Isoheptane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There is no reproductive toxicity data available for Isoheptane. However, data is available for a structural analogues, commercial hexane and cyclohexane and presented in the dossier. This data is read across to Isoheptane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Commercial Hexane:

 

NOAEC for reproductive toxicity in rats = 9000 ppm (31680 mg/m³)

 

Cyclohexane:

 

NOAEC for reproductive toxicity in rats = 7000 ppm (24080 mg/m³)

Additionally, an OECD 443 test is proposed for a structural analogue, Hydrocarbons, C7-C9, isoalkanes (EC# 921-728-3). This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the study. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - with developmental neurotoxicity (Cohorts 1A, 1B without extension, 2A and 2B)

Data waiving:

other justification

Justification for data waiving:

other:

Justification for type of information:

The 'Justification for the read across' is provided in the 'Attached justification' section below.

Species:

rat

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

31 680 mg/m³

Study duration:

subacute

Experimental exposure time per week (hours/week):

30

Species:

rat

Quality of whole database:

Two key read across studies from structural analogues available for assessment.

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There is no reproductive toxicity data available for Isoheptane. However, data is available for a structural analogues, commercial hexane and cyclohexane and presented in the dossier. This data is read across to Isoheptane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

 

Commercial Hexane

 

In a reliable two generation reproduction study performed according to OECD 416, CD (Sprague Dawley) rats were whole body exposed to vapour of commercial hexane (API, 1991). Exposure to commercial hexane (approx. 52% n-hexane) was at 0, 900, 3000 or 9000 ppm for 6 h/day, 5 days/week during a 70 day (10 weeks) pre-mating period and the 21 day (3 weeks) mating period. Females were further exposed during gestation (GD 1-19) and lactation (LD 5 to weaning). The F1 generation was treated similarly but the pre-mating exposure was 8 weeks (56 days). Animal observations included mortality, clinical signs, food consumption, and body weight. Offspring were examined for body weight, survival, and viability. Both parental animals and offspring were sacrificed and examined for gross abnormalities. Histopathological examinations were conducted on adult animals.

 

Exposure to commercial hexane did not induce adverse effects on fertility. Reproductive indices were similar in exposed and control groups. No macroscopic or microscopic alterations in male and female reproductive organs were observed. The only significant effect was reduced body weight in the F1 and F2 generations in both sexes in the 9000 ppm exposure group both in adults and offspring.

 

The NOAEC for both male and female rats (adults and offspring) was 3000 ppm (corresponding to 10560 mg/m3). The LOAEC for these groups was 9000 ppm based on reduced body weight. There were no adverse effects on reproduction; therefore the NOAEC for reproduction is 9000 ppm which corresponds to 31680 mg/m³.

 

Cyclohexane

 

In a 2-generation inhalation reproduction study (Kreckmann et al. 2000), cyclohexane was administered to 30 Crl:CD BR rats /sex/dose at dose levels of 0, 500, 2000, or 7000 ppm. Whole body exposures were conducted, and animals were exposed 6 hours/day, 5 days/week including holidays. For both generations, animals were exposed prior to mating, and pregnant females were exposed daily during gestation days 0 through 20; exposure cessed from gestation day 21 until lactation day 4. Exposure resumed on lactation day 5 until litters were weaned. Males continued to be exposed 5 days/week until sacrificed. Neonates were not exposed during lactation. Pups were culled on lactation day 4; however, there were no additional details provided on the culling procedure.

 

Decreased sound stimulus observed in 2000- and 7000 -ppm animals (both sexes in both generations) was considered to be the most sensitive indicator of parental toxicity. This effect was an expected outcome of overexposure. Additional parental effects include decreased mean body weight and mean body weight gain in 7000 -ppm P and F1 rats. Decreased male body weights observed at 7000 ppm were considered to be an artefact of body-weight deficits established as pups. Although not established by the study authors, the parental systemic LOAEC appears to be 2000 ppm (6880 mg/m3) in males and females, based on decreased sound stimulus. The parental systemic NOAEC appears to be 500 ppm (1720 mg/m3) in males and females.

 

Mean pup weight was statistically significantly reduced from postpartum day 7 throughout the remainder of the 25-day lactation period for 7000-ppm F1 and F2 litters. The offspring LOAEC is 7000 ppm (24,080 mg/m3) based on decreased litter weights. The offspring NOAEC is 2000 ppm (6880 mg/m3).

 

There were no adverse treatment regarding reproductive function. Consequently, the reproductive NOAEC appears to be 7000 ppm (24,080 mg/m³).

 

This study received a Klimisch score of 1 and is classified as reliable without restriction because this study was performed in accordance with GLP and appeared to closely followed OECD 416.

 

Additionally, an OECD 443 test is proposed for a structural analogue, Hydrocarbons, C7-C9, isoalkanes (EC# 921-728-3). This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the study. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Effects on developmental toxicity

Description of key information

There is no developmental toxicity data available for Isoheptane. However, data is available for structural analogues commercial hexane; cyclohexane; and Hydrocarbons, C7-C9, isoalkane; and presented in the dossier. This data is read across to Isoheptane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Cyclohexane

 

Prenatal Developmental Toxicity Study (OECD TG 414): Rat - Inhalation Administration - The developmental NOAEC was determined to be 7000 ppm (21000 mg/m³).

 

Prenatal Developmental Toxicity Study (OECD TG 414): Rabbit - Inhalation Administration - The developmental NOAEC was determined to be >7000 ppm.

 

Commerical Hexane

 

Prenatal Developmental Toxicity Study (OECD TG 414): Rat - Inhalation Administration - The maternal and developmental NOAECs were greater than 9000 ppm (31680 mg/m³).

