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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
853 mg/kg bw/day
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
30 400 mg/m³
Additional information

There are no data available for the reaction mass. The lowest NOAEL for fertility for the oral route, being the one from isopropanol and the inhalatory NOAEC of 30400 mg/m3 for fertility from ethanol will be taken as worst case value for the reaction mass.

Ethanol:

All available studies on ethanol use extremely high doses.  Some establish NOAELs and clearly are the most useful, whilst others do not establish NOAELs at such very high doses.  Clearly, the most useful studies are those that are closer to guideline (in terms of observations and number of dose levels used) and those that establish true NOAELs at the lowest doses.  Such studies are given greater weight in the overall interpretation of the data for this end point.

The most reliable study performed to the most appropriate protocol and the one given the greatest weight as well as the key study is a two-generation study investigated the effects of 5%, 10% and 15% ethanol in drinking water in reproduction and fertility. Male and female CD-1 mice were continuously treated for 1 week prior to mating and for a 14 week breeding period followed by a 21 day holding period when they were separated and housed individually. The F1 offspring of the 15% ethanol pairs had fewer live pups per litter but ethanol treatment had no effect on the proportion of breeding pairs producing at least 1 litter during the continuous breeding phase or the number of litters per pair. The F1 offspring from the 15% group had decreased bodyweight at weaning and mating, and a decreased weight of testis, epididymides and seminal vesicles which was no longer evident when these were adjusted for body weight. There was also a significantly decreased percentage motile sperm but no changes in sperm concentration, and percentage of abnormal sperm or tailless sperm. When reproductive performance of F1 control and 15% ethanol-treated breeding pairs was assessed at 74 days of age, there was no significant difference in mating and fertility between the groups. However, adjusted live pup weight for the ethanol group was significantly reduced compared to controls which was likely due to generalized maternal toxicity.

All other available studies are incomplete in comparison to guidelines (usually either single sex treatment or truncated exposures. However, in total, they provide useful additional information.

In a fertility study, male Sprague-Dawley rats were exposed 7 hours per day for six weeks to 10,000 or 16,000ppm ethanol by inhalation and then mated with untreated female rats. Pregnant females received the same experimental treatment from day 1 -19 of gestation and were allowed to deliver their offspring. Treatment with ethanol did not affect the weight gain of parental animals. Incidence of fertility did not differ from controls and no group differences were found for litter size, number of dead pups, or length of pregnancy. Offspring survival and weight gain was also not affected by ethanol treatment. Adult male rats were kept in a chamber providing 22, 23, 25, or 27 mg/l ethanol air concentrations continuously for a 4 to 5 weeks period. At the end of the exposure period the animals were sacrificed and plasma testosterone levels and sex organ weights for testis, seminal vesicles and prostate were determined. Blood ethanol levels of = 130mg/100ml were compatible with adequate body weight and not associated with diminished plasma testosterone levels or reduced sex organ weights, whereas blood ethanol levels >=180 mg/100ml were associated with inhibition of testosterone secretion only in those animals who failed to grow.  No adverse fertility effects were seen at the maximum dose, although weight loss was seen from 25mg/l and above.

