Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
850 mg/m³
DNEL related information
DNEL derivation method:
other: Based on occupational exposure limit
Overall assessment factor (AF):
1
Dose descriptor starting point:
other: worker OEL (8 hr TWA)
DNEL value:
850 mg/m³
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:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 700 mg/m³
DNEL related information
DNEL derivation method:
other: Based on occupational exposure limit
Overall assessment factor (AF):
1
Dose descriptor starting point:
other: worker OEL (8 hr TWA)
DNEL value:
850 mg/m³
Modified dose descriptor starting point:
other: worker OEL (peak exposure limit)
DNEL value:
1 700 mg/m³
Explanation for the modification of the dose descriptor starting point:

Substance-specific excursion factors (ratio of permitted short-term peak value to the MAK value) have been established, depending on the mode of action. IPE is Category I, with a substance specific excusion factor of 2. Therefore the peak exposure limit = 850*2 = 1700 mg/m³

AF for dose response relationship:
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:
1

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
850 mg/m³
DNEL related information
DNEL derivation method:
other: Based on occupational exposure limit
Overall assessment factor (AF):
1
Dose descriptor:
other: worker OEL (8 hr TWA)
DNEL value:
850 mg/m³
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:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
121 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: occupational exposure limit
Overall assessment factor (AF):
1
Dose descriptor starting point:
other: worker OEL (8 hr TWA)
DNEL value:
850 mg/m³
Modified dose descriptor starting point:
other: worker OEL (8 hr TWA, adjusted to dermal exposure)
DNEL value:
121 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on occupational exposure limit; 850 mg/m3* 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:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL derivation

The substance Reaction Products of C3 alcohols and C3 alkenes obtained as by-products from the manufacture of propan-2-ol by hydration of propylene is a UVCB substance. The main constituent (approximately 50%) is isopropyl ether. Minor constituents are propylene dimers (~20%, C6 hydrocarbons, mainly C6 alkenes), propylene trimers (~10%, C9 hydrocarbons), hexanols (~10%) and C3 alcohols (~10% consisting of both isopropanol and n-propanol).

The toxicological properties of the UVCB substance after repeated exposure can be predicted based on the toxicological properties of its main constituents after repeated exposure.

 

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.

 

Data on propylene dimers can be derived by reading across from data on C6 alkanes and C6 alkenes.  Information on the repeated dose toxicity for C6 alkanes can be derived from a 2-year carcinogenicity study of commercial hexane. Commercial hexane contains approximately 52% of n-hexane, and for the remaining 48% hexane isomers, including 2-methyl pentane.

In a two part study, the oncogenic effects of inhalation exposure to commercial hexane (approximately 52% n-hexane) were evaluated male and female mice and male and female rats (Daughtrey, 1999). In Part I of the study groups of 50 male and 50 female rats were exposed to 0, 900, 3000, or 9016 ppm of test substance for 6 hrs/day, 5 days/week, for 2 yrs. Mortalities of exposure groups were consistent with control groups. Body weight gain was significantly reduced in exposure groups. Histopathology revealed dose-related irritation-related effects in the nasoturbinal tissue in all exposure groups. Therefore, there was no NOAEC level for local irritation effects. The LOAEC level for both sexes was 900 ppm for irritation. No oncogenic effects were seen in the exposure groups. The NOAEC for systemic effects was 9016 ppm in rats of both sexes.

In Part II of the study groups of 50 male and 50 female mice were exposed to 0, 900, 3000, or 9018 ppm (0, 3168, 10560, 31680 mg/m3) of commercial hexane (52% n-hexane) for 6 hrs/day, 5 days/week, for 2 yrs. Mortalities of exposure groups were consistent with control groups. Histopathology revealed increased liver masses and nodules in female mice at the 9018 ppm exposure group. As referenced by the National Toxicology Program, liver tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice. Therefore, the increased incidence of liver masses and nodules in female mice are deemed of questionable relevance for human health risk assessment.  Therefore, the NOAEC level for oncogenic effects in mice is 9018 ppm (31680 mg/m3).

Additional information confirming the low repeated dose toxicity potential of 2-methyl pentane can be derived from a two-generation reprotoxicity study on commercial hexane. In this study the effect of inhalation of commercial hexane (52% n-hexane) on reproduction in rats was determined (Daughtrey, 1994). Groups of 25 male and 25 female rats were exposed to nominal concentrations of 0, 900, 3000, or 9000 ppm of commercial hexane for 6 h a day, 5 or 7 days a week, over two generations. In addition to pre-breed exposures of 10 weeks' duration, exposures continued through mating, gestation and lactation. Reproductive parameters were similar in exposure groups and control groups. There was reduced body weight in the F1 and F2 generation in both sexes in the 9000 ppm exposure group in both adults and offspring. The NOAEC is therefore 3000 ppm (10560 mg/m3), and the LOAEC is 9000 ppm (31680 mg/m3). Since there were no adverse effects in offspring without adverse maternal effects, the NOAEC for reproduction is 9000 ppm (31680 mg/m3).

