Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

384 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: ECHA REACH guidance and ECETOC

Overall assessment factor (AF):

6

Dose descriptor starting point:

NOAEC

Value:

4 589 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

2 305 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEC for repeat-dose toxicity for 2-methylpropene is 2000 ppm; 4589 mg/m³

- No pharmacokinetic data are available on C4 hydrocarbons (butenes) in humans. Therefore the default factors for uptake have been used for both systemic and local effects.

- An adjustment for duration of exposure for systemic effects of 6/8 to correct for the 6h exposure period during the chronic study compared with human exposure during an 8h working day has been applied.

- Modification for differences in respiratory function for workers at rest and workers doing light work (see adjusting for light work (R.8.4.2)). An adjustment for human respiration rates during light work of

6.7/10 m³ has been applied (see adjusting for light work in REACH Guidance Document R8 (R.8.4.2)).

The modified dose descriptor is therefore 4589 mg/m³ * 6h/8h * 6.7m³/10m³= 2305 mg/m³.

AF for dose response relationship:

1

Justification:

Default - no significant adverse effects reported in animal studies

AF for differences in duration of exposure:

1

Justification:

Default value for chronic toxicity data

AF for interspecies differences (allometric scaling):

1

Justification:

Default

AF for other interspecies differences:

1

AF for intraspecies differences:

3

Justification:

Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 was considered appropriate to account for variability present in worker groups.

AF for the quality of the whole database:

2

Justification:

High quality database for C4 butanes/butenes, database for registered substance based on read-across

AF for remaining uncertainties:

1

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

384 mg/m³

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

384 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

other: ECETOC

Overall assessment factor (AF):

6

Dose descriptor:

other: NOAEC - modified

Value:

2 305 mg/m³

AF for dose response relationship:

1

Justification:

Default - no significant adverse effects reported in animal studies

AF for differences in duration of exposure:

1

Justification:

Default value for chronic toxicity data

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

3

Justification:

Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 was considered appropriate to account for variability present in worker groups.

AF for the quality of the whole database:

2

Justification:

High quality database for C4 butanes/butenes; database for 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 based on read-across

AF for remaining uncertainties:

1

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

60 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: occupational exposure limit 8 hr TWA

Overall assessment factor (AF):

2

Dose descriptor starting point:

other: worker OEL

Value:

850 mg/m³

Modified dose descriptor starting point:

other: worker OEL

Value:

121 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation is applied according to REACH Guidance Document R8, where the default value of 10 m³for respiratory volume of a worker and 70 kg as default bodyweight is used.

The resulting dermal value is 850 mg/m³x 10 m³/d/70 kg = 121 mg/kg/d

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

Since the data from the main constituent SBE are read-across from IPE, it is deemed appropriate to include an additional assessment factor of 2.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

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.

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 oflight hydrocarbonnephropathy 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. All relevant dose descriptors for the main constituents of 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 are reflected in the table below.

