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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No data were located for dimethylbutylamine. Therefore, cross reading from data on related substances was made as follows:

Dimethylamine Hydrolchloride

A test with mice and DMA hydrochloride was performed by Guest et al. (1991): Test concentrations: 0.25, 1, 2.5 and 5.0 mmol/kg bw ( 11.3, 45.1, 112.7, 225.4 mg/kg bw).

The NOAEL for maternal toxicity was 225.4 mg/kg bw based on the absence of any adverse findings at this dose, and for developmental toxicity, including teratogenicity, the NOAEL was 112.7 mg/kg bw based on the absence of any adverse findings at this dose.

According to Lichtenberger et al. (1991), DMA concentration was over all similar when comparing the data obtained from womens milk investigated during a period of up to 15 days postnatal, additionally the presence of DMA in the amniotic fluid from 1.23 ppm in the 26 gestational week, to 2.32 in the 36 week, to 1.75 ppm in the 39 week, to 0.91 ppm to the 41 week, to 2.32 ppm in the 41.5 week and to 0.83 ppm in the 42 week.

n-butanol

There were few experimental data available with partly restricted information value to assess the toxicity to reproduction of Butan-1-ol. Additionally, relevant data are available from the analogous substances isobutanol and n-butyl acetate. Altogether, results indicate a low potential of Butan-1-ol to affect reproduction negatively.

In a reliable developmental neurotoxicity study, two concentrations of butan-1-ol (3000 and 6000 ppm = ca. 9.25 and ca. 18.5 mg/L) were administered by inhalation to separate groups of 15 pregnant Sprague-Dawley rats for 7 hr per day throughout gestation; 18 male rats were similarly exposed for 7 hr per day for 6 weeks, and mated to unexposed females (Nelson et al. 1989). Females were allowed to deliver. The offspring from these two groups were then observed for 90 d for signs of developmental neurotoxic effects. No general maternal or paternal toxicity was reported. Male or female exposure had no effect on pregnancy rate. Therefore, the NOAEL for the P/paternal and F1 generation is >= 18.5 mg/L.

Female rats (own breeding) were given aqueous solutions of n-butanol containing 0.24, 0.8 and 4% n-butanol (300; 1000 and 5000 mg/kg/day) for 8 weeks before and during gestation (Sitarek et al. 1994). The experiment was performed in two stages. The first comprised of the assessment of the oestrous cycle before exposure and then during 4-5 and 7-8 weeks of exposure, and the second stage of the fertility of female rats (11-17 per dose) and their foetal development. Clinical signs, body weights, estrous cycles, organ weights, hemoglobin concentrations, hematocrit values, fetal body weights, intrauterine mortality, corpora lutea, total implants and placental weights were unaffected due to the treatments. The NOAEL for the P/maternal is >= 5000 mg/kg bw.

In a GLP conform subchronic toxicity study, effects on reproductive organs (testes with epididymes, ovaries) were studied after oral application of up to 500 mg of butan-1-ol /kg bw for 13 weeks in male and female Sprague-Dawley rats (US EPA 1986). Effects on organ weights or histopathological changes were not observed. For further details, see chapter "repeated dose toxicity".

Butylacetate

Following absorption Butylacetate is rapidly cleaved and liberates butanol which is further metabolised to butyric acid, i.e. the same metabolite that may result from N,N-dimethybutylamine. Data for this ester may therfore be used for cross reading to N,N-dimethylbutylamine. The effect of Butylacetate on reproduction was examined in a GLP 2 -generation guideline inhalation study (OECD 416) where male and female Sprague-Dawley rats were exposed to 0, 750, 1500, or 2000 ppm for 6 hours per day, 7 days per week. There were no functional effects on reproduction (estrous cycles, mating and fertility indices, number of days between pairing and coitus, spermatogenic endpoints and gestation length) in any test article-exposed group in the F0 or F1 generations. General systemic toxicity was evident in the 1500 and 2000 ppm group F0, F1and F2 adult males and females. Decrements in mean body weights, body weight gains and food consumption were observed at 1500 and 2000 ppm. Degeneration of the olfactory epithelium in the nasal cavity was noted at 750 and 2000 ppm in F0 and F1 males and females (endpoint not investigated at 1500 ppm). This finding was considered to be a site-of-contact irritant effect and not indicative of systemic toxicity.

