Cyclopentane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There is no data available for cyclopentane. However, data is available for a structural analogue, cyclohexane and presented in the dossier. This data is read across to cyclopentane 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:

 

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

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

24 080 mg/m³

Study duration:

subacute

Experimental exposure time per week (hours/week):

30

Species:

rat

Quality of whole database:

One key read across study from a structural analogue available for assessment.

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There is no reproductive toxicity data available for cyclopentane. However, data is available for a structural analogue, cyclohexane and presented in the dossier. The literature justifies the use of the read-across approach to fill toxicokinetics and reproductive toxicity gaps for cyclopentane using data on cyclohexane.There is a dearth of literature on the toxicokinetics of cyclopentane, but information from its structural analog, cyclohexane, may be used. There is no evidence that cyclohexane is ring-opened, and it is assumed that the toxicokinetics of cyclopentane and cyclohexane are similar.  Therefore, data on the toxicokinetics and reproductive toxicity of cyclohexane can be used to fill data gaps for cyclopentane when relevant data for this chemical is missing. This data is read across to cyclopentane 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

 

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.

.

Effects on developmental toxicity

Description of key information

There is no data available for cyclopentane. However, data is available for structural analogues, pentane and cyclohexane and presented in the dossier. This data is read across to cyclohexane 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:

 

NOAEC for developmental toxicity (Rat): 7000 ppm (24080 mg/m³)

NOAEC for developmental toxicity (Rabbit): 7000 ppm (24080 mg/m³)

 

Pentane:

 

NOAEL for developmental toxicity: 1000 mg/Kg bw/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1996-07-25 to 1997-04-11

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable without restriction because it is was performed according to GLPs and in compliance with OECD principles 414.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD BR VAF/Plus

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, Michigan
- Age at study initiation: 14 to 16 weeks (females)
- Weight at study initiation: 243 to 316 grams (females)
- Fasting period before study: no
- Housing: individually-housed except during mating in suspended stainless-steel, wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24
- Humidity (%): 40 to 70
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

- IN-LIFE DATES: From: 1996-10-07 To: 1996-11-08

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test material formulations were prepared weekly by mixing appropriate amounts of test material with vehicle; test-material formulations were divided into individual samples for each day and stored in a refrigerator until needed.

VEHICLE
- Justification for use and choice of vehicle (if other than water): test material was soluble in carrier
- Concentration in vehicle: not reported
- Amount of vehicle (if gavage): not reported
- Lot/batch no. (if required): not reported
- Purity: not reported

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Test material formulations were evaluated for stability, homogeneity, and achieved concentration. Stability and homogeneity were evaluated prior to the start of the study as part of the dose-range finding study (Study no. 157533; achieved concentration was evaluated on the first and third dosing mixture preparations. Results from the dose-range finding study indicate that the test material formulations were stable for at least 7 days at 2% and 20% w/v and homogenous (with the relative standard deviation being 1% for both sample sets). Test material formulations were found to be within 16% of the nominal concentration.

Details on mating procedure:

- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: not reported
- Females were placed in cage with male. After confirmation of mating, each female was returned to its own cage. New females were then placed in the males' cages until the required number of mated females was obtained by continuous cohabitation in consideration of lab scheduling.
- Further matings after two unsuccessful attempts: not reported
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug and/or sperm in vaginal rinse referred to as day 0 of pregnancy

Duration of treatment / exposure:

gestation day (gd) 6 though 15

Frequency of treatment:

daily

Duration of test:

IN-LIFE DATES: From: 1996-10-07 To: 1996-11-08

Remarks:

Doses / Concentrations:
0, 100, 500, or 1000 mg/kg/day
Basis:
nominal conc.
Dosing volumes were 5 mL/kg and based on the most recent individual body weights

No. of animals per sex per dose:

25 dams per group

Control animals:

yes

Details on study design:

- Dose selection rationale: A dose-range finding study (Study no. 157533), in which rats were dosed with n-pentane via gavage at levels of 0, 250, 500, 750, and 1000 mg/kg. Maternal signs of toxicity were observed at 1000 mg/kg and included decreased body weight gain and food consumption over the treatment period and overall gestation interval; no other signs of toxicity were observed in dams or fetuses.
- Rationale for animal assignment (if not random): Mated females were assigned to dose groups in the order of mating.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily during treatment and at least once daily at other times during the study

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily during gestation

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 9, 12, 15, 18, and 21

FOOD CONSUMPTION: Yes
- Time schedule for examinations: gd 0, 6, 9, 12, 15, 18, and 21

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: Ovaries

OTHER: Surviving dams and those that delivered prior to scheduled necropsy were scarified by carbon dioxide asphyxiation and exsanguination. Dams that delivered prior to scheduled necropsy were examined for gross lesions, and the number of implantation sites or concepti in each horn was counted. Surviving dams were necropsied, and uterine weight with ovaries attached was recorded. Uteri of all non-pregnant females were stained with ammonium sulfide to confirm pregnancy status.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: yes
Examinations included:
- Gravid uterus weight: yes
- Number of corpora lutea: yes
- Number of implantations: yes
- Number of early resorptions: yes
- Number of late resorptions: yes
- Other: location of implantations

