Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The structural alert/rule-based SAR 'DART scheme' did not identify any structural feature in the evaluated substance associated with developmental and reproductive toxicity.

The available OECD 408 study clearly reveals no adverse effects on reproductive organs or tissues.

Link to relevant study records

Referenceopen allclose all

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING

QSAR modelling via Developmental and Reproductive Toxicity (DART) revealed that the substance 1,3-Dimethyl-4-aminouracil has no known precedent reproductive and developmental toxic potential. The structural alert/rule-based SAR 'DART scheme' did not identify any structural feature in the evaluated substance associated with developmental and reproductive toxicity.

In the available OECD 408 study, samples of cervix, clitoral gland, ovaries, seminal vesicles, testes (incl. organ weights), uterus and vagina were collected from all animals at necropsy and fixed in neutral phosphate buffered 4% formaldehyde solution.
With regard to organ weights, no alteration in all organs related to reproduction were noted except in the testes. Mean weight of the high dose group was with 2.89 g significantly reduced compared to control (3.32 g) after 13 weeks. Organ / body weight ratios were 0.70 (high dose) compared to control (0.77). After 17 weeks (recovery groups) those values of the high dose were increased compared to control, i.e. 3.31 g vs. 2.86 g (organ weights) resp. 0.75 vs. 0.61 (organ / body weight ratios).
The increased organ / body weight ratios were considered not to be treatment-related but to have resulted from slightly low control values. Further, weight and function of the gonads is usually maintained in the case of depressed growth.
Microscopic evaluation revealed no changes in any organs related to reproduction.

Last but not least, there are three different QSAR models available assessing the potential of the substance for developmental toxicity.
Teratogenicity of 6-amino-1,3-dimethyluracil was assessed using the structural feature-based DART scheme v1.1, which is implemented in the OECD QSAR Toolbox v4.1. No structural feature associated with teratogenic mode of action was identified in 6-amino-1,3-dimethyluracil. The descriptor- and structural feature-based QSAR model Leadscope (MultiCASE Inc.), which is implemented in the Danish QSAR Database, predicted the query chemical to be 'negative'. The same applies for the descriptor-based QSAR model SciQSAR (MultiCASE Inc.), which is implemented in the Danish QSAR Database. All three models gave consistently weight of evidence that 6-amino-1,3-dimethyluracil is not teratogenic.

According to REACH Annex IX, as latest amended, 8.7 Reproductive Toxicity, the studies do not need to be conducted if:
— the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented, or
— the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, or
— the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure.

Focus here clearly lays on appropriate risk management measure, insignificant human exposure, and low toxicological activity. Appropriate measures are taken to diminish human exposure, and the substance is of low toxicological activity. All observed effects in the available OECD 408 study were only minor, toxicologically nor relevant for humans due to the high threshold dose, or only of adaptive nature. Also, as stated above, QSAR modelling gave no indication of a potential toxicity on reproduction or development. Hence, further testing would not reveal any relevant additional information as a negative outcome of studies covering these endpoint can be reasonable concluded, any so, testing can be omitted due to animal welfare.

According to REACH Annex IX column 1, as latest amended, the following study is listed:
8.7.3. Extended One-Generation Reproductive Toxicity Study (B.56 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 443), basic test design (cohorts 1A and 1B without extension to include a F2 generation), one species, most appropriate route of administration, having regard to the likely route of human exposure, if the available repeated dose toxicity studies (e.g. 28-day or 90-day studies, OECD 421 or 422 screening studies) indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity.

As stated above, the available OECD 408 study clearly reveals no adverse effects on reproductive organs or tissues. Further, all available QSAR models consistently revealed no indication of a potential toxicity to reproduction or development, so there are also no other concerns in relation with reproductive toxicity revealed. In conclusion, an Extended One-Generation Reproductive Toxicity Study does not need to be conducted as the conditions for the necessity for conduction as described under REACH are not met. Testing can be omitted, also considering animal welfare.
Reason / purpose for cross-reference:
data waiving: supporting information
Remarks:
in silico DART scheme
Reason / purpose for cross-reference:
data waiving: supporting information
Remarks:
OECD 408 study
Endpoint:
reproductive toxicity, other
Remarks:
QSAR
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2017/11/23
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
please refer to 'attached justification'
Reason / purpose for cross-reference:
reference to same study
Guideline:
other: REACH Guidance on QSARs R. 6
Principles of method if other than guideline:
- Software tool(s) used including version: DART scheme v1.1
- Model(s) used: OECD QSAR Toolbox v4.1
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification'
Species:
other: not applicable
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for reproductive based on DART scheme
Critical effects observed:
not specified
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for reproductive based on DART scheme
Critical effects observed:
not specified
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for reproductive based on DART scheme
Critical effects observed:
not specified
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for reproductive based on DART scheme
Critical effects observed:
not specified
Reproductive effects observed:
no
Conclusions:
No structural feature associated with a mode of action associated with reproductive toxicity was identified in the query chemical by the DART scheme.
Executive summary:

Reproductive toxicity of 6 -amino-1,3 -dimethyluracil was assessed using the rule-based SAR DART scheme v1.1, which is implemented in the OECD QSAR Toolbox v4.1. No structural feature associated with a mode of action associated with reproductive toxicity was identified in the query chemical. This gives weight of evidence that DIMAU is not toxic to reproduction.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
700 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data quality suffices as the waiving criteria under REACH are met.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

in silico

DART scheme v1.1

Reproductive toxicity of 6 -amino-1,3 -dimethyluracil was assessed using the structural feature-based DART scheme v1.1, which is implemented in the OECD QSAR Toolbox v4.1. No structural feature associated with a mode of action associated with reproductive toxicity was identified in the query chemical. This gives weight of evidence that DIMAU is not toxic to reproduction.

In vivo

The available OECD 408 study clearly reveals no adverse effects on reproductive organs or tissues up to the highest dose tested, ca. 700 mg/kg bw/d.

Effects on developmental toxicity

Description of key information

in silico

DART scheme v1.1

Teratogenicity of 6 -amino-1,3 -dimethyluracil was assessed using the structural feature-based DART scheme v1.1, which is implemented in the OECD QSAR Toolbox v4.1. No structural feature associated with teratogenic mode of action was identified in the query chemical. This gives weight of evidence that DIMAU is not teratogenic.

Leadscope

Teratogenicity of 6 -amino-1,3 -dimethyluracil was predicted using the descriptor- and structural feature-based QSAR model Leadscope (MultiCASE Inc.), which is implemented in the Danish QSAR Database. The query chemical was predicted 'negative'. This prediction falls within the applicability domain of this model. Thus, there is weight of evidence that 6 -amino-1,3 -dimethyluracil is not teratogenic.

SciQSAR v3.1.00

Teratogenicity of 6 -amino-1,3 -dimethyluracil was predicted using the descriptor-based QSAR model SciQSAR (MultiCASE Inc.), which is implemented in the Danish QSAR Database. The query chemical was predicted 'negative'. This prediction falls within the applicability domain of this model. Thus, there is weight of evidence that 6 -amino-1,3 -dimethyluracil is not teratogenic.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Remarks:
OECD 414
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING

QSAR modelling via Developmental and Reproductive Toxicity (DART) revealed that the substance 1,3-Dimethyl-4-aminouracil has no known precedent reproductive and developmental toxic potential. In the available OECD 408 study, macroscopic and microscopic evaluation revealed no changes in any organs related to reproduction.

Most importantly, there are three different QSAR models available assessing the potential of the substance for developmental toxicity.
Teratogenicity of 6-amino-1,3-dimethyluracil was assessed using the structural feature-based DART scheme v1.1, which is implemented in the OECD QSAR Toolbox v4.1. No structural feature associated with teratogenic mode of action was identified in 6-amino-1,3-dimethyluracil. The descriptor- and structural feature-based QSAR model Leadscope (MultiCASE Inc.), which is implemented in the Danish QSAR Database, predicted the query chemical to be 'negative'. The same applies for the descriptor-based QSAR model SciQSAR (MultiCASE Inc.), which is implemented in the Danish QSAR Database. All three models gave consistently weight of evidence that 6-amino-1,3-dimethyluracil is not teratogenic.

According to REACH Annex IX, as latest amended, 8.7 Reproductive Toxicity, the studies do not need to be conducted if:
— the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented, or
— the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, or
— the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure.

Focus here clearly lays on appropriate risk management measure, insignificant human exposure, and low toxicological activity. Appropriate measures are taken to diminish human exposure, and the substance is of low toxicological activity. All observed effects in the available OECD 408 study were only minor, toxicologically nor relevant for humans due to the high threshold dose, or only of adaptive nature. Also, as stated above, QSAR modelling gave no indication of a potential toxicity on reproduction or development. Although not meant individually as a stand alone tool, the three independent give sufficient evidence to conclude that there is no potential of 1,3-Dimethyl-4-aminouracil to influence development adversely. Hence, further testing, i.e. conducting an OECD 414 study, would not reveal any relevant additional information as a negative outcome of studies covering these endpoint can be reasonable concluded, any so, testing can be omitted due to animal welfare.
Reason / purpose for cross-reference:
data waiving: supporting information
Remarks:
in silico DART scheme
Reason / purpose for cross-reference:
data waiving: supporting information
Remarks:
in silico Leadscope
Reason / purpose for cross-reference:
data waiving: supporting information
Remarks:
in silico SciQSAR
Endpoint:
developmental toxicity
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2017/11/23
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
please refer to 'attached justification'
Reason / purpose for cross-reference:
reference to same study
Guideline:
other: REACH Guidance on QSARs R. 6
Principles of method if other than guideline:
- Software tool(s) used including version: DART scheme v1.1
- Model(s) used: OECD QSAR Toolbox v4.1
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification'
Species:
other: not applicable
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for teratogenicity based on DART scheme
Abnormalities:
not specified
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for teratogenicity based on DART scheme
Abnormalities:
not specified
Developmental effects observed:
no
Treatment related:
not specified
Conclusions:
No structural feature associated with teratogenic mode of action was identified in the query chemical by the DART scheme.
Executive summary:

Teratogenicity of 6-amino-1,3 -dimethyluracil was assessed using the rule-based SAR DART scheme v1.1, which is implemented in the OECD QSAR Toolbox v4.1. No structural feature associated with teratogenic mode of action was identified in the query chemical. This gives weight of evidence that DIMAU is not teratogenic.