Constituent	Dose descriptor	Modified dose *(= NOAEC 6h/8h * 6.7 m³/10 m³)**	Assessment factor *(interintradurationdose-repdatabase)*	DNEL (ECETOC)	Contri-bution
Sec-butyl ether (SBE)	NOAEC 3300 ppm (13,800 mg/m³) (sub-chronic)	6940 mg/m³	AF = 1 * 3 * 2 * 1 * 1 = 6	1157 mg/m³	0.6
	At 3300 ppm IPE increases in liver and kidney weights were seen at in both males and females. Although these findings are not supported with histopathological changes in these organs, as a conservative approach 3300 ppm can be considered the NOAEC.	Corrected for exposure duration and ventilation rate.	The modified dose takes into account the physiological differences between rat and human. No additional AF is needed for interspecies differences. An AF of 3 for intraspecies differences is the ECETOC default. For extrapolation from subchronic to chronic exposure an AF of 2 is used.
C4 hydrocarbons (mainly butenes)	NOAEC 2000 ppm (4,589 mg/m³) (chronic)	2305 mg/m³	AF = 1 * 3 1 1 * 1 =3	769 mg/m³	0.2
	Data from chronic studies studies indicate that C4 alkenes have a NOAEC of 2000 ppm based on marginally increased hypertrophy of goblet cells lining the nasopharyngeal duct at 8000 ppm.	Corrected for exposure duration and ventilation rate.	The modified dose takes into account the physiological differences between rat and human. No additional AF is needed for interspecies differences. An AF of 3 for intraspecies differences is the ECETOC default.
C8 hydrocarbons (mainly alkenes)	NOAEC 2200 ppm (8,117 mg/m³) (sub-chronic)	4079 mg/m³	AF = 1 * 3 * 2 * 1 * 1 = 6	680 mg/m³	0.15
	The NOAEC for systemic toxicity of C8 alkanes is 2200 ppm ( 8117 mg/m³ ). The NOAEC of C6 alkenes is 3000 ppm.	Corrected for exposure duration and ventilation rate.	The modified dose takes into account the physiological differences between rat and human. No additional AF is needed for interspecies differences. An AF of 3 for intraspecies differences is the ECETOC default. For extrapolation from subchronic to chronic exposure an AF of 2 is used.
Butan-2-one (MEK)	NOAEC 5041 ppm (14,866 mg/m³) (sub-chronic)	7,470 mg/m³	AF = 1 * 3 * 2 * 1 * 1 = 6	1245 mg/m³	0.05
	Data from a sub-chronic inhalation study show a NOAEC 5041 ppm, based on a lack of toxicologically relevant findings at the highest concentration tested.	Corrected for exposure duration and ventilation rate.	The modified dose takes into account the physiological differences between rat and human. No additional AF is needed for interspecies differences. An AF of 3 for intraspecies differences is the ECETOC default. For extrapolation from subchronic to chronic exposure an AF of 2 is used.
Total DNEL				1012 mg/m³ (250 ppm)	1

Workers, Acute DNELs:

Production of 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 in excess of 10 t/y. According to the REACh "Guidance on information requirements and chemical safety assessment, Part B: Hazard Assessment", above 10 t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on repeated dose toxicity is normally sufficient to ensure that adverse effects do not occur.

The only classification for 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 upon short-term exposure is related to its potential to cause drowsiness and dizziness. This effect is known to occur upon exposure to high concentrations of hydrocarbons and is caused by central nervous depression. Data from C4 hydrocarbons, where rats and mice were exposed to 2-methylpropene at concentrations of up to 8,000 ppm, (18,359 mg/m3) showed no signs of hydrocarbon-induced narcosis (NTP, 1998). Acute effects associated with IPE vapour exposure have been investigated in human volunteers. This study evaluated 5-minute exposures in human volunteers and only slight irritation of the nose at 400 ppm progressing to slight irritation of nose, eyes and respiratory tract at 800 ppm were observed. No central nervous system effects were observed (Hine et al., 1955). Silverman et al. (1946) reported that 35% of humans exposed to IPE vapor at a concentration of 300 ppm objected to the unpleasant odour of the solvent. At 800 ppm for 5 minutes, most subjects reported irritation of the eyes and nose, and the most sensitive reported respiratory discomfort. Concentrations above 1000 ppm IPE resulted in complaints of strong irritation to the eyes and respiratory tract. The data in human volunteers indicate that exposure up to 300-400 ppm IPE does not result in acute effects. Therefore, the DNEL based on repeated dose toxicity can be assumed to be sufficiently protective for acute exposure effects.

Workers, Long-term DNELs:

For the determination of the most relevant DNEL 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.

