Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned
Study period:
Including a dose range finding study, should be available approximately 2 years following first dosing after approval to run the test.
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: Isopropylchloride (2-chloropropane)
- Name of the substance for which the testing proposal will be used [if different from tested substance]: See above
CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies
So far no extended one generation or two-generation study is known for isopropylchloride
- Available non-GLP studies
See above
- Historical human data
For isopropylchloride no reproductive effects were reported so far to our knowledge.
- (Q)SAR
No valid models currently known to us to predict reproductive toxicity, suitable to replace this study
- In vitro methods
No valid models currently known to us to predict reproductive toxicity, suitable to replace this study
- Weight of evidence
So far, no extended one generation or two-generation study is known for isopropylchloride
- Grouping and read-across
So far, no extended one generation or two-generation study is known for isopropylchloride or sufficiently appropriate surrogate substances
- Substance-tailored exposure driven testing [if applicable]
Considering that the substance is almost exclusively used by industrial workers with low exposure and the high vapour pressure of the substance, an inhalation study appears appropriate, addressing the most likely exposure (besides incidences).
- Approaches in addition to above [if applicable]
- Other reasons [if applicable]
CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- in tonnage band >1000 T/a the Extended One Generation Reproductive Toxicity Study is a mandatory data endpoint. Although toxicokinetic absorption is expected being low, exposure of industrial workers cannot be fully excluded and vapour pressure of the substance is high. However, the low acute and repeat-dose toxicity as well as insignificant differences between mutagenicity data with and without metabolic activation do suggest, that absorption and metabolism are not too relevant.
FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed [if relevant]
Inhalation exposure (via whole body) is suggested as dermal and oral exposure are not very relevant in industrial settings and considering the high vapour pressure of the substance. Any amendments by additional modules (neurotoxicity or immunotoxicity) or additional cohorts do not appear appropriate, as neither such effects are expected and no information on such effects have become known, following years of continuous use in high tonnages.
More details can be found in attached document!

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
GLP compliance:
yes
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS [please address all points below]:
- Premating exposure duration for parental (P0) animals
According to OECD443 2 weeks during pre-mating (males and females), 2 weeks during mating (males and females) and 6 weeks (males post-mating) and females during pregnancy and lactation
- Basis for dose level selection
based on a 14 days range finding study to be performed
- Inclusion/exclusion of extension of Cohort 1B
not required (see attached document)
- Termination time for F2
not required (see attached document)
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B
not required (see attached document)
- Inclusion/exclusion of developmental immunotoxicity Cohort 3
not required (see attached document)
- Route of administration
inhalation exposure via whole body application is proposed (see attached document)
- Other considerations, e.g. on choice of species, strain, vehicle and number of animals
rats as preferred species are proposed and numbers of animals to follow recommendation in OECD guideline (for more details see attached document)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study report): Isopropyl chloride

Test animals

Species:
rat
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: vapour

Results and discussion

Applicant's summary and conclusion