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Key value for chemical safety assessment

Effects on fertility

Description of key information
No data available.
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
8 300 mg/m³
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a GLP Guideline study according to OECD TG422 (BASF AG, 2004) 10 male and 10 female Wistar rats per test group were exposed to a vapor of isobutyl vinyl ether (whole body, 6h/d, 5d/week) at dose levels of 0, 50, 500 or 2000 ppm (0, 208, 2080 and 8300 mg/m³). The males were treated for approx. 13 weeks (10 weeks premating, 3 weeks mating and post mating) and females during premating (10 weeks), mating and gestation through day 4 after delivery (approx. 15 weeks). The main target organ was the upper respiratory tract at >=500 ppm. Furthermore, dose dependent changes in some blood parameters were seen in female animals at >=500 ppm. High serum triglyceride and cholesterol levels were noted in high-dose parental females; the effect was less pronounced in non-pregnant females and absent in males. Increased liver and kidney weight changes were noted in high-dose males and intermediate and high-dose non-pregnant females. Reproduction parameters (male and female fertility indices, gestation index, and duration of gestation) and histology of male and female reproductive organs were not affected at any dose. Therefore, the NOAEL for reproduction toxicity was 2000 ppm IBVE for male and female rats, i.e. 8.3 mg/l. The LOAEC for toxic effects in the parental generation was 500 ppm, the NOAEC was 50 ppm (208 mg/m³).

Exposure based adaptation of information requirements:

According to REGULATION (EC) No 1907/2006, Annex IX and Annex X, reproductive toxicity testing (section 8.7) may be omitted, if relevant human exposure can be excluded in accordance with Annex XI section 3. Furthermore and in accordance with section 3.2 (b) of Annex XI (as amended by Regulation 134/2009), testing for reproductive toxicity can be omitted when the substance is not incorporated in an article and the manufacturer can demonstrate and document for all relevant scenarios that throughout the life cycle strictly controlled as well as rigorously contained conditions as set out in Article 18(4)(a) to (f) (Regulation 1907/2006) apply.

Classification / toxicological profile:

Isobutyl vinyl ether (IBVE) is classified for skin irritation (cat. 2) according to UN GHS. The acute toxicity in rats after inhalation is low (LC50 > 21 mg/l). Apathy, staggering and depressed breathing were noted. No signs of toxicity were found in rabbits after dermal treatment with 15400 mg/kg bw. IBVE was slightly irritating to the eyes of rabbits.The availablein vitrotests for genetic toxicity gave no hint on a mutagenic or clastogenic effect.

Repeated dose toxicity was investigated in rats by the respiratory route. The main target organ of IBVE was the upper respiratory tract (hyperplasia of the respiratory epithelium, decrease of the secretory mucous cells, slight degeneration of the olfactory epithelium) at 2.08 or 8.3 mg/l IBVE. Based on these findings the NOAEL was 0.208 mg/l.

The toxicity of IBVE to reproduction was tested according to OECD TG 422 in a rat inhalation study with an extended exposure period of 90 days for parental animals at 50, 500, and 2000 ppm (i.e. 0.208, 2.08, and 8.3 mg/l). Reproduction parameters (male and female fertility indices, gestation index, and duration of gestation) and histology of male and female reproductive organs were not significantly affected. Therefore, the NOAEL for reproduction toxicity was 2000 ppm IBVE for male and female rats, i.e. 8.3 mg/l. In the progeny, no other effect than a slightly, yet significantly reduced live born index (93 versus 100 % in controls) was noted at the highest tested dose of 2000 ppm in the presence of maternal toxicity. Therefore, the developmental NOAEL was 500 ppm (2.08 mg/l).

 

Process description:

At room temperature, IBVE is a highly volatile flammable liquid and may generate explosive atmospheres. The industrial method used for the production of IBVE is the reaction of acetylene with isobutanol in the presence of potassium hydroxide in the liquid phase (Reppe vinylation). The choice of operating pressure depends on the boiling point of the alcohol to be vinylated. The alcohol isobutanol is vinylated under a pressure of ~0.8 MPa as the boiling point is below the reaction temperature. Working under pressure affords the acetylene to be diluted with nitrogen to avoid uncontrolled decomposition (75 % maximum for IBVE). Because of the applied reaction conditions and the handling of gaseous compounds the manufacturing facilities are designed as closed systems for higher pressures. The reaction is carried out in a stirred vessel type reactor. The alcohol/KOH-mixture is charged at the top, while the gaseous mixture of acetylene and nitrogen is fed in from below. The un-reacted acetylene is recycled to the reactor and supplemented with pure acetylene. IBVE is produced in a continuously run process in a closed system.

