Hydrocarbons, C10-C12, isoalkanes, <2% aromatics

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

There is no substance specific data available for Hydrocarbons, C10-C12, isoalkanes, <2% aromatics. However, OECD 443 tests are proposed for structural analogues, Hydrocarbons, C7-C9, isoalkanes and isohexadecane. 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.

 

This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies. Additionally, an OECD Guideline 422 screening reproductive/developmental toxicity study (oral route) in rodents is planned with a structural analogue Hydrocarbons, C13-C16, isoalkanes, <2% aromatics (EC# 946-885-5).

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 study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

There is data available for Hydrocarbons, C10-C12, isoalkanes, <2% aromatics. Additionally, data is available for structural analogue, Hydrocarbons, C7-C9, isoalkanes, <2% aromatics. 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.

Hydrocarbons C7-C9, isoalkanes, <2% aromatics

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.

Hydrocarbons, C10-C12, isoalkanes, <2% aromatics

In a Segment II teratology study (ExxonMobil Corp., 1978), the test material (Hydrocarbons, C10-C12, isoalkanes, <2% aromatics) was administered to pregnant female rats by inhalation exposure to vapor concentrations of 300 or 900 ppm, 6 hours/day during gestation days 6 to 15 to assess developmental toxicity. Included in this study was a negative control (chamber exposed) group and a positive control group that was treated via gastric intubation on gestational days 6-15 with 400mg/Kg/day of acetylsalicylic acid.  All surviving females were sacrificed on Day 21 of testation and fetuses examined for external, soft tissue and skeletal malformations.  Pregnancy rate, mortality, body weight gain and gross postmortem observations were unaffected by treatment. Treatment at either dose level had no effect on reproductive endpoints, fetal size, sex distribution, ossification variation, or fetal examination endpoints. Thus, there was no evidence of maternal or fetal toxicity at either exposure level of the test material tested.  Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (>= 5220 mg/m³).

Additional OECD Guideline 414 rodent and non-rodent species tests are proposed for structural analogues, Hydrocarbons, C7-C9, isoalkanes, <2% aromatics and isohexadecane. 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

Type of information:

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

Adequacy of study:

key study

Study period:

September 1978 - Dezember 1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study meets generally accepted scientific principles, acceptable for assessment, limited documentation.

Justification for type of information:

The justification for read across is provided as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

other: Food and Drug Administration 1966 "Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use", Segment II (Teratology Study).

Deviations:

yes

Remarks:

Administration via inhalation route

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: CD (SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Labs, Inc., Wilmington, Mass. 01887
- Age at study initiation: 9 wks
- Fasting period before study: no
- Housing: individually (except during mating)
- Diet (e.g. ad libitum): Standard Laboratory diet (Purina Lab Chow), fresh food presented as needed, except during each 6-hour exposure.
- Water (e.g. ad libitum): Automated water system (Elizabethtown Water Company), except during each 6-hour exposure.
- Acclimation period: 18 days


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

not specified

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 cubic meter exposure chamber
- Method of holding animals in test chamber: no data
- Method of conditioning air:
- Temperature, humidity, pressure in air chamber: room temprature, dried air
- Method of particle size determination: not applicable

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

No details given.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: no, males from in-house colony
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

GD6 - 15

Frequency of treatment:

6 hours/day

Duration of test:

until GD21 (all surviving dams), until day 21 postmating (all surviving non-pregnant females)

No. of animals per sex per dose:

20 females

Control animals:

yes, sham-exposed

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: mortality, gross signs of toxicologic or pharmacologic effects


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: GD 0, 6-15, and 21


BODY WEIGHT: Yes (including calculation of Body Weight Change)
- Time schedule for examinations: GD 0, 6-15, and 21


POST-MORTEM EXAMINATIONS: Yes, all females
- Sacrifice on gestation day # 21
- Organs examined: appendix containing the data was missing