 

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.

 

Data on propylene trimers can be derived by reading across from data on C9 alkanes and C9 alkenes.

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.

These findings are supported by a 13-week inhalation study (similar to OECD 413) with hydrocarbons, C7-C9, n-alkanes, isoalkanes, cyclic, which were administered via whole body inhalation to male rats at concentrations of 0, 280, 600, and 1200 ppm for 6 hours/day, 5 days/week, for 13

weeks (Carpenter et al., 1975). The NOAEC was estimated to be 5800 mg/m³ corresponding to 1200 ppm, the highest dose tested.

 

Information on the repeated dose toxicity for hexanol can be derived from a thirteen-week dietary feeding study in the rat. In this study rats were exposed to 1-hexanol via the diet (1% to 6%) during a 13 week treatment period. No signs of toxicity were recorded at diet concentrations of 1%. No microscopic alterations were recorded at any treatment level.  Examination of the testes and ovaries did not reveal any abnormality. The NOAEL was established at 1%, equivalent to 1127 mg/kg bw (ECB, 2000).

Information confirming the low repeated dose toxicity potential of hexanol can be derived from a developmental toxicity study, in which inhalation of saturated vapours of 1-hexanol (3500 mg/m3, 7 hr/day, GD 1-19) resulted in no significant signs of maternal or fetal toxicity. The NOAEC for both maternal and fetal effects for this study was the limit dose of 3500 mg/m3(Nelson et al., 1989).

 

Long-term repeated dose data on C3 alcohols are derived from isopropanol. No suitable long-term data on n-propanol could be located.

A GLP whole-body inhalation oncogenicity study in Fischer 344 rats with isopropanol concentrations of 0, 500, 2500, 5000 ppm for 6 hours/day 5 days/week for 104 weeks was conducted according to OECD test guideline 451 (Bushy Run Research Center, 1994). The report allows to conclude on a NOAEC of 5000 ppm (equivalent to 12,500 mg/m3). Exposure of rats to isopropanol vapour for 24 months produced clinical signs of toxicity, changes in body weight, and urinalysis and urine chemistry indicative of kidney changes in the 2500 and 5000 ppm groups. These changes were considered by the study authors to be indicative of chronic progressive nephropathy, a spontaneous lesion in aging rats which tends to be more prominent in male than female rats. Based on human and animal evidence relating to CPN, Hard et al. (2009; Gordon C. Hard, Kent J. Johnson, Samuel M. Cohen; Critical Reviews in Toxicology; 2009, Vol. 39, No. 4, Pages 332-346; A comparison of rat chronic progressive nephropathy with human renal disease) have concluded that this is a rodent-specific lesion which should not be regarded as an indicator of human toxic hazard. The only neoplastic lesion which was elevated was an increase in Leydig cell tumours in male rats. This is also a common spontaneous lesion in male rat which is very common in the rat strain used for this evaluation, F-344. The authors observed that the statistical significance attached to the frequency of this observation was probably due to the unusually low incidence in the concurrent control group. No increase in neoplastic lesions were noted in female rats.

 

Taking all repeated dose toxicity information of the constituents together, the NOAECs observed ranged from 3500 mg/m3for hexanol to 31,680 mg/m3for propylene dimers. This indicates that the UVCB substance is of low repeated dose toxicity and does not require classification for repeated dose toxicity.

IPE comprises approximately 50% of the UVCB substance and is therefore the main constituent. The C6 alkanes/alkenes are with 20% the second large constituent. The NOAECs of both IPE and C6 alkanes/alkenes, together accounting for approximately 70% of the UVCB substance, are in the same order of magnitude (3300 ppm and 3000 ppm, respectively). It is therefore reasonable to use the data of the main constituent IPE as the basis for the DNEL derivation.

 

Discussion

In a repeated dose inhalation study rats were exposed to 0, 480, 3300, and 7100 ppm IPE for 6 hours/day, 5 days/wk for 13 weeks. At 3300 ppm and 7100 ppm increases in liver and kidney weights were seen at in both males and females. Although these findings are not supported with toxicologically relevant histopathological changes in these organs, as a conservative approach 3300 ppm can be considered the NOAEC.