Because of the significant health hazards during production (high pressure, high temperature, strong alkalinity, use of acetylene as starting material), transportation and storage (flammability, peroxide generation, explosion), most stringent safety instructions and explosion protection measures must be adhered to during manufacturing, storage, and shipping. Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. IBVE is used as a starting material for polymers/copolymers, pharmaceuticals and dyes. During manufacture and processing of IBVE, worker exposure is controlled by the use of closed systems, industrial hygiene controls, and personal protective equipment. Any risk of accumulation is minimized by natural ventilation, as the chemical is produced in closed systems installed in open air. At processing sites, the exposure of workers is minimized by vapor abstraction. Prior to repair and maintenance work, vessels, pipes and other equipment are purged to remove any residual MVE. Dedicated systems designed to handle IBVE are used for loading and unloading purposes to prevent the formation of explosive atmospheres and to minimize exposure. The vent gases are either incinerated or cleaned by means of a scrubber. At the production and processing sites, workers wear personal protective equipment which includes gloves, face shields and safety goggles in view of the low pH during processing. During repair and maintenance operations, and during drum emptying operations, respiratory protective equipment is additionally used. Exposure to IBVE via air is routinely controlled by personal air sampling. Additionally, only a small, well-defined and trained group of workers will perform occasionally sampling tasks for quality control under strictly controlled conditions.

Consumer exposure to residual IBVE is considered to be negligible, since most of the marketed vinyl ether polymers and co-polymers are heat-treated and potentially existing residual IBVE is expected to evaporate during this process.

 

Rigorous containment measures:

The substance is manufactured and used under strictly controlled conditions over the entire lifecycle. Exposure is limited to occasional sampling tasks for quality control. Transport, storage tanks, reactors, processing equipment, and feeds operate in fully closed systems.

 

Procedural and control technologies are used to minimise residual emissions/exposure as well as qualitative risk considerations:

Operational and technical conditions and measures affecting and controlling workers exposure, such as local exhaust ventilation as well as personal protective equipment, such as goggles, chemically resistant gloves, and respiratory protection where potential exposure may occur.

 

 

On the basis of the described process conditions, testing of IBVE in a pre-natal developmental toxicity study (OECD 414) as well as a two-generation reproduction toxicity study (OECD 416) or an extended one-generation reproductive toxicity study (OECD 443) was not performed since the criteria of exposure based adaptation of information requirements are met.

Short description of key information:
The reproductive parameters were not affected in a GLP guideline study according to OECD TG422 (combined repeated dose/reproduction toxicity study) up to the highest dose level tested (2000 ppm or 8300 mg/m³). Local and systemic toxicity in the parental rats were detected at >= 500 ppm, the NOAEC was 50 ppm (208 mg/m³).

Effects on developmental toxicity

Description of key information
Weight of evidence:
In a combined OECD TG 422 study with IBVE (BASF AG, 2004), no other reproduction or developmental effect was noted than a slight, yet statistically significant reduced live birth index of 93 % (compared to 100 % in controls; p ≤ 0.05) at the highest tested dose that also caused maternal toxicity. The systemic NOAEL was 0.208 mg/l; the developmental NOAEL was 2.08 mg/l, and the NOAEL for teratogenicity was 8.3 mg/l.
In a developmental toxicity study with methyl vinyl ether (CAS 107-25-5) according to OECD TG414, the LOAEC for maternal toxicity was 5000 ppm or 12 mg/L (lowest dose tested). The NOEC for developmental toxic effects was 5000 ppm and the NOAEC for teratogenic effects was 19500 ppm or 47 mg/L (highest dose tested).
Based on this data, it can be reasonably concluded that IBVE will not induce developmental toxicity in the absence of maternal toxicity.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
2 080 mg/m³
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Weight of evidence:

In an OECD TG 422 study (BASF AG, 2004) pregnant Wistar rats were exposed during the gestation period to 0, 50, 500, 2000 ppm IBVE (whole body, 6h/d, 5d/week; corresponding to 0, 208, 2080 and 8300 mg/m³). No other developmental effects were noted than a significant reduced live birth index (increased resorption and reduced implantation sites) at the highest tested dose level of 2000 ppm (8300 mg/m³) that also caused maternal toxicity (reduced weight gain and clinical signs like increased respiration rate). The NOAEC for repeated dose toxicity in parental rats was 50 ppm (208 mg/m³); the developmental NOAEC was 500 ppm (2080 mg/³), and the NOAEC for teratogenicity was 2000 ppm or 8300 mg/m³ (no external or visceral malformations in pups examined day 4 post partum).

