Registration Dossier

Administrative data

Description of key information

In accordance with Annex XI Section 3 it is demonstrated and documented that exposure in all scenarios is well below an appropriate derived no-effect level (DNEL) or predicted no effect concentration (PNEC) derived under specific conditions.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
4 589 mg/m³

Additional information

REACH provides for the option that information requirements may be adapted based on the justification that exposure is absent or not significant (Annex XI, section 3.2(a) (i); Annex VIII column 2 section 8.6.1 and 8.7.1) or unlikely (Annex IX column 2 section 9.4).

 

Exposure based adaptation (EBA) is based on the general rules for adaptation of the standard testing regime laid down in Annex XI section 3: Here it is stated that ‘testing may be omitted based on the exposure scenarios developed in the chemical safety report. The justification shall be based on a thorough and rigorous exposure assessment in accordance with section 5 of Annex I (see Guidance on information requirements and chemical safety assessment Chapter R.5: Adaptation of information requirements. August, 2010).

The interpretation in this guidance document is that exposure-based adaptation of information requirements under REACH should take into account available knowledge on i) substance physicochemical properties, ii) hazard information covering a certain endpoint, iii) the conditions of use and iv) the expected releases and/exposure under these conditions.

If EBA is based on Annex XI section 3, a qualitative or quantitative risk characterisation is required, based on a rigorous exposure assessment according to Annex 1. The qualitative risk characterisation establishes control of risk by demonstrating that i) strictly controlled conditions apply or ii) that no releases are to be expected, and thus the likelihood of exposure is negligible. A quantitative risk characterisation establishes control of risk by demonstrating that the risk characterisation ratio is well below 1, taking full account of the increased uncertainty resulting from the omission of the information requirement, and that DNEL or PNEC is relevant and appropriate both to the information requirement to be omitted and for risk assessment purposes.

Reaction Products of C4 alcohols and C4 alkenes obtained as by-products from the manufacturing of butan-2-ol by sulfuric acid esterification and hydrolysis of butene is a UVCB substance. Reliable DNELs or PNECs have been derived based on the hazard information of its constituents. A rigorous exposure assessment according to Annex 1 (Guidance on information requirements and chemical safety assessment Chapter R.14 and R.15), and subsequently a quantitative risk characterization using the science-based DNELs have been performed. The RCRs for all exposure routes combined have been calculated, and the highest RCR per exposure scenario are as follows:

Exposure Scenario

Substance as such or in a mixture

Contributing scenario with highest RCR

RCR

Manufacturing

As such

Use in contained batch processes with enclosed or vented sampling points

0.09

Formulation

As such

Use in contained batch processes with enclosed or vented sampling points

0.09

Distribution

In a mixture (0.4%)

1.      General exposures (open systems);

2.      Drum and small package filling.

0.13

Industrial fuel use

In a mixture (0.4%)

Equipment maintenance

0.26

Professional fuel use (spark ignition)

In a mixture (0.4%)

Equipment cleaning and maintenance

0.29

Consumer fuel use (spark ignition)

In a mixture (0.4%)

Refuelling gardening equipment

0.00

The highest RCR for all exposure routes combined is 0.29 (Professional fuel use, Equipment cleaning and maintenance). This value is considered to be well below 1. Hence negligible risk can be demonstrated and further testing is waived.

Information about the repeated dose toxicity of the UVCB substance Reaction Products of C4 alcohols and C4 alkenes obtained as by-products from the manufacturing of butan-2-ol by sulfuric acid esterification and hydrolysis of butene can be derived from the repeated dose toxicity of the main constituents. The main constituent is 2,2’-oxybisbutane, also known as sec-butyl ether or SBE, which is present at a level of approximately 60%. The other main constituents are C4 hydrocarbons (mainly butenes, excluding 1,3-butadiene) at a level of approximately 20%, C8 hydrocarbons (mainly alkenes) at a level of approximately 15%, and butan-2-one (also known as methyl ethyl ketone or MEK) at a level of approximately 5%.

 

There are no repeated dose toxicity data available on SBE itself. However, sufficient data are available on its metabolites 2-butanol (sec-butyl alcohol or sBA; CAS No. 78-92-2) and 2-butanone (methyl ethyl ketone or MEK; CAS No. 78-93-3). SBA and MEK are toxicologically interrelated, since exposure to SBA will result in exposure to MEK, since MEK is the major metabolite of SBA. Additional data to inform the repeated-dose toxicity of SBE are available from the structural analogue IPE (or DIPE; CAS No. 108-20-3).

