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Key value for chemical safety assessment

Effects on fertility

Description of key information
NOAEL (reproductive organs, rat) = 1000 mg/kg bw/day (90-day subcutaneous treatment)
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7.1, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substances with similar structure and intrinsic properties. Read-across is justified based on structural similarity (common functional group), common metabolic pathways and overall similarities in physicochemical, ecotoxicological and toxicological properties (refer to endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.7.3, in accordance with AnnexXI, 1.5, of Regulation (EC) No 1907/2006.
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity: Screening study

A GLP-compliant Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD 422) was conducted with methylcyclohexane (MHLW, 2011). Groups of 12 male and 12 female rats per dose were given methylcyclohexane by oral gavage at 62.5, 250 and 1000 mg/kg bw/day from 14 days prior to mating to the end of the 14-day mating period (males) or until Day 4 of lactation. Concurrent male and female vehicle (corn oil) control groups were included.

Systemic toxicity effects of males and non-mating females are discussed in the Repeated dose toxicity section. There were no relevant differences between mating and non-mating females in clinical signs, detailed clinical observations (including FOB), body weight, food and water consumption and urinalysis.

No changes were found in estrous cycle between control and treated females. The number of pairs with successful copulation and conceiving days was not affected in any treatment group. One animal in the control, 62.5 and 1000 mg/kg bw/day groups, respectively, was not pregnant. However, fertility index was not statistically significantly different between control and treatment groups. Length of gestation, number of corpora lutea, implantation scars and implantation index showed no significant changes. Gestation index was 100% in all groups. Faulty nest-building was observed in one dam of the 250 mg/kg bw/day group and all pups were dead until Day 4 of lactation. However, this change was considered to be not treatment-related.

There were no changes in organ weights, gross pathology and histopathology findings between control and treated females sacrificed on Day 5 of lactation.

No statistically significant differences were found between control and treatment groups in number of born pups, stillbirths, sex ratio at birth, birth index, live birth index, number of live pups on Day 4 of lactation, sex ratio on Day 4 of lactation, viability index and external abnormalities. 13 pups of a female dosed 250 mg/kg bw/days showed hypothermia and died until Day 4 of lactation; this dam had not built a nest. This observation was considered accidental and not test item-related. No differences in pup body weight were seen between control and treatment groups at birth and at Day 4 of lactation. No gross abnormalities were found in stillbirths, dead pups and pups at Day 4 of lactation.

Based on the overall lack of adverse effects on reproductive and offspring parameters, the NOAEL for fertility (P generation) and development (F1 generation) was 1000 mg/kg bw/day.

Reproductive toxicity: Two-generation study

There are no Two-generation reproductive toxicity studies available for methylcyclohexane. In order to fulfil the standard information requirements set out in Annex X, 8.7.3, read-across from the reference substance cyclohexane (CAS No. 110-82-7) is conducted in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

A Two-generation reproduction toxicity study was conducted with cyclohexane according to OECD Guideline 416 (adopted 1983) and under GLP conditions (Kreckmann, 1997). The study involved the production of one set of litters in each generation. Throughout the study, rats (30 per sex and concentration) were exposed whole-body to clean air or atmospheric concentrations of 500, 2000 or 7000 ppm cyclohexane (corresponding to 1720, 6880 and 24080 mg/m³, respectively), 6 h/day, 5 days/week. Following at least 10 weeks of exposure, the animals were bred within their respective treatment groups, and allowed to deliver and rear their offspring until weaning (postpartum Day 25). At weaning, 30 F1 rats per sex and group were randomly selected to produce the next generation. At least 11 weeks after weaning, the F1 rats were bred within their respective treatment groups to produce F2 litters. Barring F1 weanlings selected for propagation of the next generation, twenty F1and F2 weanlings per sex and concentration were randomly designated for gross postmortem examination. The remaining unselected weanlings were sacrificed without pathological examination.

After litter production, all parental rats were given a gross pathological examination. Testes (weighed), epididymides, prostate, seminal vesicles, coagulating gland and pituitary were collected from each male. Ovaries, uterus, cervix, vagina and pituitary were collected from each female. Tissues from rats in the control and 7000 ppm groups of both generations were examined microscopically. In addition, gross lesions and target organs from adult rats in all dose groups were microscopically examined.