OTHER:
Dams showing signs of abortion or premature delivery were sacrificed and fetuses obtained 19 days or later were processed and examined for skeletal anomalies. Only grossly abnormal fetuses obtained earlier than GD19 weresaved for possible future examination.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes (evidence of implantation, but no recognizable fetus)
- Number of late resorptions: Yes (recognizable dead fetus undergoing degeneration)
- Dead fetuses: Yes (dead fetus with no visible degeneration)
- Live fetuses

Fetal examinations:

- External examinations: Yes: all fetuses (weight, crown-rump distance from the parietal-interparietal suture to the base of the tail, malformations, sex based upon anogenital distance)
- Soft tissue examinations: Yes: two-thirds of fetuses (gross dissection and examination of viscera including internal sex determination)
- Skeletal examinations: Yes: two-thirds of fetuses (malformations and ossification variations)
- Head examinations: No data

Statistics:

Comparisons between negative and positive control and between negative control and each test substance-treated group were made where applicable (incidence data) by the chi-square method or by the F-test and Student's t-test (absolute data). When variances differed significantly, Student's t-test was appropriately modified using Cochran's approximation (t'). Mean number of live fetuses, resorptions, implantations and corpora lutea were compared to control by the one-tailed t-test.

Details on maternal toxic effects:

Maternal toxic effects:no effects

Key result

Dose descriptor:

NOAEC

Effect level:

1 200 ppm (nominal)

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Key result

Dose descriptor:

NOAEC

Effect level:

1 200 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: teratogenicity

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

A) Maternal data:

Pregnancy rates were comparable between the negative control and the treated groups. No mortality occurred in the negative control and the treated groups. Mean body weight gain during the pre-dosing and the dosing intervals were comparable between negative control and treated groups, during the post-dosing interval mean weight gain was statistical significant higher in the treated groups.

Physical observations:

No indication of a treatment effect. Likewise, the data were generally comparable between the negative and the positive control groups.

Reproduction data:

Mean number of corpora lutea, implantation sites, live fetuses, resorption sites, and the incidence of dams with one or more resorption sites were comparable between the negative control and the treated groups.

Implantation efficiency values were slightly higher in the treated groups than in the negative control, in some instances differences were statistically significant, however, this was not considered indicative of an adverse effect.

In contrast, in the positive control group the mean number of live fetuses was significantly decreased and the mean number of resorption sites significantly increased compared to the negative control. Likewise, the incidence of dams with two or more resorptions was also significantly higher than in the negative control group. The mean number of corpora lutea, implantations, and the implantation efficiency value were comparable between the positive and negative control groups.

Gross postmortem examinations:

Few gross lesions were observed at necropsy of treated females (not further specified), no treatment-related effect was indicated.

B) Fetal data:

Mean fetal weights and mean crown-rump distances of both sexes were comparable for negative control and treated groups, while in the positive control group they were significantly lower. Mean numbers of male and female fetuses were comparable between negative control and treated groups. Likewise, sex ratio data was comparable for these groups. In contrast, the mean numbers of male and female fetuses in the positive control group were significantly lower compared to the negative control, due to lower numbers of fetuses in this group.

Variations in degree of ossification:

These variations may represent delays in the ossification process or slight ossification irregularities. The incidences of fetuses with ossification variations was comparable between negative control and the 400 ppm-treated group. In the 1200 ppm-treated group the incidence of fetuses with at least one ossification variation was significantly higher compared to the negative control. The incidence of litters containing fetuses with ossification variations was comparable between negative and treated groups. Likewise, the types and incidences of ossification variations were generally similar between the negative control and the treated groups.

In contrast, in the positive control group the incidence of fetuses with at least one variation was significantly higher, ossification was retarded.

