Propene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The read-across justification for C2 -C4 is included as an appendix in the CSR and in section 13 of the IUCLID.

A robust evaluation of the reproductive toxicity potential of propene is made by consideration of key information published for studies on propene and structurally-related substances. There is no 2-generation reproduction study available for propene, however, information is available from the 2-year repeat dose (NTP, 1985) and the guideline prenatal developmental toxicity (BASF, 2002) studies for propene. In addition, reproductive toxicity evaluation of the major metabolite of propene, propene oxide, and studies for C2 and C4 alkene homologues provide sufficient additional data for evaluation. Information considered key, in addition to propene studies, are for propene oxide, (Hayes, 1988, supported by Okuda, 2006) and other alkene homologues, ethylene (Hazelton, 2003), cis- and trans- 2-butene (TNO, 1992) and 1-butene (HLS, 2003). This information is summarised, with an overall conclusion giving the rationale for the weight of evidence assessment.

An extended one-generation reproductive toxicity study is proposed for ethylene. This will form part of a read-across approach to addressing this endpoint in both ethylene and the read-across target propene.

 

Information on propene

In a near-guideline combined chronic toxicity/carcinogenicity study, groups of F344/N rats (50 of each sex) and B6C3F1 mice (about 50 males and females/group) were exposed to propene in air by inhalation at concentrations of 0, 5,000 or 10,000 ppm (0, 8,600 or 17, 200 mg/m³), 6 hours per day, 5 days per week, for 103 weeks (NTP 1985). Consistent with the 90 day studies in rats and mice no gross or microscopic lesions of the reproductive organs were observed (including prostate/testes and ovaries/uterus).

In a well-conducted guideline (OECD 414) study (BASF, 2002), time-mated female Wistar rats (25 per test group) were exposed (whole body) to propene gas at concentrations of 0, 200, 1,000 and 10,000 ppm (0, 340, 1,720 and 17,200 mg/m³) for 6 hours per day on day 6 through day 19 post coitum (14 exposures). On day 20 post coitum, all animals were sacrificed and assessed by gross pathology (including weight determinations of the unopened uterus and the placentae). For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated as resorptions, live and dead foetuses) were determined. The foetuses were removed from the uterus, sexed, weighed and further investigated for any external findings. Thereafter, about one half of the foetuses of each litter was examined for soft tissue findings and the remaining foetuses for skeletal (including. cartilage) findings. The NOAEC for prenatal developmental and maternal toxicity following exposure to propene was 10,000 ppm (17,200 mg/m³), the highest dose level tested.

Information on the major metabolite of propene, propene oxide

Justification for read-across: propene oxide is the primary metabolite of propene.

A 2-generation reproduction study (OECD 416) in which Fischer 344 rats were exposed by inhalation to propene oxide has been reported (Hayes, 1988).

Thirty male and 30 female rats were exposed to concentrations of 0, 30, 100, or 300 ppm (0, 70, 240 or 710 mg/m³) propene oxide for 6 hr/day, 5 days/week for 14 weeks before mating. The exposure period was then increased to 7 days/week during mating, gestation and lactation exposure periods although dams were not exposed from day 21 of pregnancy through day four post-partum. After weaning, 30 randomly selected F1, pups/sex/group were exposed to propene oxide for 17 weeks and subsequently mated to produce the F2 litters.

Parameters including fertility, litter size, neonatal growth and survival, gross pathology and histopathology were assessed for all adults and selected weanlings.

Toxicity due to propene oxide was expressed as decreased body weights of parental F0 and F1 rats at 300 ppm (710 mg/m³). However, no treatment-related effects on fertility (mating or conception) were observed in either F0 or F1 matings. Neonatal survival indices for F1 or F2 litters revealed no treatment-related effects and overall, there was no effect on litter size. Pup weights were unaffected by parental exposure to propene oxide in either generation. Gross pathological and histopathological examination of adults and weanlings revealed no treatment-related changes.

Inhalation exposure to propene oxide at concentrations up to 300 ppm (710 mg/m³) over two generations did not produce adverse effects on reproductive function.

In another well-conducted and reported guideline (OECD 422) study (Okuda, 2006), male and female Sprague-Dawley rats (10 per sex per test group) were exposed by whole body inhalation to propene oxide at concentrations of 0, 125, 250, 500 and 1,000 ppm (0, 300, 600, 1,200, 2,400 mg/m³) for 6 hours per day, 7 days per week for 5-6 weeks including premating, mating and post mating exposure periods. The total number of exposures for female rats ranged from 35-39, depending on the start of gestation. Male rats were exposed for 6 weeks, 2-weeks premating, 2 weeks mating and 2-weeks post mating. Pregnant females were allowed to deliver naturally and dams and pups sacrificed on day 4 post-partum.