At the 7000 ppm level, adverse effects considered to be related to cyclohexane treatment included statistically significant reductions in mean body weight and overall mean body weight gain for P and F1 females; a statistically significant reduction in mean body weight for F1 males; statistically significant reductions in overall mean food efficiency for P anf F1 females during premating and in mean food efficiency for Lactation Days 21-25 for F1 females; statistically significant reductions in mean food consumption by P females for Gestation Days 0-7; Statistically significantly reduced mean pup weight from Lactation Day 7 throughout the remainder of the 25-day lactation period for F1 and F2 litters; generally diminished response or no response of the animals to a sound stimulus while in the chambers during exposure.

At the 2000 ppm level, adverse effects considered to be related to cyclohexane treatment included generally diminished response or no response of the animals to a sound stimulus while in the chambers during exposure.

No adverse compound-related effects were observed at 500 ppm. Therefore, the systemic NOAEC was 500 ppm (1720 mg/m³) and the reproductive NOAEC was 2000 ppm (6880 mg/m³) in male and female rats. The reproductive NOAEC was based solely on the decreased pup weights in both the F1 and F2 generations observed at 7000 ppm (24080 mg/m³).

For the purpose of read-across, the dose descriptors of the source chemical (cyclohexane) were taken into consideration for hazard assessment of the target chemical (methylcyclohexane). The dose descriptors of the source substance were converted into the corrected dose descriptors of the target substance with regard to the molecular weight ratio and in a worst case assumption as follows:Dose descriptor (mass-corrected) = Dose descriptor (cyclohexane) x (molecular weight methylcyclohexane / molecular weight cyclohexane)

Dose descriptor (mass-corrected) = Dose descriptor (cyclohexane) x [(98.19 g/mol) / 84.16 g/mol)]

Thus, based on read-across and mass correction, the approximate systemic and reproductive NOAEC values for methylcyclohexane are estimated to be:

NOAEC (parental toxicity) = 2010 mg/m³

NOAEC (reproductive toxicity) = 8030 mg/m³

Reproductive toxicity: Other studies

Methyl cyclohexane was tested in a subchronic toxicity study focusing on potential compound-related effects on the reproductive system (Kimet al., 2011; see Repeated dose toxicity). Groups of 5 male and female rats were exposed to methylcyclohexane at 10, 100 and 1000 mg/kg bw/day by subcutaneous injections, 5 days/week for 13 weeks. Concurrent vehicle control animals were treated with olive oil.

In regard to effects on reproductive organs, no changes in organ weights were observed in male and female animals dosed at 10, 100 and 1000 mg/kg bw/day, except for a decrease in the weight of ovaries in the high-dose female group.

No effects were observed in spermatogenic cell count and morphology at any dose level. In males, no effects were seen on the levels of prolactin, testosterone, follicle stimulating hormone and luteinizing hormone. A very slight but statistically significant and dose-dependent increase in estradiol levels was observed at 10 and 100 mg/kg bw/day. At the same dose levels, a significant decrease in progesterone levels was noted. The toxicological relevance of this finding is unclear, since no corresponding alterations were observed in testes at microscopic examination. No female data were reported. According to the authors, the hormone levels in females were dramatically changed in accordance with the estrous cycle. The menstrual cycle period was statistically significantly increased in the 4th week in the 10 mg/kg bw/day group, but this change was not dose-dependent. After the 13th week, no effects were observed.

The NOAEL for systemic toxicity was 100 mg/kg bw/day (see Repeated dose toxicity), while the NOAEL for effects on reproductive organs was 1000 mg/kg bw/day based on the reported findings.

In conclusion, the available information indicates that methylcyclohexane and the structurally similar reference substance cyclohexane are not toxic to reproduction.

 

Justification for read-across approach

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests", which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, cyclohexane (CAS No. 110-82-7) is selected as reference substance for assessment of ecotoxicological and toxicological endpoints, for which no methylcyclohexane data are available.

