Butyl 2,3-epoxypropyl ether

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEC for fertillity was determined to be <140 mg/m3 based on a study performed with rats.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

See for more information the read-across justification attached to section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEC

Remarks:

fertility - rat

Effect level:

< 140 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Dose descriptor:

NOAEC

Remarks:

systemic toxicity - rat

Effect level:

943 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Dose descriptor:

NOAEC

Remarks:

fertility - mouse

Effect level:

>= 140 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Dose descriptor:

NOAEC

Remarks:

systemic toxicity - mouse

Effect level:

140 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Key result

Critical effects observed:

no

Dose descriptor:

NOAEC

Remarks:

rat

Generation:

F1

Effect level:

< 140 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Dose descriptor:

NOAEC

Remarks:

mouse

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

140 mg/m³ air

Treatment related:

yes

Relation to other toxic effects:

reproductive effects in the absence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

yes

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

140 mg/m³

Study duration:

subacute

Species:

rat

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Studies performed with n-Butyl Glycidyl Ethers (CAS 2426 -08 -6)

To evaluate the inhalation repeated dose toxicity of the test substance male rats were exposed (whole body) to fifty 7-hour exposures to 4 different vapor concentrations (38, 75, 150, or 300 ppm) (US EPA, 1957). The vapor concentrations were monitored at intervals ranging from twice daily to once weekly, by analysis of air drawn from the sampling port of each chamber. The vapor was absorbed from the air in pyridine, and reacted with pyridinium chloride; the amount of acid consumed was then measured. At 300 ppm, there were 5 deaths, all occurring between the twentieth and thirty-fifth exposures. At the level of 150 ppm, there was one death after 20 exposures. At 38 and 27 ppm, there were no deaths. A decrease in bodyweight gain was significant (p=0.05) in the 300 ppm group as well as in the 150 ppm groups. At lower doses there was no significant effect on bodyweight (gain) observed. At 150 ppm, surviving animals were without further signs of toxicity except that weight gain was retarded. The only significant difference in organ/body weight ratios occurred in the kidneys and lungs of rats in the 300 ppm group, which were heavier than those of the control group (p=0.05). The record of the organ weights for the 75 ppm group was lost in a laboratory accident, but it may be assumed that there were no differences, since there were none at 150 ppm. There were few gross pathological findings at necropsy, other than general decrease in body fat. One rat exposed to 150 ppm had tan discoloration of the thymus, and 2 others had small areas of atelectasis in the lung. One rat exposed to 300 ppm had a consolidated lobe in the lung.; one had atelectasis of a lobe; another had very small testes; and another a brown discoloration of the thymus. No abnormalities were seen in the other exposure groups. Atelectasis was the most common histopathological finding, appearing in the lungs of 4 controls and 18 of 35 experimental animals. Lung congestion was noted in 2 controls and 4 experimental animals. These lesions would not appear to be related to the treatment. There were no other findings among controls or animals exposed to 39 ppm. One animal exposed to 75 ppm had severe pneumonia and slight patchy atrophy of the testis. Five animals exposed to 150 ppm had bronchopneumonia. Three of the five survivors in the 300 ppm group had pneumonia; two of these had atrophic testes, and one had also focal liver necrosis. Both the other animals had atrophic testes and atelectasis of the lungs, and one had fecal liver necrosis. Based on the effects seen in the rat exposed to 75 ppm showing severe pneumonia and slight patchy atrophy of the testis the NOAEC was determined to be 38 ppm (0.20 mg/L).

