decision was based on the fact that the substance contains ca. 56 % of a 80:20 mixture of 2,4-/2,6-TDI and that the direct comparison of the acute inhalation toxicity in rats revealed a lower 4-hour LC50 value (aerosol) for TDI than for the substance (107 mg/m3 vs. 160 mg/m3). Based on the sum of TDI isomers the 4-hour LC50 values are almost identical (TDI: 107 mg/m3; TDI Biuret: 112 mg/m3) (see also the expert opinion of Prof. J. Pauluhn

for comparison of acute inhalation toxicities of the substance and TDI attached below). In addition, the toxicity profiles of the two compounds show a high degree of consistency regarding the endpoints acute toxicity (oral, inhalation), skin irritation, eye irritation, skin sensitization and genotoxicity in vitro. For the endpoints acute dermal toxicity, respiratory sensitization, repeated dose toxicity, genotoxicity in vivo, carcinogenicity as well as toxicity to reproduction (fertility, developmental toxicity/teratogenicity) no data for the substance are available. Therefore, in these cases a read-across approach from TDI to the substance was made.

 

In the following the original DNEL derivation for TDI is presented:

Inhalation exposure is the most relevant route for assessing occupational risk in humans. Effects from repeated exposure of animals to toluene diisocyanate (TDI) 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 2,4/2,6-TDI (80:20) to rats and mice a LOAEC of 0.36 mg/m3 (0.05 ppm) was determined for both species based on histopathological effects in the upper and lower respiratory tract (Owen, 1980 + 1986; Loeser, 1983). Neither indications of systemic toxicity nor evidence of a carcinogenic potential were found in rats and mice. Tests assessing the mutagenic potential of TDI in vitro and in vivo provide no convincing or consistent 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. The German Committee on Hazardous Substances (Ausschuss für Gefahrstoffe - AGS) derived an OEL (Arbeitsplatzgrenzwert - AGW) for 2,4- and 2,6 -TDI which were substantiated in respective criteria documents (published in German on the website of the Federal Institute for Occupational Safety and Health (BAuA) - www.baua.de). According to the German Hazardous Substances Ordinance (Gefahrstoffverordnung) an AGW is a time-weighted average concentration in the workplace air, referring to a given period of time. The AGW states the concentration of a substance below which acute or chronic adverse health effects are generally not expected. AGWs are thus based exclusively on available occupational medical experience and toxicological findings.

For 2,4- and 2,6-TDI the AGS established an OEL of 0.035 mg/m3 (0.005 ppm) referring to an 8-hour exposure period. This OEL is used as a surrogate DNEL for long-term exposure. A ceiling limit value of 0.14 mg/m3 (0.02 ppm) was given for both isomers. This ceiling limit is used as a surrogate DNEL for short-term exposure. The justification of the OELs was based on an TDI evaluation of the German MAK Commission (DFG, 1999)* and published in criteria documents for 2,4- and 2,6-TDI (issue: January 2006) with the following statements:

From an occupational-medical point of view, the most important effects of TDI are those on the respiratory tract. The local irritant effects can cause symptoms to the eyes and airways. High concentrations cause a reduction in the respiration rate and dyspnea. TDI is a respiratory sensitizer and can cause isocyanate asthma in the form of an obstructive respiratory disease, and unspecific bronchial hyperreactivity and, in rare cases, allergic alveolitis. Unlike its oral and dermal toxicity, the acute inhalation toxicity of TDI is high. Repeated long-term exposure to TDI may cause deterioration of lung function. Also in animal experiments damage in the upper and lower airways was observed after repeated inhalation (DFG, 1999). Bronchial asthma is a known syndrome, triggered by diisocyanates like TDI. The induction of sensitization depends on the concentration/dose and the individual (Diller, 1990). No DNEL for respiratory sensitization is calculated as there is no validated method.  Human experience shows clearly that if the exposure concentrations of TDI are kept below 0.01 to 0.02 ppm, generally no new cases of TDI asthma are observed (Porter et al., 1975; Karol 1981; Olsen et al., 1989). The impairment of lung function by long-term exposure to TDI has been investigated in several studies. It can be deduced from these data that with observance of an 8-hour average value at the workplace of 0.005 ppm and limitation of exposure peaks to 0.02 ppm no significant deterioration in lung function is to be expected (DFG, 1999). Since the OEL for TDI was based on human data no additional assessment factors are required. Interindividual variability was taken into account by a large number of TDI exposed workers.