Similarity is based on:

(1) common functional group: Methylcyclohexane and cyclohexane share a 6-membered saturated alicyclic ring as a common molecular structure and are therefore allocated to the group of monocyclic hydrocarbons (cycloalkanes);

(2) common precursors and likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals: Methylcyclohexane and cyclohexane do not share a common precursor; however, both substances are produced by hydrogenation of the corresponding aromatic compounds toluene (see Section Manufacture and Use) and benzene (EC-ECB, 2004), respectively, which are in turn structurally similar substances. In general, methylcyclohexane and cyclohexane are likely to undergo the same chemical reactions characteristic of cycloalkanes, e.g. combustion to CO2 and H2O and halogenation (Breitmeier and Jung, 2005). The assessment of toxicokinetic behaviour indicates that both substances share a common main metabolic pathway, namely mono- and dihydroxylation of the alicyclic ring resulting in the respective isomers of methylcyclohexanol/-diol and cyclohexanol/-diol, followed by conjugation to the corresponding glucuronides (see Toxicokinetics); and

(3) constant pattern in the changing of the potency of the properties between substances: For methylcyclohexane and cyclohexane, the constant pattern is characterized by similarities in the potency of properties.

- Physicochemical properties:

Both substances show overall similar physico-chemical properties, being liquids, moderately volatile, lipophilic and slightly soluble in water. (see Section 4, Physical and chemical properties and EC-ECB, 2004).

- Environmental fate and ecotoxicological profile:

Methylcyclohexane and cyclohexane show similar properties in environmental fate and ecotoxicological profile: both substances are volatile, not bioaccumulative and show corresponding adsorption values (see section 5, Environmental fate and pathways and EC-ECB, 2004). Furthermore the available experimental data demonstrate that both substances exhibit a similar ecotoxicity profile. Both are acute very toxic to aquatic organisms (see Section 6, Aquatic toxicity and EC-ECB, 2004) with invertebrates and/or algae being the most sensitive organism groups. The available data on algae indicate a chronic toxicity potential with NOErC being 0.067 mg/L for methylcyclohexane and 0.94 mg/L for cyclohexane, resulting in chronic classification for both substances.

- Toxicological profile:

Methylcyclohexane and cyclohexane show similar toxicokinetic behaviour (see Section 7.1, Toxicokinetics). For those toxicological endpoints, for which both substances have been tested, similar levels of toxicity have been observed. Thus, both substances are of low acute toxicity via the oral and inhalation route, but fulfil the classification criteria for Aspiration toxicity (Category 1) and Narcotic effects (STOT-SE 3) according to Regulation (EC) No 1272/2008. Both substances were not skin and eye irritating in experimental studies, but are classified for Skin irritation (Category 2), mainly based on their defatting properties. Methylcyclohexane and cyclohexane have been extensively studied for repeated dose toxicity mainly via inhalation. For methylcyclohexane, the lowest chronic NOAEC for systemic effects is 400 ppm (1600 mg/m³) in rats, while for cyclohexane the most reliable subchronic systemic NOAEC in rats and mice is 2000 ppm (6880 mg/m³). Applying a time-extrapolation factor of 3 (ECHA, 2010), the chronic NOAEC for cyclohexane would be 667 ppm (2293 g/m³), which would be in the same order of magnitude as for methylcyclohexane. Both substances have been tested negative for mutagenicity in vitro.

Conclusion:

In order to avoid the need to test methylcyclohexane for every endpoint for which information gaps are identified, the read-across approach is applied for the assessment of environmental and human health hazards. Thus, environmental and human health effects are predicted where applicable from adequate and reliable data for cyclohexane by interpolation to methylcyclohexane in accordance with Annex XI, Item 1.5 of Regulation (EC) No 1907/2006.

A detailed justification for the read-across approach is provided in the technical dossier (see IUCLID Section 13).

References

Breitmaier, E. and Jung, G. (2005). Organische Chemie. Grundlagen , Stoffklassen, Reaktionen, Konzepte, Molekülstruktur. 5th ed. Georg Thieme Verlag, Stuttgart.

ECHA (2010). Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health. Source: European Chemicals Agency, http://echa.europa.eu/

EUROPEAN COMMISSION - European Chemicals Bureau (EC-ECB) (2004). European Union Risk Assessment Report: Cyclohexane; CAS No: 110-82-7; EINECS No: 203-806-2. European Chemical Bureau - Institute for Health and Consumer Protection.


