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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: adoption of workplace limit value
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: adoption of workplace limit value

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: adaption of workplace limit value
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: adaption of workplace limit value
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Summary

Toxicological key items

n-Butylamine is assumed to be readily bioavailable by all potential routes of exposure. Exposure may mainly occur by inhalation and by skin contact. The substance is readily metabolised by sharing common metabolic pathways or excreted from the body in unchanged form, thus not accumulating.

The primary and most relevant effect is its irritating/corrosive effect on skin and mucous membranes. This severe local insult limits exposure to doses that potentially may induce systemic lesions: There were developmental effects following oral administration of the hydrochloride salt of n-butylamine to rats at an effective dose (LOAEC) of 400 mg/(kg bw*d), which is equivalent to about 265 mg base/(kg bw*d)]. The dose that was orally effective could not be achieved by inhalation ([see IUCLID 7.8.2, Gamer et al. 2002). It is evident that the prevention of local lesions will also be protective from systemic effects.

DNEL estimation

In a subacute inhalation toxicity study in rats no systemic toxic effects have been observed up to the highest concentration tested (150 ppm; 460 mg/m3). However, local effects were already observed at the lowest test concentration of 17 ppm (51 mg/m3) indicating that local irritancy is the most relevant effect for n-butylamine after inhalation exposure. Based on the local effects in this subacute inhalation study a theoretical DNEL of 0.3 mg/m3would result after application of the default procedure according to Guidance R.8 (analytical LOAEC of 51 mg/m3* 1/(2.5 (inter) x 5 (intra) x 3 (LOAEC/NOAEC) x 6 (time) = 0.2 mg/m3). An about 10-15 fold higher value of 3 mg/m3would result if the – probably more appropriate - procedure recommended by Bruening et al. (2014, Arch. Toxicol. 88:1855ff) for sensory irritants would be applied (transformation of rat LOAEC for respiratory sensitisation to a human NOAEC and adjustment for time; for justification see also MAK-value documentation). The limit value derived by application of the methodology suggested by Bruening et al. is in the same order of magnitude as the MAK value of 2 ppm (6.1 mg/m3). A MAK value of 2 ppm is supported by observations from the workplace: Daily exposure of workers with n-butylamine concentrations in the range of 5-10 ppm resulted in irritations of the nose, throat, and eyes and caused headaches. No complaints were reported if the workplace exposure was below 5 ppm (with actual exposures usually in the range between 1 and 2 ppm; Beard and Noe, 1981). The MAK value of 2 ppm for n-butylamine is further supported by experimental data for the structural similar substance cyclohexylamine for which no sensory irritation could be detected in investigations with volunteers who were exposed to 2 ppm and peak concentrations of 4 ppm. Cyclohexylamine is probably a more potent sensory irritant (RD50 in mice of 51 ppm) than n-butylamine (RD50 in mice of 84-112 ppm).

On basis of the NOAEC for systemic toxic effects observed in the developmental toxicity study (460 mg/m3; no systemic toxic effects observed up to the highest dose tested) and applying the default assumptions of the Guidance Chapter R.8. a theoretical DNEL of 4.3 mg/m3would result (460 mg/m3 *6h/8h *7/5 *6.7m3/10m3* 1/(2.5 (inter) x 5 (intra) x 6 (time)) = 4.3 mg/m3), which is numerically very close to the MAK value and supports the derived DNEL.

In the USA, no Time Weighted Averages (TWA) for the workplace were provided for n-butylamine. The respective ceiling values for the OSHA PEL, NIOSH REL, ACGIH TLV and Cal OSHA PEL are 5 ppm (15 mg/m3). The German MAK value was revised in 2006 and reduced from 5 to 2 mL/m3(6.1 mg/m3) [DFG 2007].

In synopsis of all available data, it is proposed to adopt the latest MAK value of 2 ppm (6.1 mg/m3) as a DNEL for repeated and prolonged inhalation, while for short-term exposure a DNEL of 4 mL/m3(12.2 mg/m3) (representing the short term MAK) is considered to be sufficiently protective. The concentration of 5 mL/m3should not be exceeded at any time. This value would be protective for systemic as well as for local effects of n-Butylamine.

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Reference:

OSHA/ACGIH/NIOSH/Cal OSHA USA, see e.g.: https://www.osha.gov/chemicaldata/chemResult.html?recNo=99 (accessed 25 June 2018)

MAK-Kommission 2007:Toxikologisch-arbeitsmedizinische Begründung von MAK-Werten: n-Butylamin, sec-Butylamin, iso-Butylamin.

DFG (Deutsche Forschungsgemeinschaft); Wiley-VCH Verlag 2007

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Overview of effects data following exposure to n-butylamine

Olfactory / nasal effects markers

Exposure concentrations

Reference

Section IUCLID5

mL/m3

mg/m3

Odor threshold (human)

1 - 2

3 - 6

Beard and Noe 1981; Amoore amd Hautala 1983

7.10.3

Sensory nasal irritation threshold (human)

5

15

Beard and Noe 1981

7.10.3

RD0 (mouse, 10 min) *)

11.8

36

Nielsen and Vinggaard 1988

7.2.2

RD50 (mouse, 10 min) *)

121

380

Nielsen and Vinggaard 1988

7.2.2

RD50 (mouse, 15 min) *)

84 – 112

260 - 340

Gagnaire et al. 1989, 1993

7.2.2

NOEC (no clinical symptoms, rat, 5 d)

40

120

Gamer et al. 1999

7.5.3

NOAEC (clinical symptoms, no histopathological changes, rat, 5d)

115

350

Gamer et al. 1999

7.5.3

NOAEC (histopathological changes, rat, 14d)

<17

<51

Gamer et al. 2002

7.5.3

*) RD0 = the exposure concentration resulting in no reflectory, sensoric irritation (no suppression of respiration rate).

RD50 = the exposure concentration resulting in reflectory, sensoric irritation expressed as 50% decrease in the respiratory rate.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.77 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEC
Value:
460 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
115 mg/m³
Explanation for the modification of the dose descriptor starting point:

In the underlying experimental study rats were exposed during 6 hours and every day over a period of 14 days. Therefore, the NOAEC from the developmental toxicity study was adapted to the consumer situation with 24 h exposure during 7 days/week.

AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
6
Justification:
default value for subchronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
default value
AF for other interspecies differences:
2.5
Justification:
default value for remaining uncertainties
AF for intraspecies differences:
10
Justification:
default value
AF for the quality of the whole database:
1
Justification:
default value
AF for remaining uncertainties:
1
Justification:
default value
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

As outlined above a DNEL for systemic inhalative exposure could be derived on basis of the developmental toxicity study. Based on the NOAEL for systemic effects of 460 mg/m3, after adaption to the continuous exposure situation of consumers (x 6/24 x 7/7) and considering the default assessment factors for remaining interspecies differences (AF 2,5), intraspecies differences (AF 10) and time extrapolation (6) a DNEL 0.77 mg/m3 results. All other endpoints are evaluated in a qualitative manner, due to the acute toxicity and skin corrosivity of the substance.