 

Modification of dose descriptor

·        No pharmacokinetic data are available on IPE in humans. Therefore the default factors for uptake have been used.

·        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 is available. The German competent authorities (Deutsche Forschungsgemeinschaft - DFG) have derived an occupational exposure limit for IPE of 200 ppm or 850 mg/m3.

 

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.

 

Supporting calculations

An alternative approach to selecting the constituent with the lowest NOAEC is to use the dose descriptors of each of the constituents. Based on the concentration of the respective constituent in the substance, its contribution to the overall DNEL will be allocated.

These calculations are shown in the following Table:

 

Table: DNEL calculation based on constituent data

 

Constituent

Dose descriptor

Modified dose

(= NOAEC * 6h/8h * 6.7 m3/10 m3)

Assessment factor

(inter*intra*duration*dose-rep*database)

DNEL (ECETOC)

Contr-ibution to substance

Isopropyl ether

NOAEC 3300 ppm

(13,800 mg/m3)

(sub-chronic)

6940 mg/m3

AF = 1 * 3 * 2 * 1 * 1 = 6

 

1157 mg/m3

0.5

 

At 3300 ppm 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.

 

 

C6 alkanes /alkenes

NOAEC 3000 ppm

(10,326 mg/m3)

(chronic)

5190 mg/m3

AF = 1 * 3 *1 * 1 * 1 =3

 

1730 mg/m3

0.2

 

Data from chronic studies and reprotoxicity studies indicate that C6 alkanes have a NOAEC of 9000 ppm. Data on C6 alkenes show a NOAEC of 3000 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.

 

 

C9 alkanes /alkenes

NOAEC 2200 ppm

(8,117 mg/m³)

(sub-chronic)

4079 mg/m3

AF = 1 * 3 * 2 * 1 * 1 = 6

 

680 mg/m3

0.1

 

The NOAEC for systemic toxicity of C9 alkanes is 2200 ppm ( 8117 mg/m³ ).

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.

 

 

Hexanols

NOAEC  3500 mg/m3

NOAEL 1127 mg/kg bw

(sub-chronic  supported by sub-acute)

1759 mg/m3

AF = 1 * 3 * 2 * 1 * 1 = 6

 

293 mg/m3

0.1

 

Data from a sub-chronic dietary study show a NOAEL of 1%, equivalent to 1127 mg/kg bw. These data are supported by a NOAEC of 3500 mg/m3(highest dose tested) from a sub-acute reprotoxicity study.

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.

 

 

C3 alcohols

(isopropanol /

n-propanol)

NOAEC 5000 ppm

(12,500 mg/m3)

(chronic)

6281 mg/m3

AF = 1 * 3 * 1 * 1 * 1 = 3

 

2094 mg/m3

0.1

 

Data from a chronic carcinogenicity study show a NOAEC of 5000 ppm for isopropanol.

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.

 

 

Total DNEL

 

 

 

1231 mg/m3

(300 ppm)

1

 

Based on these data, the DNEL for the UVCB mixture, based on the DNELs for its constituents would be 1231 mg/m3, or approximately 300 ppm. The German occupational exposure limit for IPE is 200 ppm or 850 mg/m3. Since this value is more conservative than the DNEL calculated based on the constituents, it is confirmed that the IPE OEL value is the most appropriate basis for the DNEL.

 

Workers - Acute DNELs

Worker: Production of Reaction Products of C3 alcohols and C3 alkenes obtained as by-products from the manufacture of propan-2-ol by hydration of propylene 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 C3 alcohols and C3 alkenes obtained as by-products from the manufacture of propan-2-ol by hydration of propylene 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. 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 vapour 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 of 200 ppm, based on repeated dose toxicity can be assumed to be sufficiently protective for acute exposure effects.

 

Workers - Long-term DNELs

IOEL/OEL

There is no IOEL value for IPE. A German MAK was available and deemed suitable for derivation of the DNEL.

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.

 

Starting Dose Descriptor for DNEL calculation:

The German MAK of 850 mg/m3(based on occupational exposure of 8 hours/day, 5 days/week) is the starting point for the long-term DNEL. As this is a well-justified occupational exposure limit this value is taken forward as the long-term inhalation DNELs for workers.

 

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 DNEL  is 850 mg/m3x 10 m3/d/70 kg = 121 mg/kg/d

 

Summary worker DNELs

Worker – Inhalation = 850 mg/m3(no adjustment required)

Worker – Dermal =850 mg/m3x 10 m3/d/70 kg = 121 mg/kg/d

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
151 mg/m³
DNEL related information
DNEL derivation method:
other: occupational exposure limit
Overall assessment factor (AF):
2
Dose descriptor starting point:
other: worker OEL (8 h TWA)
DNEL value:
850 mg/m³
Modified dose descriptor starting point:
other: OEL adjusted for continuous exposure
DNEL value:
302 mg/m³
Explanation for the modification of the dose descriptor starting point:

The long-term DNEL for the general population was derived from the worker OEL.