Short description of key information:
NOAEL (reproductive toxicity, rat) = 1000 mg/kg bw/day (OECD 422, GLP)
NOAEL (parental toxicity, rat) = 250 mg/kg bw/day (OECD 422, GLP)
NOAEC (reproductive toxicity, rat) = 8030 mg/m³ (similar to OECD 416, GLP, based on read-across from cyclohexane and mass correction)
NOAEC (parental toxicity, rat) = 2010 mg/m³ (similar to OECD 416, GLP, based on read-across from cyclohexane and mass correction)

Justification for selection of Effect on fertility via oral route:
There is only one study available.

Justification for selection of Effect on fertility via inhalation route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information
NOAEC (pre-natal development, rat) = 28100 mg/m³ (OECD 414, GLP, based on read-across from cyclohexane and mass correction)
NOAEC (maternal toxicity, rat) = 2010 mg/m³ (OECD 414, GLP, based on read-across from cyclohexane and mass correction)
NOAEC (pre-natal development, rabbit) = 28100 mg/m³ (OECD 414, GLP, based on read-across from cyclohexane and mass correction)
NOAEC (maternal toxicity, rabbit) = 28100 mg/m³ (OECD 414, GLP, based on read-across from cyclohexane and mass correction)
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
Quality of whole database:
The available information comprises two adequate and reliable studies (Klimisch score 2) from a reference substances with similar structure and intrinsic properties. Read-across is justified based on structural similarity (common functional group), common metabolic pathways and overall similarities in physicochemical, ecotoxicological and toxicological properties (refer to endpoint discussion for further details).
The available studies are sufficient to fulfil the standard information requirements set out in Annex IX and X, 8.7.2, in accordance with AnnexXI, 1.5, of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity: Pre-natal developmental toxicity

There are no studies available in which the pre-natal developmental toxicity of methylcyclohexane has been investigated. In order to fulfil the standard information requirements set out in Annex IX and X, 8.7.2, read-across from the reference substance cyclohexane (CAS No. 110-82-7) is conducted in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Two inhalation developmental toxicity studies have been conducted with cyclohexane (Kreckmann, 1996a, b). Assumed-pregnant rats (25/concentration) and rabbits (20/concentration) were exposed whole-body to cyclohexane at 500, 2000 and 7000 ppm (corresponding to 1720, 6880 and 24080 mg/m³). Sham-exposed control groups were included. Rats and rabbits were exposed for 6 h/day on Days 7-16 and 6-18 of gestation, respectively. On Day 22 (rats) and 29 (rabbits) of gestation, animals were sacrificed for gross pathological examination. Uteri were removed and opened. The types of implants (live and dead fetuses and resorptions) were counted and their relative position recorded. Live fetuses were weighed, sexed and examined for external, visceral and skeletal alterations.

In the rat study, substance-related adverse effects were observed at 2000 and 7000 ppm. At both concentrations, a generally diminished or absent response to a sound stimulus was noted during the 6 h exposure period. A statistically significant reduction in overall maternal body weight gain and overall maternal food consumption during the treatment period was seen at 7000 ppm. At this concentration, a slight but statistically significant decrease in the number of implantations was also observed. Although the decreased mean was below the range of the historical control data of the test facility, the mean number of corpora lutea was comparable to that of the control group, thus suggesting pre-implantation loss. Since there was no exposure during pre-implantation, this finding was considered not to be substance-related.

There were no substance-related differences between control and treated groups in fertility, number of resorptions, number of live fetuses, sex ratio and mean fetal weight. No substance-related effects were observed on the incidence of fetal malformations and variations.

Based on the effects observed at 2000 and 7000 ppm, the maternal NOAEC was 500 ppm, equivalent to 1720 mg/m³. No evidence of developmental toxicity was observed at any concentration. Therefore, the developmental NOAEC was 7000 ppm (24080 mg/m³).

In the rabbit study, there were no substance-related differences between control and treatment groups in maternal body weight (gain), food consumption, fertility, number of implantations, number of live fetuses number of resorptions and mean fetal weight. There was a statistically significant decrease in the mean number of corpora lutea in the 2000 and 7000 ppm groups. The decreased mean values were well within the range of control data from previous studies of the test facility, and the mean number of corpora lutea for the concurrent control group was near the high end of that range. Since ovulation and implantation had occurred prior to exposure to the test substance, the decrease in the mean number of corpora lutea for females in the 2000 and 7000 ppm groups was considered not to be substance-related.

