Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
310 mg/m³
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor:
other: MAK value
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

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

Overall it can be noted that isobutanol did not show any adverse systemic effects up to the highest doses tested either orally or via inhalation in sub-chronic studies. In a two-generation inhalation study (6 h per day, 7 days a week for approximately 17 weeks), a 90-days repeated dose inhalation study and a 90-days oral toxicity study, transient behavioral clinical observations and transient body weight gain effects were the only changes noted following repeated isobutanol administration (a slight increase in red blood cell counts, hematocrit, and hemoglobin parameters was observed in the 7.5 mg/ L female rats in the 90-days inhalation study; although these effects were considered substance-related, they are of unknown questionable biological significance and therefore regarded as not relevant for the derivation of the systemic NOAEL). Since neither systemic effects, nor local respiratory irritation has been described in the sub-chronic inhalation studies, the NOAELs were set at the highest dose levels tested, i. e. 7.5 mg/L and 1450 mg/kg/d, respectively.

The German MAK commission conducted a detailed scientific evaluation considering all relevant data on toxicology on isobutanol. Deviation of the MAK value is based on its irritative effects on skin, the respiratory tract and especially eyes. Irritative effects of butyl alcohol isomers are most likely due to non-covalent interactions with receptors of the sensory nerve-endings in mucous membranes and are a function of their physico-chemical properties (vapor pressure, lipophilia). Even though no human data are available for isobutanol, it can be assumed that the local irritation is similar to irritation caused by n-butanol (CAS: 71-36-3), as the two structurally closely related compounds are both primary alcohols. Experiences from human exposure show that eye irritation is the critical toxic effect of n-butanol, for which changes in the cornea have been described as vacuolar keratopathy (MAK evaluation, 2000). While further local, transient effects like odor nuisance, slight headaches or dizziness and irritation of the mucous membranes of the nose and throat have been described, no signs for systemic toxicity have been reported. Vacuoles are thought to be inclusions of liquid in the corneal epithelium and can be formed as a result of penetration of n-butanol into and through the epithelial layers. As these are flushed out after the end of exposure and the corneal epithelium has a high regeneration capability, episodic exposure is not expected to cause permanent damage (MAK evaluation, 2000). A study monitoring the effects of n-butanol on eye irritation in a n-butanol plant over ten years showed that workers exposed to 200 ppm suffered from eye irritation, which in some cases was associated with inflammatory processes in the cornea, blurred vision, lacrimation and increased sensitivity to light. In contrast, when improved occupational hygiene measures have been implemented and the maximal exposure was reduced to 100 ppm, complaints of eye irritation were rare and attributed to exposure peaks (Sterner et al, 1949). This result indicates that exposure up to 100 ppm n-butanol does not induce eye lesions. In line with this finding, human volunteers that were exposed via breathing masks to concentrations up to 200 ppm for 2 hours did not feel adverse effects (Astrand et al. 1976). Considering that ocular irritation is the most prominent effect induced by n-butanol, MAK concluded that exposure up to 100 ppm (310 mg/m3) is safe and can hence be regarded as threshold value below which adverse effects are unlikely (systemic affects are also covered by this value). Considering a similar structure and toxicological profile of isobutanol, this value was also set as threshold level for isobutanol by MAK.

A similar, even higher DNEL can also be deviated if the NOAEL of 7.5 mg/L from a two-generation study is used as starting point, corrected for time (8 h vs 6 h) and respirtaory volume (10m3 for light activity versus 6.7 m3 in rest) and the assessment factors for inter-species (1), intra-species (3), exposure duration (1) and remaining differences (1) are applied -> DNEL = 1758.75 mg/m3.

Based on responsible care, the MAK value and not the calculated DNEL is used for the expouse assessment.

With the exposure conditions expected at the workplace, the amount of n-butyl alcohol taken up by the skin cannot lead to adverse effects.

Justification for assessment factors:

a) Intraspecies Factor: According to the ECHA guidance document, deviation from the default ECHA assessment factors is possible where scientific justification exists. As summarized in the ECETOC technical report No. 86, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined by various groups (Hattiset al., 1987 and 1999; Hattis and Silver, 1994; Renwick and Lazarus, 1998). These evaluations included data from healthy adults of both sexes, as well as limited data from young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The authors came to the conclusion that a factor of 3 for workers (as a more homogenous group) or 5 for the general population is sufficiently conservative to account for intraspecies variability. This holds especially true for substances of low systemic toxicity, e. g. isobutanol, for which transient behavioral clinical observations and transient body weight gain effects were the only effects noted. The most prominent effect induced by isobutanol is local irritation (skin, eye, respiratory tract), which has been observed in acute toxicity studies (when a single, high dose of isobutanol has been administered). In contrast, no systemic toxicity has been noted following repeated oral administration and inhalation (in which defects on respiratory tissue has not been described up to 7.5 mg/l). As such it is considered that the lower assessment factors proposed and justified by ECETOC in the general case apply to isobutanol. Thus, the factors proposed by ECETOC adequately address the intraspecies variability within the risk assessment.

