Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Data waiving:

other justification

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No studies are available on the reproductive toxicity of the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate. Histopathological changes in reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. In this respect, repeated dose toxicity studies should be considered to be sensitive and provide sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

Based on available datasets and chemical and structural considerations, read across from the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate to repeated dose and developmental toxicity studies on isobutanol and isobutyl isobutyrate is appropriate to address the REACH Annex VII-IX data requirements and to provide a characterisation of the reproductive hazard of the substance. No effects on reproductive parameters where seen in rats 90-day repeated dose toxicity studies using isobutanol and isobutyl isobutyrate respectively. No effects on reproductive parameters were seen in pre-natal developmental toxicity studies conducted using rats and rabbits. Isobutanol is not a reproductive toxicant – no affects on reproductive parameters were seen in a two-generation inhalation reproductive toxicity study at the highest dose tested (7580 mg/m³). On this basis, the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate is not predicted to be a reproductive toxicant.

Short description of key information:
No studies are available on the reproductive toxicity of Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate. No evidence of an effect on the reproductive organs was seen in repeated dose toxicity studies or developmental toxicity studies using the read-across substances isobutanol and isobutyl isobutyrate. On this basis, the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate is not predicted to be a reproductive toxicant. In this respect, repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

Effects on developmental toxicity

Description of key information

Based on existing datasets and structural and chemical considerations, read-across from the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate to available developmental toxicity studies on isobutanol is appropriate to meet the REACH Annex VII-IX data requirements. While rabbit dams were more sensitive to treatment than rats, no effects were seem on developmental parameters in pre-natal developmental toxicity studies in which rats or rabbits were exposed to isobutanol at concentrations up to 10,000 mg/m3 (i.e. the highest dose tested).	

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Fifteen female rabbits per group were exposed to 2-Methyl-1-propanol vapours at concentrations of 10, 2.5, or 0.5 mg/L, 6 hr/day. The rabbits were exposed on Days 7 -19 postinsemination . Control groups were exposed to clean air. The body weights of the animals were determined several times throughout the studies. All rabbits were killed on Day 29 postinsemination. The foetuses were removed from the uterus and examined for compound-related effects.

GLP compliance:

not specified

Limit test:

no

Species:

rabbit

Strain:

Himalayan

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach/Riss, Germany
- Age at study initiation: 24 - 29 weeks
- Weight at study initiation: 2.5 - 2.7 kg
- Fasting period before study: None
- Housing: Individually in wire cages
- Diet (e.g. ad libitum): KLIBA rabbit laboratory diet ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

IN-LIFE DATES: From: Not reported To: Not reported

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

clean air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Horizontal-flow whole-body exposure chamber
- Method of holding animals in test chamber: Not reported
- Source and rate of air: Not reported
- Method of conditioning air: Not reported
- System of generating particulates/aerosols: Concentrations were achieved by supplying the test substances via continuously operating pumps to evaporators maintained at 50-70°C by a water circulation thermostat.
- Temperature, humidity, pressure in air chamber: Supply and exhaust air flows were adjusted by flow meters, in order to achieve a minimal negative pressure in the inhalation chamgers. Temperature was 21-24°C amd relative humidity was 49-60%
- Air flow rate: 15 air exchanges per hour
- Air change rate: 15 air exchanges per hour
- Method of particle size determination: Not reported
- Treatment of exhaust air: Not reported

TEST ATMOSPHERE
- Brief description of analytical method used: Samples of inhalation atmospheres were analysed houly by gas chromatography.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of inhalation atmospheres were analysed houly by gas chromatography.

Details on mating procedure:

The rabbits were fertilized by artificial insemination; the day of insemination was defined as Day 0 and the following day was defined as Day 1 postinsemination

Duration of treatment / exposure:

Daily for 6 hours/day from days 7 - 19 postinsemination.

Frequency of treatment:

Daily for 6 hours/day

Duration of test:

After termination of the exposure period, the rabbits were observed up to Day 29 postinsemination.

Remarks:

Doses / Concentrations:
0.5, 2.5, 10 mg/L, 6 hr/day
Basis:
nominal conc.

No. of animals per sex per dose:

15 females/dose

Control animals:

yes, concurrent vehicle

Details on study design:

No further data on dosing rationale.
The animals were randomly allocated to the test groups.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: state of health

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 3 and 7 and from then on at 3-day intervals until Day 29 postinsemination

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Day 29 postinsemination
- Organs examined: Uterus and ovaries were removed for the following delerminations: intact uterine weight, number of corpom lutea, and number of
implants, the latter being differentiated into live fetuses and dead implants (early and late resorptions, dead fetuses). The pre- and postimplantation losses were calculated.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No data

Statistics:

The Dunnett test was used to statistically compare body weight, body weight changes, corrected body weight gain, intact uterine weight, fetal and placental weights, the number of corpora lutea. implants, resorptions, live fetuses, and pre- or postimplantat ion losses. The Fisher's exact test was used for evaluating the conception rate, maternal mortality, and all fetal findings.

