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Effects on fertility

Description of key information

KEY STUDIES READ ACROSS DATA:

Repeat-dose study with evaluation of estrous cycle and sperm morphology (OECD TG 413) - Stoddard Solven IIC - No adverse effect on sperm count, motility, morphology and testes weights in males. No adverse effect on estrous cycle in females.

NOAEC for fertility in males/females ≥2200 mg/m3 (highest dose tested).

READ ACROSS DATA: Repeat-dose study with evaluation of estrous cycle and sperm morphology (OECD TG 413) - Decalin - No adverse effect on sperm count, motility, morphology and testes weights in males. No adverse effects on estrous cycle in females. NOAEC for fertility in males/females ≥400 ppm (highest dose tested).

READ ACROSS DATA: JP-8 Fuel (C9-C16 Aliphatics, 25% aromatics) One-Generation Reproduction Toxicity Study (OECD TG 415) - Male Fertility Test – Oral Administration - 90d prior to mating, the NOAEL ≥3000 mg/kg/day, which was the highest dose tested. 

READ ACROSS DATA: JP-8 Fuel (C9-C16 Aliphatics, 25% aromatics) One-Generation Reproduction Toxicity Study (OECD TG 415) - Female Fertility Test – Oral Administration - the NOAEL ≥1500 mg/kg/day, which was the highest dose tested. 

SUPPORTING INFORMATION:

READ ACROSS DATA: C9-14 aliphatics (<2% aromatic) Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) – Oral Administration - The NOAEL for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day.

Reproduction / Developmental Toxicity Screening Test (OECD TG 421) - Oral Administration - The NOAEL for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day. 

Reproduction / Developmental Toxicity Screening Test (OECD TG 421) - Inhalation Administration - The NOAEL for developmental toxicity was ≥300 ppm (1720 mg/m3).

Additional information

The standard 2-generation reproductive toxicity requirements for C9 -C14 aliphatics (2 -25% aromatics) has been assessed with a combination of alternative tests that provide an equivalent level of information (i.e. 1-generation reproductive toxicity test/OECD TG 415 + repeat-dose toxicity tests that incorporate reproductive tissue evaluations such as sperm morphology, spermatogenesis and estrous cycle in females). Weight of evidence analysis of the overall reproductive toxicity testing strategy for category 3 solvents is attached in section 13 of IUCLID.

 

READ ACROSS DATA: JP-8 Fuel (C9-C16 Aliphatics, 25% Aromatics) 

There were several studies located for the structurally analogous test material, JP-8 fuel. JP-8 fuel was examined for reproductive toxicity in a 70-day male (plus an additional 20 -day mating period) and in a 90-day female one-generation reproductive toxicity study (OECD TG 415). For the male reproductive toxicity study, the reproductive NOAEL 3000 mg/kg/day for male rats, which was the highest dose tested. For the female reproductive toxicity study, the reproductive NOAEL 1500 mg/kg/day for female rats, which was the highest dose tested. The F1 (fetus) NOAEL = 750 mg/kg/day based on a decrease in body weight that correlated to a decrease in maternal body weight.

 

READ ACROSS DATA: Stoddard Solvent IIC (C9-C14 Aliphatics, 25% Aromatics) 

A 90 -day inhalation repeat-dose study (OECD TG 413) was located for this test substance. The study evaluated sperm parameters such as number of spermatid heads/testis, per gram testis, per cauda and per gram cauda and epididymal spermatozoal motility. Cauda, epididymis and testes were weighed also. Estrous cycle in females were evaluated. No adverse effects were noted for the assessed parameters. NOAEC for fertility in males and females was2200 mg/m3which was the highest dose tested.

 

READ ACROSS DATA: Decalin (C10 cyclics) 

A 90 -day inhalation repeat-dose study (OECD TG 413) was located for this test substance. The study evaluated sperm parameters such as number of spermatid heads/testis, per gram testis, per cauda and per gram cauda and epididymal spermatozoal motility. Cauda, epididymis and testes were weighed also. Estrous cycle in females were evaluated. No adverse effects were noted for the assessed parameters. NOAEC for fertility in males and females was400 ppm which was the highest dose tested.

 

READ ACROSS DATA: n-Butylbenzene

N-butylbenzene, a C10 aromatic hydrocarbon, was examined for toxicity in a two-generation reproductive toxicity study. N-butylbenzene was administered by oral gavage at dose levels of 0, 30, 100, and 300 mg/kg/day to male and female rats over 2 generations. n- butylbenzene did not induce reproductive toxicity in the F1 parental animals and no effects on the endocrine system were observed. Therefore, the NOAEL was determined to be 300 mg/kg bw/day.