Male rats were exposed to 6% v/v ethanol containing liquid diet (providing 35% of calories) which was increased to 10% after 1 week (58% of dietary calories), estimated as 7.2 -14.4g/kg/day. After two weeks they were paired with untreated females during the hours of darkness when they had no access to food or drink. The treatment with ethanol for males continued during the hours of light for 5 weeks. All pregnancies were terminated on day 20 of gestation. Ethanol treated animals showed signs of intoxication and weight loss compared to controls from the start of the study, suggesting a LOAEL6% for such effects. The treatment with ethanol reduced the number of successful matings, litter number, and increased the incidence of early resorptions compared to controls.  Male rats were administered 2.5 or 5g/kg ethanol daily by gavage for 3 weeks or 9 weeks. Animals in the 2.5 g/kg and control groups were pair fed to those in the 5 g/kg group. Males were bred once after 3 weeks of treatment and twice after 9 weeks of treatment. Females in the first two breedings were sacrificed on day 20 of gestation and their offspring examined. Females in the third breeding were allowed to deliver their litters. There were no apparent treatment effects on resorptions or litter size. Fecundity was reduced in females bred to the high dose ethanol-treated males when all breedings were pooled. The number of male fetuses was increased in the high dose ethanol treated group. There was a significant dose related increase in fetal weights at the week 3 and 9 breedings and a significant increase in placental weights at the 9 week breedings. However, there were no treatment related effects on newborns sired by ethanol treated males. The main finding and only finding consistent and repeated across both breedings was an increase in fetal weights of offspring sired by alcohol treated males. It is not clear if this is an adverse toxicological finding. Male adult rats were given a liquid diet with 36% of the daily calories derived from ethanol (approximately 13.6 g/kg bw/day), an isocaloric control diet, or standard laboratory chow, for 55 days. Reproductive function was assessed in two separate studies, following either natural mating, or with artificially inseminated females. Ethanol treatment impaired sexual behaviour, and only 22% of these rats reached ejaculation (compared with 50 and 70% in isocaloric and lab-chow controls, respectively). Fertility of ethanol-treated animals was significantly reduced, mainly following the natural matings. Ethanol treatment at this dose also significantly reduced serum testosterone levels, daily sperm production, and epididymal sperm count, associated with an acceleration of the sperm transit time in the cauda epididymis, decrease in sperm motility and increase in the percentage of abnormal shaped sperm cells.

Male mice were exposed to a nutritionally balanced diet providing 10% or 25% of ethanol-derived calories and mated with untreated females for 4 hours a day sequentially for 7 weeks. No toxic responses were noted in treated males other than decreased bodyweight gain at 25% ethanol-derived calories in diet. Paternal treatment did not affect fertility during the period studied nor litter size, or weight at birth or at weanling. The 25% dose is equivalent to 21.5g/kg ethanol. Male mice were treated with a diet containing 5% or 6% ethanol for 10 weeks and 5 weeks, respectively. After treatment with ethanol was completed, animals were hemicastrated (right testis and accessory organs) and were then left in an ethanol-free diet for 10 weeks to determine the recovery of reproductive effects. The treatment with ethanol diet induced a decrease in testicular weight and in seminal vesicle/prostate weight which was reversible at the end of 10 week treatment abstinence. Significant increases in frequencies of germ cell desquemation and of inactive seminiferous tubules were observed and these remained elevated except for the inactive seminiferous tubule levels in the 5% group which returned to control levels. Ethanol treatment affected the quality of spermatogenesis, caudal epididymal sperm content, sperm motility and in vitro fertilization of mouse oocytes but the changes disappeared after following 10 weeks abstinence. Forward progression of sperm was reduced in both treatments but persisted in the 6% group. No NOAEL was established (5% ethanol diet, 166mg% BAL). However, for persistent effects the NOAEL would appear to be close to 5% ethanol diet, which is estimated to be ~14g/kg/day.

