Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Reliable screening study, but not by itself considered definitive for determination of a no adverse effect level for toxicity to reproduction.
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2 100 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Well documented and reliable 2-generation study of a close chemical analogue of the registered substance. Considered reliable for NOAEC determination.
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The toxicokinetics of 2 -phenylpropene have been extensively investigated in rats with oral, intravenous and inhalation exposure (see section 7.1.1): bioaccumulation is not expected, as it is readily metabolised and excreted (chiefly in the urine). In an OECD 422 rat screening test for toxicity to reproduction, repeated oral administration of the substance produced no adverse effects on reproductive performance. Subchronic and chronic toxicities by inhalation have been tested in rats and mice over 14 and 105 weeks, respectively (NTP 2007; see sections 7.5.3 and 7.7). In the 14 week studies apart from standard pathological examinations some additional examinations on sperm motility and vaginal cytology were included: epididymal sperm concentration and motility; spermatid heads/testis; left cauda, epididymis, and testis weights were evaluated in males at terminal sacrifice while for females vaginal cytology slides

were prepared (relative numbers of leukocytes, nucleated epithelial cells, and large squamous epithelial cells were determined and used to ascertain oestrous cycle stages). Apart from an increase in the oestrous cycle lengths of female mice exposed at 600 and 1000 ppm, no effects on reproductive organs were observed. Similarly, no adverse effects on reproductive organs of rats or mice were observed in the 105 week chronic studies. Read-across from test data for the close chemical analogue styrene is justified in detail elsewhere in this dossier. In a reliable 2-generation study of toxicity to reproduction in the rat, no significant effect on reproductive performance, or on morphology or function of reproductive organs, was seen when rats were exposed to styrene (6h/day over 2 generations) at concentrations up to 500 ppm (mean measured concentration: equal to 2.1 mg/l). A NOAEC value of 50 ppm/0.21 mg/l was concluded for systemic toxicity to the F0 and F1 parental generations, together with a NOAEC value of 500 ppm/2.1 mg/l for toxicity to reproduction. In addition, a reliable study in which rats were given styrene in drinking water at 125 or 250 ppm found no evident

impairment of reproductive performance or postnatal growth and development across 3 generations (an apparent minor reduction of F2 male fertility, indicated by infertility of a single male, was seen but this is of questionable biological significance).

Based on the justification document supplied in section 13 of this dossier which supports the use of read-across from styrene to the registered substance 2-phenylpropene, it is concluded that the observed absence of toxicity to reproduction reported in these reliable styrene multigeneration studies can reasonably be considered applicable to the registered substance.


Short description of key information:
Available information on subchronic and chronic inhalation toxicity of the registered substance do not indicate adverse effects on structure or function of reproductive organs in rats or mice. An OECD 422 screening test found no effects on reproductive parameters (mating index, fertility index, gestation period, number of corpora lutea or implantations, implantation index, gestation index, delivery index or parturition) when rats were dosed orally with the substance at
0, 40, 200 or 1000 mg/kg/day or 43 days (from 14 days prior to mating to post-mating in males and from 14 days prior to mating until post-partum day 3 in females). Read-across to multigeneration study results obtained using the close chemical analogue styrene is considered justified. In a reliable 2-generation study of toxicity to reproduction in the rat, no significant effect on reproductive performance, or on morphology or function of reproductive organs, was seen when rats were exposed to styrene (6h/day over 2 generations) at concentrations up to 500 ppm (mean measured concentration: equal to 2.1 mg/l). A NOAEC value of 50 ppm/0.21 mg/l was concluded for systemic toxicity to the F0 and F1 parental generations, together with a NOAEC value of 500 ppm/2.1 mg/l for toxicity to reproduction. In addition, a reliable study in which rats were given styrene in drinking water at 125 or 250 ppm found no evident
impairment of reproductive performance or postnatal growth and development across 3 generations (an apparent minor reduction of F2 male fertility, indicated by infertility of a single male, was seen but this is of questionable biological significance).

Justification for selection of Effect on fertility via oral route:
In an OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening) test performed with the registered substance rats of both sexes were dosed at 0, 40, 200 or 1000 mg/kg/day by oral administration for 43 days (from 14 days prior to mating to post-mating in males and from 14 days prior to mating until post-partum day 3 in females). No effects on the reproductive parameters mating index, fertility index, gestation period, number of corpora lutea or implantations, implantation index, gestation index, delivery index or parturition were observed.