Therefore, the NOAEC values were 750 ppm for systemic toxicity and 2000 ppm for fertility (Nemec, 2010).


Short description of key information:
No data were located for N,N-dimethylbutylamine (DMBA). Therefore, cross reading from data on n-Butanol, n-Butylacetate und dimethylamine was made, for RAC justification please refer to section 7.1.
None of the supporting chemicals does produce adverse effects on fertility in the absence of parental local or systemic toxicity. This result may be read across to DMBA.

Justification for selection of Effect on fertility via oral route:
No data were located for N,N-dimethylbutylamine (DMBA). Therefore, cross reading from data on n-Butanol, n-Butylacetate und dimethylamine was made, for RAC justification please refer to section 7.1.

Justification for selection of Effect on fertility via dermal route:
No data were located for N,N-dimethylbutylamine (DMBA). Therefore, cross reading from data on n-Butanol, n-Butylacetate und dimethylamine was made, for RAC justification please refer to section 7.1.

Effects on developmental toxicity

Description of key information
No data were located for N,N-dimethylbutylamine (DMBA). Therefore, cross reading from data on n-Butanol, n-Butylacetate  und dimethylamine was made, for RAC justification please refer to section 7.1.
Dimethylamine Hydrochloride
The NOAEL for developmental toxicity, including teratogenicity, the NOAEL was 112.7 mg/kg bw based on the absence of any adverse findings at this dose (Guest et al., 1991).
n-Butanol:
oral, rat, gestation day 1-19: NOAEL maternal and fetotoxicity = 1454 mg/kg bw; NOAEL teratogenicity >= 5654 mg/kg bw (Ema et al. 2005)
inhalation, rat, gestation day 1-19: NOAEL maternal and fetotoxicity = 10.8 mg/L; NOAEL teratogenicity = 24.7 mg/L (Nelson et al. 1989)
oral, rat, up to 7/8 weeks before and during mating: NOAEL maternal and teratogenicity >= 5000 mg/kg bw (Sitarek et al. 1994)
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

n-Butanol:

Results from valid experimental studies showed no indication, that Butan-1-ol caused fetotoxic or teratogenic effects in doses below maternal toxic doses in rats. Results from an inhalation study in rabbits with the analogous Butyl acetate, CAS No. 123-86-4, support this assessment in a second species.

 

In a GLP conform study according to a Japanese guideline, 20 pregnant rats per dose were given drinking water containing 1-butanol at 0.2%, 1.0% or 5.0% (corresponding to ca. 316, 1454 or 5654 mg/kg/day) on days 0 to 20 of pregnancy (Ema et al. 2005). The rats were sacrificed on day 20 of pregnancy and both the dams and fetuses were examined. A significant decrease in maternal body weight gain accompanied by reduced food and water consumption was found at 5.0%. No significant increase in the incidence of pre- and postimplantation embryonic loss was observed in any groups treated with 1-butanol. Fetal weight was significantly lowered at 5.0%. Although a significant increase in the incidence of fetuses with skeletal variations and decreased degree of ossification was found at 5.0%, no increase in the incidence of fetuses with external, skeletal and internal abnormalities was detected in any groups treated with 1-butanol. The data demonstrate that 1-butanol is fetotoxic only at maternal toxic doses. No evidence for teratogenicity of 1-butanol was noted. Based on the significant decreases in maternal body weight gain and fetal weight, it is concluded that the no observed adverse effect levels (NOAELs) of 1-butanol for both dams and fetuses are 1.0% (1454 mg/kg/day) in rats.