Twenty-day old female rats were administered 2.5% or 5% ethanol in a liquid diet for period of 50 -55 days during which their oestrous cycle was determined. At the end of the treatment ovaries, uteri and vaginae were excised for histological examination. Ovarian function was suppresed only in the animals that received 5% ethanol as manifested by absence of oestrous cycles, a delay in vaginal opening, the absence of several generations of corpora lutea, inhibition of growth of the uteri and vaginae, and a reduction of ovarian and uterine weights. A NOAEL was established of approximately 8g/kg/day. Twenty eight-day old female rats were fed a liquid diet providing 36% ethanol-derived calories (5% of a liquid feed) or a pair-fed isocaloric diet for 49 days. This dose is estimated to be in the range 5.4 -11.4g/kg/day. At the end of the exposure period the animals were sacrificed and the uterus, fallopian tubes, ovaries, cervix, vagina and liver were macro- and microscopically examined. Ethanol-treated animals experienced a reduced weight gain compared to controls whilst their livers were larger and of fatty appearance. Serum liver enzymes, alkaline phosphatase, glutamic oxalo-acetic-acid-transaminase, glutamic pyruvic transaminase and gamma glutamyl transpeptidase were significantly increased compared with controls. Ethanol treatment reduced the weight of the ovaries, uterus and fallopian tubes compared with pair-fed isocaloric control group. Histological examination revealed differences in the appearance of uterus, cervix and vagina between treated and untreated animals, and absence of developing follicles, corpus lutea and corpus hemorrhagica in the ovaries of the treated animals. Compared with isocaloric controls, plasma estradiol and progesterone were reduced in ethanol-treated animals, whereas significantly higher plasma estrone levels were observed. Female rats were fed 5% ethanol in a liquid diet for 16 weeks, or for 8 weeks followed by laboratory chow and water for another 8 weeks. (Doses equivalent to 14 -21g/day and estimated to produce average serum ethanol levels of around 250mg%). Pair-fed controls and ad libitum fed controls were also included in the study. Vaginal patency was significantly delayed in the ethanol groups and irregular and longer oestrous cycles were noted in the 16-week ethanol treated group. After 16 week treatment females were mated with untreated males and their ethanol exposure was stopped till they delivered their litter. No adverse effect on fertility, litter size or neonatal bodyweight was detected.

Isopropanol:

The reproductive toxicity of isopropanol (IPA) was assessed in a GLP-compliant study equivalent to the OECD test guideline 415 (one-generation reproduction toxicity study). Wistar rats were administered IPA at concentrations of 0 (tap water), 1.25, or 2.0% in drinking water (Faber, 2008). Based on water intake, these dose concentrations corresponded to IPA dose levels of 383, 686, and 1107 mg/kg bw/day during the premating period; and 347, 625, and 1030 mg/kg bw/day for 18 weeks of treatment in males. In females, IPA intake was calculated to be 456, 835, and 1206 mg/kg bw/day during the premating period; 668, 1330, and 1902 mg/kg bw/day during the gestation period; and 1053, 1948, and 2768 mg/kg bw/day during the post partum phase. F0 Generation:There were no mortalities, abortions, or early deliveries reported. Adult male food consumption was decreased in all dose groups compared to controls. This corresponded with decreased body weights in the 2.0% dose group, and a transient slight decrease in body weight in animals treated with 0.5 and 1.0% IPA. Water intake was decreased in male rats treated with IPA; however, intake returned to normal levels in the 0.5% group. Food consumption also was decreased in adult females treated with 1.0 and 2.0% IPA; however, decreases noted in the 1.0% group had recovered by the second day of gestation. Body weights in IPA-treated adult females were lower than those reported for the control group at the start of gestation, but had recovered during gestation except in the 2.0% group. Following parturition, body weights for all dose groups were initially similar to controls; however, decreased body weights were noted in the 2.0% dose group on and after post-natal day 4. Water consumption was initially decreased in females treated with 1.0 and 2.0% IPA, but had returned to control levels in the 1.0% IPA group by the third day of treatment.

A slight-dose dependent decrease in red blood cells in the 2.0% group adult males and 1.0 and 2.0% adult females was noted. For males, a slight increase in mean cell volume in the mid- and high-dose groups was observed. Increased absolute and relative kidney weights, and relative liver and spleen weights were noted in high-dose F0males. Statistically significant increased absolute liver and kidney weight, and relative liver weight were noted in the 2.0% F0females.

There were no effects of IPA exposure on fertility. The number of pups per litter on post-natal day 1 was decreased in the 2.0% group. This increase was attributed to the cannibalism of the pups by the Dam and decreased pup survival, as a decrease in litter size was not observed in the embryotoxicity study. In the embryotoxicity study, increased preimplantation loss, a decrease in mean litter weight, and a decrease in mean fetal body weight was noted in the 2.0% group.

