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EC number: 905-806-4
CAS number: -
The test substance is covered by the category approach of
methylenediphenyl diisocyanates (MDI). Hence, data of the category
substances can be used to cover this endpoint. The read-across category
justification document is attached in IUCLID section 13. It is important
to note that the MDI category approach for read-across of environmental
and human hazards between the MDI substances belonging to the MDI
category is work in progress under REACH. Therefore the document should
be considered a draft.
In a guideline irritation study with generic MDI
(Desmodur VP.PU1806) erythema and eschar formation was observed, which
was most distinct 7 days after the application of the test substance
(Märtins, 1991). Since these effects were not reversible within an
observation period of 14 days, the test substance has to be classified
as a skin irritant according to EU (R38) and GHS (Cat.2).
Only mild irritation was observed in an older, well conducted non
GLP-study with 4,4´-MDI applied under occlusive dressings (Schreiber,
1981). The reported irritation scores would not result in a
classification as a skin irritant according to EU and GHS standards, but
the reversibility of the effects can not be adequately addressed due to
a missing reading time point 14 days following application of the test
Results obtained from an acute dermal study in rabbits and rats
with polymeric MDI (Wazeter, 1964), and further irritation studies with
technical MDI (Duprat et al., 1976) equally resulted in slight skin
Summarized the results of the key study (Märtins, 1991) together
with human occupational case reports (NIOSH 1994) support the official
classification as skin irritant (EU: R38, GHS: Cat2).
In a guideline eye irritation study with the same batch of generic
MDI (Desmodur VP.PU1806) as used for the skin irritation key study, no
irritation to the eyes according to the EU and GHS regulations was
observed (Märtins, 1991). Likewise no eye irritation was observed when
monomeric 4,4´-MDI was applied to the eyes of rabbits without rinsing
Slight eye irritation was observed in a group of 6 female rabbits
when technical MDI was applied (Duprat et al., 1976). The study result
was obtained according to the method of Kay and Calandra, but due to
incomplete reporting no classification according to EU and GHS is
Summarized the available animal data would not support
classification of MDI as an eye irritant. But together with human
occupational case reports ( NIOSH, 1994) in which symptoms of eye
irritation were reported the legal classification as eye irritant (EU:
R36; GHS: Cat2B) should be applied.
Respiratory tract irritation:
In an acute inhalation study with mice, pulmonary irritation of
4,4`-MDI was assessed by recording respiratory patterns and frequency
(Weyel and Schäfer, 1985). MDI acted primarily as a pulmonary irritant
and with a concentration of 32mg/
the respiratory rate was decreased by 50%. The magnitude of effect was
dependent on the duration of exposure and the exposure concentration.
Increases in lung weight were observed in all tested MDI concentrations
(lowest tested concentration 6.7mg/
irritation properties of MDI were confirmed by exposing mice via
tracheal cannula to 23.6 mg/m³ MDI.
The following studies on respiratory irritation are discussed in
IUCLID and CSR sections on specific investigations.
a short-term inhalation toxicity study of polymeric MDI in rats acute
irritation was correlated to the alteration of surfactant activity
(Pauluhn et al., 1999). When single exposures of various concentrations
were applied for 150 min, stimulation of pulmonary irritant receptors
was assumed to occur at exposure levels in the range of 2.4 mg/m³. In
the second part of the study, rats exposed to 3.3 and 13.7 mg/m³ for 14
days, experienced mild signs of respiratory tract irritation. Light and
transmission electron microscopy suggested that this irritation was
accompanied by an accumulation of refractile, yellowish-brownish
material in alveolar
macrophages, with concomitant activation of type II pneumocytes.
Additionally increased levels of intracellular phospholipids and an
increase of bromodeoxyuridine-labelled epithelial cells were detected.
The authors suggested that polymeric MDI appears to interact directly
with pulmonary lining fluid surfactant.
