N-methylisopropylamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4 mg/m³

Acute/short term exposure

DNEL related information

Dose descriptor starting point:

NOAEC

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Additional information - workers

Preface

- Referring to sensitization, mutagenicity or reproductive toxicity, no adverse effects were obtained from testing with the systemically available form MIPA-HCl.

- The primary routes of anticipated industrial exposure to MIPA are via skin contact and inhalation.

- Since MIPA is corrosive, the systemic DNELs are considered not appropriate for risk assessment; the local effects will cover the systemic effects. Nevertheless, the systemic DNELs have been calculated, however, for risk characterization and exposure considerations, the DNELs for local effects will be used.

- The starting point selected for systemic DNEL assessment is the NOAEL of 300 mg/kg bw obtained from a subchronic oral study with the neutralized form MIPA-HCl in rats (BASF SE, 50C0413/08S001, 2010). The NOAEL is modified as described in R8 (ECHA, May 2008) and ECETOC Guidance on Assessment Factors to Derive DNELs (ECETOC, 2010).

Short-term exposure, systemic

According to the available data, MIPA has to be classified with respect to corrosivity, (R34, Cat 1B). Moreover, study data referring to acute oral and inhalative route of exposure both would lead to classification as T R25/ Cat 3 [EU 67/548/EC / CLP] for the oral route and as R20/Cat 3 for the inhalative route. Nevertheless, the effects observed and mortalities rather were related to the corrosive potential of the test item than to systemic toxicity, thus, systemic DNELs after short term expoure are considered to be not appropriate and as a result there is no need to determine acute systemic DNELs. Furthermore, for evaluation of systemic effects the neutralized hydrochloride form of MIPA (MIPA-HCl) appears to be more adequate. In fact, for MIPA-HCl, data on acute oral toxicity and long-term oral toxicity are available, which demonstrate the absence of a systemic toxic potential of MIPA in its bioavailable form MIPA-HCl. Thus, when considering the systemically available MIPA-HCl, no classification for acute systemic toxicity in needed and consequently there is no need for determination of an acute DNEL for systemic effects.

Short-term exposure, local

MIPA is corrosive and mortalities and effects observed within acute oral and inhalative studies were rather due to the corrosiveness of the compound than to systemic toxicity. Thus, a qualitative assessment is recommended for both dermal and the inhalative route.

Long-term exposure, systemic

Due to the corrosive nature of MIPA, the systemic DNELs are considered not appropriate for risk assessment. Nevertheless, the systemic DNELs have been calculated based on the NOAEL observed with the neutralized form MIPA-HCL, however, for risk characterization and exposure considerations, the DNELs for local effects will be used.

- Inhalative route

For derivation of the worker inhalative DNEL, a route to route extrapolation of the above NOAEL was performed, and different assessment factors were applied as described below. Long term systemic DNEL derivation (inhalation route):

Description	Values	Remark
Relevant dose descriptor	NOAEL: 300 mg/kg bw/day	OECD Guideline 408; rats, 90 days
Modification of the starting point	0.38 m^3/kg bw	Conversion into NOAEC
	6.7 m^3/10 m^3	Light activity
Assessment factors
Exposure duration	2	Subchronic to chronic
Interspecies	1	Include in modification
Intraspecies	3	ECETOC for workers
DNEL	Derivation equation and value
For workers	300 mg/kg bw/day / 0.38m³/kg bw/day * 6.7m³/10m³ (2 x 1 x 3) = 88 mg/m³

- Dermal route

The DNEL for dermal long term exposure of workers are also derived from the NOAELs obtained in a subchronic oral study mentioned above. Extrapolation from oral to the dermal route has been performed assuming that 100 % of the amount applied is systemically available.

Long term systemic DNEL derivation (dermal route):

Description	Values	Remark
Relevant dose descriptor	NOAEL: 300 mg/kg bw/day	OECD Guideline 408; rats, 90 days
Modification of the starting point	Not applicable
Assessment factors
Exposure duration	2	Subchronic to chronic
Interspecies	4	Include in modification
Intraspecies	3	ECETOC for workers
Route to route	1	Assuming 100% bioavailability
DNEL	Derivation equation and value
For workers	300 mg/kg bw/day / (2 x 4 x 3 x 1)= 12.5 mg/kg bw/day