Repeat-dose toxicity: inhalation exposure

The basis for the inhalation DNEL derivation are the findings in the 2-year study on 2-methylpropene (NTP, 1998). At the highest concentration (8000 ppm; 18,359 mg/m³) the incidences of hyaline degeneration of the olfactory epithelium were marginally increased in exposed male and female rats with 100% incidence in males at the top dose, however, the severities of hyaline degeneration also increased with increasing exposure concentration in males and females. Hypertrophy of goblet cells lining the nasopharyngeal duct was also marginally increased with 100% incidence in males at the top dose.

The NTP report states that hyaline degeneration of the epithelium of the nasal cavity is a commonly observed change in inhalation studies and did not comment on the goblet cell hypertrophy. No NOAECs were suggested in the NTP report. The NOAEC for repeat-dose toxicity for 2-methylpropene is 2000 ppm; 4589 mg/m³as given in the OECD SIDS Report for Isobutylene (2003). This NOAEC defines the quantitative dose descriptor for the DNEL for the butenes category. This NOAEC is probably most relevant for local effects as these nasal effects are seen at the site of entry into the body but in case they are due to systemic involvement, a conservative approach has been taken and the same NOAEC used for the calculation of DNELs for both local and systemic effects.

Modification of dose descriptor

· No pharmacokinetic data are available on C4 hydrocarbons (butenes) in humans. Therefore the default factors for uptake have been used for both systemic and local effects.

· An adjustment for duration of exposure for systemic effects of 6/8 to correct for the 6h exposure period during the chronic study compared with human exposure during an 8h working day has been applied.

· Modification for differences in respiratory function for workers at rest and workers doing light work (see adjusting for light work (R.8.4.2)). An adjustment for human respiration rates during light work of 6.7/10 m³has been applied (see adjusting for light work in REACH Guidance Document R8 (R.8.4.2)).

The modified dose descriptor is therefore 4589 mg/m3 * 6h/8h * 6.7m³/10m³= 2305 mg/m³.

Derivation of overall assessment factors

The assessment factors for inter and intra-species differences are the default values recommended by ECETOC (2003, Derivation of Assessment Factors for Human Health Assessment, Technical Report No. 86, www.Ecetoc.org). The ECETOC technical report includes scientific justification for the magnitude of these assessment factors including:

· Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability;

· Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 was considered appropriate to account for variability present in worker groups.

· Quality of the database: although the database on C4 butenes is of high quality, the data base on 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 merely based on read-across from its constituents. In addition, the data from the main constituent SBE are read-across from IPE. Therefore it is deemed appropriate to include an additional assessment factor of 2.

The remaining assessment factors are the default values recommended in REACH Guidance Document R8.

Uncertainty	AF	Justification
Interspecies differences	1	Allometric factors not required for inhalation route, and a default residual factor is unnecessary
Intraspecies differences	3	default for workers
Differences in duration of exposure	1	default value for chronic toxicity data
Dose response and endpoint specific/severity issues	1	An AF of 1 is used as there are no significant adverse effects reported in animal studies.
Quality of database	2	High quality database for C4 butanes/butenes; database for 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 based on read-across
Overall AF	6

The resulting DNEL is 384 mg/m³(equivalent to 168 ppm).

Dermal exposure

The basis for the dermal exposure DNEL are the relevant dose descriptors for SBE, which are based on the data of its metabolites MEK and SBA and its structural analogue IPE. The most conservative value, a NOAEC 3300 ppm (13,800 mg/m³) for IPE based on minimal changes in kidney and liver weight, is taken forward as the starting point for derivation of the DNEL.

Modification of dose descriptor

· No pharmacokinetic data are available on SBE or IPE in humans. Therefore the default factors for uptake have been used for both systemic and local effects.

· An adjustment for duration of exposure for systemic effects of 6/8 to correct for the 6h exposure period during the sub-chronic study compared with human exposure during an 8h working day has been applied.

· Modification for differences in respiratory function for workers at rest and workers doing light work (see adjusting for light work (R.8.4.2)). An adjustment for human respiration rates during light work of 6.7/10 m³has been applied (see adjusting for light work in REACH Guidance Document R8 (R.8.4.2)).