In a developmental toxicity study with methyl vinyl ether (CAS 107 -25 -5; according to OECD TG414; Union Carbide 1994) 25 pregnant Sprague-Dawley rats were exposed (whole body) 6 h/day to 0, 5000, 10000, or 19500 ppm (12; 24; 47 mg/L) at gestation day 6 -15.

No mortality occurred during the study. The pregnancy rate was equivalent for all groups and ranged from 96 to 100 %. No females aborted or delivered early. At scheduled necropsy, one female each from the 5000 and 10000 ppm groups was not pregnant. There were no exposure-related clinical signs observed in any exposure group. Gestational body weight and body weight gains were reduced during the exposure period in all exposure groups. Food consumption was decreased in the 10000 and 19500 ppm groups during the exposure period. Food consumption was also reduced in the 5000 ppm group early in the exposure period (gd 6-9). The relative liver weight was increased in all exposure groups. There were no effects of exposure on gestational parameters including resorptions, pre- and post-implantation losses, percentages of live fetuses, and sex ratios. There was no effect of exposure on fetal body weights/litter. There were no effects of exposure on the incidence of visceral, skeletal, or external malformations. An increased incidence of one common external variation, ecchymosis in the trunk region, was noted in the 19500 ppm group. In addition, several skeletal variations involving various regions of the skeleton were observed for the 10000 and 19500 ppm groups. These included: unossified cervical centra #5 and #6, unossified and poorly ossified cervical centrum #7, reduced number of (ossifying) caudal segments, unossified anterior arch of the atlas, and poorly ossified sternebra #4. In the 5000 ppm group, the incidences of unossified anterior arch of the atlas and poorly ossified sternebra #4 were also increased. In addition, increased incidences of all unossified proximal phalanges (forelimb and hindlimb), and some unossified metatarsals (hindlimb) occurred only in the 19500 ppm group.

All variations characteristic of delayed ossification of the anterior arch of the atlas or sternebrae (e .g., unossified, poorly ossified and bilobed) were combined and statistically analyzed using the Censored Wilcoxon test (Dow, 2005). The combined analysis of unossified, poorly ossified and bilobed anterior arch of the atlas revealed a 100 % litter incidence in all groups, with fetal incidences of 95.2, 88.6, 95.8, and 97.0 % in the 0, 5000, 10000, and 19500 ppm groups, respectively. Similarly, combined analysis of variations characteristic of delayed sternebrae ossification showed respective litter incidences of 100, 100, 100, and 96.0 %, with fetal incidences of 83.0, 79.6, 82.1, and 84.5 %. None of these differences were statistically significant. Furthermore, the high incidence in controls indicates that these minor skeletal variations were not biologically significant.

Based on this re-analysis, 5000 ppm is considered to be the developmental toxicity NOEC for the study. Maternal toxicity was observed at all concentration levels used in this study. No embryolethality or teratogenic effects were observed. A concentration-dependent profile of delayed skeletal development was observed for mid and high dose groups, considered as transient effects secondary to maternal toxicity. In conclusion,the LOAEC for maternal toxicity was 5000 ppm or 12 mg/L (lowest dose tested). The NOEC for developmental toxic effects was 5000 ppm and the NOAEC for teratogenic effects was 19500 ppm or 47 mg/L (highest dose tested). Based on this data, it can be reasonably concluded that IBVE will not induce developmental toxicity in the absence of maternal toxicity. Exposure based adaptation of information requirements According to REGULATION (EC) No 1907/2006, Annex IX and Annex X, reproductive toxicity testing (section 8.7) may be omitted, if relevant human exposure can be excluded in accordance with Annex XI section 3. Furthermore and in accordance with section 3.2 (b) of Annex XI (as amended by Regulation 134/2009), testing for reproductive toxicity can be omitted when the substance is not incorporated in an article and the manufacturer can demonstrate and document for all relevant scenarios that throughout the life cycle strictly controlled as well as rigorously contained conditions as set out in Article 18(4)(a) to (f) (Regulation 1907/2006) apply.

Classification / toxicological profile

Isobutyl vinyl ether (IBVE) is classified for skin irritation (cat. 2) according to UN GHS. The acute toxicity in rats after inhalation is low (LC50 > 21 mg/l). Apathy, staggering and depressed breathing were noted. No signs of toxicity were found in rabbits after dermal treatment with 15400 mg/kg bw. IBVE was slightly irritating to the eyes of rabbits.The availablein vitrotests for genetic toxicity gave no hint on a mutagenic or clastogenic effect.