There was a spurious statistically significant trend in sex ratio, resulting in statistical significance assigned to the 2000 and 7000 ppm groups. However, the trend appeared to result from the disparity between the sex-ratio values for the 500 and 2000 ppm groups; those values lay near the historical control data of the performing laboratory. Because of the absence of a true dose response, those changes in sex ratio were considered not to be compound-related. No substance-related effects were observed on the incidence of fetal malformations and variations.

Based on the lack of maternal and developmental toxicity effects up to the highest concentration, the maternal and developmental NOAECs were each 7000 ppm equivalent to 24080 mg/m³.

In conclusion, cyclohexane is not considered to be uniquely toxic to the rat and rabbit conceptus.

For the purpose of read-across, the dose descriptors of the source chemical (cyclohexane) were taken into consideration for hazard assessment of the target chemical (methylcyclohexane). The dose descriptors of the source substance were converted into the corrected dose descriptors of the target substance with regard to the molecular weight ratio and in a worst case assumption as follows:

Dose descriptor (mass-corrected) = Dose descriptor (cyclohexane) x (molecular weight methylcyclohexane / molecular weight cyclohexane)

Dose descriptor (mass-corrected) = Dose descriptor (cyclohexane) x [(98.19 g/mol) / 84.16 g/mol)]

Thus, based on read-across and mass correction, the maternal toxicity and pre-natal developmental NOAEC values for methylcyclohexane are estimated to be:

NOAEC (maternal toxicity, rat) = 2010 mg/m³

NOAEC (pre-natal development, rat) = 28100 mg/m³

NOAEC (maternal toxicity, rabbit) = 28100 mg/m³

NOAEC (pre-natal development, rabbit) = 28100 mg/m³

 

Justification for read-across approach

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests", which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, cyclohexane (CAS No. 110-82-7) is selected as reference substance for assessment of ecotoxicological and toxicological endpoints, for which no methylcyclohexane data are available.

Similarity is based on:

(1) common functional group: Methylcyclohexane and cyclohexane share a 6-membered saturated alicyclic ring as a common molecular structure and are therefore allocated to the group of monocyclic hydrocarbons (cycloalkanes);

(2) common precursors and likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals: Methylcyclohexane and cyclohexane do not share a common precursor; however, both substances are produced by hydrogenation of the corresponding aromatic compounds toluene (see Section Manufacture and Use) and benzene (EC-ECB, 2004), respectively, which are in turn structurally similar substances. In general, methylcyclohexane and cyclohexane are likely to undergo the same chemical reactions characteristic of cycloalkanes, e.g. combustion to CO2 and H2O and halogenation (Breitmeier and Jung, 2005). The assessment of toxicokinetic behaviour indicates that both substances share a common main metabolic pathway, namely mono- and dihydroxylation of the alicyclic ring resulting in the respective isomers of methylcyclohexanol/-diol and cyclohexanol/-diol, followed by conjugation to the corresponding glucuronides (see Toxicokinetics); and

(3) constant pattern in the changing of the potency of the properties between substances: For methylcyclohexane and cyclohexane, the constant pattern is characterized by similarities in the potency of properties.

- Physicochemical properties:

Both substances show overall similar physico-chemical properties, being liquids, moderately volatile, lipophilic and slightly soluble in water. (see Section 4, Physical and chemical properties and EC-ECB, 2004).

- Environmental fate and ecotoxicological profile:

Methylcyclohexane and cyclohexane show similar properties in environmental fate and ecotoxicological profile: both substances are volatile, not bioaccumulative and show corresponding adsorption values (see section 5, Environmental fate and pathways and EC-ECB, 2004). Furthermore the available experimental data demonstrate that both substances exhibit a similar ecotoxicity profile. Both are acute very toxic to aquatic organisms (see Section 6, Aquatic toxicity and EC-ECB, 2004) with invertebrates and/or algae being the most sensitive organism groups. The available data on algae indicate a chronic toxicity potential with NOErC being 0.067 mg/L for methylcyclohexane and 0.94 mg/L for cyclohexane, resulting in chronic classification for both substances.