Fetal examinations:

- External examinations: yes: all per litter (number of live and dead fetuses was counted; fetuses were weighed, sexed, and examined for gross malformations)
- Soft tissue examinations: yes: half per litter
- Skeletal examinations: yes: half per litter
- Head examinations: yes: half per litter

Statistics:

Statistical methods used are presented in the table below. Statistical evaluation of equality of means was conducted by a one-way analysis of variance and a test for ordered response in dose groups. Equal variances were evaluated by Bartlett's test. Equal variances were then tested using parametric methods, otherwise nonparametric techniques were used. Percentages, where appropriate, were calculated and transformed by Cochran's transformation, followed by the arc sine transformation. Both raw and transformed percentages were tested for statistical significance. The Bartlett's test was conducted at the 1% level of significance; all other tests were conducted at the 5% and 1% level of significance.

Indices:

preimplantation loss
postimplantation loss

Historical control data:

not provided

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
There were no treatment-related changes in mean body weight, body weight gain, uterine weight, corrected body weight, food consumption, or uterine implantation data. There were no treatment-related mortalities or clinical signs of toxicity.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Key result

Abnormalities:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no treatment-related changes in growth or increased fetal death. There were no changes in total malformations or variations.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: Developmental Toxicity

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

^a Data obtained from pages 28 -29 in the study report.

Cesarean section observations^a
Observation	Dose (mg/kg bw/day)
	0	100	500	1000
No. Animals assigned (mated)	25	25	25	25
No. Animals pregnant	24	25	23	25
Pregnancy rate (%)	96	100	92	100
No. Nonpregnant	1	0	2	0
Maternal wastage
No. died	0	0	0	0
No. Died pregnant	0	0	0	0
No. Died nonpregnant	0	0	0	0
No. Aborted	0	0	0	0
No. Premature delivery	1	1	0	0
Corpora lutea/Dam	15.26±1.63	15.88±1.68	15.43±1.78	15.68±2.21
Implantations/Dam	14.52±1.70	14.88±2.33	14.83±1.83	15.16±2.32
Total No. litters	23	24	23	25
Total number of live fetuses Live fetuses/Dam	310 13.48±1.78	346 14.42±2.26	318 13.83±2.19	359 14.36±2.29
Total number of dead fetuses Dead fetuses/Dam	0 0.0±0.0	0 0.0±0.0	0 0.0±0.0	0 0.0±0.0
Total No. resorptions	24	11	23	19
Early	22	11	23	18
Late	2	0	0	1
Resorptions/Dam	1.04±0.98	0.46±0.59	1.00±0.95	0.76±0.83
Early	0.96±0.98	0.46±0.59	1.00±0.95	0.72±0.84
Late	0.09±0.29	0.0±0.0	0.0±0.0	0.04±0.20
Litters with total resorptions	0	0	0	0
Mean fetal weight (g)	0	0	0	0
Males	5.34±0.38	5.45±5.40	5.40±0.44	5.42±0.46
Females	5.13±0.40	5.12±0.37	5.21±0.37	5.14±0.55
Sex ratio (% male)	49	49	47	50
Preimplantation loss (%)	4.6±7.8	6.3±12.5	4.0±5.3	3.5±4.7
Postimplantation loss (%)	7.1±6.5	3.0±3.7	7.0±7.0	5.3±5.6

^a Data obtained from pages 32 -34 and 73 -167 in the study report.

 

External examinations^a
Observations^b	Dose (mg/kg bw/day)
	0	100	500	1000
No. Fetuses (litters) examined	309 (23)	346 (24)	318 (23)	359 (25)
No. Fetuses (litters) affected with variations	0 (0)	0 (0)	0 (0)	0 (0)
No. Fetuses (litters) affected with malformations	0 (0)	0 (0)	1 (1)	1 (1)

^a Data obtained from pages 35 in the study report.

^b Some observations may be grouped together.

^c Fetal (litter) incidence

 

Visceral examinations^a
Observations^b	Dose (mg/kg bw/day)
	0	100	500	1000
No. Fetuses (litters) examined	156 (23)	172 (24)	161 (23)	178 (25)
No. Fetuses (litters) affected with variations	0 (0)	3 (2)	2 (2)	1 (1)
No. Fetuses (litters) affected with malformations	4 (3)	7 (4)	2 (2)	9 (6)

^a Data obtained from page 35 in the study report.

^b Some observations may be grouped together.

^c Fetal (litter) incidence

 

Skeletal examinations^a
Observations^b	Dose (mg/kg bw/day)
	0	100	500	1000
No. Fetuses (litters) examined	154 (23)	174 (24)	157 (23)	181 (25)
No. Fetuses (litters) affected with variations	27 (14)	31 (13)	25 (13)	44 (17)
No. Fetuses (litters) affected with malformations	0 (0)	0 (0)	1 (1)	0 (0)

^aData obtained from page 35 in the study report.