Three dominant lethal assays were identified. Whorton et al (1983) conducted two dominant lethal studies with BDF hybrid mice. Males were 8-10 weeks old at the commencement of experiments and females were 8-10 weeks old when mated. Each male was mated with 3 virgin females per week beginning 2 weeks prior to administration of the test compound in order to determine fertility, litter size and frequency of spontaneous fetal deaths. Males of proven fertility were randomly assigned to the 3 treatment groups (0.375, 0.75, 1.5 g/kg) and the negative control. Due to its high lipophilicity, application resulted in rapid penetration of the skin without the occurrence of excess or runoff. Males were treated 3 times per week for a total of 8 weeks. Each male was weighed weekly, the group mean weight determined and the dosage adjusted accordingly. Following the last week of treatment, each male was mated to 3 virgin females per week for a total of 3 weeks. At autopsy, females were checked for total number of implants and fetal deaths. Following the final mating period, each male was sacrificed, and the testes were removed and preserved in Bouin's solution at a volume ratio of at least 10:1. After fixation, these testes were embedded in paraffin and cut on a rotary microtome. The sections were stained with hematoxylin eosin and assessed in blind pathological studies. No significant dose-related changes either in pregnancy rates or in average number of implants per pregnant female were found. Although a significant increase in fetal death rates was observed by the end of the first week after the highest dosage was administered, the results were not altogether conclusive. Moreover, analysis of the frequency and distribution of abnormal testicular cells revealed that there were no significant dose-related testicular changes, and that the number of altered cells was so low in every dosage group that it is unlikely that sperm count viability was affected.

A similar performed test was described in TSCATS document OTS0200451 (US EPA, 1978). To evaluate the potential in vivo genetic toxicity of the test substance the dominant lethal assay was performed on 10 male B6D2F1 mice of proven fertility. Only 1 dose level was assessed; 1500 mg/kg bw dermally. Approximately 15-20% of the surface area were clipped by electric shears in the dorsal area. The remaining hair was chemically depilated. Chemical depilation was only used as needed following the initial removal of hair and did not exceed one depilation per week. A minimum of 24 hours was allowed between chemical depilation and application of the test chemical and application of the test material. The group of males was weighed weekly, and the mean weight for each week was used to adjust the dosage. Following the treatment period, 3 untreated virgin females were randomly caged per treated male for one week. At the end of the first week the females were replaces with 3 other untreated virgin females for the duration of the second week. All females were sacrificed by cervical dislocation 13-14 days from the midweek of the caging and presumptive mating. In this study, there was a significant increase ( p=0.04) in the proportion deaths/pregnancy of the treated animals over the control animals. In addition there was a significant effects on the same variable due to time and a very time-treatment interaction, although not significant at the 0.05 level. Significant effects (p=0.01) were also detected in the number implants/pregnancy due to time and time-treatment dependency. The number of pregnant females in the BGE group was consistently lower than the control group and was significant with p=0.05.

In TSCATS documents OTS0206194 (US EPA, 1982) the same test was performed but, this time with three dose levels (37.5, 750, 1500 mg/kg bw. Pregnancy rate (PR) was calculated by first calculating the PR for each time period-dosage group males using the pregnancy status of three females per male. All males and females were included in the calculation and analysis of the variable. Statistical analysis was performed both for the PR as calculated for each male together with a re-expression of the PR as TPF=arc sin √PR. Average number of implants per pregnant female, IPF, was calculated for each time-does male by adding the number of implants for the pregnant females and dividing by the number of pregnant females. Proportion of dead implants (per pregnant female), DPMI, was calculated for each time-dose male by adding all deaths observed in all pregnant females and dividing by the total number of implants observed. Averaged Proportion of dead implants (per pregnant female), DPM2, was also calculated for each time-dose male by first calculating the proportion of dead implants per pregnant female and then averaging these resulting proportions. Averaged number of dead implants per pregnant female, DPF, was calculated for each time-dose male by adding the number of dead implants in all pregnant females and dividing by the resultant number of pregnant females. Results of the statistical analysis indicate that there is insufficient evidence to conclude that adverse effects due to increase dosage exist. While there was a weak suggestion of a highest dose effect at the post-treatment period 1 for the variable Averaged Proportion of dead implants (per pregnant female), this results could not be meaningfully distinguished from its corresponding saline control group. Also when tabulated in the form of percentage females in each does-time cell having one or more dead implant, data indicate that, although the 1500 mg/kg bw groups appears to result in a larger than expected number of females having one or more dead implant in the first post treatment period, the dead implant rate is not significantly elevated over the saline control group.