 

The repeated dose toxicity of isopropyl ether (IPE, also known as diisopropylether or DIPE) has extensively been assessed in several inhalation studies in multiple species, including rats, guinea pigs, rabbits and monkeys. In the most recent and well-described study, rats were exposed to 0, 480, 3300, and 7100 ppm IPE for 6 hours/day, 5 days/wk for 13 weeks. Increases in liver and kidney weights were seen at 3300 and 7100 ppm in both males and females. Some evidence of increased incidence of hyaline droplets in kidney proximal tubules was observed in high dose males only. No effects on serum chemistry, hematology, or pathology were noted at any dose level. The no observed effect concentration (NOEC) for this study was 480 ppm (Dalbey and Feuston, 1996). The authors did not derive a NOAEC, however, based on minimal kidney effects in the high-dose males, of which the relevance to man is unclear, a conservative NOAEC could be established at 3300 ppm.

Data from a developmental toxicity study with IPE confirm this NOAEC. Rats were administered 0, 430, 3095, and 6745 ppm IPE for 6 hours/day on gestations days 6-15. Maternal effects at the high dose included increased salivation and lacrimation during and immediately following exposure. A slight decrease in food consumption was noted at 3095 and 6745 ppm. A concentration-related increase in the incidence of rudimentary ribs was observed (statistically significant at 3095 and 6745 ppm), but the significance of this finding is not known. No changes in reproductive organ weights and structure or sperm and spermatid number at any dose group were noted. The NOEC for both maternal and developmental effects under conditions of this study was 430 ppm (Dalbey and Feuston, 1996). The authors did not derive a NOAEC, but since no significant adverse effects were noted at all concentrations, the NOAEC could be established at 6745 ppm.

In a whole body 90-day inhalation study in Fischer 344 rats, animals were exposed to methyl ethyl ketone at concentrations of 0, 1254 ppm, 2518 ppm, or 5041 ppm for 6 hours/day, 5 days/week for 89 or 90 consecutive days (Cavender, 1981). This GLP study was equivalent to OECD Test Guideline 413. No mortalities were observed during the study. Clinical signs noted (including irritation, swelling, ear tag crustiness, and/or crusty eye in control and treated animals) were not related to the administration of the test article. High-dose (5041 ppm) male and female body weights were transiently depressed starting at week one, while the low-dose male and mid-dose male and female body weights were elevated as the study progressed. There were no test article related changes in ophthalmoscopy and urinalysis. The mean corpuscular haemoglobin (in high-dose males and females) and mean corpuscular haemoglobin concentration (in high-dose females only) were increased compared to controls. The increase in haemoglobin corresponded to a slight (but not significant) decreased in the number of red blood cells. The serum glutamic-pyruvic transaminase (SGPT) activity in the 2500-ppm female rats was elevated while the 5000-ppm female rats exhibited significantly decreased SGPT activity. Potassium levels in high-dose (5041 ppm) females were statistically higher than control values. In high-dose (5041 ppm) rats, liver and kidney weights were significantly elevated, without showing histopathological changes. Only minor macroscopic lesions were observed and none were attributed to test article administration. Any neoplastic lesions observed were not related to test article administration. No changes in neurological function were observed. Based on the data, a NOAEC of 5041 ppm can be considered for subchronic inhalation exposure, based on no adverse effects noted in both sexes at 5041 ppm.

For C4 hydrocarbons there is ubiquitous repeated-dose toxicity available. The most long-term and most relevant study (since most of the C4 hydrocarbons are butene isomers) is the 2-year NTP study with 2-methylpropene. Rats and mice were exposed to 2-methylpropene at concentrations of up to 8,000 ppm, (18,359 mg/m3) for 105 weeks (NTP, 1998). The non-neoplastic findings from these studies were confined to effects on nasal tissues. In mice, hyaline degeneration of the olfactory and respiratory epithelium was increased in both sexes. The severities of hyaline degeneration increased with increasing exposure concentration. However, this was considered by the NTP to be a nonspecific adaptive response that had no adverse effect on affected animals. The NOAEC for toxicity in mice was therefore 8000ppm (18,359 mg/m3). Similar findings were observed in rats although the lesions were more severe. An additional finding in rats was that hypertrophy of goblet cells lining the nasopharyngeal duct was marginally increased with 100% incidence in males at 8000 ppm. The NOAEC for toxicity in the rat study was therefore 2000 ppm (4589 mg/m3), lower than that in mice (OECD SIDS Report for Isobutylene, 2003).

 

Repeated dose toxicity data on C8 hydrocarbons (mainly alkenes) are derived by reading across to data on a C7-C9-rich alkane stream, and to data on 1-hexene.