F1 Generation: Average pup weight was decreased in the 2.0% group on post-natal day 7. Increased mean relative liver weight was reported in F1males and females at the 2.0% dose level. High-dose F1males also had higher relative kidney weights. Slight increases in absolute brain weight and increased relative empty caecum weight were noted in high-dose F1males and females. There were no gross abnormalities noted in the F1generation at necropsy.

Based on a review of the data it is proposed that the NOAEL for parental toxicity be considered to be 347 mg/kg bw/day (based on the lowest calculated parental IPA intake for 0.5% IPA in drinking water). The proposed NOAEL for reproductive toxicity is 853 mg/kg bw/day (based on the lowest calculated maternal IPA intake for 1.0% IPA in drinking water) on the basis of effects noted on pre-implantation loss, mean litter and fetal body weight, and fetal survival at the 2.0% dose level.

 

A supportive oral gavage, GLP, multi-generation study equivalent to the OECD test guideline 416 (Beyer, 1992) reported aNOAEL for parental toxicity of 500 mg/kg bw/day due to increased organ weights at 1000 mg/kg bw/day. The NOAEL for reproductive effects was 1000 mg/kg bw/day. The NOAEL for offspring toxicity was 500 mg/kg bw/day due to reduced body weights and increased mortality at 1000 mg/kg bw/day.

 

A supportive GLP-compliant pilot study equivalent to the OECD test guideline 415 in rats served as a range finding study. This study did not identify a NOAEL at IPA dose concentrations of 0, 1.25, 2.0, or 2.5% in drinking water (Gaunt, 1986). Decreased adult food and water consumption, decreased adult and pup body weight gain, evidence of embryotoxicity (i.e., fewer live pups, increase in pup mortality, and reduction in pup body weight gain), signs of anaemia, and increased liver and kidney weights were noted. These effects were mainly seen at the 2.0 and 2.5% dose concentrations compared to the control.

Short description of key information:
Ethanol
Mouse (fertility unless stated)
- Key and most reliable study: NOAEL 13.8g/kg (pups/litter, sperm effects in F1 generation)
- NOAEL: 21.5g/kg (F1 male, other effects)
- NOAEL (male)>6g/kg
- LOAEL (male) ~14g/kg/day
Rat (fertility unless stated)
- NOAEC: >16000ppm (male and female), >16000ppm (male only), >14000ppm (male only) 12000ppm (males, weight gain)
- LOAEL: 7.2-14.4g/kg (fertility, weight loss), 7.2g/kg (intoxication)
- NOAEL: (female) 8g/kg
- LOAEL female <5.4-11.4g/kg depending on method of estimation.
- NOAEL: (male)>5g/kg: (female, fecundity): 2.5g/kg NOEL F1 (based on weight increase of fetus): <2.5g/kg
- NOAEL: (male)<13.8mg/kg

Isopropanol:
A GLP-compliant study in rats has provided information on the reproductive toxicity of IPA. The oral gavage study, equivalent to the OECD test guideline 416, reported a NOAEL for parental toxicity of 500 mg/kg bw/day. The NOAEL for reproductive effects was 1000 mg/kg bw/day. The NOAEL for offspring toxicity was 500 mg/kg bw/day.
Additionally, the reproductive toxicity of IPA was assessed in a GLP, one-generation study in rats, equivalent to the OECD test guideline 415. Based on a review of the data, it is proposed that the NOAEL for parental toxicity was 347 mg/kg bw/day (the lowest calculated parental IPA intake for 0.5% IPA in drinking water) and that the NOAEL for reproductive effects was 853 mg/kg bw/day (the lowest calculated maternal IPA intake for 1.0% IPA in drinking water).