Repeated dose toxicity was investigated in rats by the respiratory route. The main target organ of IBVE was the upper respiratory tract (hyperplasia of the respiratory epithelium, decrease of the secretory mucous cells, slight degeneration of the olfactory epithelium) at 2.08 or 8.3 mg/l IBVE. Based on these findings the NOAEL was 0.208 mg/l.

The toxicity of IBVE to reproduction was tested according to OECD TG 422 in a rat inhalation study with an extended exposure period of 90 days for parental animals at 50, 500, and 2000 ppm (i.e. 0.208, 2.08, and 8.3 mg/l). Reproduction parameters (male and female fertility indices, gestation index, and duration of gestation) and histology of male and female reproductive organs were not significantly affected. Therefore, the NOAEL for reproduction toxicity was 2000 ppm IBVE for male and female rats, i.e. 8.3 mg/l. In the progeny, no other effect than a slightly, yet significantly reduced live born index (93 versus 100 % in controls) was noted at the highest tested dose of 2000 ppm in the presence of maternal toxicity. Therefore, the developmental NOAEL was 500 ppm (2.08 mg/l).

 

Process description

At room temperature, IBVE is a highly volatile flammable liquid and may generate explosive atmospheres. The industrial method used for the production of IBVE is the reaction of acetylene with isobutanol in the presence of potassium hydroxide in the liquid phase (Reppe vinylation). The choice of operating pressure depends on the boiling point of the alcohol to be vinylated. The alcohol isobutanol is vinylated under a pressure of ~0.8 MPa as the boiling point is below the reaction temperature. Working under pressure affords the acetylene to be diluted with nitrogen to avoid uncontrolled decomposition (75 % maximum for IBVE). Because of the applied reaction conditions and the handling of gaseous compounds the manufacturing facilities are designed as closed systems for higher pressures. The reaction is carried out in a stirred vessel type reactor. The alcohol/KOH-mixture is charged at the top, while the gaseous mixture of acetylene and nitrogen is fed in from below. The un-reacted acetylene is recycled to the reactor and supplemented with pure acetylene. IBVE is produced in a continuously run process in a closed system.

Because of the significant health hazards during production (high pressure, high temperature, strong alkalinity, use of acetylene as starting material), transportation and storage (flammability, peroxide generation, explosion), most stringent safety instructions and explosion protection measures must be adhered to during manufacturing, storage, and shipping. Transfers, buffer/storage tanks, reactors, processing equipment and feeds are operated in fully closed systems. IBVE is used as a starting material for polymers/copolymers, pharmaceuticals and dyes. During manufacture and processing of IBVE, worker exposure is controlled by the use of closed systems, industrial hygiene controls, and personal protective equipment. Any risk of accumulation is minimized by natural ventilation, as the chemical is produced in closed systems installed in open air. At processing sites, the exposure of workers is minimized by vapor abstraction. Prior to repair and maintenance work, vessels, pipes and other equipment are purged to remove any residual MVE. Dedicated systems designed to handle IBVE are used for loading and unloading purposes to prevent the formation of explosive atmospheres and to minimize exposure. The vent gases are either incinerated or cleaned by means of a scrubber. At the production and processing sites, workers wear personal protective equipment which includes gloves, face shields and safety goggles in view of the low pH during processing. During repair and maintenance operations, and during drum emptying operations, respiratory protective equipment is additionally used. Exposure to IBVE via air is routinely controlled by personal air sampling. Additionally, only a small, well-defined and trained group of workers will perform occasionally sampling tasks for quality control under strictly controlled conditions.

Consumer exposure to residual IBVE is considered to be negligible, since most of the marketed vinyl ether polymers and co-polymers are heat-treated and potentially existing residual IBVE is expected to evaporate during this process.

 

Rigorous containment measures

The substance is manufactured and used under strictly controlled conditions over the entire lifecycle. Exposure is limited to occasional sampling tasks for quality control. Transport, storage tanks, reactors, processing equipment, and feeds operate in fully closed systems.

 

Procedural and control technologies are used to minimise residual emissions/exposure as well as qualitative risk considerations

Operational and technical conditions and measures affecting and controlling workers exposure, such as local exhaust ventilation as well as personal protective equipment, such as goggles, chemically resistant gloves, and respiratory protection where potential exposure may occur.

 

 

On the basis of the described process conditions, testing of IBVE in a pre-natal developmental toxicity study (OECD 414) as well as a two-generation reproduction toxicity study (OECD 416) or an extended one-generation reproductive toxicity study (OECD 443) was not performed since the criteria of exposure based adaptation of information requirements are met.

Justification for classification or non-classification

Classification is not warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.