The modified dose descriptor is therefore 13,800 mg/m3 * 6h/8h * 6.7m³/10m³= 6940 mg/m³.

Derivation of overall assessment factors

The assessment factors for inter and intra-species differences are the default values recommended by ECETOC (2003, Derivation of Assessment Factors for Human Health Assessment, Technical Report No. 86, www.Ecetoc.org). The ECETOC technical report includes scientific justification for the magnitude of these assessment factors including:

· Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability;

· Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 was considered appropriate to account for variability present in worker groups.

· For extrapolation of sub-chronic data to chronic data, the default factor of 2 is used.

The remaining assessment factors are the default values recommended in REACH Guidance Document R8.

Uncertainty	AF	Justification
Interspecies differences	1	Allometric factors not required for inhalation route, and a default residual factor is unnecessary
Intraspecies differences	3	default for workers
Differences in duration of exposure	2	default value for sub-chronic toxicity data
Dose response and endpoint specific/severity issues	1	An AF of 1 is used as there are no significant adverse effects reported in animal studies.
Quality of database	1	High quality database for IPE
Overall AF	6

The resulting DNEL is 1157 mg/m³(equivalent to 290 ppm).

Occupational exposure limit

Although there is no IOEL value for IPE, a German MAK was available.

Reference: Deutsche Forschungsgemeinschaft (2005) The MAK Collection Part 1: MAK Value Documentations, Vol. 21. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The basis for the MAK derivation are the human data from Silverman et al. (1946) that show that upon short-term exposure to 300 ppm IPE human subjects complained about unpleasant odour but did not experience any acute effects. In addition, information from the 90-day repeated dose inhalation rat study that resulted in a NOEL of 480 ppm for local and systemic effects. It is concluded that the effects that are observed at the 3300 ppm level are still very limited and likely not adverse. Based on this information, which takes into account the most recently available studies, the German competent authorities (Deutsche Forschungsgemeinschaft - DFG) have derived an occupational exposure limit for IPE of 200 ppm or 850 mg/m³.

The German MAK value is in agreement with the Threshold Limit Value as derived by the American Conference of Industrial Hygienists (ACGIH), who have derived an 8-hour Time Weighted Average (TWA) of 250 ppm and a Short Term Exposure Limit (STEL) of 310 ppm.

The OEL value is lower than the DNEL value when calculated directly from the data. Therefore, as a conservative approach, it is more appropriate to use the German MAK value as a starting point.

Starting Dose Descriptor for DNEL calculation:

850 mg/m³(based on occupational exposure of 8 hours/day, 5 days/week)

Modification of dose descriptor

The worker OEL, or DNEL requires no adjustments for interspecies differences, exposure duration, dose response or quality of whole database as the DNEL is based on an occupational limit for workers.

Route to route extrapolation is applied according to REACH Guidance Document R8, where the default value of 10m³for respiratory volume of a worker and 70 kg as default bodyweight is used.

The resulting dermal value is 850 mg/m³x 10 m³/d/70 kg = 121 mg/kg/d

Since the data from the main constituent SBE are read-across from IPE, it is deemed appropriate to include an additional assessment factor of 2.

The resulting dermal DNEL is 121/2 = 60 mg/kg/d

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.

All relevant dose descriptors for the main constituents of 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 are reflected in the table below.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

81 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: ECHA REACH guidance and ECETOC

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEC

Value:

4 589 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

819 mg/m³

Explanation for the modification of the dose descriptor starting point:

- No pharmacokinetic data are available on C4 hydrocarbons (butenes) in humans. Therefore the default factors for uptake have been used for both systemic and local effects.

- An adjustment for duration of exposure for systemic effects of 6/24 x 5/7 (0.178) to correct for the 6h/5d exposure period during the chronic study compared with human exposure of the general population during a 24h day and 7d week has been applied.

- The default factor for human respiration (1) has been applied.