Justification for selection of Effect on fertility via inhalation route:
Read-across from styrene to the registered substance is justified, based on considerations of chemical structure and various properties, including toxicokinetics and general toxicity profile: see detailed justification document attached in section 13 of this dossier. A reliable 2-generation study of styrene toxicity to reproduction using methods equivalent to OECD guideline 416 is available. In this study, no significant effect on reproductive performance, or on morphology or function of reproductive organs, was seen when rats were exposed to styrene (6h/day over 2 generations) at concentrations up to 500 ppm (mean measured concentration: equal to 2.1 mg/l). A NOAEC value of 50 ppm/0.21 mg/l was concluded for systemic toxicity to the F0 and F1 parental generations, together with a NOAEC value of 500 ppm (2.1 mg/l) for toxicity to reproduction. This observed low level of toxicity is compatible with the results of the OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening) oral route test performed with the registered substance itself and described above. It is concluded that the NOAEC values and observed absence of toxicity to reproduction reported in the 2-generation study of styrene can reasonably be considered applicable to the registered substance 2-phenylpropene.

Effects on developmental toxicity

Description of key information
An OECD 422 screening test found no evidence of embryo- or foeto-toxicity and no overt teratogenicity when rats were dosed orally with the substance at 0, 40, 200 or 1000 mg/kg/day (for 43 days from 14 days pre-mating in males, and 14 days pre-mating until post-partum day 3 in females). Read-across to studies performed with the close chemical analogue styrene is considered justified.  A reliable 2-generation rat toxicity to reproduction study used methods equivalent to OECD guideline 416: rats were exposed by inhalation to styrene (6h/day over 2 generations) at up to 500 ppm  (mean measured concentration: equal to 2.1 mg/l).  Detailed investigation of pup development, especially neurodevelopment indicators, found developmental delay, with delayed neurodevelopment/developmental neurotoxicity effects postweaning in progeny of dams exposed at 500 ppm (a level causing degeneration of nasal olfactory epithelium and some reduction of bodyweight but no more marked evidence of systemic toxicity in the exposed dams).  The principal indicators of such effects were somewhat inconsistent (decreased pup growth seen in F2 but not in F1, grip strength decreased and swimming trial results affected only at some time points) and for other reported effects a relationship with decreased pup growth cannot be ruled out.  A separate rat inhalation study with pregnant rats exposed to styrene at 300 ppm was also included in a Committee for Risk Assessment background document (used when considering classification of styrene): delays in certain developmental milestones (eye-opening, incisor eruption, righting reflex) were observed in test group progeny, together with reduced brain neurotransmitter levels at birth and day 21 postpartum.  Based principally on the 2-generation study findings, ECHA's Committee for Risk Assessment has concluded that there is indicative evidence for styrene causing developmental toxicity in animals. 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Reliable screening study, but not by itself considered definitive for determination of a no adverse effect level for toxicity to reproduction.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
210 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Well documented and reliable 2-generation study of a close chemical analogue of the registered substance. Considered reliable for NOAEC determination.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In an OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening) test performed with the registered substance rats of both sexes were dosed at 0, 40, 200 or 1000 mg/kg/day by oral administration for 43 days (from 14 days prior to mating to post-mating in males and from 14 days prior to mating until post-partum day 3 in females). No effects on the reproductive parameters mating index, fertility index, gestation period, number of corpora lutea or implantations, implantation index, gestation index, delivery index or parturition were observed. While this study provides valuable evidence of low or absent embryo/foeto-toxicity and teratogenicity following oral administration, it does not give definitive information on possible developmental toxicity in rats. For this and for information on developmental toxicity to other species, read-across from reliable studies using the close chemical analogue styrene is considered justified.