In a further study with a
similar study design, acute exposures to all tested pMDI-atmospheres
(10, 30, or 100 mg/m³) resulted in signs of respiratory tract irritation
(abnormal respiratory noise, breathing rate reduced and depth increased,
mucous secretions from the nose) and a pattern of lung responses that
was consistent with exposure to irritant aerosols (Kilgour et al.,
2002). An exposure concentration related body weight loss and increase
in lung weight were seen post-exposure, with complete recovery by day
10. Analysis of lung lavage fluid revealed irritation related changes in
the lung over the initial days following exposure. These consisted of a
pattern of initial toxicity, rapid and heavy influx of inflammatory
cells (alveolar macrophages) and soluble markers of inflammation and
cell damage, increased lung surfactant, with a subsequent recovery and
epithelial proliferative phase (e.g. bronchiolar and type II cell
hyperplasia). Finally (by day 30 post exposure), a return to the normal
status quo of the lung (by day 30 post exposure) was observed.
In the same report repeated
exposure over 28 days (1, 4, or 10 mg/m³) produced an increase in lung
weight in the high dose group, which resolved following the 30-day
recovery period. Other effects seen were again consistent with exposure
to irritant aerosols, but were less severe than those seen in the acute
study. 1 mg/m³ was derived as the LOAEL for effects on surfactant
homeostasis (NOAEL 1 mg/m³) and (reversible) bronchiolitis, whereas the
NOAEL for pneumonitis was less than 10 mg/m³.
Pauluhn (2000) examined the
acute pulmonary response of rats to respirable polymeric MDI aerosol
atmospheres (0.7, 2.4, 8, or 20 mg MDI/m³). The time course of the
relationship between acute pulmonary irritation and ensuing disturbances
of the air/blood barrier was determined by analyzing the bronchoalveolar
lavage (BAL) fluid for markers indicative of injury of the
bronchoalveolar region. The most sensitive markers of dysfunction of the
air/blood barrier were identified to be angiotensin-converting enzyme
(ACE), protein, and alkaline phosphatase. Except increased glutathione
in lung tissue, changes returned to the level of the air-exposed
controls on day 7.
glutathione-depleted rats exposed to 20 mg/m³ experienced a more
pronounced increase in BAL protein than normal rats (Pauluhn, 2000)
indicating that respirable polymeric MDI aerosol interacts directly with
the air/blood barrier causing increased extravasation of plasma
constituents as a result of increased permeability of capillary
A transient change of the
pulmonary epithelial air/blood barrier occurred at a level as low as 0.7
mg/m³ and was interpreted as representative of a normal homeostatic
response of pulmonary surfactant. There is currently no consensus expert
opinion, whether to define these reversible observations as an adverse
effect leading to a physiological response, and therefore whether to
define the effective concentration of 0.7 mg/m³ as LOAEL or NOAEL. Since
no cytotoxicty or pulmonary functional changes occurred at this dose
level, the exact biological significance of such transient increase in
protein and ACE in the bronchoalveolar lavage is not known.
In a further study of
Pauluhn (2002), an acute irritant threshold concentration of 0.5mg/m3
was estimated for pMDI, which may serve as a conservative NOAEL for
further risk characterization.
Summarized MDI should be
classified as a respiratory tract irritant (EU: R37, GHS: STOTsingleCat3).
Justification for selection of skin irritation / corrosion endpoint:
OECD 404 Guideline study with GLP
Justification for selection of eye irritation endpoint:
OECD 405 Guideline study with GLP
Effects on skin irritation/corrosion: irritating
Effects on respiratory irritation: irritating
The results of the key study (Märtins, 1991) together with human
occupational case reports (NIOSH 1994) support the official
classification as skin irritant (EU: R38, GHS: Cat2).
The available animal data would not support classification of MDI
as an eye irritant. But together with human occupational case reports (
NIOSH, 1994) in which symptoms of eye irritation were reported the legal
classification as eye irritant (EU: R36; GHS: Cat2B) should be applied.
available data support the classification of MDI as a respiratory tract
irritant (EU: R37, GHS: STOTsingleCat3).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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