The modified dose descriptor is therefore 4589 mg/m³ * 6h/24h * 5d/7d = 819 mg/m³.

AF for dose response relationship:

1

Justification:

No specific adverse effects

AF for differences in duration of exposure:

1

Justification:

Default: chronic toxicity study

AF for interspecies differences (allometric scaling):

1

Justification:

Default (inhalation rat to inhalation human)

AF for other interspecies differences:

1

AF for intraspecies differences:

5

AF for the quality of the whole database:

2

Justification:

High quality database for C4 butanes/butenes, database for Registered substance based on read-across

AF for remaining uncertainties:

1

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

81 mg/m³

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

81 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

other: REACH Guidance and ECETOC

Overall assessment factor (AF):

10

Dose descriptor:

other: NOACE - modified

Value:

819 mg/m³

AF for dose response relationship:

1

Justification:

No specific adverse effects

AF for differences in duration of exposure:

1

Justification:

chronic toxicity study

AF for interspecies differences (allometric scaling):

1

Justification:

inhalation route of exposure

AF for other interspecies differences:

1

AF for intraspecies differences:

5

AF for the quality of the whole database:

2

Justification:

High quality database for C4 butanes/butenes, database for Registered substance based on read-across

AF for remaining uncertainties:

1

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21 mg/kg bw/day

DNEL derivation method:

other: occupational exposure limit

Overall assessment factor (AF):

4

Dose descriptor starting point:

other: worker OEL

Value:

850 mg/m³

Modified dose descriptor starting point:

other: OEL adjusted for continuous dermal exposure

Value:

86 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The worker OEL, or DNEL requires no adjustments for interspecies differences, exposure duration, dose response or quality of whole database as the DNEL is based on an occupational limit for workers.

An adjustment for duration of exposure for systemic effects of 8/24 x 5/7 (0.178) to correct for the 6h/5d exposure period during the chronic study compared with human exposure of the general population during a 24h day and 7d week has been applied.

The resulting inhalation starting point is 850 mg/m³ x 10/6.7x 8/24 x 5/7 (amortized for continuous exposure) = 302 mg/m³

Route to route extrapolation is applied according to REACH Guidance Document R8, where the default value of 20 m³ for respiratory volume of a person and 70 kg as default bodyweight is used.

For oral and dermal routes of exposure (conservatively assuming 100% absorption for both routes) the modified dose descriptor starting points are:

302 mg/m³ x 20 m³/d/70 kg = 86 mg/kg/d

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

2

Justification:

An AF of is 2 applied for differences between workers and general population (basis: when extrapolating from animal to human, the recommended AF is 10 for general population and 5 for worker – since the starting dose is amortized for continuous exposure an additional 2 fold AF for differences was considered sufficient).

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

Since the data from the main constituent SBE are read-across from IPE, it is deemed appropriate to include an additional assessment factor of 2.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21 mg/kg bw/day

DNEL derivation method:

other: dose descriptor

Overall assessment factor (AF):

4

Modified dose descriptor starting point:

other: worker OEL adjusted for continuous oral exposure

Value:

86 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The worker OEL, or DNEL requires no adjustments for interspecies differences, exposure duration, dose response or quality of whole database as the DNEL is based on an occupational limit for workers.

An adjustment for duration of exposure for systemic effects of 8/24 x 5/7 (0.178) to correct for the 6h/5d exposure period during the chronic study compared with human exposure of the general population during a 24h day and 7d week has been applied.

The resulting inhalation starting point is 850 mg/m³ x 10/6.7x 8/24 x 5/7 (amortized for continuous exposure) = 302 mg/m³

Route to route extrapolation is applied according to REACH Guidance Document R8, where the default value of 20 m³ for respiratory volume of a person and 70 kg as default bodyweight is used.

