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Effects on fertility

Link to relevant study records

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Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD Toolbox 3.0, is a harmonized system for OSAR application and grouping chemicals into categories, which OECD principles are met
Qualifier:
according to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Vehicle:
corn oil
Dose descriptor:
LOAEL
Effect level:
3.3 mg/kg bw/day (nominal)
Sex:
male/female
Remarks on result:
other: no further information available
Remarks on result:
other: not predicted with Toolbox
Reproductive effects observed:
not specified

The prediction was based on dataset comprised from the following descriptors: LOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain logical expression: Result: Out of Domain

("a" and ("b" and "c" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Epoxides by US-EPA New Chemical Categories

Domain logical expression index: "b"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.626

Domain logical expression index: "c"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.626

Conclusions:
Epychlorohydrin caused reduced male fertility with histopathological changes in the testis and epididymidis and therefore reproductive adverse effects of the target substance cannot be ruled out. However, the read-across substance epichlorohydrin is not classified officially as toxic to reproduction therefore no decision on classification and labelling for reproductive toxicity can be assigned to the target chemical GE-100 based on this data.
Executive summary:

The target chemical was profiled as "Epoxides" by the "US EPA New Chemical Categories". Common properties of epoxides are high reactivity, cytotoxicity, and high probability of mutagenic potential and/or carcinogenicity. Therefore chemicals with the same profiling result have been retrieved from the database. The chemicals containing other chemical elements in their structure and/or other organic functional groups were considered dissimilar to the target chemical and have been removed from the domain.

The target chemical is obtained by the reaction of epichlorohydrin with glycerol. Therefore, epichlorohydrin is considered to be a suitable candidate for read-across. Moreover, its profiling results regarding binding to proteins and to DNA (properties which are likely responsible for reproductive toxicity) are similar to those of the target.

Epichlorohydrin caused reduced male fertility and an increase in the incidence of histopathological changes of the testis and epididymidis and therefore reproductive adverse effects of the target chemical cannot be ruled out as well.

Endpoint:
toxicity to reproduction
Remarks:
other: fertility; two-generation study; One-Generation study
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD Toolbox 3.0, is a harmonized system for OSAR application and grouping chemicals into categories, which OECD principles are met
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test);OECD Guideline 416 (Two-Generation Reproduction Toxicity Study);OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Species:
other: rat; mouse; guinea pig
Strain:
other: Osborne-Mendel; B6C3F1; Fischer 344
Route of administration:
other: inhalation: vapour; inhalation
Type of inhalation exposure (if applicable):
other: no data; whole body
Dose descriptor:
other: NOAEC fertility, NOAEC toxicity, conc. level:, NOAEC
Effect level:
0.164 mg/L air
Remarks on result:
other: Generation: P; F1 (migrated information)
Remarks on result:
other: not predicted with Toolbox
Reproductive effects observed:
not specified

The prediction was based on dataset comprised from the following descriptors: "NOAEC fertility","NOAEC toxicity","conc. level:",NOAEC
Estimation method: Takes average value from the 5 nearest neighbours
Domain logical expression:Result: Out of Domain

("a" and ("b" and "c" and "d" and "e" and "f" and "g" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Epoxides by US-EPA New Chemical Categories

Domain logical expression index: "b"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.0459

Domain logical expression index: "c"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.453

Domain logical expression index: "d"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 44 Da

Domain logical expression index: "e"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 114 Da

Domain logical expression index: "f"

Parametric boundary:The target chemical should have a value of Water Solubility (fragments) which is >= 1.2E005 mg/L

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of Water Solubility (fragments) which is <= 3.21E005 mg/L

Conclusions:
Allyl glycidyl ether is officially classified for reproductive toxicity and therefore reproductive adverse effects of the target substance cannot be ruledout.
Executive summary:

The target chemical was profiled as "Epoxides" by the "US EPA New Chemical Categories". Common properties of epoxides are high reactivity, cytotoxicity, and high probability of mutagenic potential and/or carcinogenicity. Therefore chemicals with the same profiling result have been retrieved from the database. The prediction was based on the experimental data of chemicals with unit "mg/L air". Two chemicals with epoxide group were assigned into the category. No chemicals have been removed from the category.