Starting Dose for DNEL calculation: 850 mg/m3 (based on occupational exposure of 8 hours/day, 5 days/week) (amortized below for continuous exposure)

Modified dose for DNEL Calculation General Population – Inhalation = 850 mg/m3x10/6.7x 8/24 x 5/7 (amortized for continuous exposure) = 302 mg/m3

Assessment Factors (AF) No adjustments required for interspecies, exposure duration, dose response or quality of whole database as DNEL is based on an occupational limit for workers. An AF of 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 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:
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 intraspecies differences was considered sufficient.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
302 mg/m³
DNEL related information
DNEL derivation method:
other: occupational exposure limit
Overall assessment factor (AF):
2
Dose descriptor starting point:
other: worker OEL (peak exposure limit)
DNEL value:
1 700 mg/m³
Modified dose descriptor starting point:
other: OEL adjusted for continuous exposure
DNEL value:
604 mg/m³
Explanation for the modification of the dose descriptor starting point:

The acute DNEL for the general population was derived from the worker OEL (peak exposure limit).

Substance-specific excursion factors (ratio of permitted short-term peak value to the MAK value) have been established, depending on the mode of action. IPE is Category I, with a substance specific excusion factor of 2.

Starting Dose for DNEL calculation:

OEL 850 mg/m³ (based on occupational exposure of 8 hours/day, 5 days/week) (amortized below for continuous

exposure)

Peak Exposure limit 850*2 = 1700 mg/m³

Modified dose for acute DNEL Calculation

General Population – Inhalation = 1700 mg/m³x10/6.7x 8/24 x 5/7 (amortized for continuous exposure) = 604

mg/m³

AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
2
Justification:
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 intraspecies differences was considered sufficient.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
151 mg/m³
DNEL related information
DNEL derivation method:
other: occupational exposure limit
Overall assessment factor (AF):
2
Dose descriptor:
other: worker OEL (8 h TWA) adjusted for continuous exposure
DNEL value:
302 mg/m³
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:
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 intraspecies differences was considered sufficient.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: occupational exposure limit
Dose descriptor starting point:
other: worker OEL
DNEL value:
850 mg/m³
Modified dose descriptor starting point:
other: OEL adjusted for continuous dermal exposure
DNEL value:
86 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The long-term DNEL for the general population was derived from the worker OEL.

Starting Dose for DNEL calculation:

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

exposure)

Modified dose for DNEL Calculation

General Population – Dermal =302 mg/m3x 20 m3/d/70 kg = 86 mg/kg/d (no adjustment for absorption)

Assessment Factors (AF)

No adjustments required for interspecies, exposure duration, dose response or quality of whole database as

DNEL is based on an occupational limit for workers.

An AF of 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 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:
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 intraspecies differences was considered sufficient.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: occupational exposure limit
Modified dose descriptor starting point:
other: worker OEL adjusted for continuous oral exposure
DNEL value:
86 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

General Population – Oral = 302 mg/m3x 20 m3/d/70 kg = 86 mg/kg/d (no adjustment for absorption)

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
AF for the quality of the whole database:
1
Justification:
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 intraspecies differences was considered sufficient.
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Discussion

General Population - Acute DNELs

Similar to above for worker, assessment of acute systemic effects should default to the long term systemic DNELs.

 

General population - Long-term DNELs

The long-term DNEL for the general population was derived from the worker OEL.

 

Starting Dose for DNEL calculation:

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

Modified dose for DNEL Calculation

General Population – Inhalation = 850 mg/m3x10/6.7x 8/24 x 5/7 (amortized for continuous exposure) = 302 mg/m3

General Population – Oral =302 mg/m3x 20 m3/d/70 kg = 86 mg/kg/d (no adjustment for absorption)

 

Assessment Factors (AF)

No adjustments required for interspecies, exposure duration, dose response or quality of whole database as DNEL is based on an occupational limit for workers.

An AF of 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)

 

General population - Final DNELs

General population – Dermal DNEL = 86 mg/kg/d/2 = 43 mg/kg/d;

General population – Inhalation DNEL 302 mg/m3/2 = 151 mg/m3;

General population – Oral DNEL = 86 mg/kg/d/2 = 43 mg/kg/d

 

References

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