For oral and dermal routes of exposure (conservatively assuming 100% absorption for both routes) the modified dose descriptor starting points are:

302 mg/m³ x 20 m³/d/70 kg = 86 mg/kg/d

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

2

Justification:

An AF of is 2 applied for differences between workers and general population (basis: when extrapolating from animal to human, the recommended AF is 10 for general population and 5 for worker – since the starting dose is amortized for continuous exposure an additional 2 fold AF for differences was considered sufficient).

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

Since the data from the main constituent SBE are read-across from IPE, it is deemed appropriate to include an additional assessment factor of 2.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population, Acute DNELs:

Production of 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 in excess of 10 t/y. According to the REACh "Guidance on information requirements and chemical safety assessment, Part B: Hazard Assessment", above 10 t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on repeated dose toxicity is normally sufficient to ensure that adverse effects do not occur.

The only classification for 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 upon short-term exposure is related to its potential to cause drowsiness and dizziness. This effect is known to occur upon exposure to high concentrations of hydrocarbons and is caused by central nervous depression. Data from C4 hydrocarbons, where rats and mice were exposed to 2-methylpropene at concentrations of up to 8,000 ppm, (18,359 mg/m³) showed no signs of hydrocarbon-induced narcosis (NTP, 1998). Acute effects associated with IPE vapour exposure have been investigated in human volunteers. This study evaluated 5-minute exposures in human volunteers and only slight irritation of the nose at 400 ppm progressing to slight irritation of nose, eyes and respiratory tract at 800 ppm were observed. No central nervous system effects were observed (Hine et al., 1955). Silverman et al. (1 946) reported that 35% of humans exposed to IPE vapor at a concentration of 300 ppm objected to the unpleasant odour of the solvent. At 800 ppm for 5 minutes, most subjects reported irritation of the eyes and nose, and the most sensitive reported respiratory discomfort. Concentrations above 1000 ppm IPE resulted in complaints of strong irritation to the eyes and respiratory tract. The data in human volunteers indicate that exposure up to 300-400 ppm IPE does not result in acute effects.

Therefore, the DNEL based on repeated dose toxicity can be assumed to be sufficiently protective for acute exposure effects.

General Population, Long-term DNELs:

For the determination of the most relevant DNEL it should be noted that although the vapour pressure of the main constituent SBE is relatively low (30 hPa), the vapour pressure of the UVCB substance is relatively high (410 hPa). This suggests that inhalation exposure is mainly to C4 hydrocarbons. Since C4 hydrocarbons have a high vapour pressure, their dermal absorption however, will be limited. This is due to the fact that most of the C4 hydrocarbons have evaporated before dermal absorption can take place.

For a dermal DNEL therefore, the dose descriptor for SBE is more relevant.

Repeat-dose toxicity: inhalation exposure

The basis for the inhalation DNEL derivation are the findings in the 2-year study on 2-methylpropene (NTP, 1998). At the highest concentration (8000 ppm; 18,359 mg/m³) the incidences of hyaline degeneration of the olfactory epithelium were marginally increased in exposed male and female rats with 100% incidence in males at the top dose, however, the severities of hyaline degeneration also increased with increasing exposure concentration in males and females. Hypertrophy of goblet cells lining the nasopharyngeal duct was also marginally increased with 100% incidence in males at the top dose.

The NTP report states that hyaline degeneration of the epithelium of the nasal cavity is a commonly observed change in inhalation studies and did not comment on the goblet cell hypertrophy. No NOAECs were suggested in the NTP report. The NOAEC for repeat-dose toxicity for 2-methylpropene is 2000 ppm; 4589 mg/m³as given in the OECD SIDS Report for Isobutylene (2003). This NOAEC defines the quantitative dose descriptor for the DNEL for the butenes category. This NOAEC is probably most relevant for local effects as these nasal effects are seen at the site of entry into the body but in case they are due to systemic involvement, a conservative approach has been taken and the same NOAEC used for the calculation of DNELs for both local and systemic effects.