 

READ ACROSS DATA: C9 aromatic naphtha

A three-generation reproductive toxicity test has been conducted on a complex C9 aromatic substance and no evidence of reproductive toxicity was found. F0 rats were exposed for 10 weeks prior and 2 weeks during mating to 0, 100, 500 or 1500 ppm(0, 505, 2430 or 7265 mg/m3) inhalation exposure for 6 hours/day, 5 days/week. Females were additionally exposed on gestation days 0-15 and lactation days 5-21. Exposures were continued through breeding of the F1 generation. No effects were reported on sperm morphology, gestational period, number of implantation sites, or post-implantation loss in any generation. The F2 generation exhibited a LOAEC of 103 ppm (505 mg/m3) based on reduced body weight and survival, while F0 and F1 generations had NOAECs of 495 ppm (2430 mg/m3) for these effects. Effects on Pups: A decrease was observed in F1 mid-dose body weights and F1 and F2 survival (F2: too few to evaluate for body weight due to poor survival in dams). No adverse developmental effects were reported in any generation at any exposure level. The reproductive NOAEC was 1480 ppm (7265 mg/m3), highest concentration tested.

 

SUPPORTING INFORMATION: C9-14 aliphatics (<2% aromatic) 

C9-14 aliphatics (2-25% aromatic) hydrocarbon fluids were examined for reproductive toxicity in a reproduction / developmental toxicity screening test (OECD TG 421). C9-14 aliphatics (2-25% aromatic) hydrocarbon fluids were administered by inhalation at a dose of 0,100, and 300 ppm to groups of rats. It was concluded that C9-14 aliphatics (2-25% aromatic) hydrocarbon fluids did not induce reproductive toxicity in the offspring or in the parental animals. Therefore, the NOAEL was determined to be 300 ppm (1720 mg/m3).

 

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids were examined for reproductive toxicity in a 28-day combined repeated dose toxicity study with the reproduction / developmental toxicity screening test (OECD TG 422).  C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids were administered oral gavage at a dose of 0, 25, 150, or 1000 mg/kg/day to groups of Sprague-Dawley rats. It was concluded that C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids did not induce reproductive toxicity in the parental animals and no effects on the endocrine system were observed.  Therefore, the NOAEL was determined to be 1000 mg/kg bw/day. 

 

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids were examined in a reproduction / developmental toxicity screening test (OECD TG 421).  C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids were administered by oral gavage at a dose of 0 (vehicle), 100, 300, 1000 mg/kg/day to groups of Sprague-Dawley rats. It was concluded that C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids did not induce reproductive toxicity in the parental animals and no effects on the endocrine system were observed.  Therefore, the NOAEL was determined to be 1000 mg/kg bw/day. 

 

Based on this study and the lack of systemic toxicity, C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids, are not expected to be reproductive toxicants.

Effects on developmental toxicity

Description of key information
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - C9-C12 normal, iso-, cyclics; 2-25% Aromatics. No treatment-related adverse effects to maternal and fetal development. NOAEC for maternal and developmental toxicity was > 300 ppm (highest dose tested).
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - C9-C11 Isoalkanes, cyclics; < 2% Aromatics. - There was no evidence of maternal or fetal toxicity at either exposure level of Hydrocarbons, C9-C11, normal, isoalkanes, cyclics, < 2% aromatics. Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (highest dose tested)
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - C9 aromatic naphtha. - Fetal effects were seen at the highest dose tested (1500 ppm) which also correlated with dose at which severe maternal effects (44% mortality) were observed. Both maternal and fetal NOAECs ranged from 100 to 300 ppm (500 – 1500 mg/m3).
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - JP-8 fuel - Fetal weights were reduced at the highest dose tested which was secondary to maternal toxicity. Overall NOAEL was 1000 mg/kg/day
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - C10-C12 Aromatic solvent. - No adverse fetal effects were noted at any dose level. Maternal NOAEL is 150 mg/kg/day (reduced body weights and food consumption) and the developmental NOAEL is greater than 450 mg/kg/day.
Additional information

READ ACROSS DATA: Hydrocarbons, C9-C12, n-, iso-, cyclics; 2-25% Aromatics

A segment II inhalation teratology study was conducted in Sprague-Dawley rats with a C8-C13 mixed aliphatic/aromatic solvent containing 19% aromatics (CAS RN 64742-82-1). In this study, pregnant female rats (20/dose group) were exposed to 0, 100, and 300 ppm of test material for 6 hours per day on days 6 through 15 of gestation. This study included a chamber-exposed negative control and an acetylsalicyclic acid positive control (400 mg/kg/day by gastric intubation from days 6 to 15). Parameters evaluated included the following: maternal mortality, pregnancy rate, body weight gain, physical observations and necropsy observations; corpora lutea and uterine implantation data; fetal size, sex ratios and ossification variation data; and fetal external, soft tissue and skeletal malformation data.

 

No mortality occurred during the study. No treatment-related physical observations were observed. Treated females gained more weight than chamber-exposed controls during the post-dosing interval. Pregnancy rates were comparable to chamber-exposed controls. The mean number of corpora lutea was significantly decreased in the 300 ppm dose group but was not considered to be a treatment-related effect since ovulation occurred prior to initiation of treatment. An increase in implantation efficiency was observed in treated groups but is not considered indicative of an adverse effect. The number of live fetuses, resorption sites and the incidence of dams with one or more resorption sites were comparable with controls. A few gross lesions were observed at necropsy but no treatment-related effects were indicated.