- Toxicological profile:

Methylcyclohexane and cyclohexane show similar toxicokinetic behaviour (see Section 7.1, Toxicokinetics). For those toxicological endpoints, for which both substances have been tested, similar levels of toxicity have been observed. Thus, both substances are of low acute toxicity via the oral and inhalation route, but fulfil the classification criteria for Aspiration toxicity (Category 1) and Narcotic effects (STOT-SE 3) according to Regulation (EC) No 1272/2008. Both substances were not skin and eye irritating in experimental studies, but are classified for Skin irritation (Category 2), mainly based on their defatting properties. Methylcyclohexane and cyclohexane have been extensively studied for repeated dose toxicity mainly via inhalation. For methylcyclohexane, the lowest chronic NOAEC for systemic effects is 400 ppm (1600 mg/m³) in rats, while for cyclohexane the most reliable subchronic systemic NOAEC in rats and mice is 2000 ppm (6880 mg/m³). Applying a time-extrapolation factor of 3 (ECHA, 2010), the chronic NOAEC for cyclohexane would be 667 ppm (2293 g/m³), which would be in the same order of magnitude as for methylcyclohexane. Both substances have been tested negative for mutagenicity in vitro.

Conclusion:

In order to avoid the need to test methylcyclohexane for every endpoint for which information gaps are identified, the read-across approach is applied for the assessment of environmental and human health hazards. Thus, environmental and human health effects are predicted where applicable from adequate and reliable data for cyclohexane by interpolation to methylcyclohexane in accordance with Annex XI, Item 1.5 of Regulation (EC) No 1907/2006.

A detailed justification for the read-across approach is provided in the technical dossier (see IUCLID Section 13).

References

Breitmaier, E. and Jung, G. (2005). Organische Chemie. Grundlagen , Stoffklassen, Reaktionen, Konzepte, Molekülstruktur. 5th ed. Georg Thieme Verlag, Stuttgart.

ECHA (2010). Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health. Source: European Chemicals Agency, http://echa.europa.eu/

EUROPEAN COMMISSION - European Chemicals Bureau (EC-ECB) (2004). European Union Risk Assessment Report: Cyclohexane; CAS No: 110-82-7; EINECS No: 203-806-2. European Chemical Bureau - Institute for Health and Consumer Protection.


Justification for selection of Effect on developmental toxicity: via inhalation route:
No study was selected, since the available studies in two different species provide both the same dose descriptor.

Toxicity to reproduction: other studies

Additional information

Methyl cyclohexane was tested in a subchronic toxicity study focusing on potential compound-related effects on the reproductive system (Kim et al., 2011; see Repeated dose toxicity). Groups of 5 male and female rats were exposed to methylcyclohexane at 10, 100 and 1000 mg/kg bw/day by subcutaneous injections, 5 days/week for 13 weeks. Concurrent vehicle control animals were treated with olive oil.

In regard to effects on reproductive organs, no changes in organ weights were observed in male and female animals dosed at 10, 100 and 1000 mg/kg bw/day, except for a decrease in the weight of ovaries in the high-dose female group.

No effects were observed in spermatogenic cell count and morphology at any dose level. In males, no effects were seen on the levels of prolactin, testosterone, follicle stimulating hormone and luteinizing hormone. A very slight but statistically significant and dose-dependent increase in estradiol levels was observed at 10 and 100 mg/kg bw/day. At the same dose levels, a significant decrease in progesterone levels was noted. The toxicological relevance of this finding is unclear, since no corresponding alterations were observed in testes at microscopic examination. No female data were reported. According to the authors, the hormone levels in females were dramatically changed in accordance with the estrous cycle. The menstrual cycle period was statistically significantly increased in the 4th week in the 10 mg/kg bw/day group, but this change was not dose-dependent. After the 13th week, no effects were observed.

The NOAEL for systemic toxicity was 100 mg/kg bw/day (see Repeated dose toxicity), while the NOAEL for effects on reproductive organs was 1000 mg/kg bw/day based on the reported findings.

Justification for classification or non-classification

Based on substance specific studies and read-across from the structurally similar reference substance cyclohexane,the available data on the reproductive toxicity of methylcyclohexane do not meet the criteria for classification according to Regulation(EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.