Long-term exposure, local

- Inhalative route

Based on the findings reported in the acute inhalation study on MIPA (see acute and short-term exposure), the risk of irritation of the respiratory tract during long-term exposure can not be excluded; this is further supported by the vapour pressure of MIPA which is about 286 hPa (20°C). Thus it can be assumed that for the worker under long-term exposure conditions, the local risk will be of greater relevancy than the systemic risk. To underline this aspect, N,N-diethylethanamine (CAS 121 -44 -8) was selected for purpose of comparison since both, MIPA and N,N-diethylethanamine show structural similarities, implying quite similar mode of actions. Due to strong alkalinity, N,N-diethylethanamine has an irritative to caustic effect on skin , and its vapours cause severe irritation to the mucous membranes (MAK, 1996). The LC50 for acute inhalation was reported to be about 1.25 and 2.6 mL/L, corresponding to 5.2 and 10.8 mg/L respectively (density at 25 °C is 0.725) , which is in the range of the LC50 obtained for MIPA which was set at 9.09 mg/L. Following exposure to 4.16 mg/L of N,N-diethylethanamine for 10 days, the respiratory tract of rats was shown to be the main target, showing inflammation and necrosis of the nose as well as metaplasia in the airways and edema in the lungs (MAK, 1996). Furthermore, The MAK commission reported that data exist on workers exposed for 8 hours to 12.5 mg/L and during short periods to more than 16.7 mg/L of N,N-diethylethanamine. According to these data, the workers suffered from visual disturbances (blue grey, cloudy or unclear vision). Similar effects also were reported in single cases under 8 hours exposure conditions to an average of 4.2 mg/L of the test item. When concentrations of N,N-diethylethanamine were higher,obvious but transient effects indicating corneal irritation were observed (MAK, 1996). In a study conducted with 33 workers in a foundry which were exposed to N,N-diethylethanamine at concentrations up to 0.039 mL/m³ (due to analytical problems, it was assumed that the concentrations were in fact higher), irritation of respiratory tract as well as burning eyes and headache were reported (NIOSH 1978, in MAK, 1996). A worker exposed to 0.82 mL/m³ of N,N-diethylethanamine with peak exposures up to 11.4 mL/m³ suffered from visual disturbances, and dryness of nose and throat (Ashland Chemical Company 1986, in MAK 1996). Local effects on skin and mucosa also were reported as defatting, dried and chapped hands, skin lesions, and corneal edema (MAK, 1996). The concentrations of N,N-diethylethanamine set by workers under 8 hours exposure conditions as resulting in no such effects as those reported above were 1.44 and 2.7 mL/m³, i.e., 0.006 and 0.01 mg/L. Thus, for N,N-diethylethanamine the MAK Commission decided to set the MAK value at 1 mL/m³, i.e, 4.2 mg/m³ (MAK, 1996, 2002).

A further aliphatic amine, diisopropylamine (DIPA, CAS 108 -18 -9), also can be considered for purpose of comparison. As MIPA, this substance also is characterized by its corrosivity, and according to a summary report by Hoechst AG (Donaubauer H, Diisopropylamin, Hoechst AG, Arzneimitteltoxikologie, 31.12.1980), the toxicity of DIPA especially as gas and vapour is high. Referring to local toxicity, DIPA vapour or gas results in strong mucosa irritation, and further, similarly to other amines, DIPA is very lipophilic, thus resulting as liquid in deep skin corrosivity (Hoechst AG, 1980). Inhalation of DIPA vapour is known to result in inflammation and alterations in the lung reaching up to hemorrhagic lung-edema. In the eye, DIPA induces chemosis, and at increased concentrations, up to corneal alterations resulting in transient and sometimes permanent blindness (Hoescht AG, 1980). In a 28 day inhalation repeated dose study by the Monsanto Company (One month inhalation study of diisopropylamine, 1988, in IUCLID Basic data det of the Amines Panel, USA, American Chemistry Council, Amines Panel, 21.11.2003) Sprague-Dawley rats of both sexes were whole body exposed 5 hours/day, 5 days/week, to 100, 600 and 2000 mg/m³ DIPA vapour. Respiratory difficulty at 600 and 2000 mg/m³, and nasal irritation at 2000 mg/m³ were observed during exposure. During post-exposure, mainly at 2000 mg/m³, mucous membrane irritations (red-brown perinasal encrustation, blood-like nasal discharge and periorbital encrustation), respiratory difficulties (rattling sounds, sneezing, labored breathing, gasping and rapid breathing), nonresponsiveness, and spontaneous deaths were reported. At 600 mg/m³ a few cases of perinasal and periorbital encrustation and sneezing were seen, whereas at 100 mg/m³ only on case was reported. At 2000 mg/m³, histopathology revealed inflammation of the eye, corneal hyperplasia, acute necrosis of the iris, inflammation of the lung (bronchi, alveoli, peribronchi), hyperplasia/metaplasia of bronchiolar epithelium, interstitial pneumonia, granuloma, inflammation of the nasal turbinates and trachea with hyperplasia/metaplasia of mucous epithelium. The findings referring to nasal turbinates also were observed at 100 and 600 mg/m³. Thus the LOAEL for local effects was set at the lowest tested concentration level of 100 mg/m³; the NOAEL for systemic toxicity was 100 mg/m³, indicating that the local effects are of higher relevancy regarding to toxic potential of the compound. Thus, for DIPA, A TLV-TWA of 5 ppm (20 mg/m³) is recommended for occupational exposure to provide a reasonable margin of safety against disturbance of vision and irritation of respiratory tract (Diisopropylamine, TLV-TWA, AGGIH 2001).