 

Mean crown-rump distances (both sexes) were considered comparable between the chamber-exposed and treated groups. Although some statistically significant differences were observed in crown-rump distances between these same groups, the differences were slight with no apparent dose-response pattern and were not considered to be treatment-related. Sex ratio was unremarkable. The incidence of fetuses with ossification variations was comparable to chamber-exposed controls. No treatment-related effects were observed for external, soft tissue and skeletal evaluations of fetuses recovered from treated females.

 

In summary, under the conditions of this test, the C8-C13 mixed aliphatic/aromatic solvent containing 19% aromatics was neither embryotoxic nor teratogenic in the rats. The NOAEC for maternal and developmental toxicity was 300 ppm.

 

READ ACROSS DATA: Hydrocarbons, C9-C11, n-, iso-, cyclics; < 2% Aromatics

A Prenatal Developmental Toxicity Study equivalent or similar to OECD Guideline 414 with Hydrocarbons, C9-C11, normal, isoalkanes, cyclics, < 2% aromatics (CAS RN 64742-48-9). The test material was administered to pregnant female Sprague-Dawley rats by inhalation exposure to vapor concentrations of 0, 300 or 900 ppm, 6 hours/day during gestation days 6 to 15 to assess developmental toxicity following guidelines similar to OECD 414. 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 gestation and fetuses examined for external, soft tissue and skeletal malformations.

 

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 variations are common as the time of normal ossification can vary and the frequencies of the variations were comparable to those of the variations 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 malformations 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 weights were significantly lower than the negative control and the percentage of resorbed fetuses was significantly higher than control. The incidence of fetuses with ossification variations 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.

 

Pregnancy rate, mortality, body weight gain and gross postmortem observations were unaffected by treatment. Hydrocarbons, C9-C11, normal, isoalkanes, cyclics, < 2% aromatics had no effect on reproductive endpoints, fetal size, sex distribution, ossification variations, or fetal examination endpoints.  Thus, there was no evidence of maternal or fetal toxicity at either exposure level of Hydrocarbons, C9-C11, normal, isoalkanes, cyclics, < 2% aromatics. Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (5220 mg/m3).

 

READ ACROSS DATA: C9 aromatic naphtha

The developmental toxicity of a C9 aromatic naphtha (mostly ethyl and trimethyl-benzenes) was evaluated in mice exposed to 0, 100, 500 and 1500 ppm from gestation days 6 -15. Delayed sternebral and cranial ossifications along with an increased incidence of cleft palate was noted. However, these effects were seen at the highest concentration tested (1500 ppm) which was associated with severe maternal toxicity (44% mortality), an indication that these defects are a result of maternal toxicity and not related to specific developmental toxicity of C9 aromatic naphtha. Both maternal and fetal NOAECs ranged from 100 to 300 ppm (500 – 1500 mg/m3).

 

READ ACROSS DATA: JP-8 Fuel (C9-C16 Aliphatics, 25% Aromatics)

JP-8, a less refined C8-C16 hydrocarbon stream with an approximate aromatic content of 22-25% can be used as a read across for mixed C9-C14 aliphatic solvents produced to narrower specifications. This substance was tested in a classical developmental toxicity test in Sprague-Dawley rats under a study design similar to OECD 414. Timed pregnant rats were given daily doses from days 6-15 of gestation at treatment levels of 0, 500, 1000, 1500 or 2000 mg/kg/day. The rats were sacrificed on gestational day 20 and the uterine contents were examined. The principal effects were maternal; 9/30 dams died in the high dose group and body weight gains were reduced in the 1000 and 1500 mg/kg/day groups. The maternal no effect level was 500 mg/kg/day. In the fetal examinations, there were no effects on fetal survival but fetal weights were reduced in the 1500 and 2000 mg/kg/day groups; secondary to maternal toxicity. There were no differences in rates of malformation or variations between groups. The overall developmental no effect level was 1000 mg/kg/day.

 

READ ACROSS DATA: C10-C12 Aromatic Solvent

In a developmental study, pregnant dams were dosed by oral gavage with 75, 150 or 450 mg/kg/day of a C10-C12 aromatic hydrocarbon solvent during gestational days 6 through 15. At 450 mg/kg/day, maternal body weight gain and food consumption were significantly decreased during the first three days of treatment. No adverse fetal effects were noted at any dose level. Thus, C10-C12 Aromatic fluids did not produce any fetal toxicity or any developmental effects in rats. Based on the study results, the maternal NOAEL is 150 mg/kg/day and the developmental NOAEL is greater than 450 mg/kg/day.

Justification for classification or non-classification

These findings do not warrant classification of C9-C14 aliphatic, 2 -25% aromatic hydrocarbon fluids as a reproductive or developmental toxin under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.