 

Prenatal Developmental Toxicity Study (OECD TG 414): Mouse - Inhalation Administration - The maternal and developmental NOAECs were greater than 3000 ppm (10560 mg/m³).

Hydrocarbons, C7-C9, isoalkanes

 

Prenatal Developmental Toxicity Study (OECD TG 414): Rat - Inhalation Administration - The developmental NOAEC was determined to be 1200 ppm.

Additionally, OECD Guideline 414 (Prenatal Developmental Toxicity) rodent and non-rodent species tests are proposed for structual analogue Hydrocarbons, C7-C9, isoalkanes. This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Data waiving:

other justification

Justification for data waiving:

other:

Justification for type of information:

The 'Justification for the read across' is provided in the 'Attached justification' section below

Species:

rat

Reference 2

Endpoint:

developmental toxicity

Data waiving:

other justification

Justification for data waiving:

other:

Justification for type of information:

The 'Justification for the read across' is provided in the 'Attached justification' section below.

Species:

rabbit

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

10 560 mg/m³

Study duration:

subacute

Species:

mouse

Quality of whole database:

Five key read across studies (Rodent and non-rodent) from structural analogues available for assessment.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

There is no developmental toxicity data available for Isoheptane. However, data is available for structural analogues commercial hexane; cyclohexane; and Hydrocarbons, C7-C9, isoalkane; and presented in the dossier. This data is read across to Isoheptane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Commercial Hexane

 

The potential developmental toxicity of commercial hexane was examined in two reliable studies performed according to OECD 414 with mice and rats, respectively (API, 1989a,b). Groups of pregnant female animals (30 CD-1 mice, 25 Sprague-Dawley rats) were whole body exposed to vapour of commercial hexane (approx. 52% n-hexane) at 0, 900, 3000, or 9000 ppm for 6 h/day during gestational days (GD) 6-15. Following exposure, animals were sacrificed on GD 18 (mice) or 21 (rats). During the study, animals were examined for clinical signs, mortality, food and water consumption, and body weight gain. After sacrifice, the internal organs were examined, and the uterus was examined for viable foetuses, number of resorptions, and number of corpora lutea. Foetuses were examined for malformations. Necropsy of mice revealed colour changes in the lungs of females in the 3000 and 9000 ppm groups. Foetuses from dams in the 9000 ppm group had a statistically significant increase in the incidence of some skeletal abnormalities. Rats showed colour changes in the lungs of females in the 9000 ppm groups along with reduced body weight gain, and reduced food consumption. No treatment-related abnormalities were seen in the foetuses.

 

The maternal NOAEC in mice was 900 ppm (3168 mg/m3), and the LOAEC 3000 ppm (10560 mg/m3) based on lung colour changes. The developmental NOAEC in mice was 3000 ppm (10560 mg/m3) and the LOAEC 9000 ppm (31680 mg/m3) based on skeletal abnormalities.

 

In rats, the maternal NOAEC was 3000 ppm (10560 mg/m3), and the LOAEC 9000 ppm (31680 mg/m3) based on lung colour changes, reduced body weight gain, and reduced food consumption. The developmental NOAEC in rats was 9000 ppm, corresponding to 31680 mg/m3.

 

Cyclohexane

 

A read-across study was identified on the developmental toxicity of rats and rabbits for cyclohexane (Kreckmann et al., 2000). Whole body exposures were used for both rats and rabbits at concentrations of 0, 500, 2000, or 7000 ppm. For rats in the 7000 ppm group, statistically significant reductions were observed in overall and adjusted maternal body weight gain while a transient diminished or absent response to a sound stimulus was apparent at 2000 ppm. Therefore the maternal no-observed-adverse-effect concentration (NOAEC) was 500 ppm (1720 mg/m3) (based upon transient sedation) or 2000 ppm (6880 mg/m3) (based upon significant reductions in overall and adjusted body weight gain). No compound-related evidence of developmental toxicity was observed at any test concentration, equivalent to a NOAEC of 7000 ppm (24,080 mg/m3). For rabbits, no compound-related maternal effects were observed at concentration levels of 7000 ppm and below. Therefore the maternal NOAEC for rabbits was 7000 ppm. No compound-related evidence of developmental toxicity was observed at any test concentration. The developmental NOAEC for rabbits was 7000 ppm (24,080 mg/m3), the highest concentration tested and the highest concentration permissible under national fire protection association standards.

 

Hydrocarbons, C7-C9, isoalkanes

 

A Segment II teratology study on hydrocarbons, C7-C9, isoalkanes, showed no evidence of embryonic or teratogenic effects in rats (ExxonMobil Chemical,1979). In this study, pregnant rats were exposed to 0, 400, or 1200 ppm for 6 h/day during gestational days 6 to 15. There was no mortality and no treatment-related effects to the dams. No treatment-related effects were observed in the number of live foetuses, foetal size, sex distribution, and external soft-tissue or skeletal examinations. Under the conditions of the study, there was no evidence of embryotoxicity or teratogenicity. The NOAEC for developmental toxicity was 1200 ppm, the highest dose tested.

 

Additionally, OECD Guideline 414 (Prenatal Developmental Toxicity) rodent and non-rodent species tests are proposed for Hydrocarbons, C7-C9, isoalkanes. This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies.

Justification for classification or non-classification

Based on the available substance specific and read across data from structural analogues, Isoheptane does not warrant classification as a reproductive or developmental toxicant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

 

Additional tests (OECD 443 and OECD 414 (rodent and 2nd species)) are proposed for Hydrocarbons, C7-C9, isoalkanes and will be conducted subsequent to ECHA's approval of the same. This endpoint will be updated upon completion of the above studies subject to ECHA's approval.