Effects on developmental toxicity

Description of key information
Ethanol: 
NOAEC (inhalation, rat) maternal toxicity 16000ppm, teratogenicity >20000ppm
NOAEL (oral diet or drinking water, mouse) maternal toxicity ~13.7, <12, 16 g/kg, <23.7g/kg; teratogenicity 13.7, <12, 16, >23.7g/kg respectively
NOAEL (oral, gavage, mouse): maternal toxicity 2.2g/kg, embryotoxicity >3.6g/kg, teratogenicity >6400g/kg
NOAEL (oral, drinking water, rat): maternal toxicity <6.7g/kg, fetotoxicity <5.7g/kg, teratogenicity >6.7g/kg
NOAEL (oral, drinking water, rabbit): maternal toxicity <14.2g/kg, teratogenicity >14.2g/kg
NOAEL (oral, liquid diet, rat): maternal toxicity 8.2g/kg, developmental toxicity =5.2g/kg
Isopropanol:
A GLP prenatal development study in rats, equivalent to OECD Test Guideline 414, identified an oral NOAEL of 0.5% (596 mg/kg bw/day) for maternal and developmental toxicity. There were no teratogenic effects reported. Supportive GLP developmental toxicity studies, similar to OECD Guideline 414, in New Zealand White rabbits and rats showed that isopropanol was not teratogenic at the dose levels administered. In rabbits, the reported maternal and developmental NOAELs were 240 and 480 mg/kg bw/day, respectively. In rats, the NOAEL for maternal and developmental toxicity was considered to be 400 mg/kg bw/day.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
596 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
39 000 mg/m³
Additional information

There are no data available for the reaction mass. The lowest NOAEL for developmental toxicity for the oral route, being the one from isopropanol and the inhalatory NOAEC of 39000 mg/m3 for developmental toxicity from ethanol will be taken as worst case value for the reaction mass.

Ethanol:

Pregnant female rats were exposed to ethanol by inhalation at concentrations of 10000, 16000, or 20000ppm in a chamber for 7 hours per day on gestation days 1 -19. On day 20 the animals were euthanized and their fetuses examined. There was no definite increase in malformations at any level of ethanol exposure, although the incidence in the 20000ppm group was of borderline significance. There was clear maternal toxicity evident at the highest dose (narcosis, food intake reduction).  A NOAEL  for maternal toxicity of 16,000ppm was established (30,400mg/m3 ethanol, 58,6000mg/m3 ethyl acetate equivalent theoretical concentration) and a NOAEL  for teratogenicity of 20,000ppm (38,000mg/m3 ethanol) was established.

Pregnant female mice were exposed to ethanol at 2200, 3600, 5000, 6400 and 7800 mg/kg/day by gavage from day 8 to 14 of gestation. Dams were sacrificed on day 18 and the content of the uterus and litters examined. Maternal mice treated at concentrations of 3600mg/kg ethanol and higher were lethargic and showed staggered gait and/or laboured breathing. Lethality in maternal animals increased dose dependently from 3600 mg/kg up to the highest dose group resulting in the death of all animals. At 5000 mg/kg, resorption of litters were increased and live foetuses/litters were decreased. This was not apparent in the one litter at 6400 mg/kg. No other fetal effects were seen.  This study determined a NOAEL of 3600mg/kg ethanol (equivalent to 6900mg/kg for ethyl acetate) for embryotoxicity and 2200mg/kg for maternal toxicity.  No teratogenic effects were seen even at the highest dose tested.

Pregnant mice were fed a liquid diet containing 17%, 25%, or 30% ethanol-derived calories from day 4 to day 9 of gestation. Dams were sacrificed on day 18 of gestation. Ethanol treatment in dams did not induce any increase in mortality or change in weight gain with respect to controls. The incidence of fetal resoprtions and congenital malformations increased in a dose-related manner with significant effects in the groups treated with 25% and 30% ethanol-derived calorie diets, but no significant adverse effects were seen in the low dose group (estimated daily dose ~13-14g/day).

Female CBA and CH3 mice were exposed to liquid ethanol diet providing between 15%, and 25% ethanol derived calories for a period of at least 30 days before mating untreated males, and throughout gestation. Females were killed on day 18 of gestation and offspring examined for skeletal and soft tissue abnormalities. The CBA mice were more sensitive: at 15% and higher doses an increase in resorptions and significant number of abnormalities were noted.  However, the high doses used in this study and the fact that no NOAEL was established makes it of limited use in predicting the effects from non-oral consumption of ethanol.