According to the US EPA definition of glycidyls, the target substance, triglycidyl ether, derivative of glycerine, belongs also to this group of chemicals and therefore the toxicity data of other category members can be taken into account. Allyl glycidyl ether is a member of glycidyl ethers category (HPV, Epoxy Resin Systems Task Group (ERSTG), 2001). Ethylene oxide is the simplest representative of epoxy compounds; therefore it was kept in the category. Moreover, the profiling results of allyl glycidyl ether regarding its binding to proteins and to DNA (properties which are likely reponsible for reprodictive toxicity) are similar to those of the target chemical.

Allyl glycidyl ether is officially classified for reproductive toxicity: Cat 2 H361: "Suspected of damaging fertility or the unborn child" and therefore adverse effects to reproduction cannot be ruled out for the target chemical GE-100.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
3.3 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
There are a lot studies publically available for structurally similar epoxides. Therefore the overall quality of the database is high.
Effect on fertility: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
164 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
There are a lot studies publically available for structurally similar epoxides. Therefore the overall quality of the database is high.
Additional information

There is no study on reproductive toxicity potential of the target substance available. Therefore, read-across from the related substances (containing glycidyloxy moiety in their chemical structures) was performed to evaluate this endpoint. The epoxy compounds are known to be potential toxicants to male fertility (please refer to read-across statement). They reduce sperm motility and sperm count and produce testicular atrophy in treated animals (NTP TR 374, 1990; NTP TR 376, 1990; BAuA, 2012; Screening Assessment, 2010; NIOSH, 1988a,b; HPV, 2002). Low molecular weight epoxides produce adverse effects in male fertility in animal studies while high molecular weight compound (containing a hydrophobic hydrocarbon chain) do not.

Prediction of the reproductive toxicity by the OECD QSAR Toolbox (v3.1)

The target chemical was profiled as "Epoxides" by the "US EPA New Chemical Categories". According to the US EPA definition of glycidyls, the target substance represents triglycidyl ether of glycerine and therewith belongs also to the epoxide group of chemicals due to the presence of epoxide moiety in glycilydoxy group of the molecule. Common properties of glycidyls are high reactivity, cytotoxicity, and high probability of mutagenic potential and/or carcinogenicity. Chemicals with the same profiling result have been retrieved from the database. The chemicals containing other chemical elements in their structure and/or other organic functional groups were considered as dissimilar to the target chemical and have been removed from the domain. The predictions were based on the experimental data of chemicals with different units (mg/kg bw, mg/L air, and ppm analytical). Therefore the substances have been grouped in three different domains (three different predictions).

The target chemical is obtained by the reaction of epichlorohydrin with glycerol. Therefore, epichlorohydrin is considered to be a suitable candidate for read-across. Further substances used in the read-across were ethyleneoxide as the simplest representative of epoxy compounds, allyl,- and phenyl glycidyl ethers which are members of glycidyl ether category according to the Epoxy Resin Systems Task Group (ERSTG) (HPV, 2001). Moreover, their profiling results regarding binding to proteins and to DNA (properties which are likely responsible for reproductive toxicity) are similar to those of the target.

Epichlorohydrin caused reduced male fertility and an increase in the incidence of histopathological changes of the testis and epididymidis. Allyl glycidyl ether induced multiple adverse effects on the reproductive system of treated animals and is officially classified for reproductive toxicity Cat. 2 H361 "Suspected of damaging fertility or the unborn child". Phenyl glycidyl ether caused testicular atrophy as well as reduced reproductive capacity in treated animals if administered orally. Based on these data reproductive adverse effects of the target chemical cannot be ruled out.