The German OELs for 2,4- and 2,6-TDI are in agreement with the threshold limit values (TLV-TWA: 0.036 mg/m3; TLV-STEL: 0.14 mg/m3) recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 2004). A plausibility check of the above mentioned national OELs revealed that the DNELs derived from animal data using assessment factors according to ECHA Guidance R.8 are in the same order of magnitude.

For TDI no repeated dose dermal toxicity studies are available. Skin penetration of TDI is considered to be low. Administration of 2,4 -TDI to the skin of rats for 8 hours resulted in less than 1 % of the applied dose reaching the systemic circulation (Fabian and Landsiedel, 2008). As mentioned above exposure to TDI via the air does not lead to systemic toxicity, therefore taking into consideration the low dermal penetration, systemic toxicity is covered by the respective DNELs for inhalation exposure and a DNEL for systemic toxicity (short-term and long-term) after dermal contact is not required. Regarding local effects the irritation potential (strongly irritative to corrosive) as well as the sensitization potential needs to be considered in the selection of the respective risk management tools at the workplaces.

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 TDI is classified as a moderate to strong skin sensitizer (Category 1) based on a guinea pig maximization test (GPMT: 5 % induction conc., ≥ 47 % incidence of sensitization; Duprat et al., 1976) and a Buehler test (5 % induction conc., 90 % incidence of sensitization; Zissu et al., 1998), respectively. The results of a local lymph node assay with TDI (LLNA: calculated EC3 value of 0.02 %; Hilton et al., 1995) were not considered for the potency categorisation on skin sensitization since this test is also sensitive against respiratory sensitizers (De Jong et al., 2009)** and does not allow differentiation of antigen-specific immune responses from non-specific inflammatory reactions (McGarry, 2007)***. For strong skin irritants like TDI the test may therefore be false positive (Independent Scientific Peer Review Panel Report, ICCVAM, 2008)****or overpredictive, as shown by pretreatment with SDS (van Och, 2000).

The DNEL for long-term exposure covers also reproductive toxicity, as TDI 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 two-generation study and the developmental toxicity study.

Details:

The following DNELs / DMELs were not derived: 

  • Dermal exposure: Strong skin irritation is the leading acute effect of dermal exposure to TDI. No signs of systemic toxicity were observed in irritation studies and in systemic oral/inhalation studies. Given the low bioavailability of TDI via the skin (Fabian & Landsiedel, 2007), the derivation of DNELs for dermal exposure would therefore be misleading. In accordance to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008) a qualitative approach was applied or the assessment and control of risks due to skin irritation and sensitization (see above).
  • Oral exposure: In principle ingestion is not an anticipated route of exposure in an industrial setting,since general workplace hygiene yield to avoid any oral ingestion. Particularly for TDI the low occupational exposure limits applied prohibit from any oral ingestion at the workplace. Accidental contamination from traces is furthermore unlikely, since TDI is highly reactive against traces of water (t 1/2 < 1 h) and therefore would result in rapid polymerisation.
  • Systemic effects - inhalation exposure: From an occupational-medical point of view, local irritation to the eyes and upper airways are the most important effects of TDI (DFG, 1999)*. Following single or repeated inhalation exposure/s to irritating concentrations of TDI, neither from human experience nor in animal studies, signs of systemic toxicity were reported. In this context, protection from irritation is protecting from any kind of potential systemic toxicity.

 

* Greim H (2003) Toluene diisocyanate. In: Occupational Toxicants: Critical Data Evaluation for MAK Values and Classification of Carcinogens, Vol.20, 291 -338, Wiley-VCH. (ISBN: 3 -527 -27797 -8). This document is included in this dossier in section 7.10.

**De Jong WH, Arts JHE, De Klerk A, Schijf MA, Ezendam J, Kuper CF, Van Loveren H (2009): Contact and respiratory sensitizers can be identified by cytokine profiles following inhalation exposure, Toxicology 261: 103 -111

 

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

 

****http://iccvam.niehs.nih.gov/docs/immunotox_docs/LLNAPRPRept2008.pdf

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

The substance is not used in the public domain and exposure of consumers is thus not to be expected.