 

In another study, groups of 15-18 female Sprague-Dawley rats were exposed at 8000, 6000, 3500, or 0 ppm (24.7, 18.5 or 10.8 mg/L) 1-butanol, for 7 hr/day on Gestation Days 1- 19 (sperm detection = day 0; Nelson et al. 1989). Dams were sacrificed on Gestation Day 20, and fetuses were individually weighed, tagged, and examined for external malformations. One-half of the fetuses were stained and examined for skeletal abnormalities, and the other half were examined for visceral defects using the technique. 8000 ppm produced narcosis in approximately one-half of the dams.  Two of eighteen dams at 8000 ppm died during the exposure period. Food consumption was decreased in the 6000 and 8000 ppm exposed dams. Foetal weights were slightly decreased at 6000 and 8000 ppm groups. External foetal malformations were not observed. There were no differences in malformation rates (skeletal or visceral) or in rates of commonly observed variations. However, there was a slight increase in the percent of fetuses with any skeletal variation or malformation (mainly rudimentary cervical ribs) in the 8000 ppm group but not in the lower two exposure groups. The NOAEL for teratogenicity is 24.7 mg/L and the NOAELs for dams and fetuses are 10.8 mg/L.

 

In the study of Sitarek et al. (1994, described above), there was a slight increase in the percent of fetuses with any skeletal variation or malformation (mainly rudimentary cervical ribs) in the 8000 ppm group but not in the lower two exposure groups .The interpretation of the results is difficult. The unit of statistical analysis in this study was the individual foetus, not the litter. The authors considered the recorded developmental effects (dilatation of the brain ventricles/spaces or renal pelvis, internal hydrocephalus, wavy or extra ribs) as being related to butan-1-ol and assessed these findings as variations or delayed development commonly seen in large historical control databases. Of significance, the incidence of all but one of the reported developmental effects in the actual control population was 0%. In the MARTA-MTA 1995 database, using Crl:CD BR rat, the incidence of "cerebral ventricle, enlargement" was 2%/foetus or 4.4%/litter, and the incidence of "renal pelvis, dilated" 0.95%/foetus or 5.2%/litter (Wise and Petrere, 1996) . The "malformations" reported that were assessed as "variations" in other databases should be classified based on the incidence within the rat strain. The incidence of variations within the rat strain used in this study is unknown, since the authors used a rat strain common only to their laboratory. The laboratory diet was also unique. Since the strain of rat and type and quality of diet can have profound effects on rates of variations and malformations, and since there is no historical database available for the strain tested, the term "variation" has to be assigned with reservation. However, the term may still be appropriate since the variations reported are also common in several frequently used rat strains. In fact, Nelson et al (1989) described some of these variations following inhalation exposure to butan-1-ol. It should not be surprising that high oral doses of butan-1-ol that alter normal maternal physiology would also cause an increase in common variations in laboratory rodents. Thus, the developmental effects seen by Sitarek et al (1994) cannot be regarded as a selective foetal effect. The NOAEL for maternal toxicity and teratogenicity is considered to be >= 5000 mg/kg bw.

In the behavioural teratogenicity study described above (Nelson et al. 1989), there were no behavioural teratogenic effects found in rats in doses up to 18.5 mg/L (6000 ppm).


Justification for selection of Effect on developmental toxicity: via oral route:
No data were located for N,N-dimethylbutylamine (DMBA). Therefore, cross reading from data on n-Butanol, n-Butylacetate und dimethylamine was made, for RAC justification please refer to section 7.1.

Justification for selection of Effect on developmental toxicity: via inhalation route:
No data were located for N,N-dimethylbutylamine (DMBA). Therefore, cross reading from data on n-Butanol, n-Butylacetate und dimethylamine was made, for RAC justification please refer to section 7.1.

Justification for selection of Effect on developmental toxicity: via dermal route:
No data were located for N,N-dimethylbutylamine (DMBA). Therefore, cross reading from data on n-Butanol, n-Butylacetate und dimethylamine was made, for RAC justification please refer to section 7.1.

Justification for classification or non-classification

No classification proposed, based on read across of data from supporting substances and structural analogues.