Endpoint:
developmental toxicity
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2017/11/23
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
please refer to 'attached justification'
Guideline:
other: REACH Guidance on QSARs R. 6
Principles of method if other than guideline:
- Software tool(s) used including version: Danish QSAR database
- Model(s) used: Leadscope Enterprise version of commercial MultiCASE MC4PC model A49 for teratogenic potential in humans, Danish SAR Group at DTU Food
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification'
Species:
other: not applicable
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for teratogenicity based on the prediction of the QSAR model Leadscope
Abnormalities:
not specified
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for teratogenicity based on the prediction of the QSAR model Leadscope
Abnormalities:
not specified
Developmental effects observed:
no

The query chemical was predicted 'negative'. This prediction falls within the applicability domain of this model.

Conclusions:
The query chemical was predicted 'negative' by the QSAR model Leadscope.
Executive summary:

Teratogenicity of 6 -amino-1,3 -dimethyluracil was predicted using the descriptor- and structural feature-based QSAR model Leadscope (MultiCASE Inc.), which is implemented in the Danish QSAR Database. The query chemical was predicted 'negative'. This prediction falls within the applicability domain of this model. Thus, there is weight of evidence that 6 -amino-1,3 -dimethyluracil is not teratogenic.

Endpoint:
developmental toxicity
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2017/11/23
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
please refer to 'Attached justification'
Guideline:
other: REACH Guidance on QSARs R. 6
Principles of method if other than guideline:
- Software tool(s) used including version: Danish QSAR database
- Model(s) used: SciMatics SciQSAR version of commercial MultiCASE MC4PC model A49 for teratogenic potential in humans, Danish QSAR Group at DTU Food v3.1.00
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification'
Species:
other: not applicable
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for teratogenicity based on the prediction of the QSAR model SciQSAR
Abnormalities:
not specified
Dose descriptor:
other: QSAR
Remarks on result:
other: see Remarks
Remarks:
no indication for teratogenicity based on the prediction of the QSAR model SciQSAR
Abnormalities:
not specified
Developmental effects observed:
no

The query chemical was predicted 'negative'. This prediction falls within the applicability domain of this model.

Conclusions:
The query chemical was predicted 'negative' by the QSAR model SciQSAR.
Executive summary:

Teratogenicity of 6 -amino-1,3 -dimethyluracil was predicted using the descriptor-based QSAR model SciQSAR (MultiCASE Inc.), which is implemented in the Danish QSAR Database. The query chemical was predicted 'negative'. This prediction falls within the applicability domain of this model. Thus, there is weight of evidence that 6 -amino-1,3 -dimethyluracil is not teratogenic.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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

in silico

DART scheme v1.1

Teratogenicity of 6 -amino-1,3 -dimethyluracil was assessed using the structural feature-based DART scheme v1.1, which is implemented in the OECD QSAR Toolbox v4.1. No structural feature associated with teratogenic mode of action was identified in the query chemical. This gives weight of evidence that DIMAU is not teratogenic.

Leadscope

Teratogenicity of 6 -amino-1,3 -dimethyluracil was predicted using the descriptor- and structural feature-based QSAR model Leadscope (MultiCASE Inc.), which is implemented in the Danish QSAR Database. The query chemical was predicted 'negative'. This prediction falls within the applicability domain of this model. Thus, there is weight of evidence that 6 -amino-1,3 -dimethyluracil is not teratogenic.

SciQSAR v3.1.00

Teratogenicity of 6 -amino-1,3 -dimethyluracil was predicted using the descriptor-based QSAR model SciQSAR (MultiCASE Inc.), which is implemented in the Danish QSAR Database. The query chemical was predicted 'negative'. This prediction falls within the applicability domain of this model. Thus, there is weight of evidence that 6 -amino-1,3 -dimethyluracil is not teratogenic.

Mode of Action Analysis / Human Relevance Framework

There is not any information given that 1,3-Dimethyl-4-aminouracil has a potential toxicity towards reproduction or development, hence, no MoAA can be performed.

Justification for classification or non-classification

There is not any information given that 1,3-Dimethyl-4-aminouracil has a potential toxicity towards reproduction or development, which was consistently revealed from four QSAR models and data derived from an OECD 408 study. Regulation 1272/2008 clearly foresees weight of evidence approaches to justify (non)-classification. Hence, no classification as reproductive toxicant (both effects on fertility and development) is triggered.

Additional information