Modification of dose descriptor

· No pharmacokinetic data are available on C4 hydrocarbons (butenes) in humans. Therefore the default factors for uptake have been used for both systemic and local effects.

· An adjustment for duration of exposure for systemic effects of 6/24 x 5/7 (0.178) to correct for the 6h/5d exposure period during the chronic study compared with human exposure of the general population during a 24h day and 7d week has been applied.

· The default factor for human respiration (1) has been applied.

The modified dose descriptor is therefore 4589 mg/m3 * 6h/24h * 5d/7d = 819 mg/m³.

Derivation of overall assessment factors

The assessment factors for inter and intra-species differences are the default values recommended by ECETOC (2003, Derivation of Assessment Factors for Human Health Assessment, Technical Report No. 86, www.Ecetoc.org). The ECETOC technical report includes scientific justification for the magnitude of these assessment factors including:

· Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability;

· Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 5 was considered appropriate to account for variability present in the general population.

· Quality of the database: although the database on C4 butenes is of high quality, the data base on 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 merely based on read-across from its constituents. In addition, the data from the main constituent SBE are read-across from IPE. Therefore it is deemed appropriate to include an additional assessment factor of 2.

The remaining assessment factors are the default values recommended in REACH Guidance Document R8.

Uncertainty	AF	Justification
Interspecies differences	1	Allometric factors not required for inhalation route, and a default residual factor is unnecessary
Intraspecies differences	5	default for workers
Differences in duration of exposure	1	default value for chronic toxicity data
Dose response and endpoint specific/severity issues	1	An AF of 1 is used as there are no significant adverse effects reported in animal studies.
Quality of database	2	High quality database for C4 butanes/butenes; database for 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 based on read-across
Overall AF	10

The resulting DNEL is 81 mg/m³(equivalent to 35 ppm).

Dermal exposure

The basis for the dermal exposure DNEL are the relevant dose descriptors for SBE, which are based on the data of its metabolites MEK and SBA and its structural analogue IPE. As shown in the workers section, a DNEL based on the German OEL value results in a more conservative value than a DNEL based on the NOAEC of 3300 ppm (13,800 mg/m3) for IPE. Therefore, analogous to the worker DNELs, the German OEL value will be used as a starting point.

Starting Dose for DNEL calculation:

850 mg/m³(based on occupational exposure of 8 hours/day, 5 days/week)

Modification of dose descriptor

The worker OEL, or DNEL requires no adjustments for interspecies differences, exposure duration, dose response or quality of whole database as the DNEL is based on an occupational limit for workers.

An adjustment for duration of exposure for systemic effects of 8/24 x 5/7 (0.178) to correct for the 6h/5d exposure period during the chronic study compared with human exposure of the general population during a 24h day and 7d week has been applied.

The resulting inhalation starting point is 850 mg/m³x 10/6.7x 8/24 x 5/7 (amortized for continuous exposure) = 302 mg/m³

Route to route extrapolation is applied according to REACH Guidance Document R8, where the default value of 20 m³for respiratory volume of a person and 70 kg as default bodyweight is used.

For oral and dermal routes of exposure (conservatively assuming 100% absorption for both routes) the modified dose descriptor starting points are:

302 mg/m³x 20 m³/d/70 kg = 86 mg/kg/d

An AF of is 2 applied for differences between workers and general population (basis: when extrapolating from animal to human, the recommended AF is 10 for general population and 5 for worker – since the starting dose is amortized for continuous exposure an additional 2 fold AF for differences was considered sufficient).

Since the data from the main constituent SBE are read-across from IPE, it is deemed appropriate to include an additional assessment factor of 2.

The resulting oral and dermal DNELs are 86 mg/kg/d / 4 = 21 mg/kg/d

Registration Dossier

Registration Dossier

Data platform availability banner - registered substances factsheets

Diss Factsheets

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

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

Workers - Hazard for the eyes

Local effects

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

General Population - Hazard via oral route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Additional information - General Population