Studies performed with structural analogue Allyl 2,3 -epoxypropyl ether (CAS 106 -92 -3)

For studies of reproductive effects (NTP, 1990), groups of 20 rats of each sex were exposed to air containing the test item (AGE) at target concentrations of 0, 30,100, or 200 ppm for 6 hours per day, 5 days per week for 8 weeks. Groups of 20 mice of each sex were exposed to air containing the test item (source substance) at target concentrations of 0, 4, 10, or30ppm on the same schedule. Mating was begun 2 days after the end of the 8- week exposure period for the reproductive effects studies--controls with controls, exposed males with control females, and control males with exposed females. Animals cohabitated up to 7 days or until sperm were detected in the vaginal lavage of female rats or a vaginal plug was detected in female mice. Males were then separated from females. Three control mice and one mouse exposed to 10 ppm were removed from the study after becoming pregnant during the exposure period; three controls from the 13-week studies were substituted for the pregnant controls. All male animals were killed 13-14 days after the last allyl glycidyl ether exposure. Both cauda epididymides were removed from eight males of each species. Sperm were counted and examined for motility and for abnormalities. Females in which copulation was detected were separated into two groups. One group of mice was killed on day 17 of pregnancy, and one group of rats was killed on day 19 of pregnancy; rats in the second group, together with mated females for which copulation was not detected, were killed along with their pups on day 21 post-partum. Animals killed during pregnancy were weighed, necropsies were performed, and uteri and ovaries were removed and weighed. Corpora lutea were counted, and implantation sites were located. The number of live and dead fetuses and resorption sites were counted in each uterine horn. Fetuses were killed, weighed, and examined for sex and malformations. Pregnant animals were observed twice per day. On days 1and4after birth, the gender of pups was determined and pups were weighed and examined for external abnormalities. Dams were weighed on day 13 post-partum. At necropsy, ovaries and uteri of dams were removed, and corpora lutea and implantation sites were counted. A necropsy was performed on all animals. Based on the results of the experiment, the mating performance of exposed male rats was markedly reduced; however, sperm motility and number were not affected. The reproductive performance of males exposed to 200.0 ppm was found to be markedly impaired. Small but statistically significant reductions were seen in the number of corpora lutea per dam and in the number of implantation sites per dam in females exposed to 200 ppm. The number of implantation sites per dam were statistically significant reduced when the in groups where males were exposed starting from 30 ppm. The number of pregnant females was statistically significantly reduced in groups where males were exposed starting from 30 ppm. The number of live pups sired by any group of exposed males was significantly lower than that sired by controls. No deficiencies were seen in the reproductive performance of exposed female rats or male or female mice. The inhalation of the test item (source substance) apparently has little potential for direct effect on reproduction in mice. Based on this the NOAEC for reproductive performance was determined to be <140 mg/m3 (<30 ppm) and 140 mg/mg3 (30 ppm), for rats and mice respectively.

Overall conclusion

The results observed in the repeated dose toxicity study and the dominant lethal assays performed with the substance itself give an indication that the substance might be reproductive toxic. However, the evidence provided is not sufficient for classification. Based on similar and additional effects observed in the rat reproductive toxicity study performed with the structural analogue AGE a conclusion can be made that BGE is considered to be reproductive toxic. The NOAEC of <140 mg/m3 of AGE is adapted for BGE.

Effects on developmental toxicity

Description of key information

The NOAEC for developmental toxicity was determined to be <140 mg/m3 based on a study performed with rats.

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

Justification for type of information:

See for more information the read-across justification attached to section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEC

Remarks:

developmental toxicity - rat

Effect level:

< 140 mg/m³ air

Based on:

test mat.

