LBX98

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Justification for type of information:

The reproductive toxicity of the individual (o-, m- and p-) cresol isomers has been investigated in three separate two-generation toxicity studies. No effects on fertility were seen in any study at the high dose level of 450 mg/kg bw/d. General toxicity (increased mortality and in clinical signs including hypoactivity, ataxia, twitches, tremors, prostration, gasping, rapid respiration and perioral wetness) were observed at dose levels of 175 and 450 mg/kg bw/d, resulting parental NOAELs of 30 mg/kg bw/d. Reduced pup weight and viability were seen at the highest (and parentally toxic) dose level of 450 mg/kg bw/d, leading to NOAEL values of 175 mg/kg bw/d. OECD 422 screening studies available for xylenol (mixed isomers) and ethylphenol (mixed isomers) both report and absence of effects on fertility and reproductive NOAEL values of 245 mg/kg bw/d. The Category substances therefore consistently demonstrate a lack of reproductive toxicity. Read-across is therefore proposed to the study with xylenol as the closest structural analogue among the Category members.
Developmental toxicity studies in the rat are available for the individual (o-, m- and p-) cresol isomers. Each study identified significant maternal toxicity (mortality, clinical signs, bodyweight deficits) at the high dose level of 450 mg/kg bw/d, resulting in maternal NOAELs of 175 mg/kg bw/d for each isomer. Slight fetotoxicity was observed at 450 mg/kg bw/d for o-cresol (one visceral variation: dilated lateral ventricles of the brain) and for p-cresol (reduced foetal weight, reduced skeletal ossification). There were no foetal effects with m-cresol at any dose level.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of 2,4-xylenol and 2,5-xylenol

EC Number:

905-287-4

Cas Number:

1638758-52-7

Molecular formula:

(CH3)2C6H3OH

IUPAC Name:

Reaction mass of 2,4-xylenol and 2,5-xylenol

Test material form:

solid: bulk

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on mating procedure:

Male and female rats were pair 1:1 and cohabited for a maximum of 14 days. Female rats with spermatozoa observed in a msear of the vaginal conents and/or a copulatory plug in situ were considered to at GD 0 and then individually housed.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Minimum of 28 days (14 days of dosing prior to cohabitation).

Frequency of treatment:

Once daily

Doses / concentrations

Remarks:

Doses / Concentrations:Basis:analytical conc.30, 100, 300 mg/kg/day

No. of animals per sex per dose:

10 male and 10 females/group

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

ca. 100 mg/kg bw/day

Based on:

other:

Sex:

male/female

Basis for effect level:

other: Due to clinical observations (urine-stained fur, increased kidney, liver and ovarian relative weight).

2

Dose descriptor:

NOAEL

Remarks:

Reproductive

Effect level:

>= 245 mg/kg bw (total dose)

Based on:

other:

Sex:

male/female

Basis for effect level:

other: Whilst a reduced mating frequency was observed, this was within the laboratory's historical control range, therefore not considered biologically relevant.

Results: F1 generation

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 245 mg/kg bw/day

Based on:

other:

Sex:

female

Basis for effect level:

clinical signs

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

All rats survived the treatment. In males, urine stained fur was observed at the 245 mg/kg/day level. Body weight gain and food consumption were unaffected by treatment. Mating frequency was reduced at the 245 mg/kg/day level. Neurotoxicity was not observed during the study and there were no treatment related effects observed at gross necropsy or histopathologically. Urine staining of the fur was observed in females at the 245 mg/kg/day level. F1 animals showed no treatment related clinical or necropsy signs. Haematology, clinical pathology and FOB parameters were unaffected.

 

Relative weights of the kidney, liver and ovaries were observed to be increased in the 245 mg/kg/day treatment group,

Decreased mating and fertility indices were reported at the highest dose level (245 mg/kg bw) in the combined repeated dose toxicity and reproduction/developmental toxicity screening test. The number of female rats that mated was reduced from 100% in the control group (10/10) to 80% at 245 mg/kg bw (8/10) but the difference was not significantly different. The historical control value was reported as 97.6% over the period 1992-2002 but as no range was given this figure was of limited value. Following a request to Argus addition all historical control data were provided on 19 April 2010. The information provided showed fertility data for individual years from 1992 to 1997 giving the range as well as the mean values and these are shown in Table 1.

 

Table 1: Fertility index for studies conducted in Crl:CD(SD) Rats

Year	Average	Minimum	Maximum	No of studies
1992	94.1	80.0	100.0	4
1993	89.5	80.0	100.0	9
1994	90.5	66.7	100.0	17
1995	93.8	89.7	100.0	5
1996	93.1	84.0	100.0	13
1997	91.7	71.4	100.0	23
1992 - 1997	91.7	66.7	100.0	71

 

It is clear from the historical control data that fertility in the mixed xylenols study was within the historical control range in several years during the period from 1992-1997 which corresponds to the time when the mixed xylenols study was conducted.

As the reduced fertility at 245 mg/kg bw was not statistically significant and was within the historical control range, this effect is considered not to be related to treatment and the NOAEL for reproductive effects in this study should be ≥ 245 mg/kg bw.

Applicant's summary and conclusion

Conclusions:

The test substance mixed xylenol isomers was administered to rats by oral gavage at 0, 30, 100 and 245 mg/kg/day. The general toxicological No Observable Adverse Effect Level was shown to be 100 mg/kg/day. The SD determined that the reproductive NOAEL was found to be 100 mg/kg/day due to reduced mating at 245 mg/kg/day, however following request of the historical control data from the laboratory, the reduction in mating frequency to 80% was within the laboratory's historical vehicle control data for this period. Therefore the reproductive NOAEL is considered to be 245 mg/kg/day

Executive summary:

The above results are suitable to be used for read across for Reaction mass of 2,4-xylenol and 2,5-xylenol, due to the category being based on structural similarity and comparable physicochemical properties, leading to similar (eco)toxicological properties.