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Key value for chemical safety assessment

Effects on fertility

Description of key information
No additional data
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
20 090 mg/m³
Additional information

There are no 2-generation reproduction studies available for isoamylene or 2-methyl-2-butene but there is sufficient weight of evidence from reproductive toxicity studies and reproductive endpoints in repeat dosing studies from other C4-C5 mono-olefins (butenes, 2-methyl-2-butene and 2-methylpropene) to conclude that the potential for effects on fertility is low and therefore further testing is scientifically unjustified (Annex XI adaptation).

In the combined repeat dose/reproductive/developmental study (OECD 422; HLS, 2004), rats were exposed to 2-methyl-2-butene (the major component of Isoamylene) at concentrations up to 7,000 ppm (20,060 mg/m3), 6 hr/day, 7 days/week for two weeks prior to breeding, during breeding and through day 19 of gestation (HLS, 2004). During the study, clinical condition, bodyweight, food consumption, oestrus cycles, mating performance, litter data, organ weights and macroscopic pathology were undertaken. No evidence of reproductive toxicity was seen. There were no significant effects on oestrus cycle, mating performance, fertility indices or gestation length.  The NOAEC for reproductive toxicity was 7,000 ppm (20,090 mg/m3).

In addition, read-across to structurally similar compounds strengthens the conclusion that isoamylene has low potential for effects on fertility.  2-Methylpropene had no effects on male and female reproductive parameters in rats and mice in 14 week inhalation exposure studies. These repeat dosing studies included parameters such as sperm analysis, oestrus cycle analysis and histopathology (although mating was not carried out). NOAECs of 8000 ppm (18,359 mg/m3) for both rat and mouse studies were established (NTP 1998).

Further weight of evidence comes from OECD 422 studies on but-1-ene and but-2-ene. Based on these data, the NOAECs for reproductive toxicity were 8000 ppm (18,359 mg/m3) for but-1-ene and 5000 ppm (11,474 mg/m3) for 2-butene, the highest concentrations tested (HLS, 2003;TNO, 1992).

There are no studies on the effects of the isoamylene or 2-methyl-2-butene on fertility in humans.

In conclusion, the weight of evidence from structural analogues and members of the isoamylene (2 -methylbutene) category indicates that they are not toxic to reproduction, including fertility. The NOAEC of 7,000 ppm (20,090 mg/m3) for fertility is based on the NOAEC for 2-methyl-2-butene in the reproductive study (HLS, 2004).

Short description of key information:
An OECD 422 combined repeated dose and reproduction/developmental toxicity study was conducted in Sprague Dawley rats. The NOAEC for reproductive toxicity was 7,000 ppm (20,090 mg/m3), the highest dose tested.

Effects on developmental toxicity

Description of key information
An OECD 422 combined repeated dose and reproduction/developmental toxicity study was conducted in Sprague Dawley rats. The NOAEC for developmental toxicity was 7,000 ppm (20,090 mg/m3), the highest dose tested. 
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
20 090 mg/m³
Additional information

There are no developmental studies available for isoamylene or 2-methyl-2-butene that fulfills Annex IX requirements, but members of the isoamylene / 2-methyl-2-butene category are considered not toxic to development by consideration of data for 2-methyl-2-butene and read across to other C4-C5 mono-olefins (butenes, and 2-methylpropene). There is sufficient weight of evidence to preclude the need for further testing (i.e. scientifically unjustified; Annex XI adaptation).

In the combined repeat dose/reproductive/developmental study (OECD 422; HLS, 2004), rats were exposed to 2-methyl-2-butene at concentrations of up to 7,000 ppm (20,090 mg/m3), 6 hr/day, 7 days/week for two weeks prior to breeding, during breeding and through day 19 of gestation (HLS, 2004). Dams were allowed to deliver their litters, which were retained until lactation Day 4. No evidence of developmental toxicity was seen. There were no adverse effects upon survival or growth of the offspring in utero or up to day 4 of lactation.  Thus, the NOAEC for developmental toxicity is 7,000 ppm (20,090 mg/m3).

Read-across to the structurally similar compound 2-methylpropene, strengthens the conclusion that 2-methyl-2-butene has low potential for developmental toxicity. 2-Methylpropene has been tested in a rat developmental toxicity study (OECD Guideline 414) by inhalational exposure at concentrations of 500, 2000 and 8000 ppm (1147, 4589, 18,359 mg/m3). 2-Methylpropene had no effect on the females during gestation. There were also no effects on the number, growth or survival of the foetuses in utero and no effects on foetal development (determined by visceral and skeletal analysis). A NOAEC of 8000 ppm (18,359 mg/m3) (the highest concentration tested) was established for maternal toxicity and foetal toxicity (CTL, 2002).

The low developmental toxicity of 2-methylpropene is consistent with that of other members of the butene category. 2-Butene and but-1-ene also had no effect on developmental toxicity when tested in OECD Guideline 422 studies by inhalation exposure. None of these isomers produced treatment-related effects on the development of pups during the reproductive toxicity element of the studies. There were no effects on pup body weight gain or observed during macroscopic examination of pups at post mortem (HLS, 2003;TNO, 1992). The NOAECs for developmental toxicity were 8000 ppm (18,359 mg/m3) for but-1-ene and 5000ppm (11,474 mg/m3) for 2-butene (the highest concentrations tested).

There are no data on the developmental toxicity of the isoamylene (2 -methylbutene) in humans

In conclusion, the weight of evidence from structural analogues and members of the isoamylene (2 -methylbutene) category indicates that they are not developmental toxins. The NOAEC of 7000 ppm (20,090 mg/m3) for developmental toxicity is based on the NOAEC for 2-methyl-2-butene in the OECD 422 study (HLS, 2004).

Justification for classification or non-classification

No classification of isoamylene is warranted under DSD or CLP.