^bSome observations may be grouped together.

^cFetal (litter) incidence

Conclusions:

There were no signs of maternal toxicity at any dose level. There were no treatment-related changes in mean body weight, body weight gain, uterine weight, corrected body weight, food consumption, or uterine implantation data. There were no treatment-related mortalities or clinical signs of toxicity. The maternal NOAEL is 1000 mg/kg/day.

There were no signs of developmental toxicity at any dose level. There were no treatment-related changes in growth or increased fetal death. There were no changes in total malformations or variations. The developmental NOAEL is 1000 mg/kg/day.

Executive summary:

In a developmental toxicity study, n-pentane was orally administered via gavage to 25 Crl:CD BR VAF rats per dose at dose levels of 0, 100, 500, or 1000 mg/kg bw/day from days 6 through 15 of gestation.  There were no signs of maternal toxicity at any dose level.  There were no treatment-related changes in mean body weight, body weight gain, uterine weight, corrected body weight, food consumption, or uterine implantation data.  There were no treatment-related mortalities or clinical signs of toxicity.  A maternotoxic dose was not used.  However, the highest dose tested was 1000 mg/kg/day, and no adverse effects were observed.  In general, the highest dose tested does not need to exceed 1000 mg/kg/day unless potential human exposure data indicate the need for higher doses.  Therefore, the study reported a maternal NOAEL of 1000 mg/kg/day.  

 

There were no signs of developmental toxicity at any dose level. There were no treatment-related changes in growth or increased fetal death. There were no changes in total malformations or variations. The developmental NOAEL is 1000 mg/kg/day.

 

This study received a Klimisch score of 1 and is classified as reliable without restriction because it was performed according to GLPs and in compliance with OECD principles 414.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

One key oral read across study from a stuctural analogue available for assessment.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

24 080 mg/m³

Study duration:

subacute

Experimental exposure time per week (hours/week):

30

Species:

other: Rat and Rabbit

Quality of whole database:

One key rodent and one key non-rodent read across inhalation study from a stuctural analogue 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 cyclopentane. However, data is available for structural analogues, pentane and cyclohexane and presented in the dossier. The literature justifies the use of the read-across approach to fill toxicokinetics and reproductive toxicity gaps for cyclopentane using data on cyclohexane. There is a dearth of literature on the toxicokinetics of cyclopentane, but information from its structural analog, cyclohexane, may be used. There is no evidence that cyclohexane is ring-opened, and it is assumed that the toxicokinetics of cyclopentane and cyclohexane are similar. Therefore, data on the toxicokinetics and reproductive toxicity of cyclohexane can be used to fill data gaps for cyclopentane when relevant data for this chemical is missing. This data is read across to cyclopentane 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

 

In a key study (Kreckmann et al., 2000), the developmental toxicity of cyclohexane was assessed in Crl:CD BR rats. The animals were exposed whole-body to nominal atmospheric concentrations of 0, 500, 2000, or 7000 ppm cyclohexane vapour. 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 (1,720 mg/m³) (based upon transient sedation) or 2000 ppm (6,880 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).

 

In a second key study (Kreckmann et al., 2000), the developmental toxicity of cyclohexane was assessed in rabbits. No compound-related evidence of maternal or developmental toxicity was observed at any test concentration. Therefore the maternal NOAEC for rabbits was 7000 ppm and the developmental NOAEC for rabbits was also 7000 ppm (24,080 mg/m³), the highest concentration tested and the highest concentration permissible under national fire protection association standards.

 

Pentane

 

In a developmental toxicity study (ExxonMobil, 1997), the test material (n-pentane) was orally administered via gavage to 25 Crl:CD BR VAF rats per dose at dose levels of 0, 100, 500, or 1000 mg/Kg bw/day from days 6 through 15 of gestation. There were no signs of maternal toxicity at any dose level. There were no treatment-related changes in mean body weight, body weight gain, uterine weight, corrected body weight, food consumption, or uterine implantation data. There were no treatment-related mortalities or clinical signs of toxicity. A maternotoxic dose was not used. However, the highest dose tested was 1000 mg/Kg/day, and no adverse effects were observed. In general, the highest dose tested does not need to exceed 1000 mg/Kg/day unless potential human exposure data indicate the need for higher doses. Therefore, the study reported a maternal NOAEL of 1000 mg/Kg/day.  

 

There were no signs of developmental toxicity at any dose level. There were no treatment-related changes in growth or increased fetal death. There were no changes in total malformations or variations. The developmental NOAEL is 1000 mg/Kg/day.

 

This study received a Klimisch score of 1 and is classified as reliable without restriction because it was performed according to GLPs and in compliance with OECD principles 414.

Justification for classification or non-classification

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