Teratology data:

No treatment-related external, gross evisceration, soft tissue and skeletal malformations were observed in the fetuses of the treated and the negative control group. One late resorption from one female of the 400 ppm group showed extreme edema, however, no other unusual observations were noted in the other late resorptions of treated and negative control groups. In contrast, in the positive control group, external malformations were noted in 14.4 % of the fetuses, the most common symptom was craniorachischisis with protruding tongue and clubbed forelimbs. The incidences of soft tissue malformations were comparable between the negative control and the treated groups, no treatment-related effect was indicated. In the positive control group, these incidences were significantly higher than in the negative control.

Conclusions:

Under the design of the study the test substance, hydrocarbons, C7-C9, isoalkanes, produced no negative effects.

Executive summary:

Under the design of the study the test substance, hydrocarbons, C7-C9, isoalkanes, produced no negative effects.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented study report which meets basic scientific principles

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Conducted according to the Food and Drug Administration 1966 "Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use", Segment II (Teratological Study)

GLP compliance:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breading Laboratories
- Age at study initiation: females (58 days); males (sexually mature)

- Housing: individually except during mating
- Diet (e.g. ad libitum): ad libitum (food removed during exposure period)
- Water (e.g. ad libitum): ad libitum (water removed during exposure period)

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Details on exposure:

Appropriate amounts of test material were transferred from a reservoir using a metering pump into a heated flask and flash evaporated. A stream of clean air was also passed through the flask and the vapor laden air transferred to a port in the chamber air inlet, where it was diluted with normal chamber intake air to give the desired concentration. Adjustments in the exposure air concentration were made by changing the rate of the flow of test material through the metering pump.

The stainless steel and glass exposure chambers and an effective exposure volume of 760 liters. They were operated dynamically at a flow rate of approximately 125 liters per minute. This provided one air change every 8 minutes and a 99% equilibrium time of 39 minutes.

Atmospheric sampling was performed using a Wilks Scientific Corp Miran IA Ambient Air Analyzer (long pathlength infrared). The infrared spectrum of the test material was measured and a strong band associated with the test material was observed at 3.4 microns. Calibration curves relating the absorption at this wavelength to the airborne concentration of the test materials were prepared. On each exposure day, three samples were drawn from each exposure chamber and the exposure concentration calculated by comparing the absorption of this sample to the standard curve.

Postive control animals were treated via gastric intubation on gestational days 6-15 with 400mg/kg/day of acetylsalicylic acid in 0.5% methocel.

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

All females selected for mating were placed with male rats nightly in a 2:1 ratio. Vaginal smears were taken early in the morning and females were considered to have mated if sperm and/or a vaginal plug was observed. The day on which evidence of mating was first observed was established as Day 0 of gestation for that animal. Mated females were assigned to groups by daily body weight gain in an attempt to equalize Day 0 mean group body weights.

Duration of treatment / exposure:

Females were exposed on gestation days 6-15 by inhalation 6h/day

Frequency of treatment:

daily gestation days 6-15

Duration of test:

Day 6 of gestation ranged from 23 January-3 February 1978
Day 15 of gestation ranged for 1-12 February 1978

Remarks:

Doses / Concentrations:
300 ppm
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
900 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

Negative control (Chamber air)- 20 mated females
Postive control (acetylsalicylic acid)-20 mated females
300 ppm- 21 mated females
900ppm- 21 mated females

Control animals:

yes, sham-exposed

other: positive control treated with 400mg/kg/day acetylsalicylic acid

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6-15, and 21 of gestation



POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: uterus (number and location recorded for each horn of the following: live fetuses, dead fetuses, late resorptions, early resorptions, implantation sites); ovaries (number of corpora lutea per ovary)

Fetal examinations:

All fetuses were weighted, crown-rump distance measured, examined externally for malformations and sex determined externally (anogenital distance)
- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes
- Skeletal examinations: Yes: [2/3 of litter ]
Fetuses designated for skeletal evaluation were eviscerated prior to initiation of the skeletal staining procedure. During the evisceration step the visceral contents of the thoracic and abdominal cavities were evaluated grossly in situ and sex was determined by internal inspection of gonads. Examination of skeleton for anomalies and ossification variations was performed after staining.
- Neural and Visceral defects: Yes: [1/3 of litter]

