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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.015 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
3 125
Modified dose descriptor starting point:
T25
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.004 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
12 500
Modified dose descriptor starting point:
T25
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Rational for choice of toxicological key values:

The main target organs of MDA´s carcinogenic and non-carcinogenic effects in rodents are the liver and the thyroid gland. Also in humans liver effects following MDA exposure were documented. Moreover MDA is a skin sensitizer in humans.

 

Dermal Absorption:

Following dermal application (2mg/kg bw onto 2cm2 application area) MDA was well absorbed in rats (50% in 96h), though to a minor extend in guinea pigs (29% in 96h) and monkeys (21% in 168h) (El-Hawari et al., 1986). The transport process exhibited saturable transport kinetics and significant amounts of MDA were recovered in the skin of the application area at the end of the observation periods. In an occlusive in vitro dermal penetration assay resorption rates of 33% were determined with isolated human skin and 13% with isolated rat skin during an observation period of 72h (Hotchkiss et al., 1993). These resorbtion rates decreased significantly when the application area was not occluded. Like in the in vivo assay major amounts of radioactivity were recovered in the skin surface.

 

Acute toxicity:

Following single oral ingestion MDA exhibits severe irreversible liver toxicity with a distinct interspecies difference in severity.

In rats gross pathological liver and eye effects were noticeable from dose levels of 400 mg/kg bw (BASF AG, 1961, 1965). Microscopically hepatocellular necrosis was observed in male rats treated with 100 mg/kg bw MDA and markers of liver injury (e.g. serum bilirubin, liver weight) were already altered at dose level as low as 25-75 mg/kg bw. These observations were supported by Dugas et al. (2001) demonstrating that a single oral dose of 25 mg/kg (female rat) or 50 mg/kg bw (male rat) is resulting in bile duct injury, and an increase in AP, GGT, ALT and bilirubin in serum.

As expected for an aromatic diamine cats were shown to be the most susceptible species for systemic MDA liver toxicity, followed by dogs, rats and rabbits (Oettel and Hofmann, 1961). In an acute gavage study performed with cats (Oettel & Hoffmann, 1961), animals at the lowest dose of 10 mg/kg were without clinical signs, though hematological, renal and hepatic disturbances were observed. Significant macroscopic liver effects (icterus) were observed with 25 mg/kg bw and higher dose levels additionally affected the kidneys and the eyes. Severe, irreversible mydriasis, followed by blindness was observed in almost all cats from dose levels of 25 mg/kg bw. Similar effects on the eyes were observed in dogs (from 100 mg/kg bw) and rabbits (at 300 mg/kg bw).

 

Repeated dose toxicity:

Subchronic uptake of MDA by rats via the drinking water resulted in irreversible hemotoxic effects, irreversible hyperplasia of small biliary ducts and stimulation of the follicular epithelium in the thyroids (Ciba-Geigy, 1982). The LOEL was identified as 7.5 mg/kg bw. With respect to organ toxicity female animals were more susceptible than males and rats were more susceptible than mice.

 

Carcinogenicity.

The point of departure for the DMEL derivation were liver tumors in rats observed in a chronic drinking water study with MDA hydrochloride (NTP, 1983). This tumor type was identified as the most critical regarding incedence and dose levels. Oral uptake of 9 mg/kg bw resulted in a significant increase in neoplastic liver nodules (LOAEL 9 mg/kg bw) withmale rats being more susceptible than female rats and rats generally being more susceptible than mice. Additionally one carcinoma was observed in each male dose group. The thyroid tumors in rats and the liver tumors in mice can not be conclusively evaluated with respect to their human relevance.

No data is available to evaluate carcinogenicity on the inhalation route of exposure and only a chronic study of very low reliabilitiy is available for the dermal route of exposure. Though, confirming the liver as primary target of liver neoplasms.

The mechanism of carcinogenicity is yet not fully understood. Genotoxic and/or secondary mechanisms (e.g. thyroid stimulation following glucuronidation in the liver) can be postulated. Based on this uncertainty, a DMEL needs to be derived for the safety assessment based on the conservative assumption of a genotoxic mechanism of liver carcinogenesis.

 

Toxicity to reproduction:

The reliability of the little data available for reproductive toxicology of MDA is low and does not allow the derivation of a reliable dose descriptor. However, the hazard and safety assessment of MDA with respect to reproductive toxicology is superimposed by its classification as a Cat 2 carcinogen.

 

Details:

The following DNELs / DMELs were not derived:

  • 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 MDA as cat2 carcinogen the low occupational exposure limits applied prohibit from any oral ingestion at the workplace.
  • acute effects: occupational exposure limits for carcinogens (DMEL for MDA, cat2 carcinogen) are established as 8 h time weighed averages, a ceiling factor for acute peak exposures is not envisioned. Acute occupational exposure limits are designed to e.g. prevent from local irritation (not relevant for MDA, see above) or adverse systemic effects. In the case of MDA the derivation of a DNEL for acute-systemic-effects is resulting in significantly higher risk numbers and would therefore be misleading with respect to the derived DMEL.