Data on epichlorohydrin (CAS 106 -89 -8)

Effects of epichlorohydrin on male and female reproduction in Long-Evans rats was studied (Toth et al., 1989). The animals were treated with epichlorohydrin (ECH) by oral gavage (males: 12.5, 25, and 50 mg/kg/day; females: 25, 50, and 100 mg/kg/day) for 21 and 14 days, respectively, prior to mating trials with untreated animals. Treated females were further dosed until delivery. Fertility was assayed in the high-dose males only and was found to be totally impaired. None of the females that mated with ECH males was pregnant, compared to a 90% pregnancy rate in controls. However, treated males showed normal copulatory behaviour. Sperm morphology and percentage motile sperm were not statistically different from control values in both ejaculated and cauda epididymal samples from ECH-treated animals. The number of sperm in ejaculates was normal while cauda epididymal sperm count was slightly decreased in males at the 50 mg ECH/kg dose level. The decreased cauda epididymal sperm count is unlikely to be responsible for the observed infertility. However, it may in part be a result of the effects of ECH on the vigour and swimming pattern of cauda epididymal sperm. Mean curvilinear velocity, straight-line velocity, and amplitude of lateral head displacement of cauda epididymal sperm were significantly reduced by ECH at 12.5 mg/kg/day and above. Sperm track linearity was also reduced, but only at 50 mg/kg/day. Beat/cross frequency of sperm was significantly increased at 12.5 mg/kg/day and above. All of the above sperm motion parameters showed dose-dependent trends. At necropsy, liver, kidney, and epididymal organ-to-body weight ratios were significantly higher in 50 mg/kg males (p<0.05) relative to controls, although all differences were marginal. Liver and kidneys are known targets for epichlorohydrin toxicity. Increased epididymis-to-body weight ratios are possibly a result of inflammation and swelling from spermatocoeles and sperm granulomas.In the second group of males used for sperm motion analyses, testis and epididymis organ-to-body weight ratios were unchanged.

Within the first week of treatment, all females in the 100 mg/kg group died or were so moribund as to warrant sacrifice. Autopsy showed haemorrhagic stomachs and kidneys with a very pale cortex and hemorrhagic medulla. Animals in the remaining groups appeared healthy and in good condition. Mean body weights across groups showed no differences neither during pregestational exposure nor during pregnancy. No measured parameters of female reproduction were changed relative to controls. No differences were seen in the number of females mating or in number of successful pregnancies. Litter size and mean pup birth weight were not significantly different. One dam in the 25 mg/kg group neglected her pups, which all died by Postnatal Day 4. This accounts for the slightly decreased percentage survival seen in the 25 mg/kg group. Male and female pup weights, measured weekly, did not significantly differ during lactation or in the 3 weeks postweaning.

In conclusion, no evidence for ECH-induced female reproductive or developmental toxicity was observed at doses up to 100 mg/kg/day. However, male rats showed reductions in sperm motion parameters at a dose as low as 12.5 mg/kg/day and total infertility at 50 mg/kg/day.

Data on phenyl glycidyl ether (CAS 122 -60 -1)

The effects of phenylglycidyl-ether (PGE) in rats following inhalation of atmospheres containing either 0, 2, 6, or 11 ppm were measured in a two-generation reproduction study (Terril et al., 1982). The potential teratogenicity effects of PGE were also evaluated in rats exposed to the same concentrations during the period of rapid organogenesis. No significant changes in reproduction parameters (fertility, progeny numbers and survival, lactational performance) were produced by PGE inhalation, and there was no evidence of dominant lethality. Exposure of pregnant rats to the compound, 6 hr/day from Gestation Days 4 through 15 resulted in no embryotoxicity or teratogenicity effect.

So, as normal fertility was observed, and there was no evidence of increased early embryonic death (dominant lethals) in the reproduction study, the test substance is not considered to bear a significant potential to change reproductive parameters. Test progenies were delivered in normal numbers; these animals survived and grew like the controls. A decrease in the number of pregnancies resulting from mating to males exposed at the highest level (11 ppm) the first week post exposure suggested a treatment relationship, but all other reproductive data appeared normal and it is concluded that this isolated finding was not related to exposure to PGE. A single pup (2 ppm) displayed an abnormal hair pattern (curly hair) which again was an isolated occurrence of doubtful biologic significance. Teratogenicity and cytogenetic (bone marrow cells) tests failed to reveal any effects which could be related to PGE exposure. It is recognized that the evaluation of the mutagenicity, teratogenicity, and reproductive effects can be measured in a wide variety of test systems. It is concluded that rats exposed to atmospheres of up to 11 ppm PGE showed no significant abnormalities in cytogenetic, teratogenicity, or reproductive evaluations.