Based on these assessments, a worst case scenario is applied and the DNEL for MIPA is based on the structural analogue with the lowest MAK value (N,N-diethylethanamine): DNEL (MIPA) = 4 mg/m³.

- Dermal route

Since MIPA is corrosive, a qualitative assessment is recommended (REACH Guidance on Information Requirements and Chemical Safety Assessment, Part E (Risk Characterisation) and Chapter R.13 (Risk Management Measures and Operational Conditions)).

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/m³

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Additional information - General Population

Preface

- Referring to sensitization, mutagenicity or reproductive toxicity, no advere effects were obtained from testing with the systemically available form MIPA-HCl.

- For the general population the dermal, inhalative and oral exposure routes are considered.

- Since MIPA is corrosive, the systemic DNELs are considered not appropriate for risk assessment; the local effects will cover the systemic effects. Nevertheless, the systemic DNELs have been calculated, however, for risk characterization and exposure considerations, the DNELs for local effects are recommended.

- As for workers, the starting point for systemic DNEL calculation is the NOAEL of 300 mg/kg bw obtained from a subchronic oral study with the neutralized form MIPA-HCl in rats (BASF SE, 50C0413/08S001, 2010). The NOAEL is modified as described in R8 (ECHA, May 2008) and ECETOC Guidance on Assessment Factors to Derive DNELs (ECETOC, 2010).

Short-term exposure, systemic and local

The considerations for the general population regarding acute and short-term exposure are the same as for the workers and are driven by the fact that MIPA is corrosive and that local effects will prevail systemic effects.

Long-term exposure, systemic

Due to the corrosive nature of MIPA, the systemic DNELs are considered not appropriate for risk assessment. Nevertheless, the systemic DNELs have been calculated based on the NOAEL observed with the neutralized form MIPA-HCL, however, for risk characterization and exposure considerations, the DNELs for local effects are recommended.

- Inhalative route

The long-term inhalative DNEL was derived with the same assumptions as for workers, but with general population specific parameters.

Long term systemic DNEL derivation (inhalation route):

Description	Values	Remark
Relevant dose descriptor	NOAEL: 300 mg/kg bw/day	OECD Guideline 408; rats, 90 days
Modification of the starting point	1.15 m^3/kg bw	Conversion into NOAEC
Assessment factors
Exposure duration	2	Subchronic to chronic
Interspecies	1	Include in modification
Intraspecies	5	ECETOC for general population
DNEL	Derivation equation and value
For general population	300 mg/kg bw/day / 1.15m³/kg bw/day * 1 / (2 x 1 x 5) = 26 mg/m³

- Oral and dermal route

The same NOAEL as for workers is chosen as the point of departure for the derivation of systemic oral and dermal DNEL (general population) using general population specific assessment factors.

For extrapolation from oral to the dermal route it is assumed that 100 % of the amount applied is systemically available.

Long term systemic DNEL derivation (dermal route):

Description	Values	Remark
Relevant dose descriptor	NOAEL: 300 mg/kg bw/day	OECD Guideline 408; rats, 90 days
Modification of the starting point	Not applicable
Assessment factors
Exposure duration	2	Subchronic to chronic
Interspecies	4	Include in modification
Intraspecies	5	ECETOC for general population
Route to route	1	Assuming 100% bioavailability
DNEL	Derivation equation and value
For general population	300 mg/kg bw/day / (2 x 4 x 5 x 1)= 7.5 mg/kg bw/day

Long-term exposure, local

-Inhalative route

As recommended in chapter R.8 of the REACH Guidance document, for general population, the DNEL was extrapolated starting from the value assessed for worker, using an assessment factor of 2, resulting in a DNEL of 2 mg/m³.

- Dermal route

MIPA is corrosive, thus a qualitative assessment is recommended.

References:

- ECETOC draft, Derivation of Assessment Factors for Human Health Risk Assessment, 2010

- Guidance for the implementation of REACH, Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health. ECCHA, Mai 2008