b) Remaining differences: According to the ECETOC guidance document (ECETOC, 2010), it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’. The use of this factor is only appropriate if data on the mode of action indicate differences in sensitivity between animals and humans. In a comparison of the repeated dose data between rats and mice, the ERASM project did not find evidence to support use of such a factor on a routine basis; any observed differences were accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. In the case of isobutanol, there is no evidence to support the use of a factor for remaining interspecies differences beyond metabolic differences, which are already covered by allometric scaling. This conclusion is supported by examining the substance specific data: Isobutanol has a low order of toxicity, with biologically significant effects from repeated dose exposure limited to transient behavioral clinical observations and transient body weight gain effects. The primary effect of isobutanol is its irritative potential. As stated in the ECHA guidance document, animals and humans will respond to local irritation in the same way with respect to toxicodynamic. Therefore, the default factor for remaining uncertainties of 2.5 seems inappropriate and can be reduced to 1. In general, it should be noted that multiplication of separate factors that are not truly independent factors leads to an unnecessarily and unjustifiably conservative overall assessment factor.

c) Exposure duration: Isobutanol did not show any systemic toxicity following oral uptake or inhalation. Increasing exposure duration from a developmental toxicity study (10 days exposure) to sub-chronic exposure (13 weeks or 17 weeks in the two-generation study) did not decrease the NOAEL, indicating that exposure duration is not a factor determining toxicity. Instead, local effects including eye, skin and respiratory irritation are induced by isobutanol. As stated in the ECHA guidance document R8, a lower factor (minimum 1) can be used for dermal effects and local effects on the respiratory tract, for which dose rather than exposure duration is the critical factor.

Taken together, using the calculation suggested by ECHA leads to an even higher DNEL (inhalation, long-term). As a conservative

approach, risk assessment will be based on the value proposed by MAK, i. e. 310 mg/m3.

Literature:

Sterner JH, Crouch HC, Brockyre HF, Cusack M, A ten-year study of butyl alcohol exposure, Am Ind Hyg Assoc J, 10:53-59, 1949

Astrand I. et al, Exposure to butyl alcohol. Uptake and distribution in man, Scand. J. Work Environ. Health 3: 165-175, 1976; cited in ECETOC JACC, n-Butanol, 2003

ECHA Guidance on information requirements and chemical safety assessment, R.8

ECETOC guidance document, Derivation of Assessment Factors for Human Health Risk Assessment, Technical Report No. 86, 2003

ECETOC Guidance on Assessment Factors to derive a DNEL, Technical Report No. 110, 2010

Hattis D, Erdreich L, Ballew M, Human variability in susceptibility to toxic chemicals - a preliminary analysis of pharmacokinetic data from normal volunteers, Risk Anal, 7: 415-426 (1987)

Hattis D and Silver K, Human variability in susceptibility to toxic chemicals - a major source of uncertainty in assessing risks for non-cancer health effects, Risk Anal, 14: 421-431 (1994)

Hattis D, Banati p, Goble R, Burmaster DE, Human interindividual variability in parameters related to human health; Risk Anal, 19: 711-726 (1999)

Renwick AG and Lazarus NR, Human variability and non-cancer risk assessment. An analysis of the default uncertainty factor, Reg Toxicol Pharmacol, 27: 3-20, 1998

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
55 mg/m³
DNEL related information
Overall assessment factor (AF):
5.6
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

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:
medium hazard (no threshold derived)

Additional information - General Population

The DNEL long-term/local effects for the general population was derived from the corresponding DNEL for workers (MAK value) as the relevant DNEL. The relevant effects were considered as depending on the exposure time of substance to the target organ (skin/ mucosa) since effect strength increased over time in a skin irritation study with rabbits (BASF AG, 1979). Therefore, single assessment factors (AF) of 3 (extrapolation from 8 to 24 h exposition) and 1.4 (extrapolation from 5 to 7 days) are used. Additionally, a potentially higher sensivity of subpopulations than workers is calculated with an AF of 2 and a lower mean respiration volume of the general population is considered with an AF of 0.67 (6.7 m3 respiration volume/ "8h with no activity" divided by 10 m3 respiration volume/ "8h with light activity"), leading to a total AF of 5.6. Considering these assumptions, no exposure above 55 mg/m3 should occur for the general population.

Calculating the DNEL for the general population based on the NOAEC of 7.5 mg/L from a 90 d repeated-dose toxicity study leads to an evene higher value of 375 mg/m3(this value is based on a correction of the starting point (24 h instead of 6 h) and the use of the assessment factors for interspecies (1), intraspecies (5), remaining differences (1) and exposure duration (1); explanations for the use of these assessment factors is described in the discussion section for workers).

Isobutanol did not induce any systemic toxicity following oral application up to the limit dose (i. e. 1000 mg/kg/d). However, local irritation of skin and eyes displays the major hazard emanating from isobutanol. Thus, systemic toxicity following oral uptake of isobutanol is unlikely to occur in the general population and an oral systemic, long-term DNEL is hence not required.

For the DNEL long term local effects and for the DNEL short term local effects no quantitative assessment can be made since no dose-response relationship is applicable from skin irritation data and no appropriate long-term dermal studies are available. In the relevant key study, skin irritation (R38 according to 67/548/EEC and skin irritation Cat. 2 according to GHS) was observed in rabbits treated with 0.5 mL of unchanged isobutanol in a variety of weight of evidence studies (see IUCLID section 7.3.1)