Short description of key information:
Structurally similar glycidyl ethers containing glycidyloxy moiety in their structures which physico-chemical properties water solubility, logPow and vapour pressure are similar to those of the target chemical, possess all reproductive toxicity potential (damage to male fertility). Therefore, based on solid weight of evidence, the target substance is considered to possess a toxicity potential to reproduction.

Justification for selection of Effect on fertility via oral route:
The prediction by the OECD QSAR Toolbox based on the experimental data of epichlorohydrin, a component of reaction mass of UVCB substance GE-100.

Justification for selection of Effect on fertility via inhalation route:
The prediction by the OECD QSAR Toolbox based on the experimental data of allyl glycidyl ether which in analogy with target substance contains glycidyloxy group in its structure.

Effects on developmental toxicity

Description of key information
Read-across substances epichlorohydrin and glycidol were not developmental toxicants in the animal studies. A variety of other related epoxides (containing glycidyloxy moieties in their structures) are reported not to possess developmental or teratogenicity activity (please refer to read-across statement attached to the IUCLID file). Therefore no developmental toxicity can be assigned for the target substance.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD Toolbox 3.0, is a harmonized system for OSAR application and grouping chemicals into categories, which OECD principles are met
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Species:
other: Mouse; Rat
Strain:
other: CD-1; Sprague Dawley; Crl:CD®(SD)IGS BR
Route of administration:
oral: gavage
Dose descriptor:
other: LOEL, NOEL, NOAEL
Effect level:
415 mg/kg bw/day
Basis for effect level:
other: other:
Remarks on result:
other: no further information available
Remarks on result:
other: not specified
Abnormalities:
not specified
Developmental effects observed:
not specified

The prediction was based on dataset comprised from the following descriptors: LOEL,NOEL,NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain logical expression:Result: In Domain

("a" and ("b" and "c" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Epoxides by US-EPA New Chemical Categories

Domain logical expression index: "b"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.1

Domain logical expression index: "c"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.37

Conclusions:
Category members were not developmental toxicants in the animal studies. Therefore no developmental toxicity can be assigned for the target substance.
Executive summary:

The target chemical was profiled as "Epoxides" by the "US EPA New Chemical Categories". Common properties of epoxides are high reactivity, cytotoxicity, and high probability of mutagenic potential and/or carcinogenicity. Therefore chemicals with the same profiling result have been retrieved from the database. The chemicals containing other chemical elements in their structure and/or other organic functional groups were considered dissimilar to the target chemical and have been removed from the domain.

The target chemical is obtained by the reaction of epichlorohydrin with glycerol. Therefore, epichlorohydrin is considered to be a suitable candidate for read-across. Glycidol is the simplest representative of glycidyl ethers category (HPV, Epoxy Resin Systems Task Group (ERSTG), 2001). 7-oxabicyclo-hept-3-ylmethyl 7-oxabicyclo-heptane-3-carboxylate is more lipophilic representative of glycidyl ethers category. Moreover, the profiling results of the category members regarding their ability to bind to proteins and to DNA (properties which are likely responsible for developmental toxicity) are similar to those of the target chemical.

Epichlorhydrin if administered to pregnant rats caused no embryotoxic, foetotoxic or teratogenicity effects (Mark et al., 1982; John, 1983). No developmental malformations were noted in mice treated with glycidol in a developmental study (Mark et al., 1982; IARC Monographs, Volume 77). No influence on embryonic or pup development was observed in the 13- week repeated dose toxicity and fertility study conducted with triglycidyl isocyanurate (HPV, No. 201 -15759).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEL
415 mg/kg bw/day
Study duration:
subchronic
Species:
other: rat, mouse
Quality of whole database:
There are a lot studies publically available for structurally similar epoxides. Therefore the overall quality of the database is high.
Additional information

There is no developmental study available for the target substance. Therefore, read-across from the related substances (containing glycidyloxy moiety in their chemical stuctures) was performed to evaluate this endpoint. The epoxy compounds are not developmental toxicants (please refer to read-across statemnent).