Statistics:

Comparisons between the negative control and treated groups and between the negative control and positive control groups were made where applicable by the chi-square method. Body weights, body weight gains, numbers of corpora lutea, implantations, resorptions, fetuses per dam, fetal and litter weights and crown-rump distances were compared to control by the F-test and Student’s t-test. When variances differed significantly, Student’s t-test was appropriately modified using Cochran’s approximation.

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Animals treated with 900 ppm exhibited a slight increase in excessive lacrimation during the treatment and post-treatment periods. This same group also exhibited an increased incidence of brown flakes in the fur covering the head area during the treatment period. Premature delivery of the litter on Day 21 of gestation prior to maternal sacrifice was observed in one negative control female, and two test material treated females. There were no remarkable gross postmortem changes in the treated adult females. All other physical observations occurred with similar frequencies in all groups and were considered to represent common observations noted in rats in the laboratory environment.

Positive control animals demonstrated statistically significant decreased body weight gain. Females had in utero litters containing fewer live fetuses and more resorption sites than untreated control litters. The implantation efficiency value was significantly reduced and the incidence of dams with two or more resorptions was increased.

Key result

Dose descriptor:

NOAEC

Effect level:

>= 5 220 mg/m³ air (nominal)

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
All fetal survival, size and sex data for groups treated with test material were considered comparable to negative control data. Slight delays or variation in the normal ossification process were observed in treated animals. However such variation are common as the time of normal ossification can vary and were comparable to the variation observed in the control animals. The incidence of fetuses with external malformations and incidences of litters containing malformed fetuses in the groups treated with test material were considered comparable to the control data. No significant difference in the incidence of visceral malformations was observed in the treated groups. The incidence of fetuses with soft tissue malformation in groups treated with test material was comparable to the negative control.

In the positive control group, the percentage of live fetuses and mean fetal size data were significantly lower than the negative control and the percentage of resorbed fetuses was significantly higher than control. The incidence of fetuses with ossification variation was significantly higher than the control value. The incidence of fetuses with soft tissue malformations was significantly higher in the positive control treated group than the negative control.

Key result

Dose descriptor:

NOAEC

Effect level:

>= 5 220 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Developmental Toxicity

Key result

Abnormalities:

not specified

Key result

Developmental effects observed:

no

Conclusions:

There was no evidence of maternal or fetal toxicity at either exposure level of MRD-77-43 tested. Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm(>= 5220 mg/m^3).

Executive summary:

MRD-77-43 was administered to pregnant female rats by inhalation exposure to vapor concentrations of 300 or 900 ppm, 6 hours/day during gestation days 6 to 15 to assess developmental toxicity.  Included in this study was a negative control (chamber exposed) group and a positive control group that was treated via gastric intubation on gestational days 6-15 with 400mg/kg/day of acetylsalicylic acid.  All surviving females were sacrificed on Day 21 of testation and fetuses examined for external, soft tissue and skeletal malformations.  Pregnancy rate, mortality, body weight gain and gross postmortem observations were unaffected by treatment.  MRD-77-43 treatment at either dose level had no effect on reproductive endpoints, fetal size, sex distribution, ossification variation, or fetal examination endpoints.    Thus, there was no evidence of maternal or fetal toxicity at either exposure level of MRD-77-43 tested.  Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (>= 5220 mg/m³).

Reference 3

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 4

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:

no adverse effect observed

Dose descriptor:

NOAEC

5 220 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

1 key read across study from a structural analogue and 1 substance specific weight of evidence study available for assessment

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on available data, Hydrocarbons C10-C12 isoalkanes, <2% aromatics 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). However, further tests (OECD 443 and OECD 414 (rodent and 2nd species)) are proposed 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.