Acute/short-term exposure – systemic effects – dermal DNEL

Not quantifiable; see above

 

Acute/short-term exposure – systemic effects – inhalation DNEL

Not quantifiable; see above

 

Acute/short-term exposure – local effects – dermal DNEL

Not quantifiable; see above

 

Acute/short-term exposure – local effects – inhalation DNEL

Not quantifiable; see above

 

Long-term exposure – systemic effects – dermal DNEL

Neoplastic liver nodules in a chronic drinking water study in male rats were identified as the most critical systemic effect (see rational above). A linear increase in the dose range tested was observed, resulting in a LOAEL of 9 mg/kg bw at which 13 out of 50 male rats were affected (12 nodules, 1 carcinoma), compared to 1 out of 50 in the control group.

 

Adaptation of starting point:

Net incidence at 9 mg/kg/d = (13-1)/50 = 0.24 = 24 %

T25oral, rat= 9 mg/kg bw * 25%/24% = 9.375 mg/kg bw

 

Route to route extrapolation:   

Basic assumptions :  100% bioavailability oral

50% bioavailability dermal in rats (El-Hawari et al, 1986).

T25dermal, rat= 9.375 mg/kg bw / 0.5 = 18.75 mg/kg bw

 

“Large assessment factor approach” for the derivation of a DMEL (see ECHA guidance chapter R8, appendix R.8-7):

following factors were:

  • Allometric scaling rat → man:         4
  • remaining differences:                    2.5 (covering e.g. differences in toxicodynamics)
  • intra-species differences:               5 (for workers)
  • point of comparison:                      10 (not having a NOEL)
  • nature of carcinogenic process:       10 (genotoxic carcinogen)
  • T25 instead of BMDL10:               2.5

Adaptation for differences in worker and experimental exposure conditions:

Workers exposure is 5 days a week, 48 weeks a year and 40 years in an average lifetime of 75.

This results in a correction factor of 2.8 (7/5 days/week * 52/48 weeks/year * 75/40 years/life). 

DMELdermal, worker = 18.75 mg/kg bw / 12500 *2.8 = 4.2 µg/kg bw

Due to the conservative nature of the DMEL derivation, systemic organ toxicity is sufficiently covered by the DMEL (DNEL derivation not presented).

 

Long-term exposure – systemic effects – inhalation DNEL

T25oral, rat= 9.375 mg/kg bw (seelong-term exposure – systemic effects – dermal DNEL for rational).

 

Route to route extrapolation:   

The bioavailability of MDA after oral application is at least 90 % (see rational) and therefore as a conservative approach similar bioavailabilities on the oral and inhalation route of exposure need to be anticipated.

 

T25inhal., human=   T25oral, rat* (1/sRVrat) * (ABSoral rat/ABShuman inhal.) * (sRVhuman/RVworker)

T25inhal., human=   9.375 mg/kg bw* (1/0.38 m³/d) 100%/100% * (6.7/10) = 16.5 mg/m³.

 (sRV:                       standard respiratory volume (for rat 0.38 m³/kg/8h or 1.15 m³/kg/24h))

 

“Large assessment factor approach” for the derivation of a DMEL (see ECHA guidance chapter R8, appendix R.8-7):

following factors were applied:

  •  Allometric scaling rat → man:       1 (Allometric scaling does not need to be applied in cases where doses in experimental animal studies are expressed as concentrations (mg/m3)).
  • remaining differences:                    2.5 (covering e.g. differences in toxicodynamics)
  • intra-species differences:               5 (for workers)
  • point of comparison:                     10 (not having a NOEL)
  • nature of carcinogenic process:      10 (genotoxic carcinogen)
  • T25 instead of BMDL10:              2.5

Adaptation for differences in worker and experimental exposure conditions:

Workers exposure is 5 days a week, 48 weeks a year and 40 years in an average lifetime of 75. This results in a correction factor of 2.8 (7/5 days/week * 52/48 weeks/year * 75/40 years/life).

 

DMELinhal., worker = 16.5 mg/m3 / 3125 *2.8 = 14.8 µg/m3

Due to the conservative nature of the DMEL derivation, systemic organ toxicity is sufficiently covered by the DMEL (DNEL derivation not presented).

 

Taking into account an acceptable risk of 4:100000 the Comittee for Hazardous Substances of the German Authority for Occupational Safety and Occupational Medicine (BAuA) derived an exposure risk value for 4,4’-Methylendianiline equivalent to 7.3 µg/m3. This value is in the same order of magnitude as the value derived above, though the derivation parameter was not as refined.

 

Long-term exposure – local effects – dermal DNEL

Not quantifiable; see above

 

Long-term exposure – local effects – inhalation DNEL

Not quantifiable; see above

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

Consumer DN(M)EL

It is possible to calculate consumer DN(M)EL long term, (dermal and inhalation route-systemic), by increasing the assessment factor for intra-species differences from 5 to 10. Though, since no exposure of the general population is supported by the CSA no DMELs are presented.