Basis for effect level:

changes in number of pregnant

pre and post implantation loss

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Dose descriptor:

NOAEC

Remarks:

systemic toxicity - rat

Effect level:

943 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: overall effects

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Dose descriptor:

NOAEC

Remarks:

developmental toxicity - mouse

Effect level:

140 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: overall effects

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Dose descriptor:

NOAEC

Remarks:

systemic toxicity - mouse

Effect level:

140 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: overall effects

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Key result

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOAEC

Remarks:

rat

Effect level:

< 140 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

Remarks on result:

other: Result read-across source CAS No. 106-93-2

Remarks:

Correction for molecular weight not performed

Dose descriptor:

NOAEC

Remarks:

mouse

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

140 mg/m³ air

Treatment related:

yes

Relation to maternal toxicity:

developmental effects in the absence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

yes

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

140 mg/m³

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Read-across approach:

The test item has been assessed using a read across approach. The source susbstance selected is the Allyl 2,3-epoxypropyl ether (CAS 106 -92 -3) which is a structural analogue of the test item (target substance).

Summary of the study of the source substance:

For studies of reproductive effects (NTP, 1990), groups of 20 rats of each sex were exposed to air containing the test item (source substance) at target concentrations of 0, 30,100, or 200 ppm for 6 hours per day, 5 days per week for 8 weeks. Groups of 20 mice of each sex were exposed to air containing the test item (source substance) at target concentrations of 0, 4, 10, or 30 ppm on the same schedule. Mating was begun 2 days after the end of the 8- week exposure period for the reproductive effects studies--controls with controls, exposed males with control females, and control males with exposed females. Animals cohabitated up to 7 days or until sperm were detected in the vaginal lavage of female rats or a vaginal plug was detected in female mice. Males were then separated from females. Three control mice and one mouse exposed to 10 ppm were removed from the study after becoming pregnant during the exposure period; three controls from the 13-week studies were substituted for the pregnant controls. All male animals were killed 13-14 days after the last allyl glycidyl ether exposure. Both cauda epididymides were removed from eight males of each species. Sperm were counted and examined for motility and for abnormalities. Females in which copulation was detected were separated into two groups. One group of mice was killed on day 17 of pregnancy, and one group of rats was killed on day 19 of pregnancy; rats in the second group, together with mated females for which copulation was not detected, were killed along with their pups on day 21 post-partum. Animals killed during pregnancy were weighed, necropsies were performed, and uteri and ovaries were removed and weighed. Corpora lutea were counted, and implantation sites were located. The number of live and dead fetuses and resorption sites were counted in each uterine horn. Fetuses were killed, weighed, and examined for sex and malformations. Pregnant animals were observed twice per day. On days 1and4after birth, the gender of pups was determined and pups were weighed and examined for external abnormalities. Dams were weighed on day 13 post-partum. At necropsy, ovaries and uteri of dams were removed, and corpora lutea and implantation sites were counted. A necropsy was performed on all animals. Based on the results of the experiment, the mating performance of exposed male rats was markedly reduced; however, sperm motility and number were not affected. The reproductive performance of males exposed to 200.0 ppm was found to be markedly impaired. Small but statistically significant reductions were seen in the number of corpora lutea per dam and in the number of implantation sites per dam in females exposed to 200 ppm. The number of implantation sites per dam were statistically significant reduced when the in groups where males were exposed starting from 30 ppm. The number of pregnant females was statistically significantly reduced in groups where males were exposed starting from 30 ppm. The number of live pups sired by any group of exposed males was significantly lower than that sired by controls. No deficiencies were seen in the reproductive performance of exposed female rats or male or female mice. The inhalation of the test item (source substance) apparently has little potential for direct effect on reproduction in mice. Based on this the NOAEC for developmental toxicity was determined to be <140 mg/m3 (<30 ppm) and 140 mg/mg3 (30 ppm), for rats and mice respectively.

Justification for classification or non-classification

Based on the available information, the substance is classified as Repr. 2, H361 (Suspected of damaging fertility or the unborn child) in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.