35XY60

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: combined repeated dose and reproduction/developmental study

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26 July 2004 - 17 Sept 2004

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

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:

Xylenols isomer mixture

IUPAC Name:

Xylenols isomer mixture

Details on test material:

- Name of test material (as cited in study report): 2,5-xylenol (CAS 95-87-4), 3,4-xylenol (CAS 95-65-8), 2,4-xylenol (CAS 105-67-9), 3,5-xylenol (CAS 108-68-9), 2,3-xylenol (CAS 526-75-0), 2,6-xylenol (CAS 576-26-1). Test substancec was a mixture of xylenol isomers.
- Analytical purity: 99.74%
- Isomers composition: 2,5-xylenol (CAS 95-87-4): 16.4 mole %, 3,4-xylenol (CAS 95-65-8): 16.9 mole %, 2,4-xylenol (CAS 105-67-9): 22.7 mole %, 3,5-xylenol (CAS 108-68-9): 11.1 mole %, 2,3-xylenol (CAS 526-75-0): 18.2 mole %, 2,6-xylenol (CAS 576-26-1): 14.7 mole %.
- Lot/batch No.: 20NOV2003

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.

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 al 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 245 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 in excess of 245 mg/kg/day