Although severe parental and foetal toxicity affected survival at 1000 ppm (2,400 mg/m³), the highest dose level tested, in contrast exposure to 500 ppm (1,200 mg/m³), or less, did not adversely affect reproductive performance or foetal survival, even in the presence of some paternal toxicity.

The results of both reproduction studies on propene oxide have demonstrated very similar results with NOAEC for reproductive parameters reported as 300 ppm (710 mg/m³) (Hayes, 1988) and 500 ppm (1,200 mg/m³) (Okuda, 2006). To place these in context it is necessary to consider the toxicokinetics of propene.

The total uptake of propene is less than 10% in rats and is mainly driven by saturable metabolism (Filser, 2000). The proximate metabolic product is propene oxide. In rats, this metabolic process is saturated at external concentrations of 3,000 ppm propene (5,160 mg/m³), resulting in the blood concentration of propene oxide never exceeding 2000 nmol/L (Filser 2008).

In contrast rats exposed to 500 ppm (1,200 mg/m³) propene oxide, directly by inhalation, exhibit much higher blood levels of propene oxide (29,000 – 38,000 nmol/L), (Ostermann-Golkar, 1999).

Such high concentrations are only achieved when propene oxide is administered directly. In contrast, the maximum propene oxide concentration formed by the saturable metabolic step following propene administration to rats, is some 15 to 20-fold less, at about 2,000 nmol/mL. It follows that the concentration of propene oxide, formed as a metabolite during any propene reproduction study could never reach concentrations of 29,000-38,000 nmol/mL achieved with rats directly exposed to propene oxide.

The propene oxide reproduction and developmental studies (Okuda 2006 and Hayes 1988) reported clear NOAEC’s for reproduction parameters at 300 and 500 ppm (710 and 1,200 mg/m³), respectively. At a concentration of 500 ppm (1,200 mg/m³), propene oxide in blood would be expected to be 29,000-38,000 nmol/L. Therefore these studies assessed the reproductive toxicity of propene oxide (the major metabolite of propene), to systemic concentrations some 15-20-fold greater than could ever be achieved through propene exposure. In consequence they provide a valuable, if somewhat severe, surrogate for assessment of the reproductive potential of propene in rats.

In humans propene oxide is also formed and metabolism saturates such that the concentration of the oxide in human blood following exposure to 25 ppm propene is about 60-fold lower than in rats exposed similarly (Filser 2008). Consequently, humans maintain considerably lower blood levels of propene oxide than rats following exposure to similar concentrations of propene.

Information on alkene homologues - ethylene

Justification for read-across: ethylene, propene, and butenes represent a homologous series of hydrocarbon gases with a single, terminal carbon-carbon double bond. Chemically, the series is characterised by high volatility and flammability. Biologically, the member substances of this series are absorbed via inhalation and either re-expired or metabolised to the epoxide in the first instance. The epoxides may be further hydrolysed to diols or may react with macromolecules (proteins and oliogonuceleosides). In a guideline study (OECD 421), ethylene was administered by head only inhalation to male and female rats (10/sex/group) for 6 hrs, daily, at concentrations of 0, 200, 1000, and 5000 ppm (0, 230, 1150 and 5740 mg/m³) (Hazleton, 2003). Administration began 2 weeks prior to mating, continued during the pairing, and finished on the day prior to necropsy for the males (Day 28) or until Day 20 of gestation for the females. The females and the F1 pups were sacrificed on Day 4 post-partum.

It was concluded that there were no ethylene-induced effects on fertility or fecundity with all females becoming pregnant. Histopathological examination of the ovaries, testes and epididymides of the control and high dose group revealed no treatment-related findings. The NOAEC was 5,000 ppm (5,740 mg/m³).

Information on alkene analogues - butenes

Justification for read-across: ethylene, propylene, and butylenes represent a homologous series of hydrocarbon gases with a single, terminal carbon-carbon double bond. Chemically, the series is characterised by high volatility and flammability. Biologically, the member substances of this series are absorbed via inhalation and either re-expired or metabolised to the epoxide in the first instance. The epoxides may be further hydrolysed to diols or may react with macromolecules (proteins and oliogonuceleosides).