A 13-week inhalation toxicity study was conducted using wholly vaporized light alkylate naphtha distillate (a stream containing mainly C7-9 alkanes) (Schreiner et al., 1998). Male and female rats were exposed by inhalation in whole-body exposure cages 6 hours/day, 5 days/week for 13 weeks at analytical concentrations of 0, 668, 2220, and 6646 ppm. No test-related observations were noted in the exposure chambers during

any exposure period for any treatment groups or during non-exposure periods. From weekly clinical observations, the only apparent treatment-related finding was an increased incidence of red facial staining in both male and female rats in the high dose group. At week 13, there were statistically significant dose-related increases in absolute and relative kidney weights in males of all 3 treatment groups. The kidney weights of high-dose males remained elevated after the recovery period. These increases correlated with microscopic observations of hyaline droplet formation in the proximal convoluted tubules considered to contain an alpha2-microglobulin-hydrocarbon complex as well as an increase in incidence and severity of nephropathy and dilated tubules at the corticomedullary junction. These microscopic finding are characteristic of light hydrocarbon nephropathy also known as hyaline droplet nephropathy and are male rat specific. Therefore these effects are not considered to be relevant to humans. Statistically significant increases in absolute and relative liver weights were observed in high-dose male and female rats at week 13 after sacrifice. Differences were not present after the recovery period and had no microscopic correlate. Thus, the NOAEC for systemic toxicity was 8117 mg/m³ corresponding to 2200 ppm.

A 90-day inhalation study with hex-1-ene is representative for the C6 alkene repeated dose toxicity. In this study, Neodene 6 alpha olefin was administered to forty Fischer 344 rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 300, 1000, or 3000 ppm (corresponding to 0, 1033, 3442, or 10,326 mg/m3) for 6 hours a day, 5 days a week, for 13 weeks (Bennick et al., 1984). Ten of the animals/sex/concentration were used for neuromuscular testing, ten of the animals/sex/concentration were sacrificed after 7 weeks of exposure, and twenty animals/sex/concentration were sacrificed after 13 weeks of exposure. Subchronic inhalation of Neodene 6 alpha olefin for 13 weeks did not produce any adverse respiratory, neuromuscular, or testicular effects in rats. Decreased body weight was observed in 3000 ppm females (statistically significant) and males (statistically significant only sporadically). Decreased absolute liver and kidney weights were observed in 3000 ppm females; however, these findings were considered secondary to reduced body weight in the absence of histopathological findings in these organs. There were statistically significant differences in haematology and clinical chemistry values, but the changes were slight (generally within 5% of the control), were not dose related, and/or not associated with any histopathology findings. Increased phosphorus levels were reported in males at all treatment levels and females exposed to 1000 and 3000 ppm hex-1-ene. The toxicological significance of these findings is doubtful. The NOAEC is 3000 ppm (10,326 mg/m3) based on a lack of toxicologically relevant findings at the highest concentration tested.

 

Taking all information on the constituents together, it can be expected that the Reaction Products of C4 alcohols and C4 alkenes obtained as by-products from the manufacturing of butan-2-ol by sulfuric acid esterification and hydrolysis of butene is of low repeated-dose toxicity. Available data do not warrant classification for this endpoint.

Based on the information of the constituents, the NOAECs observed ranged from 4589 mg/m3 for C4 hydrocarbons (butenes) to 14,866 mg/m3for MEK. This indicates that the UVCB substance is of low repeated dose toxicity and does not require classification for repeated dose toxicity.

For the determination of the most relevant value for the CSA it should be noted that although the vapour pressure of the main constituent SBE is medium (30 hPa), whereas the vapour pressure of the UVCB substance is relatively high (410 hPa). This suggests that inhalation exposure is mainly to C4 hydrocarbons (15% present in the liquid UVCB substance, vs. 60% SBE). Since C4 hydrocarbons have a high vapour pressure, their dermal absorption however, will be very low. This is due to the fact that most of the C4 hydrocarbons will have evaporated before any dermal absorption can take place. For a dermal DNEL therefore, the dose descriptor for SBE is more relevant.

References

Bennick, J. E., Malley, L. A., Patterson, D. R., Lu, C. C. (1984). 90-Day vapor inhalation study in rats with Neodene® 6 alpha olefin. Testing laboratory:,,. Report no.: WRC RIR-362. Owner company: Shell Development Company. Report date: 1984-04-03.

 

Cavender(1981). A 90-Day Toxicology Study in Fischer-344 Rats Exposed to Methyl Ethyl Ketone. Testing laboratory: TOXIGENICS, INC.,. Owner company: American Chemistry Council, Inc. Study number: 420-0305. Report date: 1981-11-20.

 

Dalbey W. and Feuston M. (1996) Subchronic and developmental toxicity studies of vaporized diisopropyl ether. J. Toxicol. Environ. Health 49: 29-43.

 

National Toxicology Program(NTP) (1998). NTP Technical report on the toxicology and carcinogenesis studies of isobutene (CAS NO. 115-11-7) in F344/N rats and B6C3F1 mice (inhalation studies). NIH publication. Testing laboratory: Battelle Pacific Northwest Laboratories (,,). Report no.: NIH Publication No. 99-3977. Owner company: National Toxicology Program,,,. Study number: NTP TR 487. Report date: 1998-12-01.

 

Schreiner, C. et al. (1998). Toxicity evaluation of petroleum blending streams: inhalation subchronic toxicity/neurotoxicity study of a light alkylate naphtha distillate in rats. J. Toxicol. Env. Health (Part A) 55:277-296.

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) NO. 1272/2008.