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Key value for chemical safety assessment

Effects on fertility

Description of key information
Frog embryo teratogenesis assay: Xenopus (FETAX) (Dawson, 1996)
In a frog embryo teratogenesis assay performed according to a standard guide of ASTM (E1439-91) using isobutyric acid as test substance, a LC50 of 7925 mg/L and an EC50 (malformation) of 2567 mg/L was determined.
Supp. subst. isobutanol
Andrological measures (Fail/Res. Triangle Inst., 1996)
In one study, three anthrological measures were investigated (stage - the cycle of seminiferous epithelium - frequency and normalcy, number and concentration of testicular spermatides, number and concentrations of epididymal spermatozoa; Res. Triangle Inst. 1996). The results are defective, as the testes were damaged (compressed and flattend by pressure) during transport. Observations were not significant or invalid due to the distortion of the three-dimensional structure of the testes.
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
9 150 mg/m³
Additional information

Toxicity data has been read across primarily from isobutyric acid, which is the hydrolysis product of isobutyric anhydride. The hydrolysis is rapid, and thus the read-across is valid. A hydrolyis study is presented in section 5.1.2 of this dossier, and illustrates that at physiological pH the half life is between 5 and 10 minutes. This indicates that read-across to isobutyric acid is appropriate for all studies where water is present, as the anhydride will quickly hydrolyze to the acid.

For isobutyric acid, no study concerning reproductive toxicity could be identified. As substitute, data for isobutanol will be used based on following reasons (for detaild information on toxicokinetics/metabolism and justification of supporting substances see Section 7.1, endpoint summary).

 

After administration, isobutanol will rapidly be metabolized in vivo to isobutyraldehyde by alcohol dehydrogenases and subsequently to isobutyric acid by aldehyde dehydrogenases. In the course of metabolic transformation of isobutanol, isobutyric acid is generated rapidly and predominantly as intermediary metabolite. Thus, it is justified to use isobutanol as supporting substance in the evaluation of the systemic effects of isobutyric acid.

 

Effect levels derived for the supporting substance isobutanol will be converted to effect levels for isobutyric acid using the respective molecular weights. These values are used to evaluate the toxic potential of isobutyric acid.

Supporting substance: isobutanol

 

Toxicity to reproduction has been evaluated in one valid study of high reliability, which is used as key study (OPP/ACC, 2003).

 

In a valid 2-generation reproduction inhalation study under GLP, isobutanol (99.9%) was administered to groups of male and female Crl:CD(SD)IGS BR rats (30/sex/dose) by whole body exposure at dose levels of 0, 500, 1000 and 2500 ppm (0, 1476, 2952, and 7380 mg/m³). The animals were exposed 6 hours per day 7 days per week from the commencement of the study (F0 generation) or postnatal day 28 (F1 generation) until sacrifice after weaning of the pups (F0 generation postnatal day 28, F1 generation postnatal day 21). For dams, exposure was discontinued after day 20 of gestation until lactation day 5.

 

F0 and F1 parental survival were unaffected by isobutanol exposure in all exposure groups. No exposure-related effects were observed on F0 and F1 reproductive performance, body weights, food consumption and food efficiency in males or females. Spermatogenic endpoints were unaffected by exposure to isobutanol in all F0 and F1 exposure groups. There were no exposure-related macroscopic findings or changes in mean organ weights in the F0 or F1 males and females in all treatment groups. Microscopic evaluation of the F0 and F1 males and females revealed no isobutanol-related histopathologic lesions, including for animals that failed to breed or produce a litter.

 

No treatment-related effects on primordial follicle counts and corpora lutea counts were observed in the F1 2500 ppm group females (only group examined).

 

F1 and F2 pup survival and the general physical condition of the pups were unaffected by exposure to isobutanol. No treatment-related effects on mean pup body weights were observed in F1 or F2 pups. In addition, no macroscopic findings were observed in F1 or F2 pups that were found dead or euthanized at the scheduled necropsy. There were no isobutanol-related changes in mean organ weights for the F1 or F2 pups and no effects were seen on the maturation of the F1 pups.

 

The NOAEC of isobutanol for parental systemic, reproductive and neonatal toxicity is 2500 ppm (7700 mg/m³, maximum dose applied) in males and in females of the F0, F1 and F2 generation (OPP/ACC, 2003).

 

Deduction of the NOAEC for isobutyric anhydride

The NOAEC for isobutyric acid will be calculated on basis of the NOAEC of isobutanol (OPP/ACC, 2003) using the mass concentration/m³ and the respective molecular weights (88.11 and 74.12).

 

The deduced NOAEC (parentel systemic, reproductive and neonatal toxicity) for isobutyric anhydride is ca. 9150 mg/L (2500 ppm).