The target chemical was profiled as "Epoxides" by the "US EPA New Chemical Categories". Common properties of epoxides are high reactivity, cytotoxicity, and high probability of mutagenic potential and/or carcinogenicity. Therefore chemicals with the same profiling result have been retrieved from the database. The chemicals containing other chemical elements in their structure and/or other organic functional groups were considered as dissimilar to the target chemical and have been removed from the domain.

The target chemical is obtained by the reaction of epichlorohydrin with glycerol. Therefore, epichlorohydrin is considered to be a suitable candidate for read-across. Glycidol is the simplest representative of glycidyl ethers category (HPV, Epoxy Resin Systems Task Group (ERSTG), 2001). 7-oxabicyclo-hept-3-ylmethyl 7-oxabicyclo-heptane-3-carboxylate is more lipophilic representative of glycidyl ethers category. Moreover, the profiling results of the category members regarding their ability to bind to proteins and to DNA (properties which are likely responsible for developmental toxicity) are similar to those of the target chemical.

Epichlorohydrin if administered to pregnant rats caused no embryotoxic, fetotoxic or teratogenicity effects (Marks et al., 1982; John, 1983). No developmental malformations were noted in mice treated with glycidol in a developmental study (Marks et al., 1982; IARC Monographs, Volume 77). No influence on embryonic or pup development was observed in the 13- week repeated dose toxicity and fertility study conducted with triglycidyl isocyanurate (HPV, No. 201 -15759).

Pregnant outbred albino rats (CD) and mice (CD-1) were given epichlorohydrin by gastric intubation on day 6-15 of gestation (Marks et al., 1982). The rats were killed on day 21 (day 18 for mice) and the offspring checked for gross, visceral, and skeletal malformations. Epichlorohydrin caused a significant reduction in the weight gain of pregnant rats at 80 mg/kg/d as compared with the control group treated only with the vehicle. However, there was no evidence of teratogenicity in the rat foetuses even at a dose level (160 mg/kg/d) that caused the death of some of the treated dams. Epichlorohydrin also did not produce a statistically significant increase in the average per cent of malformed mouse foetuses, even at 160 mg/kg/d, a dose that killed 3 of 32 treated dams. The 120 and 160 mg/kg/d levels did cause a significant (p < 0.05) reduction in the average foetal weight as compared with controls. In addition, the 120 mg/kg/d dose produced a statistically significant increase in the liver weight of the pregnant mouse. These observations indicate that the 120 and 160 mg/kg/d dose levels were toxic toward the dams and their unborn offspring. In a similar mouse study, glycidol showed no evidence of teratogenicity. There was a significant increase in the number of stunted foetuses at 200 mg/kg/d, but all of these were present in a single litter. Further, the same dose killed 5 of 30 dams.


Justification for selection of Effect on developmental toxicity: via oral route:
The prediction by the OECD QSAR Toolbox based on the experimental data of epichlorohydrin, a component of reaction mass of UVCB substance GE-100. Other read-across substances contain glycidyl/glycidyloxy group in their moieties relevant for the exerting of developmntal toxicity.

Justification for classification or non-classification

Toxicity to reproduction

Related substances that contain glycidyloxy moieties in their structures produced damage of male fertility and testicular atrophy. The pattern of toxicity was similar in numerous animal studies. Based on the significant body of evidence, reproductive toxicity of the target substance GE-100 can not be ruled out. Therefore, it does meet the criteria for classification and will require labelling for this endpoint, according to the European regulation (EC) No. 1272/2008.

Proposed C&L: Toxicity to reproduction, Cat 2, H361f (suspected of damaging fertility (males).

Developmental toxicity

No evidence of developmental toxicity was found in the numerous studies available for structurally similar chemicals. Therefore, in analogy to other epoxides, no developmebntal toxicity can be assigned for the target substance. Therefore, it does not meet the criteria for classification and will not require labelling for this endpoint, according to the European regulation (EC) No. 1272/2008.

Additional information