Pregnant rats were exposed to 15% ethanol in drinking water from day 6 through 15 of gestation. Animals were sacrificed on day 21 of gestation and their litters examined for resorption, number, vitality, weight, size, sex, cleft palate and external alterations of fetuses. Mean consumption of food and liquid by rats given ethanol was significantly less that that of control rats during the experimental period. As a result, mean gain in body weight of the exposed rats was also significantly less between days 6 and 16 of gestation. Ethanol ingestion did not affect fetal survival adversely, but mean fetal body weight was significantly less than that of the control litters. No malformed fetuses were found in the experimental litters. Some skeletal variants consisting of unfused bones of the skull and cervical vertebra with missing centra occurred in the ethanol litters at an incidence significantly greater than in the control litters. It was suggested this was an expected manifestation of the decreased fetal body weight observed.

Pregnant female CD-1 mice were exposed to 15% ethanol in drinking water from day 6 through 15 of gestation. Animals were sacrificed on day 18 of gestation and their litters examined for resorption, number, vitality, weight, size, sex, cleft palate and external alterations of fetuses. Maternal body weight gain reflected the decreased consumption of food and liquid in ethanol treated mice. The incidence of exencephaly, open eye, and cleft palate did not differ significantly from control values. Skeletal malformations were not detected but the incidence of several minor skeletal variants e.g. delayed ossification of the centra of cervical vertebra, non-fused sternebrae and delayed ossification of sternebrae was significantly increased among the litters of mice ingesting ethanol. It was suggested that this increase was an expected manifestation of the decreased fetal body weight observed.

Pregnant female New Zealand rabbits were exposed to 15% ethanol in drinking water from day 6 through 18 of gestation. Animals were sacrificed on day 29 of gestation and their litters examined for resorption, number, vitality, weight, size, sex, cleft palate and external alterations of fetuses. There was an increase in resorptions, primarily due to the complete resorption of two litters in the ethanol group which was attributed to the reduction of liquid intake and loss of weight observed in this group. Fetal body measurements and the number of malformed fetuses were comparable between the control and experimental litters.

Groups of female Sprague-Dawley rats were given liquid diets with 15, 25, or 36% ethanol-derived calories, or without ethanol (pair-fed isocaloric or ad libitum control) for 3 weeks prior to mating, and throughout 21 days of gestation. Prenatal ethanol exposure at 36% ethanol-derived calories (E36, about 10.4 g ethanol/kg bw/day) decreased fetal body weight and length, and skeletal ossification, compared with pair-fed (PF36) and ad libitum controls at GD21. Significant effects on ossification, but not body weight or length, were seen at E25 (corresponding to a dose of about 8.2 g ethanol/kg bw/day), compared to PF25 isocaloric controls. No significant effects on fetal growth or ossification were seen in the E15 group (a dose of about 5.2 g ethanol/kg bw/day from 3 weeks prior to mating to GD 21) compared to the PF15 isocaloric controls. A delay in the development of body weight and skeletal ossification was seen in the ethanol-treated (E25 and E36) fetuses on GD21, compared to the ab libitum controls.

Ethanol clearly can cause developmental toxicity.  However, the doses required to cause such effects in animals are exceeding high compared to doses normally used to assess the hazards of chemical substances.  Such doses are clearly also associated with maternal toxicity and are likely to cause significant disturbance of homeostasis, e.g. through nutritional effects.  In addition, the blood ethanol concentrations required to cause adverse developmental consequences, known as 'foetal alcohol syndrome' in humans, have been found to be in the range commonly found in alcoholics (150-200 mg/100 ml) and higher (350-800 mg/100 ml). Adverse effects similar to those reported for humans have been induced in rats by large doses of ethanol that result in similar blood ethanol concentrations. However, inhalation exposure of up to 20,000 ppm ethanol did not cause fertility, developmental or neurotoxic effects. Blood ethanol concentrations following the 0, 10,000, 16,000 and 20,000 ppm ethanol inhalation exposures were 0, 3, 50 and 180 mg/100 ml respectively.

