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Compound n-Heptane Data collection sheet
N°CAS 142 - 82 - 5
1 ppm = 4.13 mg/m³ EU- Classification: CLP: Skin irrit. 2, Asp. tox. 1, STOT SE 3 Organisation name ACGIH^ DFG^ SCOEL^ TPHCWG^ EPA^ Reach registrants Risk value name TLV/STEL MAK TWA / STEL Inhalation RfC Inhalation RfC DNEL Risk value (μg/m^3 ) 1640 (400^ ppm)^ 2085 (500 ppm)^ 2085 (500 ppm)^ 7.6 (1.8 ppm)^ 0.4 mg/m³ (0. ppm) 447 (107 ppm)* Reference period Chronic (worker) Chronic (worker) Chronic (worker) Chronic Chronic Chronic (DNEL^ Gen. Pop. long term) Risk value (mg/m³) / Short term (15 min) 2050 (500 ppm) 2085 (500 ppm) - - - - Year 2001 1958, updated 1995 and 2000 1995 1997 2016 2011, updated 2017 Key study No key study, comparison to pentane, hexane and octane Confirmation of value of 1958 by more recent data, no key study Takeuchi et al (1980,
No key study, comparison to neurotoxicity of n- hexane Simonsen und Lund (1995) Not indicated. Study by Takeuchi et al (1980, 1981) reported as key study for repeated dose inhalation Study type - - 16 weeks inhalation study (0, 3000 ppm = 12510 mg/m^3 )
- 28 days inhalation study (0, 800 and 4000 ppm, 3336 und 16680 mg/m^3 ) 16 weeks inhalation study (0, 3000 ppm = 12510 mg/m^3 ) Species - - Wistar rats ( males/group) -^ Long-Evans rats (9- 11 males per group) Wistar rats ( males/group) Duration of exposure in key study
12 h/d, 7 d/w for 16 weeks -^ 6 h/d for 28 days^ 12 h/d, 7 d/w for 16 weeks Critical effect Narcotic and irritative effects -^ No critical effect^ Neurotoxicity^ Ototoxicity^ No critical effect
Critical dose value - - NOAECsystemic: 12510 mg/m³ 38 - times lower formation of 2,5- heptandione compared to 2,5- hexandione BMCL1SD NOAECsystemic: 12510 mg/m³
- LOAEC determinedsystemic: not^ LOAEC determinedsystemic: not Adjusted critical dose - - Not indicated 0.2 mg/m³ for n- hexane Human equivalent BMCL1SD: 1170 mg/m^3 NOAECtimeadjusted: 6150 mg/m³ ( h/d, 7 d/w) Single assessment factors (see table R.8.6) Not indicated - Overall factor of 5 - UFA: 3 UFH: 10 UFD: 10 UFS: 10 Not indicated Other effects Remarks No time adjust Read-across Endpoint not sufficiently confirmed UFH Intraspecies variability; UFA interspecies variability; UFS Used subchronic study UFD data deficiencies *calculated in the context of this evaluation
Other adjustment factors Quality of whole database
Completeness and consistency Reliability of alternative data (R8-6 d,e)
Result Summary of assessment factors 27 Total Assessment Factor (TAF)^840 POD/TAF 28 Calculated value (μg/m^3 and ppb) 15000 μg/m^3 and 3.6 ppb Molar adjustment factor 29 Used in read-across Rounded value 30 [μg/m^3 ] 15000 Additional comments 31 Rationale section 32 Data compilation and evaluation for n-heptane are based on a project funded by the German Environment Agency (Voss, 2018). Rationale for critical effects The reliability of data on human effects (haematological changes, unspecific symptoms, neurological effects) is limited due to mixed exposure with other (neurotoxic) solvents. Animal studies showed no clear or unambiguous adverse effects up to the highest concentrations tested. The derivation of the EU-LCI is based on the NOAEC of a 26-week rat study by Bio/Dynamics (1980). This study is unpublished, but is sufficiently referenced in detail in the reviews and the REACH registration dossier (there considered as ‘reliable with restrictions, RL 2’) (ECHA Dissemination, 2017). In the study, Sprague-Dawley rats (15 M + 15 F/group) were exposed 6 hours/day, 5 days/week for 26 weeks to n-heptane (98.5 % pure) at concentrations of 400 or 3000 ppm (1668 or 12510 mg/m³). Other studies support the lack of adverse effects at comparable exposure concentrations. One study documenting ototoxicity in rats at higher concentrations is a stand-alone result and needs confirmation (Simonsen and Lund, 1995 ; Greim, 1995). Rationale for point of departure (POD) The derivation of the EU-LCI value is based on a subchronic inhalation study (26 weeks) in rats. Slight transient narcotic effects at the beginning of the study were not considered adverse effects, in view of other studies without effects at comparable and even higher concentrations. The NOAEC of 3000 ppm (12510 mg/m³), the highest concentration tested, serves as a POD. Rationale for assessment factors
- adjustment factor for exposure duration: 5.
- adjusted study length factor: 2 (subchronic study)
- interspecies differences: 2.5 (default value for systemic effects)
- intraspecies differences: 10 (default value)
- other adjustment factors: 3 (lack of data on reproductive and developmental endpoints). The total assessment factor is 840, leading to a calculated value of 14900 μg/m³ and a rounded EU-LCI value for n-heptane of 15000 μg/m³. The derived value is higher than the lowest reported odour threshold of 2.8 mg/m³ (Nagata, 2003), but lower than other reported odour thresholds (≥ 167 mg/m³) (Greim, 1995).
References Bio/Dynamics (1980) A 26-week inhalation toxicity study of heptane in the rat, Project no. 78-7233 (elsewhere: EPA (1981) A 26-week inhalation toxicity study of heptane in the rat with cover letter. Bio Dynamics Inc. EPA/OTS #FYI-AX- 1081 - 0135), cited from DGMK, 1986; Snyder, 1987, ECHA 2017 ECHA Dissemination (2017) n-Heptane. European Chemicals Agency (ECHA), Annankatu 18, P.O. Box 400, FI- 00121 Helsinki, Finland. https://echa.europa.eu/registration-dossier/-/registered-dossier/14228 (last retrieved on 4.12.2019). Greim, H. (1995) Gesundheitsschädliche Arbeitsstoffe, Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten, Loseblattsammlung, 21. Lfg. DFG Deutsche Forschungsgemeinschaft, VCH Verlag Weinheim Nagata Y (2003) Measurement of odor threshold by triangle odor bag method. In: Odor Measurement Review. Office of Odor, Noise and Vibration. Environmental Management Bureau. Ministry of the Environment, Government of Japan, S 118- 127 Simonsen, L.; Lund, S.P. (1995) Four weeks inhalation exposure to n-heptane causes loss of auditory sensitivity in rats. Pharmacology & Toxicology, 76, 41- 46 Voss, J.-U. (2018) Toxicological basic data for the derivation of EU-LCI values for 5 substances from building products. UBA Texte 91/2018. https://www.umweltbundesamt.de/publikationen/toxicological-basic-data-for- the-derivation-of-eu- 0 (last retrieved on 4.12.2019).