Indices:

No further data

Historical control data:

No further data

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: slight maternal toxic effects at the highest dose (10 mg/L) of 2-Methyl-1-propanol

Details on maternal toxic effects:
Only slight maternal toxic effects were induced in Himalayan rabbits after exposure to 10 mg/L of 2-Methyl-1-propanol

Dose descriptor:

NOAEL

Effect level:

ca. 2.5 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

> 10 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No treatment related effects. All effects were concidered incidental and were within the normal variations for the species.

Dose descriptor:

NOAEL

Effect level:

> 10 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: teratogenicity

Dose descriptor:

NOAEL

Effect level:

> 10 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: embryotoxicity

Dose descriptor:

NOAEL

Effect level:

> 10 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: fetotoxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

No further data

Conclusions:

The highest concentration of 10 mg/L appeared to be a borderline concentration for causing maternal toxicity. 2.5 mg/L was therefore the NOAEL after exposure to 2-Methyl-1-propanol.
The highest concentration level of 10 mg/L was found to be a clear NOAEL for the fetal organisms.

Executive summary:

Fifteen female rabbits per group were exposed to 2-Methyl-1-propanol (isobutanol) vapours at concentrations of 10, 2.5, or 0.5 mg/L, 6 hr/day. The rabbits were exposed on Days 7 -19 postinsemination. Control groups were exposed to clean air. The body weights of the animals were determined several times throughout the studies. All rabbits were killed on Day 29 postinsemination. The foetuses were removed from the uterus and examined for compound-related effects. The high concentration of 10 mg/L caused a slight retardation of body weight gain in the dams exposed to 2-Methyl-1-propanol during the first days of the exposure period.. The foetuses exhibited no signs of embryotoxicity, fetotoxicity or teratogenicity effects caused by 2-Methyl-1-propanol. Under the experimental conditions, 2.5 mg/L was found to be a no-observable-adverse-effect level (NOAEL) for the dams exposed to 2-Methyl-1-propanol. For both substances 10 mg/L was defined as the NOAEL for the conceptuses.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

10 000 mg/m³

Study duration:

subchronic

Species:

rabbit

Quality of whole database:

Klimisch score = 2. The key study is an acceptable, well documented prenatal developmental toxicity study which meets scientific principles and is therefore reliable for the determination of the sub-chronic endpoint.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No studies on the developmental toxicity of the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate are available. Read-across from the substance to developmental toxicity studies on isobutanol is appropriate to meet the REACH Annex VII-IX data requirements.Read-across is scientifically justified and also enables the REACH requirements to be adequately addressed, while avoiding unnecessary animal testing in accordance with EU Directive 86/609/EEC.

The potential for isobutanol to cause developmental toxicity was investigated in two definitive inhalation studies conducted according to OECD Test Guideline 414 using rats and rabbits respectively (Klimisch and Hellwig, 1995). In the studies, groups of pregnant female rats (25/group) or rabbits (15/group) were exposed via inhalation to isobutanol at concentrations of 0, 500, 2,500 or 10,000 mg/m³(0, 151, 758, or 3030 ppm, respectively) for 6 hours/day during gestation (rats - days 6-15; rabbits – days 7-19). Rabbit dams exposed to 10,000 mg/m³had slight decreases in body weight gain during gestation while exposures in rats had no treatment-related effects. No evidence of developmental or fetotoxicity was reported in either the rats or the rabbits. The NOAEL for developmental toxicity in rats and rabbits was considered to be 10,000 mg/m³, i.e. the highest dose tested.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Based on existing datasets and structural and chemical considerations, read-across from the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate to available developmental toxicity studies on isobutanol is appropriate to meet the REACH Annex VII-IX data requirements. While rabbit dams were more sensitive to treatment than rats, no effects were seem on developmental parameters in pre-natal developmental toxicity studies in which rats or rabbits were exposed to isobutanol at concentrations up to 10,000 mg/m3 (i.e. the highest dose tested).

Justification for classification or non-classification

Based on read-across to developmental toxicity studies in rats and rabbits conducted using isobutanol, the Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate is not predicted to be a developmental toxicant.The substance does not meet the criteria for classification for developmental toxicity according to Directive 67/548/EEC or Regulation 1272/2008/EC.