Isopropanol:

The developmental toxicity of isopropanol (IPA) was assessed in a GLP, prenatal development toxicity study equivalent to the OECD test guideline 414 (Faber, 2008). Wistar rats were administered 0 (tap water), 0.5, 1.25, or 2.5% IPA in drinking water. These dose levels were equivalent to 0, 596, 1242, and 1605 mg/kg bw for the low-, mid-, and high-dose groups, respectively. There were no mortalities reported. Reduced food and water consumption was noted at the 1.25 and 2.5% dose levels. A slight decrease in water consumption was observed in the 0.5% dose group on the first day of dosing, but this did not achieve statistical significance. Body weight loss was noted from gestation days 6 to 8 in the 2.5% dose group, and decreased body weight gain was noted thereafter during the dosing period. Decreased body weight gain was noted in the low dose group on the first day of treatment, and for the first two days of treatment in the mid-dose group. After cessation of treatment, the dams in the 2.5% dose level reported increased weight gain comped to controls. Overall, body weights of the 2.5% dose group were lower than those reported for control animals from gestation day 7 through to termination. There were no effects on embryotoxic pameters. A slight dose-dependent decrease in fetal litter weight was observed. Statistically significant decreased mean fetal weight was noted at the 1.25 and 2.5% dose levels. A statistically significant increase in variations was reported in treated animals, and was indicative of a lower degree of ossification. These changes may have been secondy to decreased water and food consumption, secondary to palatability problems. The authors proposed that fetotoxicity, as manifested by reduced fetal body weights, only occurred at dose levels that also caused maternal toxicity (decreased food and water consumption).

 

A NOAEL was not reported by the study authors. It is proposed that the NOAEL for maternal toxicity be considered to be 0.5% (596 mg/kg bw/day) due to decreased food and water consumption, and corresponding effects on body weight at higher dose levels. The NOAEL for fetal toxicity is proposed to be 0.5% (596 mg/kg bw/day) on the basis of reduced body weights at higher dose levels.

 

Supportive studies have shown that there is no evidence of fetotoxicity or teratogenicity following IPA administration. A GLP-compliant, oral gavage, prenatal development study in rats, equivalent to the OECD Test Guideline 414 (Tyl et al., 1990a, cited in Faber et al. 2008) identified a NOAEL for maternal and developmental toxicity of 400 mg/kg bw/day in rats. The basis of this NOAEL was maternal mortality noted at doses up to 1200 mg/kg bw/day. In another GLP-compliant developmental toxicity study similar to the OECD Guideline 414 in New Zealand White rabbits (Tyl et al., 1990b, cited in Faber et al. 2008), maternal mortality, reduced body weight gain, reduced food consumption and severe clinical signs of toxicity were noted at 480 mg/kg bw/day. These findings were mild and nonspecific at lower dose levels. There was no evidence of fetotoxicity or teratogenicity at any dose tested.  The NOAEL for maternal toxicity was determined to be 240 mg/kg bw/day and the NOAEL for developmental toxicity was 480 mg/kg bw/day.

Justification for classification or non-classification

Based on the data available for the two constituents it can be concluded that the reaction mass does not need to be classified as reproductive toxicant according to DSD or CLP.

Ethanol:

Overall, it can be concluded that adverse effects from the effects of ethanol treatment are only seen at very high doses only relevant to deliberate and repeated oral consumption of ethanol.  The most important studies are the 2-generation study which shows a NOAEL of 13.8g/kg and the inhalation studies that show a NOAEC of 16000ppm (the maximum tested exposure, which is close to or exceeding 50% of the lower explosive limit.)  On this basis, it can be concluded that it is impossible to reach the doses of ethanol required to produce any sort of adverse reproductive response other than by repeated oral consumption of large amounts of ethanol, doses normally only associated with problem drinking, and therefore classification for reproductive or developmental toxicity in the context of a chemical substance is not appropriate or warranted.

Isopropanol:

The substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) No. 1272/2008.

Additional information