In a reliable 2-generation study of styrene toxicity to reproduction using methods equivalent to OECD guideline 416, rats were exposed by inhalation to styrene (6h/day over 2 generations) at concentrations up to 500 ppm (mean measured concentration: equal to 2.1 mg/l). Detailed investigation of pup development, especially indicators of neurodevelopment, found evidence of toxicity manifested as developmental delay, with delayed neurodevelopment/developmental neurotoxicity effects postweaning in progeny of dams exposed at 500 ppm (a level causing no overt maternal toxicity). The principal indicators of such effects were somewhat inconsistent (decreased pup growth seen in F2 but not in F1, grip strength decreased and swimming trial results affected only at some time points) and for other reported effects a relationship with decreased pup growth cannot be completely ruled out. However expert evaluation of the study findings, taken together with other available information on developmental toxicity, led ECHA's Committee for Risk Assessment to conclude that there is indicative evidence that styrene caused developmental toxicity in animals.

Studies of the developmental toxicity of styrene in other species are also available. When pregnant rabbits were exposed by inhalation (7h/day on gestation days 6 -18) at 300 or 600 ppm, no evidence of embryo/foeto-toxicity or teratogenicity was found. Repeated exposure of other pregnant animals by inhalation at up to 250 ppm (mice) or 1000 ppm (Chinese hamsters) produced no evidence of teratogenic activity and no clear evidence of embryo/foeto-toxicity (although at 1000 ppm the latter effect seemed evident in Chinese hamsters, group sizes were too small for a definitive conclusion to be drawn).

Based on the justification document supplied in section 13 of this dossier which supports the use of read-across from styrene to the registered substance 2-phenylpropene, it is considered that the concluded activity profile of styrene can reasonably be applied to the registered substance.


Justification for selection of Effect on developmental toxicity: via oral route:
In an OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening) test performed with the registered substance rats of both sexes were dosed at 0, 40, 200 or 1000 mg/kg/day by oral administration for 43 days (from 14 days prior to mating to post-mating in males and from 14 days prior to mating until post-partum day 3 in females). No effects on gestation period, number of corpora lutea or implantations, implantation index, gestation index, delivery index or parturition were observed. Two dams dosed at 1000 mg/kg/day lost all their offspring during the lactation period (reducing postnatal day 4 viability in this group to 75% compared to 99.3% in controls: some decrease in bodyweight partum was also seen in this group at this time). There were no significant differences in numbers of offspring or live offspring at birth, sex ratio, livebirth index, external abnormalities, clinical signs or necropsy findings in the offspring of treated dams. NOELs for reproductive and developmental toxicity were 200 mg/kg/day for both parental females and offspring.

Justification for selection of Effect on developmental toxicity: via inhalation route:
A reliable 2-generation study of styrene toxicity to reproduction using methods equivalent to OECD guideline 416 is available: rats were exposed by inhalation to styrene (6h/day over 2 generations) at concentrations up to 500 ppm (mean measured concentration: equal to 2.1 mg/l). Detailed investigation of pup development, especially indicators of neurodevelopment, found evidence of toxicity manifested as developmental delay, with delayed neurodevelopment/developmental neurotoxicity effects postweaning in progeny of dams exposed at 500 ppm (a level causing degeneration of nasal olfactory epithelium and some reduction of bodyweight but no more marked evidence of systemic toxicity in the exposed dams). The principal indicators of such effects were somewhat inconsistent (decreased pup growth seen in F2 but not in F1, grip strength decreased and swimming trial results affected only at some time points) and for other reported effects a relationship with decreased pup growth cannot be completely ruled out. However expert evaluation of the study findings, taken together with other available information on developmental toxicity, led ECHA's Committee for Risk Assessment to conclude that there is indicative evidence that styrene caused developmental toxicity in animals.
Based on the justification document supplied in section 13 of this dossier which supports the use of read-across from styrene to the registered substance 2-phenylpropene, it is considered that the concluded activity profile of styrene can reasonably be applied to the registered substance.

Justification for classification or non-classification

Based on the findings of post-weaning developmental delay in progeny of rats exposed to styrene across 2 generations

at levels causing only limited maternal toxicity), it is concluded that there is indicative evidence of developmental toxicity in at least one animal species. Because delayed achievement of various developmental milestones can be associated with slowed postnatal/post-weaning growth, the available evidence is insufficient to conclude clear and dose-related developmental toxicity (disturbance of neurological development). However it is sufficient to raise concern over possible health effects and to warrant classification as Repr.2, H361d under the criteria of CLP.

Based on the justification document supplied in section 13 of this dossier which supports the use of read-across from styrene to the registered substance 2-phenylpropene, it is considered that the concluded activity profile of styrene and its applied CLP classification should reasonably be applied to this registered substance.