Reproduction toxicity studies (OECD Guideline 422) via inhalation exposure are available for 1-butene (HLS, 2003) and 2-butene (TNO, 1992). Male and female rats were exposed to the butene isomers for two weeks prior to and during mating, until day 19 of gestation. The dams were then allowed to deliver their litters, which were retained until post-natal day 4. Target concentrations were: but-1-ene 500, 2,000, 8,000 ppm (1,150, 4,590, 18,360 mg/m³) and 2-butene 2,500 or 5,000 ppm (5,740 or 11,470 mg/m³).

 

There was no evidence of systemic toxicity for but-1-ene in parents. Slight reductions in maternal body weight occurred with 2-butene. There were no effects on mating behaviour, fertility or gestation indices, the number of implantation sites and corpora lutea per dam, numbers of pups delivered, viability of pups at and after birth and the pup sex ratio when compared to the control group (HLS, 2003, TNO, 1992). Based on these data, the NOAECs for reproductive toxicity were 8000 ppm (18,360 mg/m³) for but-1-ene and 5000 ppm (11,470 mg/m³) for 2-butene, the highest concentrations tested.

 

The study results are similar for all 3 propene homologues reviewed - no evidence of reproductive toxicity up to the highest dose levels tested.

 

Summary & Conclusions

 

Overall, there is a considerable amount of information available from well conducted and reported guideline studies with adequate and reliable coverage of key parameters for the assessment of the reproductive toxicity potential of propene. Information is available for propene, its proximate metabolite, propene oxide and other alkene homologues. On the basis of this information, there is no evidence to indicate potential for adverse reproductive effects due to propene. Indeed, information from reproduction studies where rats were directly exposed to propene oxide, the consequence of which is systemic exposure to propene oxide at much higher concentrations that could ever be achieved through propene exposure, may be considered as particularly strong evidence supporting this overall conclusion.

Therefore a significant weight of evidence exists indicating a lack of reproductive toxicity:

- lack of findings in reproductive tissues (histopathological examination of the gonads) in repeated dose studies up to 2 years (propene specific studies);

- lack of prenatal developmental effects (propene specific study);

-a 2-generation reproduction study (OECD 416) and a reproduction/developmental toxicity test (OECD 422) study with propene oxide, the proximate metabolite of propene, did not report reproduction effects, and

- lack of effects in reproduction/developmental toxicity screening tests of closely related homologues ethylene (C2) and butenes (C4). Within the OECD HPV Program, these substances are concluded to be of no concern for effects on fertility, based on these studies.

Short description of key information:
The weight of evidence from studies on propene, its proximate metabolite and 3 alkene homologues indicates no evidence of reproductive toxicity.

Justification for selection of Effect on fertility via oral route:
This exposure route is not relevant for a gas and therefore the study is not necessary or scientifically justified.

Effects on developmental toxicity

Description of key information

No developmental effects were induced in rats exposed to propene up the 10,000 ppm (17,200 mg/m3), half the lower explosive limit.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

The developmental toxicity of propene has been reported in a guideline (OECD 414) rat study (BASF, 2002).

Time-mated female Wistar rats (25 per test group) were exposed to propene gas (BASF, 2002) at concentrations of 0, 200; 1,000 and 10,000 ppm (0, 340, 1,720 and 17,200 mg/m³) for 6 hours per day on day 6 through day 19 post coitum (14 exposures). Clinical observations, food and water consumption, and body weight of the animals were frequently recorded. On day 20 post coitum, all animals were sacrificed and assessed by gross pathology (including weight determinations of the unopened uterus and the placentae). For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated as resorptions, live and dead foetuses) were determined. The foetuses were removed from the uterus, sexed, weighed and further investigated for any external findings. Thereafter, about one half of the foetuses of each litter was examined for soft tissue findings and the remaining foetuses for skeletal (including cartilage) findings.

No maternal toxicity was expressed at any concentration up to 10,000 ppm (17,200 mg/m³). There were no treatment-related influences on the gestational parameters and no signs of prenatal developmental toxicity, in particular no indications of teratogenicity. The NOAEC for prenatal developmental and maternal toxicity from inhalation exposure to propene is 10,000 ppm (17,200 m/m³).

Further testing is required to address data requirements. An OECD 414 in rabbits is therefore proposed, with ethylene as the testing material. The results of this study will be read-across to propene.

Justification for classification or non-classification

There is adequate information available from which to assess the potential of propene to induce reproductive or developmental effects and to conclude that classification under the DSD or CLP is not warranted.