Short description of key information:
For isobutyric anhydride, no data on toxicity to reproduction could be located.
To compensate for this lack of data, information resulting from isobutanol as supporting substances will be used as substitute. Data are available for inhalation exposure.
In a 2-generation reproductive inhalation study in rats, isobutanol did not show any effects on fertility up to a concentration of 2500 ppm (7700 mg/m³) for the F0, F1 and F2 generation.
The NOAEL for isobutyric acid (conversion using the respective molecular weight) is 9150 mg/m³.

Effects on developmental toxicity

Description of key information
For isobutyric acid, no data on developmental toxicity/teratogenicity could be located.
To compensate for this lack of data, information resulting from isobutanol as supporting substances will be used as substitute. Data are available for inhalation exposure.
In a developmental toxicity inhalation study in rats, isobutanol did not exhibit treatment-related effects on maternal toxicity up to the highest dose applied (10,000 mg/m³). Similarly, no signs of treatment-related embryo-/fetotoxicity or teratogenicity were observed. Thus, the maternal and developmental NOAEC in rats was 10,000 mg/m³ (Klimisch/BASF, 1990).
For rabbits, the maternal NOAEC was determined to be 2500 mg/m³ while the developmental/teratogenic NOAEC was the same as for rats (10,000 mg/m³; Klimisch/BASF, 1990).
The developmental NOAEC for isobutyric acid (conversion using the respective molecular weight) is 11,890 mg/m³.
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
11 890 mg/m³
Additional information

For isobutyric acid, no study concerning developmental toxicity/teratogenicity could be identified. As substitute, data for isobutanol will be used based on following reasons.

 

After administration, isobutanol will rapidly be metabolized in vivo to isobutyraldehyde by alcohol dehydrogenases and subsequently to isobutyric acid by aldehyde dehydrogenases. In the course of metabolic transformation of isobutanol, isobutyric acid is generated rapidly and predominantly as intermediary metabolite. Thus, it is justified to use isobutanol as supporting substance in the evaluation of the systemic effects of isobutyric acid.

 

Effect levels derived for the supporting substance isobutanol will be converted to effect levels for isobutyric acid using the respective molecular weights. These values are used to evaluate the toxic potential of isobutyric acid.

 

Supporting substance: isobutanol

 

Developmental toxicity/teratogenicity has been evaluated in one valid study of high reliability, which is used as key study (Klimisch/BASF 1990). This study was performed using two species (rat and rabbit).

 

Data are presented for rats only because results for developmental toxicity are not different for the two species and rat is the species preferred according to OECD TG 414. Species differences were found for maternal toxicity (NOAEC 10000 mg/m³ for rats and 2500 mg/m³ for rabbits).

 

The developmental toxicity of isobutanol (purity 99.8%) was tested in an inhalation study in pregnant wistar rats. 25 female animals were exposed to vapors of isobutanol at concentrations of 0, 0.5, 2.5 and 10 mg/L for 6 hours/day from day 6 through 15 of gestation. All animals were killed on day 20 of gestation. The fetuses were removed and examined for compound-related effects.

 

There were no treatment-related effects on maternal toxicity (no mortality, no significant differences between controls and treated groups in clinical signs, body weight development, and gross pathology) even at the highest dose.

 

The maternal NOAEC in rats is 10 mg/L.

 

The fetuses did not exhibit any signs of treatment-related embryo-/fetotoxicity or teratogenic effects.

 

The developmental NOAEC in rats is 10 mg/L.

 

(Klimisch/BASF, 1990)

Toxicity to reproduction: other studies

Additional information

Frog embryo teratogenesis assay: Xenopus (FETAX) (Dawson, 1996)

In a frog embryo teratogenesis assay performed according to a standard guide of ASTM (E1439-91) using isobutyric acid as test substance, a LC50 of 7925 mg/L and an EC50 (malformation) of 2567 mg/L were determined. The DHI (Developmental Hazard Index) calculated to 3.1 indicating that the effective dose of isobutyric acid causing malformation was about 3-fold lower than the dose causing lethality. In general, the toxicity of isobutyric acid on frog embryos observed in the present test is relatively low.

 

The test system used is not comparable to in vivo developmental toxicity tests with mammals. Exposure, intake, distribution and metabolism do not match. It may be used for screening. But to decide under REACH about developmental toxicity effects of a test substance in humans, test procedures laid down in OECD or EU test guidelines on developmental toxicity have to be followed.

Justification for classification or non-classification

Based on read across results from the supporting substance Isobutanol, Isobutyric acid has not to be classified for reproductive toxicity.

Additional information

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