Carbamic acid ester

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 mg/kg bw/day

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

722 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see under discussion, based on 100% absorption of metabolite in inhalation study and 10% absorption of parent via dermal route

AF for dose response relationship:

1

Justification:

default factor

AF for differences in duration of exposure:

2

Justification:

semi-chronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

rat study is the key study

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

5

Justification:

worker exposure, default factor

AF for the quality of the whole database:

3

Justification:

study on potential metabolite used

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

DNEL derivation for Carbamic acid ester

 

In absence of information on repeated dose on Propylene carbonate, oligomeric reaction products with 2-methylpentane-1,5-diamine ,information available in the public domain on the degradation products is taken into account. It is assumed that Propylene carbonate, oligomeric reaction products with 2-methylpentane-1,5-diamine is metabolised by esterases and/or amidases after absorption and that the degradation products, 2-methylpentane-1,5-diamine and propylene glycol will be responsible for any adverse effects. Both metabolites are volatile substances with mainly data on inhalation exposure available. Local effects related to this specific route will not be taken into account, as the inhalation route is not relevant for Propylene carbonate, oligomeric reaction products with 2-methylpentane-1,5-diaminel, which has a very low vapour pressure.

For 2-methylpentane-1,5-diamine no data are available in the public domain and therefore data on the very close analogue hexamethylenediamine will be used.

 

Data Required	Carbamic acid ester	CAS 124-09-4; hexamethylenediamine (data as disseminated by ECHA in red)	CAS 57-55-6; propane-1,2-diol (data as disseminated by ECHA in red)
Average molecular weight	320	116	76
State of the substance at 20°C and 101,3 kPa	liquid	solid	liquid
Acute toxicity by oral route	>5000 mg/kg	ca. 1000 mg/kg bw	22000 mg/kg bw
Acute toxicity inhalation	waiver	waiver	> 317042 mg/m³ air (2 h)
Acute toxicity dermal route	>2000 mg/kg	ca 1000 mg/kg bw	> 2000 mg/kg bw
Skin irritation (in vivo)	non irritant	corrosive	non irritant
Eye irritation (in vivo)	non irritant	severe irritant	non irritant
Skin sensitization	negative (Bühler) kl 3	waiver	not sensitizing
Repeated dose study	Read-across	NOAEL 150 mg/kg bw (2 gen study)	NOAEL 1700 mg/kg bw (chronic study)
		NOAEC systemic 90 day inhalation rat/mouse 160 mg/m3	1000 mg/m³ air (90 d)
In vitro gene mutation study in bacteria - Ames test	negative	negative	negative
In vitro cytogenicity study in mammalian cells (chromosome aberration…)		negative	negative
In vitro gene mutation study in mammalian cells		negative	negative
In vivo micronucleus test	Read-across	negative	negative
Screening for reproduction/developmental toxicity	Read-across	NOAEL 150 mg/kg bw (2 generation study)   NOAEC 160 mg/m3 (rat and mice NTP mating trial)	NOAEL 10100 mg/kg bw (continuous breeding)

 

Both 2-methylpentane-1,5-diamine and hexamethylenediamine are classified as harmful to the skin and if swallowed. For other endpoints the results as shown in the table above are indicative for a low toxicity of both metabolites with the toxicity of propylene glycol being lower compared to the toxicity of the diamine. Therefore this evaluation will concentrate on the effects as found in studies on hexamethylenediamine.

Rat and mice 90-day studies (rat key study) on hexamethylenediamine dihydrochloride gave a systemic NOAEC of 160 mg/m3 (100 mg/m3 when corrected for the hydrochloride). From data on absorption in humans as well as from theoretical evaluation (based on the low molecular weight, the logKow and the water solubility) it can be concluded that absorption via the gastro-intestinal tract and via the lung of hexamethylenediamine is high (set at 100% default). The aerosols generated in the inhalation studies with hexamethylenediamine dihydrochloride contained particles in the respirable range, which means that the substance can reach the alveoli and is expected to be absorbed. Based on the 6 hour exposure regimen used in the studies the total daily inhalation volume for rats is 6*60*200 mL=0.072 m3/day, leading to a dose of 7.2 mg/rat = 26 mg/kg bw[1]. This is an internal dose of the amine, because inhalation absorption for the amine is set at 100%.

This value is corrected for the molecular weight of Carbamic acid ester

(320/116), taking into account that forCarbamic acid ester uptake via the gastro-intestinal tract 100% and the skin is 10% (see toxicokinetic assessment, high water solubility is expected to limit the uptake of Carbanic acid ester via the skin). The internal NOAEL for Carbamic acid ester would be 72.2 mg/kg bw. The external NOAEL for Carbamic acid ester for oral exposure would be 72.2 mg/kg bw and for dermal exposure 722 mg/kg.

Based on the NOAEL in rats from the two-generation study in feed hexamethylenediamine (150 mg/kg bw, a similar calculation can be performed. The NOAEL oral is 150 mg/kg bw (absorption 100%). Correction for Carbamic acid ester (320/116) -> internal NOAEL Carbamic acid ester 414 mg/kg bw. This leads to an external NOAELdermal (based on 10% dermal absorption, see toxicokinetic assessment) of 4140 mg/kg bw

 

A DNEL can be derived from both studies

90-day study: assessment factor 100 and an additional 3 for uncertainty of the data base -> 722/300 = 2.4 mg/kg bw

This DNEL is considered to be a worst case, as when taking the oral studies with the amine as starting point the value would have been higher.

Two-generation study: assessment factor 100 and an additional 3 for uncertainty of the data base -> 4130/300 = 13.8 mg/kg bw

For risk assessment the worst case approach will be taken. Thus a DNEL dermal of 2.4 mg/kg bw will be taken as starting point.

[1]Default inhalation volume rat (90d) 200 mL/min (REAC guidance); default body weight rat (90 d) 275 g (EU TGD part I)

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

Additional information - General Population

No consumer exposure anticipated